WO2019221959A1 - Méthode de traitement, de réduction ou de soulagement d'une pathologie chez un patient - Google Patents

Méthode de traitement, de réduction ou de soulagement d'une pathologie chez un patient Download PDF

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Publication number
WO2019221959A1
WO2019221959A1 PCT/US2019/030931 US2019030931W WO2019221959A1 WO 2019221959 A1 WO2019221959 A1 WO 2019221959A1 US 2019030931 W US2019030931 W US 2019030931W WO 2019221959 A1 WO2019221959 A1 WO 2019221959A1
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Prior art keywords
inhibitors
patient
implant
rock
eye
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PCT/US2019/030931
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English (en)
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Gholam A. Peyman
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Individual
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Priority claimed from US16/246,618 external-priority patent/US11045352B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
    • A61K38/4893—Botulinum neurotoxin (3.4.24.69)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A61K9/0051—Ocular inserts or implants
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6489—Metalloendopeptidases (3.4.24)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/24—Metalloendopeptidases (3.4.24)
    • C12Y304/24069—Bontoxilysin (3.4.24.69), i.e. botulinum neurotoxin

Definitions

  • the invention generally relates to a method for treating, reducing, or alleviating a medical condition in a patient. More particularly, the invention relates to a method for treating, reducing, or alleviating a medical condition in a patient that involves an
  • Conventional ocular drug delivery systems include medication dissolved or suspended in a physiological solutions applied as drops to the cornea and conjunctiva bathing the superficial structure of the eye.
  • the drops can have also particulate matter for faster tissue penetration or slow release of medication potentially lasting 1-2 days or months, etc.
  • the medication when applied as drops, partially penetrates the barrier of the corneal epithelium and reaches in sufficient concentration in the aqueous fluid of the anterior chamber.
  • the aqueous is constantly produced in the eye from the ciliary body epithelium in the back or the iris in the posterior chamber and moves through the pupil in the anterior chamber, and is removed from the eye through the trabecular meshwork located in the angle of the eye between the iris and the cornea.
  • a part of the aqueous mixes with the vitreous.
  • topically-applied medication reaches the back of the eye in lower concentrations and slower than when injected in the vitreous cavity.
  • the polymeric slow release systems release the medication inside the eye and have been implanted in the vitreous cavity, over or under the retina, providing medication only to the back of the eye for a period of 3 months to a year.
  • a drug delivery device has been implanted in most places of the eye, except in the cornea.
  • a non-biodegradable device can be injected in the vitreous cavity if they are very small otherwise, they can move around scratching the retina or move to the anterior chamber damaging the comeal endothelial cells.
  • they can be sutured in the sclera with their anchoring section, while the drug delivery section is located inside the eye, i.e., in the vitreous cavity to release the medication.
  • stem cellular drug delivery devices such as ciliary body neurotrophic factors that produce needed factors for the retinal survival in certain degenerative diseases can be only be implanted inside the vitreous cavity where it is considered an immune- privileged space. Otherwise, it becomes encapsulated by the scar tissue and become less effective.
  • the vitreous cavity is considered an immune privileged space meaning that blood vessels have no access to it to produce a cellular immune response that would attack and destroy the stem cells or surround a device with a fibrous membrane which would make the system useless.
  • the cornea has not been considered a suitable location to implant a slow release drug delivery device because of concern that it becomes vascularized affecting the transparency of cornea, which is vital for passing the light through it to reach the photoreceptors of the retina creating sensation of vision.
  • Wnt proteins bind to receptors of the Frizzled and LRP protein families causing accumulation of beta-catenin in the cytoplasm and its translocation in the nucleus that forms a complex with transcriptional cofactor (TCF) to activate the transcription of Wnt targeted genes.
  • TCF transcriptional cofactor
  • the Wnt pathway is considered canonical when it is dependent on beta-catenin, or non-canonical when it is independent.
  • the canonical Wnt/ -catenin plays an important role in the expression of several inflammatory molecules during acute or chronic inflammatory diseases affecting mucosal surfaces of the body.
  • an improved treatment method is needed for an inflammatory process that involves the conjunctiva, sclera, optic nerve, nasal, oral and throat including dry eye syndrome, mucosal form of lichen planus, psoriasis, and inflammatory bowel diseases, plantar fasciitis, skin form of lichen planus or chronic pain caused by inflammatory disease affecting the nerves such as in diabetes or after surgery or trauma, etc.
  • the present invention is directed to a drug delivery implant and a method using the same that substantially obviates one or more problems resulting from the limitations and deficiencies of the related art.
  • a method of treating, reducing, or alleviating a medical condition in a patient includes administering a drug delivery implant to a patient in need thereof, the drug delivery implant comprising one or more Rock inhibitors, one or more Wnt inhibitors, one or more integrin inhibitors, and/or one or more glycogen synthase kinase-3 (GSK-3) inhibitors, the patient having a medical condition selected from the group consisting of dry eye, glaucoma, lichen planus, arthritis, psoriasis, plantar fasciitis, pars planitis, scleritis, keratitis, chronic meibomian gland inflammation, optic nerve neuritis, uveitis, papillitis, diabetic neural pain, diabetic retinopathy, a cataract, postoperative inflammation, a side effect occurring after refractive surgery, a side effect occurring after comeal transplant, a side effect occurring after retinal de
  • the step of administering the drug delivery implant comprises implanting the drug delivery implant in one or more eye locations selected from the group consisting of under the conjunctiva, under the sclera, over the sclera in the choroid, in the retina, and in the sub-retinal space.
  • the drug delivery implant further comprises a slow release compound selected from the group consisting of porous silicon, polycaprolactone, polylactic acid, polyglycolic acid, poly anhydride, lipids, chitosan polymers, and
  • the drug delivery implant further comprises biodendrimers or liposomes
  • the step of administering the drug delivery implant to the patient further comprises administering the one or more Rock inhibitors and/or one or more Wnt inhibitors with the biodendrimers or liposomes.
  • the medical condition of the patient is dry eye
  • the patient prior to the step of administering the drug delivery implant to the patient, the patient has undergone refractive surgery on one or more eyes for correcting refractive errors of the one or more eyes, the refractive surgery involving the cutting of corneal nerves, thereby resulting in the dry eye of the patient, and wherein the administration of the drug delivery implant enhances nerve regeneration.
  • the refractive surgery performed on the patient is laser-assisted in situ keratomileusis (LASIK).
  • LASIK laser-assisted in situ keratomileusis
  • the step of administering the drug delivery implant comprises administering one or more Rock inhibitors in the form of botulinum toxin, Fasudil, or Fasudil derivatives.
  • the step of administering the drug delivery implant to the patient comprises administering one or more Wnt inhibitors in the form of
  • demethoxycurcumin CCT036477, KY02111, WAY-316606, SFRP, IWP, LGK974, C59, Antl.4Br/Ant 1.40, niclosamide, ivermectin, or sulforaphane and vitamin D.
  • the drug delivery implant further comprises another medication selected from the group consisting of steroids, nonsteriodal anti-inflammatory drugs (NSAIDs), dexamethasone, cyclosporine A, mycophenolic acid, anti-proliferative agents, antimetabolite agents, antibiotics, low molecular weight heparin, metalloproteinase inhibitors, and combinations thereof.
  • NSAIDs nonsteriodal anti-inflammatory drugs
  • dexamethasone dexamethasone
  • mycophenolic acid mycophenolic acid
  • anti-proliferative agents antimetabolite agents
  • antibiotics low molecular weight heparin
  • metalloproteinase inhibitors and combinations thereof.
  • a method of treating, reducing, or alleviating a medical condition in a patient includes administering to a patient in need thereof a biocompatible drug comprising one or more Rock inhibitors, one or more Wnt inhibitors, one or more integrin inhibitors, and/or one or more glycogen synthase kinase-3 (GSK-3) inhibitors, the patient having a medical condition selected from the group consisting of dry eye, glaucoma, lichen planus, arthritis, psoriasis, plantar fasciitis, pars planitis, scleritis, keratitis, chronic meibomian gland inflammation, optic nerve neuritis, uveitis, papillitis, diabetic neural pain, diabetic retinopathy, a cataract, postoperative inflammation, a side effect occurring after refractive surgery, a side effect occurring after comeal transplant, a side effect occurring after retinal detachment surgery,
  • the administration of the biocompatible drug to the patient treats the medical condition, reduces the symptoms associated with the medical condition, enhances nerve regeneration, prevents scarring, and/or alleviates the medical condition.
  • the step of administering the biocompatible drug to the patient comprises administering the biocompatible drug topically, by spraying, by injection, by implantation, or orally.
  • the biocompatible drug is in the form of topical drops, a topical suspension, a topical ointment, a topical spray, an injectable solution, or a surgical implant with slow release capabilities.
  • the biocompatible drug further comprises
  • biodegradable microspheres made of biodegradable microspheres, the biodegradable microspheres being formed from porous silicon, polylactic acid, polyglycolic acid, or polycaprolactone.
  • the biocompatible drug further comprises
  • biocompatible drug to the patient further comprises administering the one or more Rock inhibitors and/or one or more Wnt inhibitors with the biodendrimers, liposomes, or micelles.
  • the step of administering the biocompatible drug to the patient comprises administering the biocompatible drug to the cornea, conjunctiva, under the conjunctiva, in the vitreous cavity, in the suprachoroidal space, or in the anterior chamber of an eye of the patient.
  • the step of administering the biocompatible drug comprises administering one or more Rock inhibitors in the form of botulinum toxin, Fasudil, or Fasudil derivatives.
  • the step of administering the biocompatible drug to the patient comprises administering one or more Wnt inhibitors in the form of
  • demethoxycurcumin CCT036477, KY02111, WAY-316606, SFRP, IWP, LGK974, C59, Antl.4Br/Ant 1.40, niclosamide, ivermectin, or sulforaphane and vitamin D.
  • the step of administering the biocompatible drug to the patient comprises administering one or more integrin inhibitors in the form of abegrin, cilengitide, abciximab, tirofiban, natalizumab, eptifibatide, or risuteganib.
  • the step of administering the biocompatible drug to the patient comprises administering one or more glycogen synthase kinase-3 (GSK-3) inhibitors in the form of GSK inhibitor SB-216763 or GSK inhibitor SB-216368.
  • the step of administering the biocompatible drug to the patient comprises administering one or more Rock inhibitors together with one or more integrin inhibitors and an anti-vascular endothelial growth factor (anti-VEGF).
  • anti-VEGF anti-vascular endothelial growth factor
  • the medical condition of the patient is postoperative inflammation resulting from undergoing laser cosmetic surgery involving the patient’ s skin or mucosa.
  • the biocompatible drug is used to prevent comeal scarring resulting from refractive surgery performed on the patient.
  • the medical condition of the patient is glaucoma
  • the method further comprises the step of applying selective laser trabeculoplasty (SLT) to an eye of the patient using laser pulses having a femtosecond pulse, nanosecond pulse, micropulse, or millipulse pulse time duration so as to encourage renewal of the remaining cells in the eye, and thereby treat the glaucoma.
  • SLT selective laser trabeculoplasty
  • the step of administering the biocompatible drug to the patient comprises administering the biocompatible drug topically to the nasal mucosa to seek access through the olfactory nerve to the hippocampus and the rest of the brain.
  • FIG. 1A illustrates a first exemplary shape for the drug delivery implant described herein, which is in the form of a rod-shaped implant;
  • FIG. 1B illustrates a second exemplary shape for the drug delivery implant described herein, which is in the form of a curved implant;
  • FIG. 1C illustrates a third exemplary shape for the drug delivery implant described herein, which is in the form of a two-part semi-circular implant
  • FIG. 1D illustrates a fourth exemplary shape for the drug delivery implant described herein, which is in the form of a one-part semi-circular implant;
  • FIG. 2 illustrates an exemplary coated drug delivery implant, wherein the drug delivery implant is coated with a polymer and a photosensitizer;
  • FIG. 3A illustrates a first exemplary form of the drug delivery implant described herein, which is in the form of a solid tubular implant;
  • FIG. 3B illustrates a second exemplary form of the drug delivery implant described herein, which is in the form of a porous tubular implant
  • FIG. 3C illustrates a third exemplary form of the drug delivery implant described herein, which is in the form of a tubular implant with open ends;
  • FIG. 4 illustrates another exemplary form of the drug delivery implant described herein, wherein the implant is tubular-shaped with holes formed in the side thereof;
  • FIG. 5 illustrates yet another exemplary form of the drug delivery implant that is similar to that which is depicted in FIG. 4, except that the tubular- shaped implant of FIG. 5 has larger-sized holes formed in the side thereof;
  • FIG. 6 illustrates still another exemplary form of the drug delivery implant described herein, wherein the implant is in the form of a rectangular flat tube;
  • FIG. 7 illustrates yet another exemplary form of the drug delivery implant described herein, wherein the implant is in the form of a semi-solid or silicone tubular implant with one closed end and one open end;
  • FIG. 8 illustrates still another exemplary form of the drug delivery implant described herein, wherein the implant is in the form of a rectangular tube that is refillable by injection;
  • FIG. 9 illustrates yet another exemplary form of the drug delivery implant described herein, wherein the tubular implant comprises a needle for tissue penetration and the tubular implant is capable of being penetrating by a needle for taking liquid biopsies;
  • FIG. 10A is a front view of a cornea of an eye illustrating a two-part semi-circular drug delivery implant disposed in a cross-linked pocket in the peripheral portion of the cornea that is spaced apart from the central visual axis of the eye so as not to obstruct the central portion of the eye;
  • FIG. 10B is a partial side cross-sectional view of the eye of FIG. 10A illustrating the two-part semi-circular drug delivery implant disposed in the cross-linked pocket in the peripheral portion of the cornea;
  • FIG. 11A is a front view of a cornea of an eye illustrating a generally linear drug delivery implant disposed in a cross-linked pocket in the peripheral portion of the cornea that is spaced apart from the central visual axis of the eye so as not to obstruct the central portion of the eye;
  • FIG. 11B is a partial side cross-sectional view of the eye of FIG. 11 A illustrating the generally linear drug delivery implant disposed in the cross-linked pocket in the peripheral portion of the cornea;
  • FIG. 12A is a front view of a cornea of an eye illustrating a tubular drug delivery implant disposed in a cross-linked pocket in the peripheral portion of the cornea, wherein the implant comprises a needle fluidly coupling the implant to the anterior chamber of the eye;
  • FIG. 12B is a partial side cross-sectional view of the eye of FIG. 12A illustrating the tubular drug delivery implant with the needle extending into the anterior chamber of the eye;
  • FIG. 13A is a front view of a cornea of an eye illustrating a pupil, cornea, sclera, and limbus of the eye;
  • FIG. 13B is a partial side cross-sectional view of the eye of FIG. 13A illustrating an anterior chamber, iris, and lens of the eye;
  • FIG. 14A is a front view of a cornea of an eye illustrating a one-part semi-circular drug delivery implant disposed in a cross-linked pocket in the peripheral portion of the cornea;
  • FIG. 14B is a partial side cross-sectional view of the eye of FIG. 14A illustrating the one-part semi-circular drug delivery implant disposed in the cross-linked pocket in the peripheral portion of the cornea;
  • FIG. 15A is a front view of a cornea of an eye illustrating a doughnut-shaped drug delivery implant disposed in a cross-linked pocket in the peripheral portion of the cornea;
  • FIG. 15B is a partial side cross-sectional view of the eye of FIG. 15A illustrating the doughnut-shaped drug delivery implant disposed in the cross-linked pocket in the peripheral portion of the cornea;
  • FIG. 16A is a front view of a cornea of an eye illustrating a generally linear drug delivery implant disposed in a cross-linked pocket in the peripheral portion of the cornea;
  • FIG. 16B is a partial side cross-sectional view of the eye of FIG. 16A illustrating the generally linear drug delivery implant disposed in the cross-linked pocket in the peripheral portion of the cornea;
  • FIG. 17A is a front view of a cornea of an eye illustrating a drug delivery implant disposed in a cross-linked pocket in the peripheral portion of the cornea, wherein the implant comprises a needle fluidly coupling the implant to the anterior chamber of the eye; and
  • FIG. 17B is a partial side cross-sectional view of the eye of FIG. 17A illustrating the tubular drug delivery implant with the needle extending into the anterior chamber of the eye with the aqueous fluid of the eye.
  • the device is placed in the far corneal periphery so that it will not affect the vision or visual field of the patient, and so that it has created a so-called artificial“immune -privilege” which does not generate an immune response from the body while fluid, soluble medications or nano-particulates and micro particulates can travel through it. See, for example, FIGS. 10A-17B.
  • the released medication bypasses the epithelial barrier of the cornea, while providing medication in a slow manner by diffusion to the anterior part of the cornea, to the sclera, to the conjunctival tissue, and to the posterior segment of the eye including the retina, choroid, and the optic nerve head.
  • This technique can provide similar immune -privileged spaces in other part of the body so that devices implanted there are not encapsulated.
  • the drug delivery system of the embodiments described herein may be constructed so that it can have direct access to the anterior chamber, if needed, for both obtaining repeatedly a fluid biopsy from the eye or deliver medication(s) directly inside the eye in a fast or slow release manner, or for reducing the intraocular pressure of the eye by creating a minor flow through a porous implanted stent or tube through the comeal limbus without inducing a fibrous encapsulation of the stent.
  • the stent can ameliorate also comeal dryness caused by dry eye syndrome.
  • the stent can also be equipped with a pressure sensor indicating directly the intraocular pressure and communicating it with a radiofrequency device to outside the eye to a receiver or a processor. As one example, as shown in FIG.
  • the implant 44 may comprise a closed end 46 and a needle 48 for tissue penetration so that the implant 44 is capable of being used for taking liquid biopsies.
  • stem cells or other cells can reside in, for example, a tubular implant, while having access to the oxygen and nutrients through the artificial barrier in an appropriately prepared comeal pocket.
  • porous tubular implant permits these cells to migrate elsewhere in the eye or remain in place without being attacked by body’s cellular response. Because the cellular body immune response is dependent on the production of the cells close to the implant or a foreign body to be taken up by the dendritic cells of the body at that location by creating a cell free space around the implant made of transparent amorphous cross-linked collagen.
  • the invention of the embodiments described herein has eliminated the incentive for a Major Histocompatibility Complex (MHC) to occur. Because these MHC are present on the cell surface of the body cells to be activated in the production of an immune response.
  • MHC Major Histocompatibility Complex
  • cytokines activates the cellular immune system of the body to either eliminate the threat or isolate the device from the body completely by fibrocytes, thereby building a dense membrane (i.e., scar) around the implant.
  • the cross-linked collagen permits the diffusion of water and small molecules permitting the needed growth factors from the incorporated stem cells placed inside the tubular implant needed for survival and the health of the cornea, retina etc.
  • this mechanism is very effective and useful, it affects the function of an implant that usually either releases a needed medication or measures or controls the release of a medication (e.g., measuring the blood glucose level and/or releasing insulin according to the glucose level found in the blood, etc.).
  • tissue fluid e.g., aqueous fluid levels of glucose
  • Aqueous level of most if not analytes found in the blood and could be used effectively to provide information on the health or disease processes affecting the eye or the body as a whole.
  • implantation of a drug delivery device is described for the release or monitoring and controlling of a disease process in the eye, while crosslinking the tissue around the implant or implants (if more than one implant is provided).
  • a plurality of drug delivery implants may be used (e.g., for delivering different medications), rather than a single drug delivery implant.
  • the technology described herein may be applied for any other device implantation in the body regardless of the location in the body.
  • One of the benefits of the technology is that, if the device needs to be replaced, it can be done easily without dealing with the scar tissue formation that otherwise forms and makes the removal or replacement of the implant very complex because the tissue adhesions that usually forms between the tissue and the device.
  • a two dimensional intrastromal corneal incision is created that is subsequently converted into a pocket in the corneal stroma using a femtosecond laser or a mechanical cutting system.
  • the femtosecond laser passes through the clear media of the cornea.
  • the laser beam is focused inside the cornea, one can produce a two-dimensional cut or a three-dimensional cut around a thin part of the tissue that is removed to desired space, shape, depth, and location.
  • a knife or a syringe needle ending in a sharp cutting tip to cut a pocket in the tissue. If needed, the incision simultaneously involves removal of a three-dimensional tissue surrounding the surgical pocket to create some additional space for the implant using a similar cutting instrument, in the skin or soft tissue. In general, a cut creates a flexible three-dimensional
  • the implant is placed inside the needle and can be expelled from the needle by the syringe into the space created by knife.
  • an injectable anesthetic e.g., lidocaine or
  • Bupivacaine in a desired non- toxic preparation or concentration of 0.1-2 % or more in a physiologic solution with, but preferably without, a preservatives, is injected in the comeal pocket to anesthetize the cornea postoperatively for a period up to 8-12 hours (e.g., if a PRK procedure is contemplated or after a corneal inlay implantation to prevent pain sensation completely in the postoperative period).
  • This eliminates subjecting the entire corneal epithelium or the conjunctival epithelial cells to the damaging effect of topical anesthesia, which delays comeal re-epithelialization or conjunctival epithelial cells.
  • the topical preservatives present in the topical anesthesia damages the cells that are bathed in them, and at times affects the regeneration of these cells (i.e., comeal epithelial or conjunctival cells) if applied frequently. Also, it may produce addiction to the topical anesthesia for eliminating the pain sensation caused by the loss of the comeal epithelial cells, whereas the injectable anesthetic does not damage the epithelial cells, including the nerve cells or their axons, except for blocking temporarily the neuronal transmission.
  • the collagen cross-linker is mixed with the intracorneal locally injectable anesthetic, and injected simultaneously or sequentially in the corneal pocket.
  • the pocket is filled with a biocompatible implant or implants (if more than one implant is provided) made of organic or non-organic material, or a mixture of it, and the implant is used for drug delivery.
  • the implant may further be coated with a biocompatible material, such as collagen, elastin, polyethylene glycol, biotin and streptavidin, etc., as known in the art, or a composition thereof, to make the implant more biocompatible.
  • the implant and/or the coating can be cross-linked with a cross-linker with the desired thickness and shape before or after implantation.
  • the diameter of the comeal pocket can be 0.1 to 4 millimeters (mm), as needed. Only flat implants need a larger space with more than 0.2 mm.
  • the pocket can be circular, semicircular, C-shaped, doughnut-shaped, rectangular, or any other shape.
  • the implant or implants can be located at a desired distance from the Bowman’s membrane or from the corneal periphery, that is located away from the center of the visual axis (i.e., the implant
  • FIGS. 10A- 17B may be off-centered, or ring-shaped in the peripheral cornea). See, for example, FIGS. 10A- 17B.
  • the implant or implants (if more than one implant is provided).is made to the desired shape, and size in diameter and length that fits with ease inside the comeal pocket without exerting pressure on the corneal tissue (i.e. without bulging it).
  • a photosensitizer or cross-linker such as riboflavin
  • a photosensitizer or cross-linker is injected at the desired concentration in a biocompatible fluid or a viscous fluid prior to the implantation of the implant.
  • it can be also administered simultaneously with the implant in the corneal pocket sufficiently to cover the internal wall of the pocket for a desired duration so that it penetrates at least 20 micron or wider, taking 5-30 seconds after injection prior to the cross-linking of the cornea, which prevents cell proliferation, encapsulation, or rejection of the implant while preserving an acellular barrier.
  • UV radiation at the desired power (e.g., 1 to 4mW/mm 2 ) and duration of 1-15 minutes, as needed, depending on the concentration of the photosensitizer or other radiation if another cross-linker is used (e.g., visible or infrared (IR) or another wave length) is applied externally to activate the photosensitizer in the corneal pocket, and to cross-link the collagen of the corneal stroma surrounding the corneal pocket, thereby killing only the cells located within the cross-linked cornea while preventing encapsulation of the drug implant while providing a physical stability to the cornea and preventing the wall of the pocket from adhering together or to the implant. This permits the implant to be replaced, if needed, with another implant with ease.
  • IR infrared
  • the implant is coated with an organic material, such as collagen, dipped in a photosensitizer, or the implant can be coated with nanoparticles of the photosensitizer and implanted in the corneal pocket and ultraviolet (UV) radiation is applied with the desired power and duration using a painting technique using a small diameter fiber optic or other radiation with another wave length is applied if another cross linker is used, externally or internally inside the pocket via a fiber optic to activate the photosensitizer in the corneal pocket and to cross-link the collagen of the corneal stroma surrounding the comeal pocket, thereby killing all cells located within the cross-linked cornea and cross-link the implant simultaneously.
  • the corneal cross-linking prevents implant encapsulation with fibrous tissue, but provides a physical stability to the cornea without gluing the wall of the pocket together or to the implant.
  • an injection of a small amount of hyaluronic acid in the pocket simplifies insertion of the drug implant in the comeal pocket.
  • the drug implant has a tube-like structure with a size of 0.01 to 3 micron diameter holes in its wall, or having one micron or larger-sized holes for diffusion of fluid across it.
  • the implant can be silicone, acrylic, methacrylate, hydroxyethyl methacrylate (HEMA), cross-linked organic or any other biocompatible transparent or non-transparent material, metallic or non-metallic, or a mixture thereof or coating other polymers, such as collagen or elastin with the desired thickness of 2 microns or more, as needed.
  • HEMA hydroxyethyl methacrylate
  • the implant is made of various drug delivery polymers, such as polylactic acid or polyglycolic acid, or a combination thereof or polycaprolactone, or chitosan or other organic materials that can deliver the medication at a certain concentrations and dissolve within time ranging from 3-12 months or more.
  • drug delivery polymers such as polylactic acid or polyglycolic acid, or a combination thereof or polycaprolactone, or chitosan or other organic materials that can deliver the medication at a certain concentrations and dissolve within time ranging from 3-12 months or more.
  • the biodegradable or non-biodegradable implant can be replaced with another one as before or a non-biodegradable material, but having biocompatible material or coating where the drug release occurs either through the small holes in the body of the implant at a certain rates depending on the size of the holes, or from one or both ends of the implant for drug delivery, as needed.
  • the implant is a porous biodegradable polymer.
  • the material inside the tubular implant is liquid, nanoparticles, suspension, powder, porous polymeric drug, etc.
  • the implant is made using 3-D printing technology to the desired shape, size and/or coated with more biocompatible polymer(s) and cross-linked prior to the implantation, or it is implanted in a cross-linked pocket.
  • the cross-linked comeal implant can be loaded with one or multiple medications needed for a short biocompatible drug delivery, or
  • prophylactically to prevent an infection, or other used therapeutically medications to treat a disease process e.g., inflammation, intraocular pressure (IOP), neovascularization, infection, or a cytokine, etc.
  • a disease process e.g., inflammation, intraocular pressure (IOP), neovascularization, infection, or a cytokine, etc.
  • an organic cross-linked material can be used as above for a short term drug delivery of 1 to 4 weeks.
  • an organic cross-linked material can be used as above for a short term drug delivery of 5 to 50 weeks or longer.
  • the implant is a C-shaped flexible or semi-flexible structure, and can be implanted in the prepared comeal pocket according to the size or the shape of the implant (e.g., centered around the visual axis having a string shape, rod-like shape, or flat shape), while removing a small 3-D tissue from the stroma for the pocket formation to provide space for the implant for drug delivery to the cornea or the anterior chamber, trabecular meshwork, conjunctiva, or diffusing toward the posterior segment, such as the retina, choroid or the optic nerve of the eye.
  • the drug delivery implant may be rod-shaped 10, C-shaped 12, two-part semi-circular 14, or one-part semi-circular 16.
  • the implant may also be in the form of a rectangular flat tube 34.
  • a two-part semi-circular drug delivery implant 56 disposed in a cross-linked pocket in the peripheral portion of the cornea 52 that is spaced apart from the central visual axis 54 of the eye so as not to obstruct the central portion of the eye.
  • the two-part semi-circular drug delivery implant 56 is disposed adjacent to the anterior chamber 57 of the eye, and anteriorly with respect to the iris 53 and lens 55 of the eye.
  • a generally linear drug delivery implant 60 is disposed in a cross-linked pocket in the peripheral portion of the cornea 52.
  • an eye generally includes a lens 63, an iris 65, cornea 66, an anterior chamber 67, a pupil 68, and a limbus 70.
  • a one-part semi-circular drug delivery implant 72 is shown disposed in a cross- linked pocket in the peripheral portion of the cornea 66.
  • a doughnut shaped or ring-shaped drug delivery implant 74 is shown disposed in a cross-linked pocket in the peripheral portion of the cornea 66.
  • a generally linear drug delivery implant 76 is shown disposed in a cross-linked pocket in the peripheral portion of the cornea 66.
  • the implant is inserted in the corneal pocket through a small external incision made into the corneal pocket.
  • the pocket itself can be filled with biodegradable nanoparticles for drug delivery to the entire ocular structures from the cornea to the optic nerve, and all tissues in between.
  • the medication(s) can be anti-inflammatory, anti-infective, immune-suppressants, AntiVEGFs, biologies, Anti-PDGF, Anti IL-6, Rho kinase inhibitors, Wnt inhibitors, nerve growth factors, anti-glaucoma medications, gene(s) delivery in conjugation with viral or non-viral nanoparticles, such as nanoparticles, quantum dots, biodendrimers, etc. coated with polyethylene glycol (PEG) or cell penetrating agents along with an antibody to the specific tissue.
  • PEG polyethylene glycol
  • photoreceptors retinal and optic glial or nerve cells or their axons etc.
  • the one or more medications in the drug implant may be anti-inflammatory agents, such as steroids, Dexamethasone, NSAIDS, Anti IL-17, Anti IL-6 and other Anti-ILs or antibiotics, fluoroquinolones, macrolides, cephalosporin A, vancomycin, aminoglycosides, penicillin and its derivatives or combination of antibiotics, etc., anti-virals, ganciclovir, valcyclovir, etc., anti-fungals, amphotericine B, etc., Anti- VEGFs, Avastin, lucentis, Aflilbercept, Anti-IL-6, anti-parasitic, etc., or other anti inflammatory agents, such as NSAIDs or Rho kinase inhibitors, after any comeal surgery and act therapeutically to various diseases affecting the conjunctiva (e.g., dry eye), immune- suppressants, such as cyclosporine A, Mycophenolic acid, anti-
  • anti-inflammatory agents such as steroids,
  • repeated crosslinking of the pocket can be performed as needed to prevent new cellular ingrowth and adhesion around the implant from the comeal tissue so that the implant’s barrier is maintained, and the implant can be removed or replaced as needed (e.g., if the eye needs another or a combined medication to regulate disease process, such age related macular degeneration, glaucoma, uveitis, choroiditis or an infectious process of any origin).
  • the peripheral cross-linked pocket is used to insert or inject medications needed to treat a comeal disease or glaucoma or a disease of the posterior segment.
  • the medication can be in a form of nanoparticles, microspheres, lipid coating or PEG, streptavidin, biotin coating, etc., micelles, liposomes, thermosensitive chitosans, etc.
  • the diameter of these rod or flat-shaped shape implants can vary between 10 microns to 1 millimeter (mm) in diameter or larger with a length of 1 to 50 mm or longer.
  • the porous tube can be made of semi-permeable non- biodegradable material that permits only the diffusion of the fluid/medication, etc. in and out of the tube, implanted in the peripheral cross-linked pocket.
  • the tube can be refilled with medication as needed.
  • the implant 40 in the form of a rectangular tube is refillable by injection with a needle 42.
  • the drug implant tube contains stem cells, embryonic stem cells, ciliary hormone producing cells, or other hormone or factors producing stem cells, neuronal or glial stem cells, Mesnchymal stem cells, trabecular meshwork stem cells, limbal stem cells, modified skin stem cells, etc. in a biocompatible fluid that permits nutrition to reach the cells injected in the tube where the cells are immortalized to produce one or the other medication, growth factors, such as ciliary neurotrophic growth factor, RPE growth factor, nerve growth factors , anti-VEGFs, or other medications needed.
  • growth factors such as ciliary neurotrophic growth factor, RPE growth factor, nerve growth factors , anti-VEGFs, or other medications needed.
  • the non-biodegradable tube with pores for drug and cell delivery is implanted in a cross-linked pocket with an implant in any part of the body for medication and cell delivery for various medications and functions.
  • the implant is coated with biocompatible polymer(s) that is used for delivery of stem cells with medication in a corneal pocket.
  • the implant has larger diameter holes of 5 microns and more in its wall permitting the cells to escape from the tubular implant into any tissue (e.g., corneal pocket containing stem cells, embryonic stem cells, ciliary body factor producing stem cells, neuronal or glial stem cells, Mesnchymal stem cells, trabecular meshwork stem cells, Limbal stem cells, modified skin stem cells, etc. in a biocompatible fluid) that permits nutrition to reach the cells injected in the tube where these cells can grow and pass through the holes of the implant and move toward a tissue.
  • tissue e.g., corneal pocket containing stem cells, embryonic stem cells, ciliary body factor producing stem cells, neuronal or glial stem cells, Mesnchymal stem cells, trabecular meshwork stem cells, Limbal stem cells, modified skin stem cells, etc. in a biocompatible fluid
  • the tubular implant 26 has small holes 28 disposed in the circular peripheral side thereof, whereas the tubular implant 30 in FIG. 5 has large holes 32 disposed in the circular peripheral side thereof.
  • the implant contains stem cells, embryonic stem cells, cilliary body hormone producing stem cells, neuronal or glial stem cells, Mesnchymal stem cells, trabecular meshwork stem cells, limbal stem cells, modified skin stem cells, etc. in a biocompatible fluid that permits nutrition to reach the cells injected in the tube along with Rho kinase inhibitors or Nerve growth factors to stimulate their regeneration and migration of theses cell and repair the pathology in the tissue.
  • genetically modified cells are used to produce needed enzymes and medications.
  • the combination of cross-linking of the cornea and killing the comeal cells and lack of vessels in the comeal makes it a suitable place for these cells in the tube implant to survive inside the tube without being attacked by the cellular body’s response, thereby creating an immune privileged space for these cells to survive and produce medications needed locally or systemically (e.g. in many genetic diseases of the cornea such as Fuchs dystrophy, etc.).
  • the pocket can be filled with a polymeric material that can become more semisolid, or becomes a gel, and contains medication for slow release of medication.
  • the medication can be injected in the peripheral pocket along with corneal stem cells from the limbus or genetically modified skin stem cells, embryonic or pluripotential stem cells, or mesenchymal stem cells grown in the culture for implantation, in cases of cell loss of endothelium, or in genetically caused corneal opacification, such as macular dystrophy or trauma.
  • the stem cells are mesenchymal stem cells injected in the comeal pocket along with ROCK inhibitors to replace or repair a cloudiness of the cornea.
  • the stem cells are nerve cells to induce regeneration of the damaged corneal nerve (e.g., in diabetic patient) and after traumatic comeal injuries or after LASIK surgery.
  • all tubular dmg implants or devices are replaceable with ease.
  • the tube can be refilled with medication to be used as slow release drug delivery that releases the drug in the cornea and anterior of the posterior segment of the eye.
  • the tube is used for taking fluid samples from the eye.
  • vasoconstrictive medication such as 0.5%-l% phenylephrine applied locally with a Q-tipped applicator using a femtosecond laser.
  • a small knife can be used to create a pocket in the cornea or elsewhere under the skin etc. if needed.
  • the pocket width is more toward the corneal side than the scleral side or vice versa.
  • the circumferential extent of the pocket can be 1 degree to 360 degrees of the comeal periphery (see FIGS. 10A, 10B, 14A, 14B, 15A, and 15B).
  • a curved probe to separate the comeal adhesion for injection of a photosensitizer cross-linker, such as riboflavin, at the desired concentration of 0.5% -4% in a biocompatible fluid, such as a physiological saline solution, etc.
  • a photosensitizer cross-linker such as riboflavin
  • ml milliliters
  • mm milliliter
  • 0.01 ml to O.lml of 0.02-2% lidocaine or bupivacaine solution can be injected alone or along with the photosensitizer in the corneal pocket to anesthetize the cornea for the next 1-15 hours, thereby eliminating pain sensation or discomfort of the surgery, and dry eye after surgery.
  • the width of the comeal pocket can be 1-3 mm as needed.
  • the peripheral corneal pocket can be circular, semi-circular, C-shaped, doughnut shaped, straight, curved, or any other shape.
  • the cross-linked pocket can be located at a desired distance from the Bowman’s membrane in the comeal periphery.
  • the ultraviolet (UV) radiation or other appropriate wave length of light at the desired power 0.5-50 mW/Cm2 and duration of 1-15 minutes, or other radiation with another wave length is applied externally in a stationary pattern or as a continuous painting/oscillatory technique with a focused small sized spot of 1-4 mm and a high energy to cover the width of the pocket, or on a painting oscillatory fashion entering the corneal pocket with a small diameter fiber optic and to activate the photosensitizer in the corneal pocket and crosslink the collagen of the comeal stroma surrounding the corneal pocket, and preventing the wall from adhering to itself or to a future implant, while providing a physical stability to the wall of the corneal pocket and preventing cell migration and rejection of an implant.
  • UV ultraviolet
  • ultraviolet (UV) radiation at the desired power in a stationary or focused light for a duration of 10 seconds to 15 minutes for the stationary radiation, or for a duration of 10 seconds to 20 minutes for the painting approach, depending on the power of the radiation and the length of the pocket used (or other radiation with another photosensitizer and wave length) is applied externally or via a fiber optic inserted inside the pocket to activate the photosensitizer and cross-link the collagen of the comeal stroma surrounding the comeal pocket while preventing cell migration, encapsulation, or rejection of the implant and protecting the anterior corneal stroma and the stem cells.
  • UV radiation ultraviolet
  • the comeal pocket is three-dimensionally cut in order to remove a part of the stroma and create a space for the implant.
  • the wall of the corneal pocket can absorb the photosensitizer from the implant after it is dipped in a photosensitizer solution or the implant is coated with nanoparticles of the cross-linker and placed in the corneal pocket to leak out, which is then followed by UV radiation at the desired power and duration or other radiation with another wave length applied externally or internally via a fiber optic to activate the photosensitizer in the corneal pocket and cross-link the collagen surrounding the implant.
  • This technique provides a physical stability to the cornea preventing adhesion or gluing the implant to the surrounding tissue and preventing fibrous ingrowth or encapsulation or rejection of the implant, which can lead to implant rejection. This makes it possible to exchange the implant when needed without much trauma to the cornea surrounding the implant.
  • the photosensitizer is conjugated to the surface of the implant having a polymeric coating, such as collagen, that releases the photosensitizer (e.g., riboflavin) from the implant once it is exposed to the water content of the tissue in the comeal pocket surrounding it.
  • the riboflavin is released and stains the wall of the implant which is subsequently cross-linked with UV light. This prevents tissue adhesion between the implant and the corneal tissue and maintains a potential space between the comeal wall and the implant, thereby preventing activation of an immunologic response or neovascular tissue response by releasing from the tissue vascular endothelial cell factors (VEGF) in response to a foreign implant.
  • VEGF tissue vascular endothelial cell factors
  • the cross-linking process can be repeated as needed every 6 months to a year or more as needed.
  • the cross-linking of the collagen protects the implant containing particulate medication(s), which releases the drug for a long time, and prevents the pocket from being invaded by the immune cellular elements and keeps the lumen of the tube shaped implant open.
  • the comeal pocket remains pristine not allowing cell traffic or access to the pocket surrounded by the cross-linked amorphous collagen or other cross-linked tissues located in that area.
  • the crosslinking can be repeated again in the postoperative period after implantation by injecting a cross-linker in the comeal pocket through a needle inside the wall of the pocket, which diffuses readily through the potential space around the implant and the wall of the pocket, and then is irradiated with UV light from the outside.
  • the implant can be made of silicone, acrylic, methacrylate, HEMA, metallic or non-metallic, synthetic, organic, polymeric biodegradable, etc., coated with another or a biocompatible polymeric materials or a mixture thereof or coated with, for example, collagen or elastin, formed with a desired thickness of 2 microns to 100 microns, and conjugated with a cross-linker or the cross-linker is injected in the potential pocket space in the tissue and is cross-linked.
  • the implant is made by the use of 3-D printing technology with the desired material, shape, size or thickness, transparent or non-transparent organic or non-organic or a mixture of them, a material such as collagen elastin, synthetic polymers can be coated again with riboflavin nanoparticles with one or more biocompatible polymer(s), and cross-linked with UV light prior to or preferably after implantation.
  • a material such as collagen elastin, synthetic polymers can be coated again with riboflavin nanoparticles with one or more biocompatible polymer(s), and cross-linked with UV light prior to or preferably after implantation.
  • the implant is coated with a collagen polymer to a desired thickness or in combination with another polymer, such as polyvinyl alcohol, chitosan, polycaprolactone, etc., conjugated with riboflavin or another cross-linker and cross- linked before or after implantation in a preformed pocket with an appropriate wavelength of light or UV radiation to cross-link the polymeric coating inside the body allowing the cross linker to be released in the tissue, and then cross-link the tissue surrounding the implant in order to, after implantation, release the incorporated medication from the implant slowly without inciting cellular attraction or encapsulation of the implant which inhibits a release of the medication(s) from the implant that is unpredictable.
  • the implant 18 is coated with a polymer and/or a photosensitizer.
  • the non-biodegradable flexible porous tube made of polymeric material or a non-organic compound in combination with cross-linked organic polymer coating is filled with microspheres, drug nanoparticles incorporated in a polymeric material, such as polylactic glycolic acid, chitosan, liposomes, polycaprolactone, or lipid- coated nanoparticles, etc. containing the medication so as to release the medication slowly from the tube implant.
  • a polymeric material such as polylactic glycolic acid, chitosan, liposomes, polycaprolactone, or lipid- coated nanoparticles, etc.
  • the implant can serve as a reservoir that releases the medications though the pores of 1 to 3 microns in diameter in its wall, and then can be refilled repeatedly by injecting in the tubular implant the medication through a 33-34 gauge needle through the cornea surrounding the tube.
  • the implant releases immunosuppressive agents, such as cyclosporine, calcineurin inhibitors, mycophenolic acid, tacrolimus, siraliums, steroids, MPP inhibitors, NSAIDs, antimetabolytes, polycolonal antibodies, monocolonal antibodies, TNF inhibitors, Fingolimod, antibiotics, intraocular pressure (IOP) lowering agents, such as Rho kinase inhibitors, Fasudil, and other agents, pilocarpine, prostaglandin analogues, Brimonidine, etc., anti-virals, Anti-VEGFs, biologies, or neuroprotective releasing medication.
  • immunosuppressive agents such as cyclosporine, calcineurin inhibitors, mycophenolic acid, tacrolimus, siraliums, steroids, MPP inhibitors, NSAIDs, antimetabolytes, polycolonal antibodies, monocolonal antibodies, TNF inhibitors, Fingolimod, antibiotics, intraocular pressure (IOP) lowering agents, such as Rh
  • the implant can be positioned at any place in the body to control a function or release a medication without being encapsulated by the surrounding tissue, due to the cross-linking of the polymeric coating or the pocket being cross-linked prior to the implantation, while the medication can be an anti-VEGF, neuroprotective agents, such as nerve growth factors, Rho kinase inhibitor such as Fasudil, antibiotics, antiproliferative agents, anti-inflammatory agents, etc. at a non-toxic, beneficial concentration.
  • neuroprotective agents such as nerve growth factors, Rho kinase inhibitor such as Fasudil, antibiotics, antiproliferative agents, anti-inflammatory agents, etc. at a non-toxic, beneficial concentration.
  • the implant is made using 3-D printing technology to the desired shape, size or thickness from any material coated with collagen, elastin, or made of collagen, elastin, etc. or synthetic polymers which are further coated with more biocompatible polymer(s), such as acrylic, organic, etc., which are cross-linked prior to the implantation or coated with a cross-linker or the crosslinking nanoparticles are done subsequent to its release in the tissue prior to radiation with the UV light.
  • the implant is formed from glass using 3-D printing technology (i.e., the implant is 3-D printed glass).
  • the implant is implanted in another part of the eye, such as under the conjunctiva, under the sclera, in the retina or sub-retinal space, under the skin using an implant containing medications such as Botox, or in other parts of the body using an implant which is coated with collagen to a desired thickness, dipped in a photosensitizer or has photosensitizer nanoparticles, such as riboflavin, etc. or the photosensitizer is injected surrounding the implant and implanted in desired location, such as under or over the sclera in the choroid, under the conjunctiva, etc.
  • UV radiation or another wavelength of light is used to cross-link the tissue at the desired power and duration depending on what technique is used.
  • a focused UV or another wavelength of light is applied externally, in a painting oscillatory fashion only to the desired areas or internally through a fiber optic, etc. to activate the photosensitizer in the surrounding tissue where the implant is located.
  • the cross-linked collagenous tissues surrounding the implant prevent creating an adhesion between the tissue and the implant or gluing the wall of the pocket together or to the implant.
  • the cross-linked collagenous tissues surrounding the implant also have these additional benefits: (1) it is easier to replace the implant if needed, (2) fibrous ingrowth or encapsulation is prevented, (3) it permits injection of the cross-linker again to repeat the cross-linking process if needed, and (4) it prevents rejection of the implant and contributes to the slow release of the medication from the implant.
  • these implants can act as a shunt for glaucoma, or drainage shunt for cerebrospinal fluid, or other part of the body, such as a bladder neck for urine if the drainage system is provided with a unilateral valve that only opens when the bladder pressure increases to certain level, etc.
  • the injection of a small amount of hyaluronic acid or other viscous fluid in the pocket simplifies the inserting of the implant in the peripheral corneal pocket or a pocket created in another tissue.
  • the implant can be a biodegradable polymer carrying various medications and can be replaced.
  • the implant is a tube-like structure having a thickness or diameter of 0.02 millimeters (mm) to 0.4 millimeters (mm) in one direction and up to 8 mm in another (flat) width, and being 1- 60 mm long covering the entire corneal periphery without pressing the corneal tissue in any direction.
  • the implant may be filled with a medication(s), a fluid, or a combination of them.
  • the tube is not biodegradable having holes made in the wall of the tube with 0.2 to 3 microns in diameter, or 5 microns to 500 microns in diameter, to permit diffusion of the medications or cells placed in it to produce desired needed proteins, hormones, nerve growth factors, or other products needed for other body cell survival, such as cornea, retina, brain, etc.
  • the tube has holes that are 5 to 15 microns in diameter so as to permit stem cells to exit the tube.
  • the tube can be biodegradable implanted in a lightly cross-linked corneal pocket permitting, for example, stem cells to proliferate and/or migrate to the cornea.
  • the stem cells can be obtained from limbal stem cells or mesenchymal stem or skin and cultured cells prior to the injection in the cornea or in another part of the body.
  • the device is implanted in the wall of the vitreous cavity with one end closed and one end open to the vitreous cavity, or the implant can be under the retina or it can penetrate both the retina and the choroid and permit release of medication or the cells.
  • the implant is implanted in the tissue surrounding the eye, on the face, etc. with one end closed and one end open to the tissue.
  • the implant can be removed after the drug is released, and then replaced.
  • the repeated crosslinking of the tissue surrounding the pocket can be performed as needed to prevent cellular ingrowth, and the implant can be removed and replaced as needed (e.g. in age related macular degeneration) to maintain delivery of the anti-glaucoma medication, anti-VEGFs, immunosuppressive or anti inflammatory agents, or nerve growth factors, or Rho kinase inhibitors.
  • the peripheral cross-linked pocket is used to insert or inject medications needed to treat a comeal disease, glaucoma, or a disease of the posterior segment.
  • the medication can be in a form of nanoparticles, microparticles, micelles, liposomes, chitosans, polycaprolactone as nanoparticles, dendrimers, etc.
  • the implant may be in the form of a solid implant 20, a porous implant 22, or a solid tubular implant 24 with an open end.
  • the implant may be in the form of a semi-solid or silicone tubular implant 36 with one closed end 38 and one open end 39.
  • the diameter of the rod or flat-shaped implant can have a length of 1 microns to a few millimeters (mm), or the length can be 1 to 40 millimeters (mm) or longer.
  • the non-biodegradable tube is open-ended so that the medication exits only from one or both ends of the tube.
  • the medication can be released for a duration of from 3 months to 3 or more years, such as when containing nanoparticles of fluoroquinolone dexamethasone, diclofenac, etc., and the implant can be replaced or removed if the desired effect has been achieved or reinjected in the corneal pocket.
  • the tube is closed ended, but has pores for diffusion of the medication.
  • the implant can be placed near any joint in the body and the cross-linking is done using ultraviolet (UV) radiation through the skin or through the fiber optic as described for localized drug delivery.
  • UV ultraviolet
  • the porous tube can be made of semipermeable non- biodegradable material that permits only the diffusion of fluid/medication, etc. in and out of the tube, and the tube is implanted in the peripheral cross-linked comeal pocket, wherein the tube can be refilled with medication as needed via an injection using a 33-34 gauge needle.
  • the tube can be made of semipermeable non- biodegradable material that permits only the diffusion of fluid/medication, etc. in and out of the tube, and the tube is implanted in the peripheral cross-linked comeal pocket, wherein the tube can be refilled with medication as needed via an injection using a 33-34 gauge needle.
  • the tube contains cells in a biocompatible fluid that permits nutrition to reach the cells which are injected in the tube where the cells are immortalized to produce one or more medications, growth factors, such as a ciliary neurotrophic growth factor, RPE growth factor, nerve growth factors, anti-VEGFs, or other medications needed.
  • growth factors such as a ciliary neurotrophic growth factor, RPE growth factor, nerve growth factors, anti-VEGFs, or other medications needed.
  • the implant contains genetically modified cells producing other needed enzymes and medications.
  • the combination of crosslinking of the cornea produces a wall of amorphous, acellular collagen and the comeal location that lacks vessels provides a suitable place for these cells in the tube implant to survive and produce medications as needed, which otherwise would have to be given repeatedly either locally or systemically, and in many genetic diseases of the cornea, such as Fuchs dystrophy, the cells have to be injected in the subconjunctival space where the cells could be attacked by the normal cellular body’s immune response.
  • the cross-linked pocket with the implant creates an immune-privileged space in the cornea or elsewhere for these cells to survive. For example, refer to FIGS. 10A-17B.
  • the medication in the implant can be in any form or composition, such as antibiotics, anti-inflammatory, immune suppressants, anti-glaucoma medication, anti-vascular proliferation, stimulatory, such as Rho inhibitors.
  • the polymers can be made of bio-degradable compounds, such as polylactic, polyglycolic acid or a combination of them, polycaprolactone, etc.
  • the comeal cross-linked pocket contains a tubular implant filled with particulate immunosuppressive agents, such as cyclosporine etc., that release the medication at a constant, but low concentration of micrograms as needed.
  • the medication diffuses in the cornea, sclera, and/or conjunctiva, thus eliminating the burning sensation of topical cyclosporine drops and the need for daily drop admiration in dry eye syndromes, or after refractive surgery or other diseases.
  • the medication can be injected in the peripheral pocket along with corneal stem cells taken from the limbus or genetically modified stem cells and grown in the culture for implantation.
  • a non- biodegradable implant tube 62 as described herein is implanted in the cross-linked corneal pocket of the cornea 52 of the eye with iris 53 and lens 55, and the implant tube 62 is connected to the anterior chamber 57 with the aqueous fluid via a thin 23-34 gauge needle 64, where biomarkers such as VEGFs, glucose, and analytes, etc. are present both inside the aqueous and the tube system made of soft silicone.
  • biomarkers such as VEGFs, glucose, and analytes, etc.
  • an implant 78 is implanted in the cross-linked corneal pocket of the cornea 66 of the eye with iris 65, and the implant 78 is connected to the anterior chamber 67 with the aqueous fluid via a needle 80.
  • the implants 62, 78 can be penetrated with a 30-34 gauge needle from outside and the aqueous can be aspirated in a volume of less than 0.50 microliters repeatedly over a long period of time without causing a collapse of the anterior chamber.
  • the volume of the anterior chamber is 25 times more than the sample fluid taken. The minimal amount of aqueous fluid withdrawn will be replaced by the eye in less than 10 minutes.
  • the fluid sample can be examined in chronic disease processes, such as uveitis for biomarker of a disease, viral infection that persist in the eye long after the body has healed, such as Ebola, Zika, Herpes viruses or other viral diseases or non- viral infections that can be detected and treated appropriately.
  • chronic disease processes such as uveitis for biomarker of a disease, viral infection that persist in the eye long after the body has healed, such as Ebola, Zika, Herpes viruses or other viral diseases or non- viral infections that can be detected and treated appropriately.
  • the biomarkers can be obtained from the implanted tube, and can provide valuable information on many metabolic diseases of the body or the eye, a systemic disease (e.g., Alzheimer disease), age related macular degeneration, glucose level, or other analytes (e.g., diabetes) in diabetic retinopathy and other slow progressive degenerative eye diseases, tumors, infection, uveitis, poisoning or drug overdose, etc.
  • a systemic disease e.g., Alzheimer disease
  • age related macular degeneration e.g., glucose level
  • analytes e.g., diabetes
  • slow progressive degenerative eye diseases e.g., tumors, infection, uveitis, poisoning or drug overdose, etc.
  • a plurality of implants are implanted in the cornea of the eye.
  • each of the implants is used for a different purpose.
  • a first one of the implants may be in form of a comeal drug delivery implant used for delivering one or more medications to the eye, as described above.
  • a second one of the implants may be used for taking liquid biopsies from a portion of the eye, as described herein (e.g., extracting a liquid biopsy of the aqueous fluid from the anterior chamber of the eye).
  • a third one of the implants may be used for stem cell delivery and/or gene therapy in the manner described above.
  • a fourth one of the implants may be used for measuring the intraocular pressure of the eye of the patient (i.e., intracorneal implant comprising a pressure sensor). That is, the fourth implant may contain a pressure sensor configured to measure an intraocular pressure of an eye and to output a signal based on the measured intraocular pressure of the eye, the pressure sensor configured to be implanted in a cornea of the eye; a processor operatively coupled to the pressure sensor, the processor configured to generate intraocular pressure data based upon the signal outputted by the pressure sensor; and a transmitter device operatively coupled to the processor, the transmitter device configured to transmit the intraocular pressure data generated by the processor to a remote receiver located outside of the eye, the transmitter device configured to be implanted in the cornea of the eye.
  • a pressure sensor configured to measure an intraocular pressure of an eye and to output a signal based on the measured intraocular pressure of the eye
  • the pressure sensor configured to be implanted in a cornea of the eye
  • a processor operatively coupled to the pressure
  • the third implant may further comprise a needle configured to penetrate a posterior portion of the cornea of the eye, the needle configured to open into the anterior chamber of the eye so as to measure the intraocular pressure of the eye without obstructing vision through the central cornea.
  • a needle configured to penetrate a posterior portion of the cornea of the eye, the needle configured to open into the anterior chamber of the eye so as to measure the intraocular pressure of the eye without obstructing vision through the central cornea.
  • one can measure the amount of VEGF present in the aqueous providing information on the disease progression requiring treatment (e.g., anti- VEGFs or no treatment).
  • Anti-VEGFs or another medication can be administered directly in the tube to reach the posterior segment avoiding repeated intraocular injection through the sclera, without having the risk of retinal detachment or lens injury.
  • liquid biopsy of aqueous in a patient with diabetic retinopathy, where the retina is in need of treatment with the laser coagulation provides the information regarding whether the disease process is under
  • the aqueous biopsy for the first time one can obtain from the aqueous biopsy, instant information needed for the doctor to diagnose a disease process at the bedside and be able to follow the process over a long period of time with ease.
  • nanoparticles carrying other medications can be delivered as slow release nanoparticles from the tube in the anterior chamber to treat glaucoma for a long period of time, thereby eliminating the need for repeat therapy.
  • These medications may include pilocarpine, prostaglandin analogues for treatment of glaucoma,
  • Rho kinase inhibitors or neuroprotective agents or Brimonidine, etc.
  • the implanted tube is filled with desired medications, as described above, and is coated with collagen or albumin loaded with riboflavin particles that are diffused after implantation in the pocket.
  • the ultraviolet (UV) radiation used for cross-linking permits the diffusing of the medication from the implant as a slow release device, and prevents vascular growth around the implant containing the medication.
  • the implanted tube can be 100 microns to 1 millimeters (mm) in diameter and 4 mm to 40 mm long, or less thanlOO micron in diameter and no longer than a few millimeters in length.
  • the implanted tube maybe filled with any desired medication to be implanted in any tissue and cross-linked after implantation.
  • methods are disclosed herein which include administering Wnt inhibitors either alone, or in combination with Rho kinase inhibitors (i.e., Rock inhibitors), that are useful for alleviating the effects of conditions that are caused by acute or chronic inflammatory processes, such as chronic inflammatory dry eye disease, lichen planus, arthritis, psoriasis, plantar fasciitis, pars planitis, papillitis, optic nerve neuritis, scleritis, keratitis, chronic Meibomian gland inflammation, and uveitis.
  • Rho kinase inhibitors i.e., Rock inhibitors
  • Wnt inhibitors or Rho kinase inhibitors are used as topical drops, ointment, gel, non-toxic injectable formulation to treat the dry eye syndrome or mucosal inflammatory diseases, such as lichen planus, chronic joint disease, arthritis, chronic choroiditis, plantar fasciitis, pars planitis, scleritis, LTDis, scleritis gingivitis, pars planitis and uveitis.
  • inflammatory diseases such as lichen planus, chronic joint disease, arthritis, chronic choroiditis, plantar fasciitis, pars planitis, scleritis, ulceris, scleritis gingivitis, pars planitis and uveitis.
  • a method of treating dry eye with deficiency or aqueous production which is associated often with the Meibomian gland disease, affecting about7% to 34% of all Americans, pathophysiology of chronic dry eye disease including a cycle of inflammation involving both innate and adaptive immune responses is also disclosed herein.
  • dry eye syndrome or keratoconjunctivitis sicca, a disease affecting tear production leading to damage to the corneal surface, associated often with disturbance of Meibomian gland, lachrymal gland, conjunctival goblet cells, nasolacrimal duct and pain sensation is treated by Wnt inhibitors or Rho kinase inhibitors used as topical drops, ointment, gel, non-toxic injectable formulation.
  • the method used for treatment of the eye utilizes over the counter physiological saline solutions with some other components to affect the inflammatory component of the dry eye or improve on the composing of the tear film, such as tear film osmolarity, or adding lipids, mucin, etc.
  • Topical medications include TheraTears ® (Advanced Vision Research), Refresh ® and Celluvisce ® (Allergan), Tears Natural ® and Bion Tears ® (Alcon), GenTeal ® and HypoTears ® (CIBA Vision), each of which contain electrolytes and has varying pH levels, osmolarities, Restasis ® (0.05% cyclosporine, Allergan), and Xiidra ® (5% lifitegrast, Shire), which attacks the inflammatory process by a different mechanism than cyclosporine.
  • the administration of Rock inhibitors not only reestablishes the tear production by reducing the conjunctival inflammatory cytokines and inflammatory response, but also enhances the nerve fibers to grow and reestablish the function of conjunctival goblet cells to produce mucin, which is essential for tear film lubrication.
  • Rho- associated protein Kinase (Rock) is a kinase belonging to the family of serine-threonine Kinase involved in regulating the shape and the cytoskeleton of the cells, it is an important regulator of cell migration, stimulates PTEN phosphatase activity, leading to uncontrolled cell division in cancer.
  • Rock is active in inflammatory processes, cancer, Parkinson’s disease, diabetes, and many neurodegenerative diseases and produces and stiffens collagen in tumors, such as pancreatic cancer. Therefore, Rock inhibitors inhibit inflammatory processes, blocking cell migration.
  • Rock inhibitors may be used in combination with
  • a potent ROCK inhibitor orally bioavailable Fasudil hydrochloride, inhibitor of cyclic nucleotide dependent- and Rho-kinases GSK 269962 is used.
  • potent and selective ROCK inhibitor GSK 429286, Selective Rho-kinase (ROCK) inhibitor H1152 dihydrochloride, or Botox is used.
  • selective Rho-kinase (ROCK) inhibitor Glycyl H 1152 dihydrochloride, or another selective Rho-kinase (ROCK) inhibitor is administered as topical ointment, drop, or gel.
  • a more selective analogue of H1152 that is cell-permeable, a selective Rho-kinase inhibitor OXA 06 dihydrochloride, a potent ROCK inhibitor PKI1447 dihydrochloride, potent and selective ROCK inhibitor antitumor SB 772077B, a potent Rho- kinase inhibitor, vasodilator SR 3677 dihydrochloride, a potent, selective Rho-kinase (ROCK) inhibitor TC-S7001, a potent and highly selective ROCK inhibitor, orally active Y- 27632 dihydrochloride or Botox also may be administered.
  • a selective Rho-kinase inhibitor OXA 06 dihydrochloride a potent ROCK inhibitor PKI1447 dihydrochloride
  • potent and selective ROCK inhibitor antitumor SB 772077B a potent Rho- kinase inhibitor
  • vasodilator SR 3677 dihydrochloride a potent, selective
  • aqueous tear-deficient dry eye occurring as a result of not enough tears being produced due to a dysfunction of the lacrimal glands, is treated with Wnt inhibitors or Rho kinase inhibitors as topical drops, ointment, gel, or a non-toxic injectable formulation.
  • the Wnt inhibitors compound that is used includes FH535, IWP-2, PNU-74654, IWR-lendo, IWR-exo, demethoxycurcumin, sulforaphane and vitamin D, CCTO36477,KY02ll l, WAY-316606, SFRP , IWP , LGK974, C59, Antl.4Br/Ant 1.4C1, ivermectin, niclosamide, apicularen and bafilomycin, XAV939, XAV939, G007-LK and G244-LM, NSC668036, SB-216763, gemtuzumab, and akinumab.
  • patients with moderate-to- severe dry eye having both elements of evaporative dry eye and aqueous tear-deficient dry eye, and that are on topical medications for other diseases, such as glaucoma, drops, or antibiotics containing preservative that over time damage the conjunctival goblet cells and other cells and induce dry eye syndrome are treated with Wnt inhibitors or Rho kinase inhibitors as topical drops, ointment, gel, or a non toxic injectable formulation.
  • Wnt inhibitors such demethoxycurcumin, sulforaphane and vitamin D, or Rho kinase inhibitors, such as Fasudil derivatives
  • administration of Wnt inhibitors is done as topical drops, a gel, a non-toxic injectable formulation, or injectable Botox, 1-100 units as needed, administered locally at multiple locations or Rock inhibitors molecules at doses of lPg- nanograms to a few micrograms as slow release delivery system.
  • patients who are on topical medications for other diseases such as glaucoma, drops or antibiotics containing preservatives and over time damage the conjunctival goblet cells and other cells and induce dry eye syndrome, or patients with dry eye and glaucoma are treated either by implanting matrices of polylactic acid or poly glycolic acid, polyanhydride, or chitosan polymers under the conjunctiva with slow release polymers containing either Wnt inhibitors or Rock inhibitors, such as Botox or Fasudil derivatives, releasing the medication over months or years locally at multiple locations to release the non toxic doses of the medications from 1 picogram (pg) to 1 nanograms (ng) or more each day.
  • Wnt inhibitors or Rock inhibitors such as Botox or Fasudil derivatives
  • patients who develop dry eye as a result of systemic medication are treated either by Wnt inhibitors or Rock inhibitors with slow release polymers containing either Wnt inhibitors, such as demethoxycurcumin, CCT036477, KY02111, WAY-316606, SFRP, IWP , LGK974, C59, Antl.4Br/Ant 1.4C1, ivermectin, niclosamide, sulforaphane and vitamin D, or Rock inhibitors, such as Botox or Fasudil derivatives, etc., releasing the medication over months or years locally at multiple locations to release the non-toxic doses slow release medications from 1 pg to 10 ng each day or more.
  • Wnt inhibitors such as demethoxycurcumin, CCT036477, KY02111, WAY-316606, SFRP, IWP , LGK974, C59, Antl.4Br/Ant 1.4C1, ivermectin, niclosamide,
  • the Sjorgen syndrome is associated with low salivary flow, lymphocytic infiltration of the lacrimal gland and salivary gland auto antibodies in serum, rheumatoid factor, connective tissue diseases, such as Sjogren's syndrome, to the list of immune-related adverse events that can develop during cancer treatment with immune checkpoint inhibitors are treated with Rock inhibitors and Wnt inhibitors at non-toxic concentrations of sulforaphane and vitamin D, CCT036477, KY02111, WAY-316606, SFRP , IWP, LGK974, C59, Antl.4Br/Ant 1.4C1, ivermectin, niclosamide, or Rock inhibitors such as Botox or Fasudil etc., releasing the medication slowly over months or years locally at multiple locations to release the non-toxic doses slow release medications from 1 picogram (pg) to 10 nanogram (ng) each day locally.
  • the patients being treated have a dry eye syndrome
  • SS Sjogren’s syndrome
  • KCS non-SS keratoconjunctivitis sicca
  • Other symptoms are increased tear film osmolality, decrease in tear breakup time, increase in the conjunctival enzymes metalloproteinase 9 and 17, and changes in impression cytology of the conjunctival cells.
  • Rock inhibitors such as injectable Botox, 1-10 units, or in combination with metalloproteinase inhibitors doxycycline, low molecular weight heparin, lovenox, and dexamethasone at concentration of 0.l%-5%.
  • inflammation is one of the mechanisms that causes damage to the ocular surface in dry eye disease seen in autoimmune diseases such as
  • the pathological conditions resulting in dry eye include pemphigus and Sjogren’s syndrome, which affect the eye by either damaging the conjunctival cells responsible for maintaining the wetness of the cornea and the conjunctiva, or by damaging the lacrimal glands of the eye and/or the meibomian glands of the eye lid or other pathological conditions resulting in dry eye include hypolacrimation, alacrima, Stevens- Johnson syndrome, marginal blepharitis pemphigus, ocular pemphigoid, scleritis, or diabetes are treated with the Rock inhibitor Fasudil, Botox, etc. at a picogram to nanogram
  • metalloproteinase inhibitors concentration or in combination with metalloproteinase inhibitors, doxycycline 0.l%-5% solution, low molecular weight heparin 0.l%-5% solution, or dexamethasone 0.1-2% solution in combination with MTOR inhibitors at 0.l%-5% solution.
  • the dry eye of patients occurring in post-comeal surgery including but not limited to post-LASIK surgery
  • surgical damage to the corneal nerves including the aging process, environmental factors (e.g., dry home and/or work environments), and extended use of visual display terminals (e.g., employment, recreation)
  • Rock inhibitors or in combination with metalloproteinase inhibitors, low molecular with heparin, or Wnt inhibitors or Rock inhibitor, such as Botox, 1-100 units administered locally at multiple locations, small doses or Rock inhibitors molecule, Fasudil and its derivatives, etc., at doses of 1 nanogram (ng) to a few micrograms (pg) as a slow release polymer.
  • the dry eye can also occur after cataract surgery and refractive surgery (i.e., the LASIK procedure) and photorefractive keratectomy, smile procedure, partial or complete corneal transplants, which are the majorities of present refractive surgery where these procedures are performed, but dry eye is more common with LASIK where the superficial nerves are cut, and where the eye dries out because the corneal reflex is affected and the eye subsequent to these surgeries becomes dry while many eyes experience regeneration of the nerves, but it takes about one year or more to achieve it all.
  • refractive surgery i.e., the LASIK procedure
  • photorefractive keratectomy, smile procedure i.e., smile procedure
  • partial or complete corneal transplants which are the majorities of present refractive surgery where these procedures are performed, but dry eye is more common with LASIK where the superficial nerves are cut, and where the eye dries out because the corneal reflex is affected and the eye subsequent to these surgeries becomes dry while many eyes experience regeneration of the nerves, but it takes about one
  • Rock inhibitors or in combination with metalloproteinase inhibitors, low molecular with heparin, or Wnt inhibitors or Rock inhibitors, such as Botox, 1-100 units administered locally over the cornea as drops 1-4 times daily or injectable preparation at multiple locations, small doses or Rock inhibitors molecule, such as Fasudil or its derivatives, etc., at doses of 1 nanogram or a few micrograms as a slow release non-toxic preparation.
  • patients with paresis or paralysis of the fifth or seventh cranial nerves causing dry eye as a result of interfering with proper lid closure are treated with Rock inhibitors, such as Botox, 1-10 units administered topically over the cornea at multiple locations, and in small doses, or Rock inhibitors, such as the molecule Fasudil, or its derivatives, etc. at doses of 1 nanogram to a few micrograms as topical ointment, drop, gel, etc.
  • Rock inhibitors such as Botox, 1-10 units administered topically over the cornea at multiple locations, and in small doses, or Rock inhibitors, such as the molecule Fasudil, or its derivatives, etc.
  • the patient has lichen planus associated with a chronic inflammatory disease of the skin, mucous membranes, and nails presenting a burning sensation in the mouth, throat esophagus, vagina and the mucosa appears as a lattice-like network of white lines near sites of erosion.
  • Lichen planus can also affect the skin accompanied with sensation of itching, reddish-purple polygon-shaped skin lesions on the lower back, wrists, and ankles. Lichen planus very rarely leads to oral cancer in about 5% of the patients.
  • the cause of lichen planus is unknown, but it is thought to be the result of an autoimmune process with an unknown initial trigger. It is known that tobacco, alcohol, and stress aggravate the lesions.
  • the patients with lichen planus are treated either by Wnt inhibitors or Rock inhibitors as a topical solution drops, gel, non-toxic injectable formulation, ointment or oral, or if needed, systemic administration of these medications or Rock inhibitor, such as Botox, 1-100 units administered locally as ointment over the lesion or injectable preparation at multiple locations, small doses or Rock inhibitors as Botox or molecule Fasudil, and its derivatives etc. at doses of 1 nanogram to a few micrograms.
  • Wnt inhibitors or Rock inhibitors as a topical solution drops, gel, non-toxic injectable formulation, ointment or oral, or if needed, systemic administration of these medications or Rock inhibitor, such as Botox, 1-100 units administered locally as ointment over the lesion or injectable preparation at multiple locations, small doses or Rock inhibitors as Botox or molecule Fasudil, and its derivatives etc. at doses of 1 nanogram to a few micrograms.
  • the patients with lichen planus are treated locally, by topical or injection subcutaneously with either by Wnt inhibitors or Rock inhibitors, such as Botox, 10- 100 units as needed administered locally at multiple locations or Rock inhibitors, such as Fasudil, etc. molecules at doses of 1 nanogram to a few micrograms.
  • Wnt inhibitors or Rock inhibitors such as Botox
  • Rock inhibitors such as Botox
  • Fasudil Fasudil
  • Wnt signaling is involved in the control of stem cell proliferation.
  • Wnt mutation causes developmental defects in many disease processes including inflammation and cancer.
  • the Wnt inhibitors compounds used are: FH535, IWP-2, PNU- 74654, IWR-lendo. IWR-exo, demethoxycurcumin, sulforaphane and vitamin D,
  • the oral doses for the Wnt inhibitor niclosamide is 1 to 2 gram tablet once, or to repeat in 7 days, if needed.
  • the small molecule Fasudil a rock inhibitor Fasudil (HA- 1077), a selective RhoA/Rho kinase (ROCK) inhibitor, or Y-27632, small molecule inhibitor of ROCK1 and ROCK2, Botulinum toxin a is rock inhibitor marketed under the brand names Botox, Dysport Myobloc. Xeomin, etc.
  • Botulinum toxin all having good penetration into the cornea, and do not increase intraocular pressure or cause cataracts and may be dissolved in an organic solvent such as DMSO or alcohol or sterol, lanosterol, squalene, and/or squalamine, or containing a polyanhydride, poly(glycolic) acid, poly(lactic) acid, or polycaprolactone polymer for the treatment of the lid, conjunctiva, lacrimal gland comeal diseases and glaucoma.
  • an organic solvent such as DMSO or alcohol or sterol, lanosterol, squalene, and/or squalamine, or containing a polyanhydride, poly(glycolic) acid, poly(lactic) acid, or polycaprolactone polymer for the treatment of the lid, conjunctiva, lacrimal gland comeal diseases and glaucoma.
  • Fasudil is used as a single, oral 40-80 milligram (mg) dose orally as two 40 mg Fasudil tablets are administered.
  • the methods include administering Wnt inhibitors, either alone or in combination with Rho kinase inhibitors, orally, locally by injection or drops, spray or ointment for alleviating the effects of conditions that result in lack of moisture or wetness in the eye.
  • Rho kinase inhibitors may be administered orally, locally by injection or drops, spray or ointment for alleviating the effects of conditions that result in lack of moisture or wetness in the eye, such as the inflammatory conditions resulting in dry eye including pemphigus and Sjogren’s syndrome, which affect the eye by either damaging the conjunctival cells, or by damaging the lacrimal glands of the eye and/or the meibomian glands of the eye lid.
  • Rho kinase inhibitors such as Botox in 1-2 units
  • the required treatment of Rho kinase inhibitors may be administered locally by injection or drops, spray or ointment for other inflammatory processes resulting in dry eye include hypolacrimation, alacrima,
  • xerophthalmia xerophthalmia
  • Stevens- Johnson syndrome pemphigus
  • ocular pemphigoid marginal blepharitis
  • nerve pain diabetes, and/or post-corneal surgery after cutting the corneal nerves (including but not limited to post-LASIK surgery).
  • Other conditions resulting in dry eye include the aging process, environmental factors (e.g., dry home and/or work environments), and extended use of visual display terminals (e.g., employment, recreation, etc.).
  • inhibition of Wnt signaling or ABC transporters by RNA interference may be a valuable therapeutic strategy in dry eye including hypolacrimation, alacrima, xerophthalmia, and Stevens-Johnson syndrome.
  • a number of Rock inhibitors are used in non-toxic doses in combination with functionalized nanoparticles, conjugated with polymeric coatings, such as chitosan, polyanhydride, cyclodextrin as a potent ROCK inhibitor; bioavailable Fasudil hydrochloride, inhibitor of cyclic nucleotide dependent- and Rho-kinases GSK 269962, potent and selective ROCK inhibitor GSK 429286, selective Rho-kinase (ROCK) inhibitor H1152 dihydrochloride, selective Rho-kinase (ROCK) inhibitor Glycyl H 1152
  • ROCK selective Rho-kinase
  • OXA 06 dihydrochloride selective Rho-kinase inhibitor
  • potent ROCK inhibitor PKI1447 dihydrochloride potent and selective ROCK inhibitor
  • antitumor SB 772077B potent Rho-kinase inhibitor
  • vasodilator SR 3677 dihydrochloride potent, selective Rho-kinase (ROCK) inhibitor TC-S7001, potent and highly selective ROCK inhibitor, orally active Y-27632 dihydrochloride and may be dissolved in an organic solvent such as DMSO or alcohol or sterol, lanosterol, squalene, and/or squalamine, or containing a polyanhydride, poly(glycolic) acid, poly(lactic) acid, or polycaprolactone polymer to reduce the
  • Wnt inhibitors such as canakinumab, ivermectin, or niclosamide may be dissolved in an organic solvent such as DMSO or alcohol or sterol, lanosterol, squalene, and/or squalamine, or containing a polyanhydride, poly(glycolic) acid, poly(lactic) acid, or polycaprolactone polymer prior to its application.
  • small molecule Wnt inhibitor PKF118-310, the Wnt/ -catenin pathway inhibitor and Fasudil, a rock inhibitor Fasudil (HA- 1077), a selective RhoA/Rho kinase (ROCK) inhibitor, or Y-27632, small molecule inhibitor of ROCK1 and ROCK2, etc. may be dissolved in an organic solvent such as DMSO or alcohol or sterol, lanosterol, squalene, and/or squalamine, or containing a polyanhydride, poly(glycolic) acid, poly(lactic) acid, or polycaprolactone polymer to release non-toxic medication slowly at a desired concentration.
  • early management includes the use of lubricants, artificial tear substitutes, ointment, gel, or emulsion.
  • Topical anti-inflammatory agents include topical Rock inhibitors, anti-interleukin (IL1) TNF-alfa TNF-a, hyaluronic acid, low molecular heparin 0.1-5% solution alone, or in combination with metalloproteinase inhibitors doxycycline 0.1- 5% solution immunosuppressive agent or inhibitor, e.g., mycophenolic acid, as local or systemic therapy.
  • topical Rock inhibitors are applied to the cornea as drops or spray or subconjunctival injection as a slow release compound combined with chitosans in 0.1 microgram/ml to 40 microgram/ml or more for topical application.
  • the Rock inhibitors are coated with the slow release polymers, such as lactic acid, glycolic acid, etc. at a concentration of 200 nanograms to 1 micrograms/ml or more and administered topically, subconjunctival, or inside the eye subcutaneously inside the plantar fascial.
  • the slow release polymers such as lactic acid, glycolic acid, etc.
  • the Rock inhibitors are released from a polymeric explant or implant (e.g., an implant as depicted in FIGS. 1 A-5) either placed over or under the conjunctiva and sutured to the sclera to release, e.g., Fasudil, etc. at concentrations of 0.01 micrograms/ml to 40.0 micrograms/ml or more per day.
  • a polymeric explant or implant e.g., an implant as depicted in FIGS. 1 A-5
  • Fasudil e.g., Fasudil, etc. at concentrations of 0.01 micrograms/ml to 40.0 micrograms/ml or more per day.
  • the Rock inhibitors release, after placement in the upper or lower cul-de-sack of the conjunctiva or as a slow release punctal plaque or implanted subconjunctivally, at a rate of 1 picogram to a 10 nanograms/day of the medication.
  • the Rock inhibitors release, after placement in the
  • suprachoroidal space inside the eye, behind the eye, inside the gingiva, subcutaneously in plantar fascia, or as a slow release polymeric plaque or implanted to release medication at a rate of 1 picogram to a 10 nanograms/day of the non-toxic medication.
  • the nanoparticles or dendrimers are conjugated with Rock inhibitors and chitosan delivered as a slow release system that can be released from a temperature sensitive polymer that melts at 42-43 degrees C and is used with a warm compressor over or under the lid, or light thermal application, or the use of a compressive focused ultrasound applied to lid, conjunctiva, cornea, or the lid releasing 1 picogram to a 10 nanograms/day of the medication.
  • the Rock inhibitors or Wnt inhibitors are delivered with simultaneous application of amniotic membrane and slow release nanoparticles applied post corneal surgery, such as LASIK, cataract comeal transplant, or any other corneal surgical intervention at 10 picograms to 20 nanograms of medication per day.
  • the Rock inhibitors or Wnt inhibitors are delivered with simultaneous application of amniotic membrane and low molecular weight heparin slow release nanoparticles applied post corneal surgery, such as LASIK, cataract, corneal transplant uveitis scleritis or chemical injury to the cornea or conjunctiva at concentrations of 0.001 micrograms/ml to 40 micrograms/ml or more or topical or subconjunctival Botox, at 1- 100 units or topical at 1-5 units or more in a physiological solution of Botox, or similar preparations.
  • LASIK corneal transplant uveitis scleritis or chemical injury to the cornea or conjunctiva
  • topical or subconjunctival Botox at 1- 100 units or topical at 1-5 units or more in a physiological solution of Botox, or similar preparations.
  • the Rock inhibitors or Wnt inhibitors are delivered with simultaneous application of low molecular weight heparin (levonox) with other medications, such as tetracycline, Doxycycline or metalloproteinase inhibitors, dexamethasone 0.1% -1% concentration as slow release polymeric nanoparticles or liposomes applied post comeal surgery such as LASIK, cataract, corneal transplant, uveitis, scleritis or thermal or chemical injury to the cornea or conjunctiva, e.g., Fasudil derivatives, etc., at 0. 1 micrograms/ml to 40 micrograms/ml or more, or Botox at 1-3 units.
  • other medications such as tetracycline, Doxycycline or metalloproteinase inhibitors, dexamethasone 0.1% -1% concentration as slow release polymeric nanoparticles or liposomes applied post comeal surgery such as LASIK, cataract, corneal transplant, uveitis, scle
  • Rock inhibitors at doses of 0. 1 micrograms/ml to 40 micrograms/ml or more for topical application or Wnt inhibitor can be injected in the anterior chamber, or applied as drops in the post operative period to replace prednisolone or other steroids, or NASIDs, and encourage regrowth of the cut neurons in the cornea.
  • Wnt inhibitors, or Rock inhibitors such as botulinum toxin (Botox) can be injected under the conjunctiva or applied as drops in the post-operative period to encourage regrowth of the cut neurons in the cornea after LASIK or other corneal surgery at doses of 1 to 10 units of Botox injected under the conjunctiva or 1-2 drops daily at concentration of 10 picograms to 500 picograms of Botox in physiological solution or topical as drops.
  • Botox botulinum toxin
  • Rock inhibitors or Wnt inhibitor such as botulinum toxin (Botox) can be applied as drops or injected subconjunctivally to eliminate the inflammatory component of the dry eye at doses of 1-10 units once a month or once every 2 to 3 months with slow release nanoparticle conjugates in biodegradable polymers.
  • Botox botulinum toxin
  • Rock inhibitors such as botulinum toxin (Botox), Fasudil, etc. or Wnt inhibitors, such as niclosamide, ivermectin, FH535, IWP-2, PNU-74654, IWR-lendo.
  • IWR-exo, demethoxycurcumin, sulforaphane and vitamin D can be given orally at the tolerated dose or 40 mg Fasudil or 1 gram niclosamide or 10-100 units of Botox to eliminate the inflammatory component of dry eye, sulforaphane at 400 micrograms and Vitamin D 3000-5000 IU.
  • the Rock inhibitors such as Fasudil derivatives at
  • Botox solution of 0.1 units of Botox can be administered with small molecule Wnt inhibitors at a low concentration 1-10 microgram.
  • a topical or subconjunctival or intraocular administration of the Rock inhibitors, such as Fasudil derivatives, etc., at concentrations or 10 picograms to 100 nanograms/0.25 ml or Botox solution of 0.1-1 units can be administered with small molecule Wnt inhibitors or a low concentration of sulforaphane and vitamin D to inhibit the inflammatory processes or auto-immune response.
  • the Rock inhibitors such as Fasudil derivatives, etc.
  • Rock inhibitors are administered with antibody coated nanoparticles conjugated with thermosensitive nanoparticles and Adalimumab, a humanized antibody administered topically or subcutaneously at a non-toxic dose.
  • Rock inhibitors are administered with antibody coated nanoparticles, dendrimers, liposomes, etc. to the conjunctiva as liposomes or ointment in Meibomian gland inflammation to release medication at a concentration of 1 picogram to 100 units or more picograms/0.25ml to 0.5 ml along with an antibiotic.
  • Wnt inhibitors or Rock inhibitors such as Fasudil derivatives, etc. are administered with nanoparticles, dendrimers, thermosensitive polymers conjugated with polylactic or polyglycolic acid or chitosan, microspheres, liposomes, dendrimers, and combinations thereof, and they are administered as drops, or injected in the conjunctival or lacrimal glands along with immunosuppressive agents, such as mycophenolic acid, etc.
  • topical administrations, subconjunctival injections, sub-tenon injections, suprachoroidal injections, intravitreal injections can be combined with small molecule Wnt inhibitors or standard anti-inflammatory agents (e.g., steroids, dexamethasone, etc.), nanoparticle implants, biodegradable or non-biodegradable polymers, NASIDs, immunotherapy immunosuppressants, etc. to treat inflammatory processes of the lid conjunctiva or the cornea and the lid or throughout the day.
  • a dose of about 50 picograms/ml to about 200 micrograms/ml may be used, or a surgical implant may be used, for example, in a diffusible walled reservoir (e.g., as shown in FIGS. 3B, 4, and 5) sutured to the wall of the sclera, or may be contained within an inert carrier, such as microspheres, dendrimers, or liposomes to provide a slow-release drug delivery system.
  • a diffusible walled reservoir e.g., as shown in FIGS. 3B, 4, and 5
  • an inert carrier such as microspheres, dendrimers, or liposomes to provide a slow-release drug delivery system.
  • a formulation of Wnt or Rock inhibitors is used from the group consisting of topical administration at a concentration of about 50 picograms/ml to less than 1 micrograms/ml, subconjunctival injection at a dose in the range of about 1 picogram/ml to about 200 micrograms/ml, intravitreal injection at a dose in the range of about 0.1 picogram/ml to about 20 micrograms/ml, or retrobulbar injection at a dose in the range of about 2 micrograms/ml to about 200 micrograms/ml in slow release microspheres or dendrimers.
  • a formulation of Wnt or Rock inhibitors is used comprising intraocularly administering to a patient after corneal surgery at picogram to nanogram concentrations.
  • a formulation of Wnt or Rock inhibitors is used as a composition consisting essentially of Rock inhibitors in a pharmaceutically acceptable formulation and in an amount effective to enhance post-surgical to enhance ocular moisture, nerve regeneration in the patient wherein the composition is administered at a concentrations up to about 10 micrograms/ml by at least one of slow release polycaprolactone, polylactic, or poly glycolic acid, etc. over many months, intraocular administration of the composition, or is administered topically at a concentration in the range between about 10 picograms/ml to less than 1 microgram/ml depending on the composition of the medication.
  • the polymeric composition is administered by subconjunctival injection at a dose in the range of about 1 picogram/ml to about 20 micrograms/ml
  • intravitreal injection at a dose in the range of about 1 picogram/O.l ml to about 20 nanograms/ml
  • retrobulbar injection at a dose in the range of about 20 nanograms/ml to about 2 micrograms/ml.
  • a formulation of Wnt or Rock inhibitors is used to enhance post-surgical ocular moisture or in papilitis, optic nerve neuritis, uveitis or scleritis in the patient wherein the composition is administered at a concentration up to about 50 picograms/ml by at least one of intraocular injection, or the composition is administered topically at a concentration in the range between about 50 picograms/ml to less than 1 micrograms/ml.
  • a formulation of Wnt or Rock inhibitors is used wherein the composition is administered by subconjunctival injection at a dose in the range of about 1 picograms/ml to about 2 micrograms/ml, intravitreal injection at a dose in the range of about 1 nanogram/0.1 ml to about 20 nanograms/ml, or retrobulbar injection at a dose in the range of about 200 nanograms/ml to about 2 micrograms/ml.
  • a method to treat an ocular condition in a patient comprises intraocularly administering to the patient a pharmaceutically acceptable formulation of a drug selected from the group consisting of Rock inhibitors, such as Fasudil or derivatives in nanogram to microgram concentrations in microspheres, dendrimers, physiological solution, botulinum toxin in picogram concentrations in polymeric microspheres or 0.3-5 units injectable, or Wnt inhibitors, such as niclosamide, ivermectin, nanogram to microgram concentration in microspheres, dendrimers, suspension or another polymer, sulforaphane 10- 400 nanograms in microspheres, dendrimers, or another polymer and Vitamin D taken orally in 1000-5000 IU etc., Fasudil derivatives taken orally 1-40 mg, niclosamide orally in 10-500 mg tablets, sulforaphane in capsule 10-40 mg or more ivermectin taken orally 1-400 mg or more and topical formulation as drops,
  • Rock inhibitors such as Fa
  • non- toxic doses of Rock inhibitors in an amount up to about 1- 200 micrograms/ml effective to treat dry eye or another ocular condition selected from diabetic retinopathy, retinitis pigmentosa, or age related macular degeneration without substantial toxicity and at least one Wnt inhibitor or Rock inhibitor, wherein the composition is administered by at least one of intraocular injection at a concentration up to about 2 picograms/ml, or the composition is administered topically at a concentration in the range between about 1 picograms/ml to less than 10 nanograms/ml.
  • a formulation of Wnt or Rock inhibitors is used as topical administration at a concentration between about 50 picograms/ml to 200 nanograms/ml, subconjunctival injection at a dose in the range of about 1 picograms/ml to about
  • a method to treat an ocular condition in a patient by intraocularly administering a pharmaceutically acceptable formulation of Wnt inhibitors or rock inhibitors in an amount effective to treat the condition provides treatment while avoiding systemic administration of systemic medication.
  • a sustained release pharmaceutically acceptable formulation is implanted intraocularly in a polymeric slow release compound having about 20 nanograms to 1 microgram or more of Fasudil to about 0.1 micrograms to 40 micrograms or 1 milligram of Fasudil or other Rock inhibitors implanted in or on the eye and may continuously deliver Fasudil for five or more years.
  • a concentration up to about 10 or more micrograms of Rock inhibitors is administered intraocularly without substantial toxicity.
  • Fasudil derivatives are taken orally 1-40 mg
  • niclosamide is taken orally in 10-500 mg tablets
  • sulforaphane is taken orally in capsule 10-40 mg or more
  • ivermectin is taken orally 1-400 mg or more
  • topical formulations may be administered as drops, ointment, or gel in a non-toxic formulation.
  • Rock inhibitors at a concentration in the range of about 1 picogram/ml (0.0000000001%) to less than 0.1 micrograms/ml (less than 0.001%) is administered topically.
  • Fasudil or another Rock inhibitor at a concentration in the range of about 1 nanogram/ml to about 200 micrograms/ml is injected under the conjunctiva, or a concentration in the range of about 1 picogram/O.l ml to about 200 micrograms/ml is injected in the vitreous, or a concentration in the range of about 20 picograms/ml to about 200 nanograms/ml is injected behind the eyeball.
  • the Rock inhibitors such as Fasudil, etc., or Wnt inhibitors, such as niclosamide
  • the Rock inhibitors are administered as topical or a spray at non-toxic concentrations of 1 picogram/ml to 20 nanograms/ml in a physiological pH balanced, with osmolarity of 310 to prevent and treat, decrease the time of onset, or lessen the severity of a wide variety of diseases such as lichen planus, ocular conditions, such as retinitis pigmentosa, ocular irritation following corneal surgery (e.g., LASIK surgery), age related macular degeneration, diabetic retinopathy, dry eye disease, scleritis, papillitis, and uveitis, scleritis pars planatis, vogt-koyanagii syndrome, psoriasis, Lichen Planus, etc.
  • ocular conditions such as retinitis pigmentosa, ocular irritation following corneal surgery (e.g.
  • the Rock inhibitors such as Fasudil, etc., or Wnt inhibitors, such as niclosamide
  • the Rock inhibitors are administered as topical or a spray at non-toxic concentrations of 1 picogram/ml to 20 nanograms/m, or in an ointment or cream, or suspension of microspheres and dendrimers in meibomian gland disease.
  • the Rock inhibitors such as Botulinum toxins are administered as topical or a spray at non-toxic concentrations of 1 picogram/ml to 1 nanograms in a cream, ointment, suspension of microspheres or dendrimers, etc. for topical application in lichen planus, nerve damage after LASIK or refractive surgery procedures, or diabetes or wrinkle treatment.
  • the Rock inhibitors such as Fasudil 40-80 mg/kg, etc., or Wnt inhibitors, such as niclosamide, 100-500 mg or ivermectin, 250 mg to 2000 mg are administered orally to prevent and treat, decrease the time of onset, or lessen the severity of a wide variety of diseases, such as optic nerve neuritis, papillitis, variety of idiopathic uveitis, scleritis, or ocular conditions, such as retinitis pigmentosa, ocular irritation following comeal surgery (e.g., LASIK surgery), age related macular degeneration, diabetic retinopathy, dry eye disease, papillitis, uveitis, and lichen planus.
  • diseases such as optic nerve neuritis, papillitis, variety of idiopathic uveitis, scleritis, or ocular conditions, such as retinitis pigmentosa, ocular irritation following comeal surgery (e.g.,
  • the Rock inhibitors or Wnt inhibitors are administered as topical or a spray at non-toxic concentrations of 1 picogram/ml to 20 nanograms/ml in a physiological pH balanced solution with osmolality of 310 to treat the comeal nerve cuts after LASIK surgery to decrease inflammatory process and encourage fast regrowth of neurons from the cut end of the corneal nerves and enhance corneal sensation recovery time and prevent dry eye formation.
  • the Rock inhibitors (40-80 mg/kg) or Wnt inhibitors are administered orally after LASIK surgery to decrease inflammatory process and to encourage fast regrowth of neurons from the cut end of the comeal nerves and enhance comeal sensation recovery time and prevent dry eye formation.
  • Another embodiment of the invention is a method to treat ocular conditions including ocular irritation following comeal surgery, conjunctivitis, canaliculitis or
  • Rock inhibitors such as Fasudil or its derivatives in nanogram to microgram concentrations in microspheres, dendrimers, physiological solution, Botulinum toxin in picogram
  • a sustained release pharmaceutically acceptable formulation is implanted intraocularly (e.g., using an implant as depicted in FIGS. 1A-5).
  • a matrix containing in the range of between about 0.4 to 1 mg Fasudil can last for ten or more years.
  • a concentration up to about 1 microgram Fasudil or others, or Rock inhibitors is administered intraocularly, inside the joint in arthritis, or subcutaneously or subgingival injection in lichen planus without substantial toxicity.
  • Rock inhibitors at a concentration in the range of about 1 nanogram/ml (0.0000001%) to less than 1 microgram/ml (less than 0.0001%) are administered topically.
  • Fasudil at a concentration in the range of about 1 nanogram/ml to about 20 microgram/ml is injected under the conjunctiva, or a concentration in the range of about 1 nanogram/0.1 ml to about 200 micrograms/ml is injected in the vitreous, or a concentration in the range of about 20 nanograms/ml to about 20 micrograms/ml is injected in a slow release polymer, such as polycaprolactone or polylactic or glycolic, in the vitreous cavity or behind the eyeball or other part of the body as needed.
  • a slow release polymer such as polycaprolactone or polylactic or glycolic
  • Rock inhibitors at a concentration in the range of about 1 nanogram/ml (0.0000001%) to less than 1 microgram/ml (less than 0.0001%) are administered topically.
  • Fasudil at a concentration in the range of about 1 nanogram/ml to about 20 micrograms/ml is injected under the conjunctiva, or a concentration in the range of about 1 nanogram/0.1 ml to about 200 micrograms/ml is injected in the vitreous, or a concentration in the range of about 20 nanograms/ml to about 20 micrograms/ml is injected in a slow release polymer, such as polycaprolactone or polylactic or glycolic, in the vitreous cavity or behind the eyeball in subconjunctival space, or subcutaneously as needed.
  • a slow release polymer such as polycaprolactone or polylactic or glycolic
  • a composition is formulated for intraocular administration and dosing with Fasudil derivatives in a pharmaceutically acceptable formulation (e.g., in a physiologically acceptable solvent, such as sterol, lanosterol, squalene, and/or squalamine, buffered to a physiological pH, etc.) ⁇
  • a pharmaceutically acceptable formulation e.g., in a physiologically acceptable solvent, such as sterol, lanosterol, squalene, and/or squalamine, buffered to a physiological pH, etc.
  • the composition may be in a solution, a suspension, an emulsion, etc., and it may be administered in the form of eye drops, a cream, an ointment, a gel, an injectable, etc., to the eye and/or the eye lid.
  • the composition contains niclosamide or Fasudil in an amount effective to treat an ocular condition without substantial toxicity or mucosal or joint inflammatory diseases.
  • the non-toxic doses of Wnt inhibitors, Rock inhibitors, or Botox act as an anti-inflammatory agent.
  • the botulinum toxin or botox preparation may be administered topically to the eye or eye lid, forehead skin atl pictogram to 1 nanogram concentrations, 1 pictogram to 5 nanogram concentrations, for example, using drops, an ointment, a cream, a gel, a suspension of microspheres, dendrimers , etc.
  • a dose of botulinum toxin in 100- 2000 picograms will not be toxic if injected subcutaneously, or 750 picograms (100 units) 1-2 times a month will not be toxic. Higher doses can be used with caution and it would be desirable not to exceed these levels to prevent an immune response to the medication.
  • a dose of botulinum toxin in 100-2000 picograms will not be toxic if injected subcutaneously, or 750 picograms (100 units) 1-2 times a month will not be toxic. Higher doses can be used with caution and it would be desirable not to exceed these levels to prevent an immune response to the medication.
  • the concentrations 1-20 picograms of Botox in a physiological solution, or up to 30 picograms conjugated with antibody coated nanoparticles would be non- toxic to the body or when conjugated with thermosensitive polymeric coating of the nanoparticles in a physiologic solution or used as drops or injectable.
  • the Wnt inhibitors or Rock inhibitors may be injected into the eye, for example, injection under the conjunctiva or tenon capsule, intravitreal injection, or retrobulbar injection.
  • the agent(s) may be administered with a slow release drug delivery system, such as polymers, matrices, microcapsules, or other delivery systems formulated from, for example, glycolic acid, lactic acid, combinations of glycolic and lactic acid, liposomes, silicone, polyanhydride polyvinyl acetate alone or in combination with polyethylene glycol, etc.
  • the delivery device can be implanted intraocularly, for example, implanted under the conjunctiva, implanted in the wall of the eye, sutured to the sclera, for long-term drug delivery or injected in the vitreous cavity (e.g., using an implant as depicted in FIGS. 1A-5).
  • the agent(s) has wide safety and efficacy, permitting specific doses or administration protocols to be formulated for specific applications. For example, some patients may prefer once a day administration compared to administration more than once a day, so a higher concentration of agent(s) may be used for these patients.
  • Rock inhibitors such as Fasudil
  • Intraocular injection may be desirable or necessary, for example, for conditions in which topical administration is either not advised or is inadequate, for patients who have difficulty self-administering medications, etc.
  • the volume injected is less than 0.3 ml.
  • the volume injected is in the range of about 0.01 ml to about 0.3 ml.
  • Rock inhibitor concentrations in the range of about 1 nanogram/0.1 ml to about 20 microgram/ml (0.002%) may be used without toxicity or adverse side effects.
  • niclosamide used in amounts ranging from about 1 nanogram to about 10 micrograms is contained in an aqueous-based cream excipient.
  • the amount of Fasudil, etc., or other Rock inhibitors ranges from about 1 nanogram to about 10 micrograms, and is contained in an aqueous-based cream excipient.
  • Fasudil and niclosamide or mycophenolic acid are present in an aqueous-based cream excipient in various proportions.
  • the dmg(s) may be incorporated directly into the cream in solution, or may be contained in liposomes or microspheres, dendrimers, either in solution or in an anhydrous form.
  • the cream formulation is usually applied to the eye at bedtime, but it may be applied any time throughout the day if the cream does not cause blurred vision.
  • the agent(s) is formulated as a solution or suspension and is applied topically in the form of eye drops.
  • a matrix housing containing the agent(s) may be implanted into the eye.
  • a reservoir containing in the range of about 1 milligram to about 5 milligrams of agent(s) is estimated to be able to release about 1 microgram agent(s) per day.
  • continuous, sustained dosing may occur over 1000 to 5000 days. If less than 1 microgram of agent(s) per day is released, sustained dosing may last up to or more than a decade. In one embodiment, less than 50 micrograms/day of agent(s) is released from the matrix.
  • agent(s) is released form the matrix at a rate in the range of about 50 picograms/day to about 50 micrograms/day. In another embodiment, agent(s) is released from the matrix at a rate in the range of about 1 microgram/day to about 5 micrograms/day.
  • a surgically implanted intraocular device or matrix may be provided with a reservoir container (e.g., as shown in FIGS. 3B, 4, and 5) having a diffusible wall of polyvinyl alcohol or polyvinyl acetate or polycaprolactone and containing milligram quantities of a Rock inhibitor or Wnt inhibitor, or a combination of them may be implanted in the sclera.
  • a reservoir container e.g., as shown in FIGS. 3B, 4, and 5
  • a diffusible wall of polyvinyl alcohol or polyvinyl acetate or polycaprolactone and containing milligram quantities of a Rock inhibitor or Wnt inhibitor, or a combination of them may be implanted in the sclera.
  • milligram quantities of agent(s) may be incorporated into a polymeric matrix having dimensions of about 1 millimeter (mm) by 2 millimeter (mm), and made of a polymer such as polycaprolactone, poly(glycolic) acid, poly(lactic) acid, or a polyanhydride, or a lipid such as sebacic acid, and may be implanted on the sclera or in the eye.
  • a polymer such as polycaprolactone, poly(glycolic) acid, poly(lactic) acid, or a polyanhydride, or a lipid such as sebacic acid
  • liposomes may be prepared from dipalmitoyl phosphatidylcholine (DPPC), preferably prepared from egg phosphatidylcholine (PC) since this lipid has a low heat transition.
  • DPPC dipalmitoyl phosphatidylcholine
  • PC egg phosphatidylcholine
  • liposomes are made using standard procedures as known to one skilled in the art.
  • the agent(s) in amounts ranging from picogram to microgram quantities, is added to a solution of egg PC, and the lipophilic drug binds to the liposome.
  • the implantable formation may be in the form of a capsule of any of the polymers previously disclosed (e.g., polycaprolactone, polyglycolic acid (PGA), polylactic acid (PLA), poly anhydride) or lipids that may be formulated as microspheres or dendrimers.
  • PGA polyglycolic acid
  • PLA polylactic acid
  • anhydride lipids that may be formulated as microspheres or dendrimers.
  • Fasudil may be mixed with polyvinyl alcohol (PVA), the mixture then dried and coated with ethylene vinyl acetate, then cooled again with PVA.
  • Niclosamide bound with liposomes may be applied topically, either in the form of drops or as an aqueous based cream, or may be injected intraocularly.
  • the drug is slowly released over time as the liposome capsule degrades due to wear and tear from the eye surface.
  • the liposome capsule degrades due to cellular digestion, other slow release polymers, such as PLA, PGA, polycaprolactone, microspheres, dendrimers are also utilized.
  • the time-release administration is formulated so that the concentration released at any period of time does not exceed a toxic amount. This is accomplished, for example, through various formulations of the vehicle (coated or uncoated microspheres, coated or uncoated capsule, lipid, dendrimers, or polymer components, unilamellar or multilamellar structure, and combinations of the above, etc.). Other variables may include the patient’s pharmacokinetic -pharmacodynamic parameters (e.g., body mass, gender, plasma clearance rate, hepatic function, etc.). The formation and loading of microspheres, dendrimers, microcapsules, liposomes, etc. and their ocular implantation are standard techniques known by one skilled in the art.
  • a combination of Rock inhibitors or Wnt inhibitors may be dissolved in an organic solvent, such as DMSO or alcohol or sterol, lanosterol, squalene, and/or squalamine, or containing a poly anhydride, poly(glycolic) acid, poly(lactic) acid, or polycaprolactone polymer.
  • an organic solvent such as DMSO or alcohol or sterol, lanosterol, squalene, and/or squalamine, or containing a poly anhydride, poly(glycolic) acid, poly(lactic) acid, or polycaprolactone polymer.
  • Rock inhibitors such as Fasudil or Botox, etc. or Wnt inhibitors, such as niclosamide, alone or in combination with low molecular weight heparin and metalloproteinase inhibitors, such as doxycycline, tetracycline, etc.
  • Wnt inhibitors such as niclosamide
  • low molecular weight heparin and metalloproteinase inhibitors such as doxycycline, tetracycline, etc.
  • doxycycline, tetracycline can be used at non toxic concentrations with or without dexamethasone, for dry eye or lichen planus lesions of the mucosa, or skin or other inflammatory diseases of the retina, cornea, conjunctival sclera or optic nerve neuritis, scleritis, uveitis in an appropriate physiological solution or ointment, etc.
  • the intravenous solution form of Rock inhibitors or Wnt inhibitors may be diluted to achieve the indicated concentration using 0.9% NaCl or 5% dextrose, or an organic solvent such as dimethyl sulfoxide (DMSO) or sterol, lanosterol, squalene, and/or squalamine.
  • Intraocular administration may be any of the routes and formulations previously described. For injection, either a solution, emulsion, suspension of a liquid, capsular formulation of microspheres, dendrimers, or liposomes, etc. may be used.
  • Rock inhibitors or Wnt inhibitors or Botox may be injected subconjunctivally to treat uveitis at a dose in the range of about 1 picogram/ml to about 200 picograms/ml, or intravitreally at a dose of about 1 gram/0.1 ml to about 200
  • the dose is about 50 picograms/0.1 ml.
  • Rock inhibitors or Wnt inhibitors or Botox may be injected to treat scleritis involving the posterior sclera, may be administered by retrobulbar injection at a dose in the range of about 20 picograms/ml to about 800 picograms/ml or more and dissolved in DMSO or a very low concentration of alcohol or sterol, lanosterol, squalene, and/or squalamine.
  • Rock inhibitors may be administered by retrobulbar injection at a dose in the range of about 200 picograms/ml to about 800 nanograms/ml of Fasudil and its derivatives, etc.
  • Rock inhibitors e.g., Fasudil
  • Fasudil may be administered orally at a dose in the range of about 40-80 milligrams of Fasudil tablets, etc. or one time niclosamide 1-2 grams orally.
  • the ocular solutions contain at least one Rock inhibitor or Wnt inhibitor such as sulforaphane and provide anti-inflammatory, anti-cell proliferation, anti-cell migration effects if given orally with Vitamin D, topically as dendrimer or microsphere delivery or an injectable non-toxic preparation.
  • Rock inhibitor or Wnt inhibitor such as sulforaphane
  • the solution is administered intraocularly after cataract surgery before insertion of a replacement intraocular lens, resulting in reduced post-operative inflammation, which may eliminate the need for a steroid therapy.
  • the solution may be one that is invasively administered, for example, an irrigation or volume replacement solution containing at least one Rock inhibitor, such as Botox, or Wnt inhibitor.
  • a Rock inhibitor such as Botox, or Wnt inhibitor.
  • the solution may be one that is non-invasively or topically administered in the form of drops, ointments, gels, creams, etc. and may include eye lubricants and contact lens solutions.
  • the solution may contain a supratherapeutic concentration of agent(s), such as 40 micrograms/ml or to 80 micrograms/ml or more for topical application ranges, 40 nanograms/ml to 4 micrograms/ml Fasudil and its derivatives, etc. so that a therapeutic concentration of a topically administered solution accumulates in a diseased ocular structure sufficient to treat the disease.
  • medications are administered with antibody coated nanoparticles, dendrimers, thermosensitive polymers, nanoparticles, dendrimers, lactic or glycolic acid, chitosan or combinations, etc.
  • Immunosuppressives are all conjugated with the antibody coated nanoparticles for slow release as topical drops or an injectable preparation for dry eye after LASIK, meibomian gland inflammation, optic nerve neuritis, uveitis, scleritis, etc.
  • Rock inhibitors or Wnt inhibitors are administered by topical drops, spray, subconjunctival injection, sub-tenon injection, suprachoroidal injection, intravitreal injection in combination with standard anti-inflammatory agents, etc. and steroids, dexamethasone, etc. as a nanoparticle implant formed from biodegradable or non- biodegradable polymers.
  • a method of using Rock inhibitors or Wnt inhibitors where Rock inhibitors or Wnt inhibitors are administered at non-toxic doses to lichen planus of the skin or mucosa.
  • Lichen which is associated with is a chronic inflammatory disease of the skin, mucous membranes and nails, presents a burning sensation in the mouth, throat esophagus, vagina, pharynx, stomach, anus, bladder, conjunctiva, and the mucosa appears as a lattice-like network of white lines near sites of erosion can also affect the skin accompanied with sensation of itching, reddish-purple polygon- shaped skin lesions on the lower back, wrists, and ankle thought to be the result of an autoimmune process with an unknown initial trigger.
  • a formulation of Wnt or Rock inhibitors is used to treat the lesion of Lichen planus conditions using Rock inhibitors and Wnt inhibitors as topical drop spray application or injection into the subcutaneous tissue around or inside the lesion, or implantation in multiple sites close to the lesion releasing, e.g., Fasudil, etc., at doses or 1- 500 picograms or injection of Botox around the lesion or inside the lesion at 10-100 units once a month or once every 2-3 months.
  • a formulation of Wnt and/or Rock inhibitors is used to treat the lesion of lichen planus conditions using Rock inhibitors and/or Wnt inhibitors used as topical or drop spray application, mouth wash preparation of Fasudil derivatives at 1 nanogram to 1 microgram or more preparation or Wnt inhibitors, such as niclosamide, ivermectin, nanogram to microgram concentration in microspheres, dendrimer suspension or, sulforaphane 10-400 nanograms in microspheres, dendrimers, or in another polymer in addition to Vitamin D taken orally in 1000-5000 IU, etc.
  • Fasudil derivatives at 1 nanogram to 1 microgram or more preparation or Wnt inhibitors, such as niclosamide, ivermectin, nanogram to microgram concentration in microspheres, dendrimer suspension or, sulforaphane 10-400 nanograms in microspheres, dendrimers, or in another polymer in addition to Vitamin D taken orally in 1000-5000 IU, etc
  • a topical administration may contain between about 10 picograms/ml drug to about 50 micrograms/ml of Fasudil, etc. or other Rock inhibitors in a formulation which may be applied at bedtime or throughout the day or as an injection, a dose of about 50 picograms/ml to about 200 micrograms/ml around or inside the lesion.
  • the medication may be used as a surgical implant, for example, in a diffusible walled reservoir (e.g., as shown in FIGS.
  • sutured to the surrounding tissue or may be contained within an inert carrier, such as microspheres, dendrimers, or liposomes, to provide a slow-release drug delivery system to release the medication at 1 picogram to 100 picograms (e.g., Fasudil, etc.) per day.
  • an inert carrier such as microspheres, dendrimers, or liposomes
  • a formulation of Wnt or Rock inhibitors is used to treat ocular conditions, such as dry eye disease, as well as other conditions, is disclosed.
  • Rock inhibitors and Wnt inhibitors are used as s topical drop spray application or injection into the eye, or implantation in or on the eye (e.g., using an implant as depicted in FIGS. 1A-5).
  • a topical administration may contain between about 10 picograms/ml drug to about 50 micrograms/ml drug in a formulation which may be applied at bedtime.
  • the patient is administered with Rock inhibitors or Wnt inhibitors alone or in combination with NSAIDs or to treat plantar fasciitis associated with chronic pain in the bottom of the foot and heal it, which is caused by being overweight, with more less inflammatory processes as seen also in other conditions such as osteoarthritis, spondylitis, reactive arthritis due to over use of immune response.
  • Rock inhibitors or Wnt inhibitors alone or in combination with NSAIDs or to treat plantar fasciitis associated with chronic pain in the bottom of the foot and heal it, which is caused by being overweight, with more less inflammatory processes as seen also in other conditions such as osteoarthritis, spondylitis, reactive arthritis due to over use of immune response.
  • non-toxic doses of Rock inhibitors such as Fasudil, etc.
  • Botox 200 picograms to 2 nanograms or as Botox (10-100 units) is administered locally at multiple locations in treatment of plantar fasciitis or diabetic neuronal pain.
  • the purpose is to reduce and eliminate the potential of comeal transplant rejection by the survived host corneal epithelial cells or the host stromal cells that produce cytokines against the transplanted cornea and vice versa
  • the comeal endothelial cells in general, are not affected if the riboflavin is applied over the comeal surface through which it penetrates inside the stroma, it is desirable to enhance cellular penetration of the cross-linker, and simultaneously penetration through the corneal stroma, which is made of collagen.
  • a technique and formulation for expediting the cell penetration of riboflavin and the crosslinking of the cornea for comeal crosslinking and elsewhere in the body is very desirable.
  • cell penetrating peptides are used that comprise the short peptide lysine or arginine, which are known as cell penetrating peptides (CPP) and activatable-cell penetrating peptides (ACPP).
  • CPP and ACPP may be conjugated to dendrimers (ACPPDs) or other nanoparticles (e.g., riboflavin) or any other cross-linkers.
  • ACPPDs dendrimers
  • nanoparticles e.g., riboflavin
  • the ACPP may be labeled with a polycationic CPP.
  • ACPP and CPP may be naturally-occurring or artificially constmcted protein segments ( ⁇ 30 amino acids) rich in arginine, lysine, cysteine, histidine, ornithine, etc.; preferably .alpha. -helices and about 17-amino acids.
  • the ACPP and CPP may include a penetration accelerating peptide sequence (Pas) or an INF7 fusion peptide sequence.
  • CPP and/or ACCP can be linked to cargoes either covalently or non-covalently.
  • Nanoparticles may be delivered by cell-penetrating peptides comprised of nona-arginine and a penetration accelerating sequence.
  • nona-arginine may be used to facilitate the delivery of the riboflavin cross-linker into cells via multiple pathways.
  • Exemplary, but not limiting ACPP and CPP may include transportan, penetratin, TAT, VP22, MAP, KALA, ppTG20, proline-rich peptides, MPG-derived peptides, Pep-l, nona-arginine, and the carboxy-terminal tail of TFPI-2, polyproline helices having cationic amino acids and/or cationic-functionalized amino acids within the helix).
  • Nanoparticles may be coated or otherwise associated with organic or non-organic biodegradable compounds, aliphatic biodegradable polymers, as needed.
  • the nanoparticles may comprise organic nanoparticles, non-organic nanoparticles, synthetic nanoparticles, or non-synthetic nanoparticles.
  • riboflavin or other cross-linkers may be linked to, associated with, complexed or conjugated with nanoparticles using linking agents and methods including but not limited to the following: amino groups, carboxyl groups, S— S deprotected sulfhydril groups in biomolecules, carbodiimide conjugation, sulfosuccinimidylsuberyl linkage, synthetic tripyrrole-peptide linkage, NHS-esters and other esters, etc.
  • the riboflavin or a cross-linker conjugated to dendrimers is applied to a cornea which has developed neovascular tissue, where the penetration of the riboflavin is very minimal in the endothelial cells or the neovascular tissue, so that subsequent UV radiation will not damage these cells or close the neovascular tissue of the cornea.
  • Dendrimers and other types of nanoparticles do not need to have an antibody attached to them as long as they are applied topically for the crosslinking of the cornea. Although, nanoparticles do need to have a specific antibody attached to them if they are injected in the circulation of the patient for targeting a tumor.
  • the cross-linker is conjugated with nanoparticles in the form of dendrimers or functionalized dendrimers conjugated with CPP or ACPP and administered locally, topically or injected in body cavity, to be absorbed by normal or abnormal tissue or tumor with their neovascular tissue and subsequently cross-linked by UV radiation or other laser wavelength absorbed by the cross-linker, not only damaging the neovascular tissue, but also the tumor cells, as an example.
  • the cross-linker conjugated with the dendrimers or functionalized dendrimers conjugated with CPP or ACPP may be applied to a surface lesion/tumor on the skin, mucosa or conjunctiva of the eye or inside a body cavity.
  • the nanoparticles carrying riboflavin or another cross-linker are made of lactic acid, glycolic acid, or polycaprolactone and conjugated with a cell specific or organism specific antibody to attach to their cell membrane receptors.
  • the nanoparticles are made of lactic acid, glycolic acid, polycaprolactone, or chitosan, or are in the form of dendrimers, and are conjugated with riboflavin, CPP and antibodies to target specific cells, such as tumors of neovascular cells, and to attach to the cell membrane receptors of these cells or to one or more organisms and to penetrate the cell walls of specific cells or organisms, thus carrying the photosensitizer or riboflavin inside the cell, while activated with a light or UV light, thereby crosslinking the cytoplasmic proteins and kill the cells or the organism.
  • the photosensitizer is in the form of drops, and the drop solution or suspension of nanoparticles or dendrimers comprises between about 0.05% and about 1 % riboflavin or a photosensitizer therein.
  • the photosensitizer or riboflavin is in the form of drops or suspension of nanoparticles, and the drop solution comprises between about 0.0005% and about 5% riboflavin therein.
  • riboflavin or the cross-linker solution may have
  • ethylenediaminetetraacetic acid or Disodium Edetate Dihydrate 0.1 w/w%, Sodium Chloride 0.4 w/w%, Polycarbophil 0.95 w/w%, Octoxynol 40 (70% Solution), 2N NaOH (active dissolution @ pH 7.9 ), q.s. to adjust pH to about 7.4-7.7 as desired, Mannitol 0.15 w/w%, Sodium thiosulfate 0.3 w/w%, Water q.s. to 100%.
  • the riboflavin or the cross-linker solution may have an osmolarity of about 300 mOsm/L.
  • the riboflavin or the cross-linker solution may also contain a cell penetrating agent (e.g., CPPs or ACPPs).
  • a cell penetrating agent e.g., CPPs or ACPPs.
  • the riboflavin or the cross-linker solution may be provided with or without a poloxamer and with or without dextran.
  • the cross-linker is applied through a circular gel with the desired diameter of 1 millimeters (mm) to 15 millimeters (mm) or more to be placed on the surface of the cornea or other surfaces so that the cross-linker penetrates the desired area of the cornea selectively, etc.
  • the gel has a thickness of 0.01 mm to 3 mm or more.
  • the diameter of the gel is 5-10 mm.
  • the gel is circular with an opening of 1-8 mm.
  • the gel is made of an organic or synthetic material.
  • the gel is made from cellulose derivatives.
  • the gel is soaked with the photosensitizer, such as riboflavin or another chemical, at a desired concentration that can diffuse from it inside the tissue within the desired time.
  • the photosensitizer such as riboflavin or another chemical
  • the circular gel fits on the surface of the cornea or another desired surface and has strategically made holes to selectively release the photosensitizer in that area, so that during the crosslinking, only specific areas are selectively cross-linked, while the other areas are left alone to have specific effect either in the refractive power, elasticity on the cornea or for specific selective implantation of an implant.
  • the cross-linker or riboflavin/CPP are conjugated with functionalized nanoparticles, such as acrylic or acrylic derivatives or crystalline silicon or other organic transparent nanoparticles, to enhance cell penetration and penetration of the nanoparticles through the comeal stroma to kill the stromal cells and entrap the acrylic or crystalline silicon nanoparticle in the cross-linked stromal collagen and inside the cells after irradiation with UV radiation applied externally of through a fiber optic and crosslinking their cytoplasmic proteins and the collagen.
  • functionalized nanoparticles such as acrylic or acrylic derivatives or crystalline silicon or other organic transparent nanoparticles
  • the corneal stroma and nanoparticles’s index of refraction can be changed in the same session or later, using a femtosecond or multi photon laser and a Shack-Hartmann unit to achieve a perfect refractive power for the cornea.
  • a comeal inlay is soaked in a solution having a cross-linker or riboflavin/CPP are conjugated with coated nanoparticles, such as acrylic or acrylic derivatives or crystalline silicon nanostmcture or organic transparent nanoparticles, to enhance cell penetration and penetration of the nanoparticles through the comeal stroma to kill the stromal cells and entrap the acrylic or crystalline silicon nanoparticle in the cross- linked stromal collagen and inside the cells after irradiation with UV radiation applied externally before implanting inside a corneal pocket or after implantation inside the stromal pocket using a fiber optic and crosslinking their cytoplasmic proteins where the comeal stroma and subsequently the refractive index of the inlay and the cornea with the
  • nanoparticles can be changed using a femtosecond or multi-photon laser and a Shack- Hartmann unit to achieve a perfect refractive power for the cornea or modifying it for astigmatic, presbyopic, myopia, or hyperopia correction.
  • the comeal inlay is prepared from a 3-D stromal tissue culture or an eye bank eye cornea where the inlay is soaked in a solution having a cross-linker or riboflavin/CPP conjugated with PEGylated nanoparticles, such as acrylic or acrylic derivatives or crystalline silicon nanostmcture or organic transparent, organic nanoparticles to enhance cell penetration and penetration of the nanoparticles through the corneal stroma to kill the stromal cells and entrap the acrylic cross-linked nanoparticles or crystalline silicon in the cross-linked stromal collagen and inside the cells after irradiation with UV radiation applied externally before implanting inside a corneal pocket or after implantation inside the stromal pocket using a fiber optic and crosslinking their cytoplasmic proteins where the corneal stroma and subsequently the refractive index of the inlay or the cornea with the nanoparticles or the comeal collagen of the implant, or the crosslinked comeal transplant can be changed using a femto
  • the cross-linker or riboflavin/CPP are conjugated with antibody coated nanoparticles or dendrimers, to reach specific cells targeted to kill after irradiation with UV radiation applied externally of through a fiber optic and crosslinking their cytoplasmic proteins, etc.
  • the targeted cells are tumor cells.
  • the tumor cells are located on the skin or mucosa.
  • the riboflavin/CPP conjugated with antibody coated nanoparticles are injected inside the body cavity where the nanoparticles are attached to the tumor cells, then treated with UV radiation brought in using a fiber optic crosslinking their cytoplasmic proteins, etc.
  • the riboflavin/CPP conjugated with antibody coated nanoparticles are administered intravenously to reach an internally located tumor and to attach to their cell membranes and kill them after locally administered UV radiation.
  • the tumor is in the mouth, nose, throat, eye, conjunctiva, or lid of the eye, or lung and can be reached with a UV laser with a fine fiber optic to irradiate the tumor and kill them by crosslinking their cytoplasmic proteins, etc.
  • the lesion is an infected ulcer of the cornea, skin or mucosa, nasal, throat, etc. that can be treated by topical application of the riboflavin/CPP or ACPP conjugated with antibody coated nanoparticles to kill the bacteria, viruses, fungi, protozoal infections treated with UV radiation applied through a fiber optic and crosslinking their cytoplasmic proteins, etc.
  • the lesion is an infected ulcer of the cornea, skin or mucosa, nasal, throat, etc. that can be treated by topical application of the riboflavin/CPP or ACPP conjugated with antibody coated nanoparticles or dendrimers to kill the bacteria, viruses, fungi, protozoal infections treated with UV radiation applied through a fiber optic and crosslinking their cytoplasmic proteins, etc.
  • the ulcer is an infected comeal ulcer treated by topical application of the riboflavin/CPP or ACPP conjugated with antibody coated nanoparticles or dendrimers to kill the bacteria with UV radiation applied through a fiber optic or an external UV light and crosslinking their cytoplasmic proteins, etc. as described before.
  • the ulcer is an infected skin or mucosal ulcer treated by topical application of the riboflavin/CPP or ACPP conjugated with PEGylated nanoparticles/ dendrimers to kill the bacteria, with UV radiation applied through a fiber optic or an external UV light by crosslinking their cytoplasmic proteins, etc., as described before.
  • the keratoprosthesis 504 described above is coated with biocompatible nanoparticles, such as gold or silica, or a combination thereof, etc. in a manner that does not cover the central optical lens to prevent rejection.
  • biocompatible nanoparticles such as gold or silica, or a combination thereof, etc.
  • the riboflavin nanoparticle/dendrimer and CPP is used as a surface coating for any intracorneal implantation followed with UV radiation to kill the cells surrounding it by crosslinking their cytoplasmic proteins etc.
  • the riboflavin nanoparticle or dendrimers and CPP is administered after extracapsular lens removal followed by administration of CPP/cross-linker conjugated with polyethylene glycol (PEG) coated nanoparticles in the capsular bag, then followed by lens implantation where the CPP enhances the penetration of the riboflavin into the lens epithelial cells and kills them by crosslinking their cytoplasmic proteins etc., thereby preventing capsular opacification.
  • PEG polyethylene glycol
  • a glaucoma stent surface is coated with biocompatible nanoparticles, such as gold or silica, or a combination thereof, etc. to prevent rejection of the stent, then coated with CPP/riboflavin nanoparticles or dendrimers prior to the implantation of the glaucoma stent and then irradiated with UV radiation after the implantation to kill the cells by crosslinking their cytoplasmic proteins, etc. around the stent and prevent ingrowth of the cells blocking the stent and prevent ingrowth of the cells blocking the stent using a fiber optic.
  • biocompatible nanoparticles such as gold or silica, or a combination thereof, etc.
  • a cardiac/vascular stent is coated with biocompatible nanoparticles, such as gold or silica, or a combination thereof, etc. to prevent rejection, then coated with CPP/riboflavin nanoparticles or dendrimers prior to the implantation of the vascular stent and irradiated with UV radiation after the implantation to kill the cells by crosslinking their cytoplasmic proteins, etc. around the stent and preventing ingrowth of the cells blocking the stent using a fiber optic.
  • biocompatible nanoparticles such as gold or silica, or a combination thereof, etc.
  • the pathway of inflammation and scarring in the cornea after refractive surgery is blocked by inactivation of Rho Kinase, GSK and Wnt pathway by using either a polymeric implant, or biodegradable polymeric nanoparticles or microparticles that release Rock inhibitors, such as fasudil, netarsudil, or a Wnt combination with Rock inhibitors, such as fasudil, netarsudil, botox, SAR407899, etc.
  • Wnt inhibitors such as FH535, IWP-2, PNU-74654, IWR-lendo, IWR-exo, or GSK inhibitors SB-216763 without having the side effects of steroid in the eye that can produce an increased intraocular pressure or can reduce the immune defense activation that combats infection.
  • the comeal nerves are cut or ablated by administration of a laser, thus producing loss of comeal sensitivity, epithelial erosion and inflammation/infection, due to the loss of the comeal reflex and lid reflex that normally keeps the corneal surface moist and prevents dry eye formation.
  • These complications can be prevented by topical application of Rock inhibitors, Wnt inhibitors, integrin inhibitors , or GSK inhibitors to encourage the nerve growth while inhibiting TGF beta production and scarring.
  • the patient developed a dry eye condition with loss of cornel reflex and low tear film production as measured with Schirmer’s test and slightly reduced visual acuity.
  • the ocular examination demonstrated loss of comeal sensation and reduced tear film production and presence of debris in the conjunctiva and the lid margin with a mild inflammation of the conjunctiva.
  • the patient felt relieved of the discomfort within two (2) weeks, and the tear production increased from the previous exam. In three months, the patient was symptom free, the visual acuity improved, and the treatment was reduced to once a day drops.
  • one uses Rock inhibitor alone or in combination with GSK 3 inhibitors SB-216763, etc. to encourage the comeal nerve growth and faster recovery of the corneal sensation and rehydration that maintains the health of the mucin producing cells of the conjunctiva and meibomian gland.
  • a topical application or polymeric slow release delivery of Rock inhibitors, Wnt inhibitors, integrin inhibitors, or GSK inhibitors are used to treat dry eye.
  • the following anti-inflammatory Rock inhibitors are administered to the external adnexa and conjunctiva as drops in the form of polymeric nanoparticles or microparticles, or are implanted under the conjunctiva or skin affecting the inflammatory cell pathway, and are readily available.
  • the Rock inhibitors are administered at non- toxic concentrations of 0.01 ng to 30 ng or more microgram/ml release for a short time or a long duration.
  • the Rock inhibitors may be potent ROCK inhibitors, such as Ropresa, netarsudil, Fasudil
  • hydrochloride inhibitor of cyclic nucleotide dependent- and Rho-kinases GSK 269962
  • ROCK selective Rho-kinase
  • OXA 06 dihydrochloride potent ROCK inhibitor PKI1447 dihydrochloride, potent and selective ROCK inhibitor
  • antitumor SB 772077B potent Rho-kinase inhibitor
  • vasodilator SR 3677 dihydrochloride potent, selective Rho-kinase (ROCK) inhibitor TC-S7001, potent and highly selective ROCK inhibitor or Botulinum toxin, such as Botox in 1-100 international units or very slow release with porous silicon implant; orally active Y-27632 dihydrochloride and SAR407899 as a topical solution, polymeric nanoparticles or microparticles with or without cell penetrating peptides or implant.
  • a preparation of Rock inhibitors, Wnt inhibitors, integrin inhibitors, or GSK -3 inhibitors alone, or in combination can be used to reduce the inflammatory side effects of inflammation and scarring or loss of comeal sensation.
  • one uses a bioerodible implant comprising a non-anti- inflammatory agent acting on cell pathways of inflammation including Wnt inhibitors, Rho inhibitors, integrin inhibitors ,GSK inhibitors SB- 216763, or lithium chloride at micro to millimolar (mM) concentrations or in combinations, wherein the inflammation is mediated by various conditions.
  • a bioerodible implant comprising a non-anti- inflammatory agent acting on cell pathways of inflammation including Wnt inhibitors, Rho inhibitors, integrin inhibitors ,GSK inhibitors SB- 216763, or lithium chloride at micro to millimolar (mM) concentrations or in combinations, wherein the inflammation is mediated by various conditions.
  • a 67-year female patient with a history of dry eye and cataract extraction in both eyes is complaining of discomfort, with the sensation of foreign body and dryness, hyperemia, mucoid discharge photophobia, and reduced visual acuity, which is not relieved by over-the-counter eye drops.
  • the patient had typical symptoms of dry eye disease with meibomian gland dysfunction, with reduced Schirmer’ s test results for tear film production, blepharitis, and redness of the lid margins and crusting of the lashes.
  • the patient was initially treated with over-the-counter artificial tear preparation, hyaluronic acid and gel, and ointment at night, and absorbable punctal plug, which did not improve the symptoms significantly, and subsequently topical anti-inflammatory topical agent, such as a steroid and cyclosporine that moderately improved the condition. Since her inflammation was not significantly reduced, she was treated with an off label use of a Rock inhibitor at concentration of 2 micrograms/ml twice daily drops combined with topical tetracycline along with application, low molecular weight heparin, 1% solution (Lovenox ), a light shampooing of the lashes at night, and an ointment at night. The symptoms were relieved significantly after a month of therapy.
  • topical anti-inflammatory topical agent such as a steroid and cyclosporine that moderately improved the condition. Since her inflammation was not significantly reduced, she was treated with an off label use of a Rock inhibitor at concentration of 2 micrograms/ml twice daily drops combined with topical tetra
  • a preparation of a bioerodible implant comprising of Rock inhibitors, Wnt inhibitors, or integrin inhibitors alone or in combination can be used to reduce the inflammatory and side effects, such as scarring on the external eye or inside the eye, or on the skin or mucosa.
  • integrin inhibitors after refractive surgery, and/or in a case of dry eye, integrin inhibitors ,are administered with cell penetrating peptides (CPP) or activatable cell penetrating peptide (ACPP) coated dendrimers or nanoparticles or macrolides, such as cyclosporine A, mycophenolic acid, tacrolimus or ascomycin as nanoparticles or conjugated with the dendrimers, or in a preparation in the early stage of glaucoma as a topical medication at concentrations of Rock inhibitors of 1-5 microgram/ml once or twice per day and macrolides at concentrations of 0.000000001% to 1% in a physiological solution.
  • CPP cell penetrating peptides
  • ACPP activatable cell penetrating peptide
  • lasers are used to cut and/or coagulate the tissue (e.g., exam or infrared (IR) lasers).
  • tissue e.g., exam or infrared (IR) lasers.
  • lasers may be used for refractive surgery, cosmetic surgery, excision, or ablation of the tumors, etc.
  • GSK-3 Glycogen Synthase Kinase-3
  • lasers are used to treat diabetic retinopathy, macular edema, etc. to reduce the ischemic retina and VEGF production or externally, such as skin or mucosa.
  • any laser application including when used as cosmetic skin or mucosal resurfacing and skin tightening, is associated with minor or major thermal release with damage to the cells exposed to it and causes cytokine release, activation of inflammatory cell pathways with leakage of the fluid from the capillaries.
  • Rock inhibitors, Wnt inhibitors, integrin inhibitors and/or inhibition of GSK-3 by SB-216368 are applied to the laser treated areas, before or after treatment, thereby reducing the unwanted side effects of laser application, such as inflammation and activation of TGF-beta and scarring.
  • the Rock inhibitors, Wnt inhibitors, integrin inhibitors ,, and GSK-3 inhibitors are used in combination with cosmetic fillers as slow release polymeric implants, or nano- or micro-particulates or liposomes or micelles to reduce the inflammatory process
  • the available fillers include Juvederm and Juvederm Voluma (hyaluronic acid filler, Allergan); Belotero (hyaluronic acid, Merz Pharmaceuticals); Sculptra (poly-L-lactic acid, Sanofi); and Artefill/Bellafill (polymethylmethacrylate, Suneva).
  • Rock inhibitors, Wnt inhibitors, GSK-3 inhibitors, and/or Integrin inhibitors can be added to any solution, ointment, cream with antibiotics, antifungals, antivirals after cosmetic laser application or after the application of focused ultrasound for tissue tightening.
  • laser cosmetic resurfacing e.g., application of laser, visible or infrared , C0 2 , or Erbium laser or radiofrequency or focused ultrasound can be associated with excessive inflammation, fluid release from the skin and subdermal tissue, or from the mucosal tissue in mouth or after vaginal laser resurfacing causing pain and unforeseen scaring.
  • Rock inhibitors e.g., netarsudil, Fasudil hydrochloride, or topical solution
  • inhibitor of cyclic nucleotide dependent- and Rho-kinases GSK 269962, potent and selective Rock inhibitor GSK 429286, or Lithium chloride selective Rho-kinase (ROCK) inhibitor H1152 dihydrochloride at non- toxic concentration when released alone, or with integrin inhibitors, or Wnt inhibitors alone or in combination with a preparation of lanosterol, squalene or squalamine as a topical preparation, or polymeric slow release nano
  • microparticles reduces the inflammatory process and enhances the healing process, while squalamine has the advantage of acting as anti-bacterial, anti-fungi, antiviral etc., thus preventing infection of the superficial wound created after laser surgery of the skin or mucosa.
  • the anti-inflammatory agents such as squalene, lanosterol or squalamine can contribute to the health of these cells and assist in dissolving the debris from the skin or mucosa, and in combination, e.g. rock inhibitors act as anti-inflammatory without producing side effects of steroids or NSAIDs, such as coronary disease, gastric ulcer, infection, bacterial, fungi or viral infection.
  • NSAIDs such as coronary disease, gastric ulcer, infection, bacterial, fungi or viral infection.
  • Topical steroidal ointment was avoided out of fear of infection, since the edema swelling lasted more than ten days the patient was, in addition to the standard therapy, administered a physiological solution having 1 microgram/ml Rock inhibitor and at night with a cream having similar concentration of Rock inhibitor. The patient was advised to return if the swelling did not decrease and increased exudate was noted. Seven days after final examination the erythema and swelling was reduced and the face regained its normal appearance.
  • the cosmetic facial or mucosa surgery utilizes laser thermal energy to damage superficial skin or mucosal layer end encourage their rejuvenation.
  • the depth of and size of the laser application is decided upon by the need of the condition.
  • the pulsed carbon dioxide (C0 2 ) and erbium: yttrium- aluminum-gamet (Er:YAG) or other infrared lasers are the most common laser used in skin/mucosal resurfacing though radio frequency wave and focused ultrasound also are used for one or the other indication .
  • the absorption of (Er:YAG) laser is more by subcutaneous tissue whereas the (CO2) is by the water molecules producing deeper skin lesion of 50-100 pm, creating a thermal necrosis.
  • skin evaporation requires a fluence about 5 -7 J/cm 2
  • the Er:YAG laser requires fluence of 0.5 and 1.7 J/cm 2 .
  • the advantage of the Er:YAG laser is reduction of leakage of fluid from the tissue; however, the applications of these lasers depend on the location and degree of tissue tightening that is needed.
  • the contra indications are active inflammatory lesions of the skin, or viral, bacterial, fungal infections, etc.
  • the skin is treated postoperatively with topically applied anti-bacterial ointment, cream such as mupirocin 2% (Bactroban), or other antibiotics or antiviral medications such as valcyclovir taken orally and skin treatment with topical Silver sulfadiazine.
  • cream such as mupirocin 2% (Bactroban)
  • other antibiotics or antiviral medications such as valcyclovir taken orally
  • topical Silver sulfadiazine topical Silver sulfadiazine.
  • the complications are sever erythema, edema that might last for weeks that requires application of steroidal cream with hydrocortisone 2.5% cream etc.
  • Retin -A 0.05% might lead to dermatitis or in combination with hydroquinone 5%, for a month or more.
  • Hyperpigmentation is also another side effect of the laser surgery that might require micropeels with 30-50% glycolic acid, etc.
  • Rock inhibitors such as SB- 216763 in a physiological solution, cream or polymeric slow release nano- or micro-particles, liposomes or micelles to reduce the inflammatory process without being in need of steroidal medications.
  • a 55-year patient underwent a routine C0 2 laser facial resurfacing and was treated initially with the routine postoperative therapy including complete closed dressing, and application of antibiotic Bactroban ointment and skin treatment with topical
  • Silversulfadiazine and later the patient’ s face was washed with Cetaphil, in addition to application of steroidal ointment, to reduce postoperative inflammation and systemic ciprofloxacin to prevent infection.
  • Cetaphil in addition to application of steroidal ointment, to reduce postoperative inflammation and systemic ciprofloxacin to prevent infection.
  • Two days post-operative the patient noticed pain and sever exudation from the treated areas with associated red exudate.
  • the patient was given additional antibiotics to cover pseudomonas infection, but because of the worsening of the condition, the patient was given systemic penecilin and carbapenem to treat a potential propionibacterium infection.
  • the laser-treated area was cleansed and washed with a physiological solution having 500microg clindamycin/ml and 1 microgram Rock inhibitor per day and dressed with a cream containing the same medications without riboflavin daily.
  • the systemic medication was continued with carbapenem, the healing process continued for another week as gradually the wound healing took place in an additional 10 days and the skin gradually gained its normal appearance.
  • the infection might be caused by antibiotic resistant bacteria
  • the disease is Acne vulgaris, one of the most common skin diseases in the United States characterized by chronic skin disease of the hair follicles and their accompanying sebaceous gland.
  • the disease initiates without inflammation in the mild early stages but it is accompanied by inflammatory processes associated with infection caused by the Propionibacterium acnes, an anaerobic bacteria leading to severe nodulocystic acne.
  • Acne vulgaris is treated initially with topical tretinoin, clindamycin and benzoyl peroxide, isotretinoin topical Retinoi; however, retinoid can induce dermatitis, and should be used with topical and systemic antibiotics, such as doxycycline, tetracycline, minocycline, in combination with topical or intradermal injection of Rock inhibitors, Wnt inhibitors, integrin inhibitors,, GSK inhibitors and/or oral medication, such as a combination of ethinyl estradiol, drospirenone.
  • topical and systemic antibiotics such as doxycycline, tetracycline, minocycline
  • the Retinoids are comedolytic and reduces desquamation when given along with antibacterial benzoyl peroxide applied topically twice daily.
  • the patients can develop dermatitis after application within 2 weeks.
  • the lesion was treated administration of a 2% solution of riboflavin containing 20 microgram/ml Rock inhibitor Fasudil nanoparticles conjugated with CPP in addition GSK inhibitor SB-216368 in millimolar concentrations for 1-2 hours, followed by UV radiation of 5mW/cm2 for a period of ten minutes, followed by daily administration of a cream dressing having squalamine in addition to polymeric nanoparticles of Rock inhibitors and GSK inhibitors for daily application, and oral carbapenem.
  • the lesion gradually decreased indicating that the local therapy of antibiotic resistant bacteria is possible with the riboflavin crosslinking combined with an antibiotic to which a bacterium might be resistant.
  • any therapy resistant acne is treated with application of solution or mixture of riboflavin, antibody-coated nanoparticles in addition to Rock inhibitors, conjugated with cell penetrating agents (CPP) to penetrate the skin and attached to the C. acne bacteria, and they are damaged by UV radiation which crosslinks the protein of the bacteria and the collagenous tissue around the gland and also simultaneously damages the comedone producing cells of the gland and reduce inflammation ⁇
  • CPP cell penetrating agents
  • the polymeric implant or polymeric nano- or micro-particles with CPP can be combined with antibiotics, antifungals, antivirals, antineoplastic, macrolides, etc. as needed.
  • biodegradable polymeric compositions orthoesters, anhydrides, amides, calcium alginate polysaccharides functionalized celluloses,
  • carboxymethylcellulose polycaprolactone copolymers of glycolic and lactic acid polymers of D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid, preferably about 2-150 micrometers in diameter and 20 microns to 4 mm in length, porous silicon implant or nano- or micro-particles are used to deliver the Rock inhibitors, Wnt inhibitors, GSK inhibitors, and integrin inhibitors.
  • the skin glands of the skin are treated with a solution of viscous gel, or ointment containing Rock inhibitors, Wnt inhibitors, integrin inhibitors and/or GSK -3 inhibitors at non-toxic doses to inhibit inflammatory response in the tissue.
  • One procedure involves topical administration of a 1-10% or more solution of riboflavin in a physiological solution having the osmolarity of 200-400 or more mOSm and the pH of 5-8, with or without low molecular weight heparin in 0.1-1% or combined with cell penetrating peptides (CPP) or activatable cell penetrating peptides (ACPP) for enhance cell penetration, with or without dextran, or cyclodexterin or metallic nanoparticle or organic nanoparticles conjugated with riboflavin that are also UV light absorbing to simultaneously heat up the nanoparticle and damage the cell wall of the bacteria, fungi, or the viral proteins, and the prions.
  • CPP cell penetrating peptides
  • ACPP activatable cell penetrating peptides
  • the crosslinking solution also contains an antibiotic to which the C. acne is generally sensitive, such as doxycycline tetracycline, minocycline, and/or clindamycin, and is used with Rock inhibitors, Wnt inhibitors, integrin inhibitors, and/or GSK -3 inhibitors individually or in combination.
  • an antibiotic to which the C. acne is generally sensitive such as doxycycline tetracycline, minocycline, and/or clindamycin, and is used with Rock inhibitors, Wnt inhibitors, integrin inhibitors, and/or GSK -3 inhibitors individually or in combination.
  • the crosslinking solution can contain riboflavin and/or retinoids along with another medication and riboflavin, and Rock inhibitors, Wnt inhibitors, integrin inhibitors and/or GSK -3 inhibitors, where the UV radiation does not affect these medications except for activating the photosensitizer riboflavin, which after UV exposure, creates singlet oxygen and reactive spices that crosslinks the protein, damaging or killing the bacteria, fungi, or viruses including prions and comedone producing sebaceous glands or sweat glands or the skin debris preventing recurrent of infection in these areas or undesirable odor.
  • one uses the riboflavin alone or in combination with Rock inhibitors, for topical application, or if needed micro-puncture with radiofrequency needle of the area, and crosslinking the superficial skin glands with UV radiation and eliminating the sweat glands and sebaceous glands in the areas needed to eliminate undesirable odor from the secretion of these glands along with microbiota the accumulate and grow in that area.
  • the crosslinking solution can contain squalamine, squalene or lanosterol to encourage with or without CPP or ACPP for dissolving the comedone and debris that accumulate in the outflow channels and seal and sebaceous gland, or along with another medication, such as riboflavin or psoralens, in nanoparticles or microparticles or in combination of both, with UV radiation by two different mechanisms, riboflavin crosslinks the proteins of the bacteria, while psoralens damages their DNA.
  • squalamine, squalene or lanosterol to encourage with or without CPP or ACPP for dissolving the comedone and debris that accumulate in the outflow channels and seal and sebaceous gland
  • another medication such as riboflavin or psoralens, in nanoparticles or microparticles or in combination of both, with UV radiation by two different mechanisms, riboflavin crosslinks the proteins of the bacteria, while psoralens damages their DNA.
  • the UV radiation can be applied with l-30mW or more for a short period of 1 minute to 60 minutes depending on the surface areas that are treated to eliminate the bacteria, microbiota, and eliminate the sebaceous glands and sweat glands, or the infected skin areas as needed.
  • the crosslinking solution in addition to riboflavin has a Rock inhibitor, such as Fasudil and its derivatives, netarsudil or SAR407899, and is coated with slow release polymers, such as lactic acid and/or glycolic acid at a concentration of 200 nanograms to 1 micrograms/ml or more and is administered topically, or subcutaneously inside the acne lesion using nano- or microparticles with (alpha)-cyclodextrin, or (beta)- cyclodextrin, or (gamma)-cyclodextrin, hydroxypropyl-b-cyclodextrin (bHPCD) for slow release and tissue penetration with or without cell penetrating agents.
  • Rock inhibitor such as Fasudil and its derivatives, netarsudil or SAR407899
  • slow release polymers such as lactic acid and/or glycolic acid at a concentration of 200 nanograms to 1 micrograms/ml or more and is administered topically, or subcutaneously inside
  • Botulinum toxin botox can be used as a Rock inhibitor in solution, or in polymeric nanoparticles, to release the medication at a slow rate of 1 picogram or more a day to 1 nanogram or 1-100 international units along with a cream with or without squalene in addition, or as solution with polymeric nanoparticles for administration on the skin, mucosa, or cornea as solution of suspension, etc.
  • the polymeric component such as PLA, PGLA ,or combination thereof by erosion of the polymer
  • Rock inhibitors such as Fasudil derivatives, Netarsudil C28H27N303 ( Rhopressa), or SAR407899, netarsudil etc. at concentrations of 10 picograms to 100 micrograms/0.25 ml or Botox solution of 0.1-1 to 25- 100 international units can be administered as a slow release implant or injectable as nano- or microparticles with CPP or (alpha)-cyclodextrin, or (beta)-cyclodextrin, or (gamma)- cyclodextrin, hydroxypropyl-b-cyclodextrin (bHPCD) in the dermis or subdermal tissue or inside the acne lesion as a slow release polymeric plaque or implanted to release medication at a rate of 1 picogram to 10 nanograms/day or more of the non-toxic medication along with a nontoxic dose of a macrolide such as cyclosporine, mycophenolic
  • the nanoparticles or dendrimers are conjugated with Rock inhibitors, CPP and integrin inhibitors such as abciximab, Eptifibatide, Tirofiban, a.II b3 antagonists, Natalizumab, 3 mg to ⁇ 52 pg/mL, MLN-00002, Firategrast, IVL745, antagonists of anb3 and/or anb5 integrins, LM609, Vitaxin, Abegrin, CNT095, Cilengitide.
  • Rock inhibitors such as abciximab, Eptifibatide, Tirofiban, a.II b3 antagonists, Natalizumab, 3 mg to ⁇ 52 pg/mL, MLN-00002, Firategrast, IVL745, antagonists of anb3 and/or anb5 integrins, LM609, Vitaxin, Abegrin, CNT095, Cilengitide.
  • integrin inhibitors
  • MLD- based disintegrins L000845704, SB273005, or risuteganib, Volociximab, JSM6427, or GSK inhibitors and chitosan or PEG delivered as a slow release system that can be released as a temperature sensitive polymer that melts at 42-43 degrees C using a warm compressor over or under the lid, or thermal application with light, low level laser light, or the use of a compressive focused ultrasound applied to lid, conjunctiva or cornea or the lid releasing 1 picogram to 10 nanograms/day or more of the medication.
  • Rock inhibitors or integrin inhibitors are injected after crosslinking in the acne lesion at non-toxic concentrations in the lesion to reduce inflammatory processes and reduce cellular proliferation, blocking TGF beta, and scar formation.
  • the Rock inhibitors such as Fasudil derivatives at
  • Botox solution of 0.1 units of Botox can be administered with small molecule Wnt inhibitors, such as FH535, IWP-2, PNU-74654, IWR-lendo, IWR-exo, Demethoxycurcumin, CCTO36477,KY02l ll, WAY-316606, SFRP or integrin inhibitors, such as abegrin cilengitide, abciximab, tirofiban, natalizumab eptifibatide or at a low concentration of 1 microgram to 10 micrograms as a solution, or in an ointment containing squalene or lanosterol or squalamine to combat bacterial, viral, and fungal infections, while reducing simultaneously the inflammatory processes without steroidal medication that creates the side effect of encouraging bacterial, viral, or fungal infections or parasitic infection of a lesion.
  • Wnt inhibitors such as FH535, IWP-2, PNU-74654, IWR-
  • CCTO36477,KY02111, WAY-316606, SFRP or integrin inhibitors such as abegrin cilengitide, abciximab, tirofiban, natalizumab eptifibatide.
  • the Rock inhibitors are selected from the group consisting of Fasudil, Ripasudil, RKI-1447, Y-27632, GSK429286A, Y-30141, Botox and combinations thereof where the device such as porous silicon or polylactic acid or polycaprolactone releases the Rock inhibitor for 1 year to 3 years at a rate of about 1 micrograms/day to 5 micrograms/day, and botox as a concentration of 1-100 international unit or more released at 1 units or more per day.
  • Rock inhibitors such as Fasudil (HA-1077 a selective RhoA/Rho kinase (ROCK) inhibitor), Y-27632, small molecule inhibitor of ROCK1 and ROCK2 which acts as an anti-inflammatory agent and Ripasudil, netarsudil etc. in form of drops or combined with polymeric nanoparticles or implants for slow release delivery are administered at non-toxic concentrations for daily use or slow release after laser cosmetic, ocular, laser facial, mucosal resurfacing, or after transurethral resection of benign prostate, vaginal laser resurfacing, the ablation of cervical localized tumors or precancerous lesions on the skin or mucosa.
  • Fasudil HA-1077 a selective RhoA/Rho kinase (ROCK) inhibitor
  • Y-27632 small molecule inhibitor of ROCK1 and ROCK2 which acts as an anti-inflammatory agent
  • Ripasudil netarsudil etc.
  • Wnt inhibitors are compounds, such as FH535, IWP-2, PNU- 74654, IWR-lendo, IWR-exo, Demethoxycurcumin, CCTO36477,KY02ll l, WAY-316606, SFRP, IWP, LGK974, C59, Antl.4Br/Ant 1.4C1 or oral ivermectin, niclosamide, or apicularen and bafilomycin, XAV939, XAV939, G007-LK and G244-LM, NSC668036, SB- 216763, gemtuzumab, etc. are used in form of drops at pico and nM concentrations, or integrin inhibitors, as solution, or combined with polymeric nanoparticles for slow release delivery of polymeric implants or injectable, or as an ointment.
  • the conventional signaling receptors and integrins serves as linkers between the actin cytoskeleton and extracellular intracellular signaling matrix, stimulating the cell survival, growth, and cell proliferation.
  • the anti-integrins are used as a solution of polymeric erodible nanoparticles, microparticles, and are administered to inhibit cell proliferation and migration and scar formation where the integrin inhibitors are selected from the group consisting of abegrin cilengitide, abciximab, tirofiban, natalizumab, and eptifibatide, and the drug delivery system includes dendrimers, PGLA, PLA or combination of them to treat skin or mucosal inflammation after surgical laser surgery, or in acne vulgaris, etc.
  • the cell penetrating peptides extend the agent penetration to at least one of the posterior segment of the eye or anterior segment of the eye or from the cornea to the retina using Rock inhibitors.
  • the mucophilic preparation comprises a compound selected from the group consisting of chitosan, a dendrimer, cell penetrating peptide (CPP), activatable cell penetrating peptide (ACPP), hyaluronic acid, low molecular weight heparin, squalene and its derivatives and combinations thereof.
  • the Rock inhibitors are administered with macrolides, such as cyclosporine A, mycophenolic acid, tacrolimus, or ascomycin in the early stages of glaucoma as a topical medication at concentrations of Rock inhibitors 1-5 micrograms/ml once or twice per day and macrolides at concentrations of 0.000000001% to 1% in a physiological solution.
  • macrolides such as cyclosporine A, mycophenolic acid, tacrolimus, or ascomycin
  • one administers polymeric nanoparticles or dendrimers of Wnt inhibitors compounds such as FH535, IWP-2, PNU- 74654, IWR-lendo, IWR-exo, Demethoxycurcumin, CCTO36477,KY02111, WAY-316606, SFRP , IWP , LGK974, C59, Antl.4Br/Ant 1.4C1, ivermectin, niclosamide, XAV939, XAV939, G007-LK and G244-LM, NSC668036, SB-216763, gemtuzumab as topical or local injections at non-toxic doses to reduce the inflammatory processes as treatment or prophylactically in cosmetic skin or regenerative surgery.
  • Wnt inhibitors compounds such as FH535, IWP-2, PNU- 74654, IWR-lendo, IWR-exo, Demethoxycurcumin, CCTO36477,KY
  • Rock is active in inflammatory processes, and activates TGF-b formation, that creates scar formation specifically after any surgery, such as skin, intraocular surgery such as retinal detachment, vitrectomy with or without air or silicone oil, tamponade, leading to cell proliferation and redetachment of the retina and Rock inhibitors prevent side effects of excessive scar formation, such as proliferative retinopathy and keloids in cosmetic surgery.
  • Rock and other enzymes are activated by inflammatory processes that can be prevented prophylactically before or after the surgery, to reduce TGF-b formation, that creates undesirable scar formation specifically after any surgery, such as skin, mucosa, intraocular surgery such as retinal detachment, vitrectomy with or without air or silicone oil, tamponade, leading to cell proliferation and re-detachment of the retina and Rock inhibitors prevent side effects of excessive scar formation such as proliferative retinopathy and keloids in cosmetic surgery or laser surgery for acne and/or in psoriasis using Rock inhibitors, such as fasudil, rhopressa, netarsudil, and in nano- to microgram concentrations in 1 ml or more or Botulinum toxin as Botox etc.
  • any surgery such as skin, mucosa
  • intraocular surgery such as retinal detachment, vitrectomy with or without air or silicone oil, tamponade
  • tamponade leading to cell proliferation
  • absorbable polymers such as lactic acid or hyaluronic acid or in slow absorbable implant, such as porous silicon
  • Wnt inhibitors such as FH535, IWP-2, PNU-74654, IWR-lendo, IWR-exo, Demethoxycurcumin, CCTO36477,KY02l ll, WAY-316606, SFRP or integrin inhibitor such as abegrin, cilengitide, abciximab, tirofiban, natalizumab, eptifibatide, GSK inhibitors or integrin inhibitors at non-toxic doses and applied in a physiological solution or as slow release polymeric nanoparticles, microparticles, or as biodegradable implant or inside the space provided in a non-biodegradable implant that can be removed and replaced as needed.
  • Wnt inhibitors such as FH535, IWP-2, PNU-74654, IWR-lendo, IWR-exo, Demethoxycurcum
  • rock inhibitors are used in hair transplantation to reduce inflammatory responses of the transplanted cells at concentrations of 1 nanogram to 30 microgram/ml.
  • Rock inhibitors with GSK inhibitors are used after comeal transplantation to reduce corneal transplant rejection as polymeric nano- or microparticles, etc.
  • the Rock inhibitor in tissue or hair transplantation is Botox used at picogram concentrations or as international units 1/0. lml to 20 IU or more /O.lml in the post-operative period to prevent rejection and inflammation ⁇
  • the Botox or similar compound such as Fasudil, botulinum toxin, (Botox), rhopressa, netasudil, etc. or Wnt inhibitor such as FH535, IWP-2, or integrin inhibitors, are used with squalamine to prevent inflammation and rejection after tissue transplantation.
  • Rock inhibitors are used with GSK inhibitors and/or integrin inhibitors in sub-chronic inflammation of hair follicles leading to hair loss, the preparation can be used as a solution, polymeric nanoparticles or microparticles for slow release of picogram release/day.
  • Rock inhibitors and a macrolide such as cyclosporine, mycophenolic acid, or tacrolimus, etc. is used with Rock inhibitors as in a solution, cream, ointment or slow release polymeric nanoparticles or microparticles with biodegradable polymers for treatment of chronic inflammatory processes, such as glaucoma, male hair loss, or alopecia areata, acne vulgaris, in the form of a solution, cream etc. to slow down the loss of hair or prevent it, or in psoriasis to reduce the inflammatory component of the disease without the use of steroidal ointment, or after cosmetic surgery to reduce thermal damage and inflammation ⁇
  • chronic inflammatory processes such as glaucoma, male hair loss, or alopecia areata, acne vulgaris, in the form of a solution, cream etc. to slow down the loss of hair or prevent it, or in psoriasis to reduce the inflammatory component of the disease without the use of steroidal ointment, or after
  • alopecia is hormonal and genetic. It occurs during the puberty and continues thereafter. This process though is not considered inflammatory, it is hard to not expect that a very slow progressive inflammation might cause the apoptotic loss of hair stem cells and the hair bulb. However inflammatory processes cause more rapid loss of the hair, such as alopecia areata, psoriasis, or other skin diseases.
  • the standard therapy for the hair loss is the use of topical minoxidil a blood pressure lowering medication applied twice daily.
  • Minoxidil (Rogaine) is available at 2% to 5% concentrations preparations where it slows down the loss of hair, the mechanism of its action are local vasodilatation and/or nonspecific replacement of dihydrotestosterone (DHT)- binding sites in the hair bulb and nonspecific occupation of dihydrotestosterone (DHT)- binding sites in the hair.
  • the alternative medication is finistride, a 5 -alpha reductase inhibitor that blocks conversion of testosterone to DHT. Finasteride is taken orally and is more effective than minoxidil.
  • the other method that may help with the maintaining the hairs longer in women’s hair loss, and potentially in men, is the use of laser light radiation to heat up the skin and potentially open the skin capillaries.
  • the surgical techniques is done as strip transplantation or mini-grafts and micrografts.
  • Minigrafts and micrografts are removed with the size of 1-3 mm in diameter using a knife and a fine forceps or trephine and implanting them in the slit or holes in the recipient skull.
  • the skin is treated locally with oral prednisone to reduce the swelling of the tissue, and the pain is controlled with ibuprofen, acetaminophen, or codeine etc.
  • the postoperative side effects are bleeding, tissue swelling, edema, potentially infection, scar or keloid as a result of cytokine release activation of Wnt pathway rho enzymes producing TGF beta that induces excessive scar and keloids.
  • the standard medication such as anti-infective solution and dressing to the area to prevent infection with simultaneous administration of oral proscar (finastride) and topical Rock inhibitors, Wnt inhibitors, and/or GSK-3 inhibitors or integrin inhibitors as slow release polymeric nanoparticles or microparticles with or without CPP or ACPP to inhibit the inflammatory component of hair transplantation after the surgery, or in combination with other anti inflammatory medications, such as squalamine or lanosterols to combat infection
  • a therapy such as oral finasteride or topical application of a solution or cream having Rock inhibitors, such as fasudil, Netarsudi, or SAR407899 as a lotion with or without polymeric slow release nanoparticles or microparticles with or without CPP or ACPP, with or without squalamine to inhibit the inflammatory component at non-toxic concentrations or picogram to 100 nanograms or more, or in case of Botulinum toxin at 1-10 international units or more per milliliter applied using a Q-tipped applicator followed with femtosecond, nanosecond, micropulses, millipuses or pulses of less than one second to two second duration or more of laser with wavelength of green to infrared, preferably yellow or red wavelength with an energy length that does not produce any injury or scratches to the skin, but has the effect of tissue
  • a therapy such as oral finasteride or topical application of a solution or cream having Rock inhibitors, such as fasudil, Netarsudi, or
  • the Rock inhibitor is one of Botulinum toxin at 1-10 international units or more per milliliter applied to the skin of the scalp with a Q-tipped applicator as polymeric nanoparticles or microparticles of polylactic or glycolic acid or orthoesters with or without CPP or ACPP, with or without squalamine to release the medication slowly over time to prevent inflammatory processes of the hair bulbs.
  • alopecia In one embodiment of early stage male alopecia, or alopecia areata that is localized to one or more areas of the skull, one can administer oral finasteride or topical application of a solution having Rock inhibitors, such as fasudil, Netarsudi, or SAR 407899 as a solution with or without polymeric slow release nanoparticles or microparticles with or without CPP or ACPP but no Botox to inhibit inflammatory component at non-toxic concentrations or picogram to 100 nanogram concentrations applied using a Q-tipped applicator followed with femtosecond, nanosecond micropulses or millipulses or pulses of less than one second to two second pulse duration or more of a laser with the wavelength of green to infrared preferably yellow or red wavelength with an energy length that produces no or minimal injury or scratches to the skin to stimulate the stem cells of the hair follicles, using a thin laser probe with a transparent smooth surface and no sharp edges that can pass through the hair to reach the skull directly,
  • the topical administration of Rock inhibitors, anti-integrin inhibitors or other anti-inflammatory medications such as squalamine or lanosterols alone or in combination with a macrolide as drops, polymeric nanoparticles or implants for slow release over a long period of time to reduce the inflammation and scarring.
  • Psoriasis is a genetic disease associate with an autoimmune response with elevated tumor necrosis factor (TNF), release of cytokines, interleukin IL-12 , IL17, IL 23
  • the lesions may affect any part of the body and may be associated with exfoliation and inflammation which is in general treated with systemic and, in addition to phototherapy, systemic cyclosporine, injectable secukinumab, Adalimumab, etanercept, with their systemic side effects including lymphoma and topical application cooking oil, sea salt, topical steroids and Vitamin D as Calcipotriol with some limited beneficial effect.
  • a patient suffering from skin psoriasis which is treated with the standard topical medications and steroid, causes thinning of the skin, bruising and bleeding.
  • the psoriasis lesions of a patient are treated with a combination of Rock inhibitors such as Fasudil, botulinum toxin, (Botox), rhopressa, netasudil, etc.
  • Rock inhibitors such as Fasudil, botulinum toxin, (Botox), rhopressa, netasudil, etc.
  • Wnt inhibitor compounds such as FH535, IWP-2, PNU-74654, IWR-lendo, IWR-exo, Demethoxycurcumin, CCTO36477,KY02l ll, WAY-316606, SFRP or integrin inhibitor such as abegrin cilengitide, abciximab, tirofiban, natalizumab eptifibatide, risuteganib alone or in combination locally used in non-toxic concentrations or picogram to 1-30 or more micrograms as nanoparticles or dendrimers with ACPP or CPP for better tissue penetration, microparticles, PLA, PGLA, or combination, or polycaprolactone, or as liposomes, or micelles to reduce the inflammation processes locally alone or in combination with systemic immune therapy.
  • integrin inhibitor such as abegrin cilengitide, abciximab, tirofiban, natalizumab eptifibatide, risutegan
  • psoriasis lesions of a patient are treated with a combination of Rock inhibitors such as Fasudil, botulinum toxin, (Botox), rhopressa, netasudil, etc. or Wnt inhibitor compounds, such as FH535, IWP-2, PNU-74654, IWR-lendo, IWR-exo,
  • Rock inhibitors such as Fasudil, botulinum toxin, (Botox), rhopressa, netasudil, etc.
  • Wnt inhibitor compounds such as FH535, IWP-2, PNU-74654, IWR-lendo, IWR-exo
  • integrin inhibitors such as abegrin, cilengitide, or Wnt inhibitor with ACPP or CPP for better tissue penetration or integrin inhibitors alone or in combination locally used in non-toxic concentrations or picogram to 1-30 or more micrograms as nanoparticles or dendrimers in combination with Calcipotriol in treatment of psoriasis as lotion, ointment, or cream
  • a 15 year old female patient was suffering from early stage psoriasis around the elbows and neck that did not improve despite the topical therapy, steroids, Vitamin D analogues, Calcipotriene (Dovonex calcineurin inhibitors, Salicylic acid, topical retinoids, coal tar and moisturizers in an ointment, light and UVB radiation, the patient refused to have systemic immune suppressants such as methotrexate, cyclosporine or biologies such as secukinumab (Cosentyx) and ixekizumab (Taltz)etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), ustekinumab (Stelara), golimumab (Simponi), apremilast (Otezla), the patient was treated with therapies without steroids but administering Rock inhibitors, such as nanoparticles, or microparticles conjugated with C
  • the psoriasis lesions of a patient are treated with a combination of Rock inhibitors such as Fasudil, botulinum toxin, (Botox), rhopressa, netasudil, etc. or Wnt inhibitors such as FH535, IWP-2, PNU-74654, IWR-lendo, IWR-exo, Demethoxycurcumin, CCT036477, KY02111, WAY-316606, SFRP or integrin inhibitors such as abegrin cilengitide, abeiximab, tirofiban, natalizumab eptifibatide, risuteganib alone or in
  • polycaprolactone or as liposomes, or micelles or implantable along with fillers such as Juvederm and Juvederm Voluma (hyaluronic acid filler; Allergan), Belotero (hyaluronic acid; Merz Pharmaceuticals), Sculptra (poly-L-lactic acid), Sanofi or combination or as porous implantable porous silicon injected under the skin to release the medication over 1- 3 years, and gradually reduce the inflammation processes locally alone or in combination with systemic immune therapy.
  • fillers such as Juvederm and Juvederm Voluma (hyaluronic acid filler; Allergan), Belotero (hyaluronic acid; Merz Pharmaceuticals), Sculptra (poly-L-lactic acid), Sanofi or combination or as porous implantable porous silicon injected under the skin to release the medication over 1- 3 years, and gradually reduce the inflammation processes locally alone or in combination with systemic immune therapy.
  • the joint psoriasis is treated with injection inside the joint of preparation of Rock inhibitors such as Fasudil, botulinum toxin, (Botox), rhopressa, netasudil, etc. or Wnt inhibitors such as FH535, IWP-2, PNU-74654, IWR-lendo, IWR-exo, Demethoxycurcumin, CCTO36477,KY02111, WAY-316606, SFRP or integrin inhibitors such as abegrin cilengitide, abeiximab, tirofiban, natalizumab eptifibatide alone or in combination locally used in non-toxic concentrations or picogram to 1-3 or more
  • Rock inhibitors such as Fasudil, botulinum toxin, (Botox), rhopressa, netasudil, etc. or Wnt inhibitors such as FH535, IWP-2, PNU-74654, IWR-lendo, IWR
  • micrograms as nanoparticles dendrimers, microparticles, PLA, PGLA, or combination or polycaprolactone or as liposomes, or micelles or implantable erodible polymers with the size of 0.1-3 mm and diameter of 10-100 or more microns.
  • one administers the combination of Rock inhibitors in nano and picogram concentrations such as fasudil, Netarsudil and macrolides such as cyclosporine, mycophenolic acid, tacrolimus, or ascomycin etc.
  • the integrins are transmembrane receptors that act as mechanosensors and signal transduction platforms, adhesion molecules in many diseases processes, and their inhibition can prevent or treat the development of the inflammatory diseases and their sequelae.
  • one administers polymeric nanoparticles or dendrimers with the anti-integrins such as Risuteganib, vedolizumab, integrin-targeted therapeutics, abegrin cilengitide, abciximab, tirofiban, natalizumab eptifibatide are used alone or in combination with Rho-kinase inhibitors or Wnt inhibitors among others, or anti-VEGFs, GSK-3 inhibitors, or GSK 429286 to reduce the inflammation and reduce cell proliferation, and can be used simultaneously for drug delivery purposes in cutaneous inflammatory diseases.
  • the anti-integrins such as Risuteganib, vedolizumab, integrin-targeted therapeutics, abegrin cilengitide, abciximab, tirofiban, natalizumab eptifibatide are used alone or in combination with Rho-kinase inhibitors or Wnt inhibitors among others, or anti-VEGFs, GSK
  • one administers polymeric nanoparticles or dendrimers with Rock inhibitors, Wnt inhibitors, integrin inhibitors, or GSK inhibitors that are used in a slow release form as polymeric nanoparticles such as biodegradable polylactic acid, polyglycolic acid, (PLGA) copolymer, PLGA copolymer, about 10% to 90% by weight of the implant, or a 50/50 PLGA copolymer for about 3-months to a year, or in porous silicon for 1-3 years in concentrations of 0.01 microgram/day to 5 micrograms/day as needed.
  • the GSK-3 inhibitor lithium choloride at mM concentrations or SB-216763, a GSK-3 cell-permeable inhibitor can be added to the solution of Rock inhibitors or the ointments to interrupt the Wnt pathway and reduce localized skin inflammation and enhance the nerve growth after the skin surgery or inflammatory skin or mucosa diseases preventing severe fibrosis of the tissue.
  • the Rock inhibitors, Wnt inhibitors, integrin inhibitors, or GSK inhibitors are used along with antiproliferative medications after removal of cutaneous precancerous lesion or after skin or tumor resection or with antibiotics in infection caused by bacteria using nanoparticles, dendrimers, and microparticles of PLA, PGLA, with crosslinking the tissue using riboflavin and UV radiation.
  • Wnt inhibitors such as FH535, IWP-2, or GSK inhibitors are used along with macrolides, anti -infective medication with or without squalamine are administered in a physiological preparation with polymeric nanoparticles, microparticles, or cream for surface application after thermal or chemical burns of the skin or mucosa such as conjunctiva, mouth, accidental ingestion of hot fluid or chemical, etc. face, hand, legs or skull etc. as a solution, cream, etc. to reduce inflammation and scarring.
  • FH535, IWP-2, or GSK inhibitors are used along with macrolides
  • anti -infective medication with or without squalamine are administered in a physiological preparation with polymeric nanoparticles, microparticles, or cream for surface application after thermal or chemical burns of the skin or mucosa such as conjunctiva, mouth, accidental ingestion of hot fluid or chemical, etc. face, hand, legs or skull etc. as a solution, cream, etc. to reduce inflammation and scarring.
  • nanoparticles deliver Rock inhibitors, Wnt inhibitors, integrin inhibitors, Fasudil, rhopressa, netasudil, etc. or Wnt inhibitors such as FH535, IWP-2, or GSK inhibitors are used along with macrolides, anti -infective medication with or without squalamine are administered in a physiological preparation with polymeric nanoparticles, microparticles, or cream with or without squalamine/antibiotics or with semifluorinated alkane/siloxane for surface application after thermal or chemical burns of the skin or mucosa such as conjunctiva, mouth, accidental ingestion of hot fluid or chemical etc. face, hand, legs or skull etc. as solution, cream, etc. to reduce activation of TGF-beta and scarring.
  • Wnt inhibitors such as FH535, IWP-2, or GSK inhibitors
  • anti -infective medication with or without squalamine are administered in a physiological preparation with polymeric nanoparticles
  • nanoparticles deliver rock inhibitors, Wnt inhibitors, integrin inhibitors, Fasudil, rhopressa, netasudil, etc. or Wnt inhibitors such as FH535, IWP-2, or GSK inhibitors are used along with macrolides, anti-infective medication with polymeric nanoparticles, microparticles, surface application after thermal or chemical bums of the skin or mucosa such as conjunctiva, mouth, accidental ingestion of hot fluid or chemical etc. face, hand, legs or skull to the respiratory tract to reduce activation of TGF-beta and scarring, and fibrosis after inflammatory diseases of the lung.
  • the distribution of the medication through inhalation is fast and can be also localized to specific lobes of the lung if delivered through a nasal tube under bronchoscopy visualization of the catheter or a tube, after local spray anesthesia of the surfaces of the nasal, throat and trachea.
  • the respiratory tract include nose pharynx followed by trachea, bronchi and lung alveoli.
  • the right lung has three lobes whereas the left lung has two lobes. Both have alveoli, blood that are covered with a layer of mucin and fluid and function as gas exchange, in addition to its vessels and lymph nodes.
  • the clearance of the medication from the lung occurs mostly by systemic absorption, mucociliary or macrophage enzymatic activity.
  • Liquid nebulizers or pressure metered doses are used to deliver aerosolized medications in the respiratory system, however, the use of standard methodology has suffered from short half life time necessitating repeated applications.
  • the particles of 2-3 microns are deposited in the upper respiratory tract, whereas the smaller than 2 micron particles reach the lung alveoli and the particles smaller than 0.5 micron can also be exhaled. Therefore, the size of the particles determines where the particles travel and also the length of the duration of the drug delivery. The majority of deposited particles are cleared by mucociliary clearance that is increased by inflammatory diseases of the lung.
  • the aerosolized particles have a size of 0.001 to about 100 microns.
  • particulate-based drug delivery system includes the use of large porous microparticles (LPPs) with size greater than 5 pm, but with a density of less than 0.1 g/L or less.
  • LPPs large porous microparticles
  • the LPPs showed an appealing ability to escape macrophage uptake and deposit homogeneously in the lung.
  • the nanoparticles or microparticles can be can be the size of 0.1-5 microns, can be swellable after administration, crosslinked or noncrosslinked chitosan, or pegulated poly chitosans, micelles, hyaluronic acid, HA-conjugated medication, PEG- microspheres of lactic acid or glycolic acid or combination liposomes filled with medication, solid lipid nanoparticles or PEG-SLN, chitosan, poly(lactic-co-glycolic) acid, poly(lactic) acid, poly(butylcyanoacrylate), and poly(lactic-co-lysine, poly butylcyanoacrylate (PCL) or Polymeric micelles, amphiphilic macromolecules self-assemble to core-shell nanostructure or Cyclodextrins (CDs) are cyclic polymers of a-D-glycopyranose composed of cyclic oligosaccharides., CDs; a-,
  • the antibody-coated polymeric nanoparticles can carry antibiotics, antifungals, antiviral medication, macrolides, antiproliferative agents in addition to Rock inhibitors, or Wnt inhibitors or GSK inhibitors or integrin inhibitors to reduce inflammatory components of the lung disease, prevent pulmonary fibrosis, in patients with tumors of the lung along with antiproliferative agents, multiple checkpoint inhibitors, or immune stimulators such as IL-2, Tumor Necrotic Factors, Toll-like receptors, etc.
  • the antibody coated polymeric nanoparticles are delivered with nebulizers, or pressure metered dose devices.
  • the antibodies are coated to deliver the medications etc.
  • the nanoparticles are delivered locally in the lung under the control of a bronchoscope in aerosolized polymeric nanoparticles.
  • the polymeric nano- or microparticles are delivered in semifluorinated alkane that evaporates fast while leaving the medication at the desired location locally or diffusely in the lung carrying Rock inhibitors, or Wnt inhibitors, or GSK inhibitors or anti-integrins in conjunction with antibiotics, antifungal, antivirals, anti neoplastic medication to control the inflammatory process in the lung and eliminating the side effects of steroids or NSAIDS.
  • the polymeric nano or microparticles are delivered in semifluorinated alkane that evaporates fast while leaving the medication at the desired location locally or diffusely in the lung carrying Rock inhibitors, or Wnt inhibitors, or GSK inhibitors or ant-integrins in conjunction with medications that stabilize heart rhythm, or treat atherosclerotic disease of the coronary vessels, aorta, lung vessels or acrotic artery and the entire circulatory diseases.
  • SFA semifluorinated alkane
  • polymeric compounds such as polymeric compositions orthoesters, Anhydrides, amides, calcium alginate polysaccharides functionalized celluloses, carboxymethylcellulose, polycaprolactone, copolymers of glycolic and lactic acid, polymers of D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid, or porous silicon (not silicone oil), etc.
  • SAF delivery of medication using nanoparticles of 1-100 nm limits the duration of the medication release, which occurs fast.
  • polymeric nanoparticles can be made from preferably about 1 nm-l50 micron in diameter and 20 micron - 1 mm or more in length depending if it is used for inhalation or on the surface of the skin or mucosa and use the SAF for their carrier while the polymeric compound remains on or inside the tissue for days or even months if desired for the release of the medication depending on the percentage of the drug per volume of the polymer such as 10% w/v to 50% w/v or more is selected and the polymeric compound.
  • This combination of SAF with polymeric slow release compound(s) delivers the medication longer than described previously for the semifluorinated alkane/medication alone and eliminates the need for daily multiple applications.
  • the active component of the SFA/Polymer for use in the present preparation are compounds that inhibit or stimulate one or the other cellular activity such as Wnt inhibitors, Rock inhibitors, GSK inhibitors, or integrin inhibitors; though practically any other medications can be delivered with this system such as abtibacterials, antifungals, anti-virals anti-parasitics, anti-inflammatory agents , including prostaglandin analogues, antihistaminic, growth hormones, or biologies, anti-VEGFs, macrolides, anti proliferative, vasoconstrictive or vasodilatators.
  • perfluorocarbon liquids or semifluorinated alkane such as F4H5, F4H6, F4H8, F6H6 F6H8 etc. alone or in combination with one siloxane can be used as a carrier formulation to carry slow release polymeric nano- to microparticles of polylactic, micelles, or polycaprolactone, copolymers of glycolic and lactic acid of Rock inhibitors, such as fasudil netarsudil, SAR407899, etc. and/or Wnt inhibitors such as FH535, IWP-2, PNU- 74654, IWR-lendo, IWR-exo, or GSK inhibitors SB- 216763 etc.
  • perfluorocarbon liquids or semifluorinated alkane such as F4H5, F4H6, F4H8, F6H6 F6H8 etc. alone with or without siloxane with polymeric slow release nano-microparticles of polylactic, polyglycolic acid, or polycaprolactone or porous silicon dispersed in the semifluorinated alkane formulation, conjugated with or without an additional amphiphilic cationic polymer such as such as CPP or ACPP, poly ⁇ N-[N-(2- aminoethyl)-2-aminoethyl]aspartamide] (PEG-pAsp(DET) / semifluorinated alkane complex etc.
  • F4H5, F4H6, F4H8, F6H6 F6H8 etc. alone with or without siloxane with polymeric slow release nano-microparticles of polylactic, polyglycolic acid, or polycaprolactone or porous silicon dispersed in the semifluorinated alkane formulation
  • Rock inhibitors such as fasudil, netarsudil, SAR407899, etc. and/or Wnt inhibitors such as FH535, IWP-2, PNU-74654, IWR-lendo, IWR-exo, etc.
  • integrin inhibitors such as abciximab, Eptifibatide, Tirofiban, a 11 h b 3 antagonists, Natalizumab, 3 microgam/ml or GSK inhibitors at non-toxic concentrations of 1 picogram to nanograms or more daily release from the nanoparticles at a concentration as needed with or without squalamine, lanosterol, squalene preparation for topical application after refractive surgery of the cornea, cataract, LASIK or smile procedure or glaucoma surgery or after cosmetic facial laser surgery or skin resurfacing, vaginal laser surgery, or after acne laser surgery or without surgery etc.
  • Intraocular inflammation affects the trabecular meshwork of the eye, blocking the outflow channel of the intraocular fluid.
  • inflammation incites production of cell adhesion molecules, cell adhesion, cell proliferation, cell migration and production of the fibrous membrane leading to damage to the trabecular meshwork and outflow channels of the aqueous.
  • Rock inhibitors block the activity of the Rho enzyme which is a part of the serine- threonine family that acts when the Wnt signaling is activated during the inflammation and cell proliferation, and scar formation. Its inhibition reduces the inflammation and cell proliferation, and in addition, it enhances the vascular blood flow and prevents
  • an exemplary dosing of netarsudil 0.02% (0.2 mg per ml) 0.02% (0.2 mg per ml)
  • one administers the Rock inhibitors with a slow release drug delivery system such as polymers, matrices, microcapsules, nanoparticles or microspheres, microparticles of porous silicon or other delivery systems formulated from, polyglycolic acid, lactic acid, combinations of glycolic and lactic acid, liposomes, silicon, as nano- or microparticles with (alpha)-cyclodextrin, or (beta)-cyclodextrin, or (gamma)-cyclodextrin, hydroxypropyl-b-cyclodextrin (bHPCD) or polyanhydride polyvinyl acetate alone or in combination with polyethylene glycol, etc.
  • a slow release drug delivery system such as polymers, matrices, microcapsules, nanoparticles or microspheres, microparticles of porous silicon or other delivery systems formulated from, polyglycolic acid, lactic acid, combinations of glycolic and lactic acid, liposomes, silicon, as nano- or
  • the delivery of the polymeric implant for slow release of medication such as porous silicon implant, polycaprolactone can be implanted intraocularly where the inflammation is mediated by various conditions of the eye such as post ocular surgery procedures such as refractive surgery, such as LASIK, smile procedure, trauma, cataract surgery, glaucoma surgery, or glaucoma selective laser trabeculoplast (SLT) for glaucoma, vitreoretinal surgery, vitrectomy, sub-retinal surgery, recurrence of retinal detachment, and laser surgery of the retina in diabetic retinopathy or diabetic macular edema.
  • refractive surgery such as LASIK, smile procedure, trauma, cataract surgery, glaucoma surgery, or glaucoma selective laser trabeculoplast (SLT) for glaucoma, vitreoretinal surgery, vitrectomy, sub-retinal surgery, recurrence of retinal detachment, and laser surgery of the retina in diabetic
  • Integrins are transmembrane proteins which are active in cell proliferation and cell- to-cell adhesion in many disease processes and scarring.
  • one administers integrin inhibitors as a slow release drug delivery system such as polymers, matrices, microcapsules, nanoparticles or microspheres, microparticles of porous silicon or other delivery systems formulated from poly glycolic acid, lactic acid, combinations of glycolic and lactic acid, liposomes, silicone, as nano- or microparticles with (alpha)-cyclodextrin, or (beta)-cyclodextrin, or (gamma)-cyclodextrin, hydroxypropyl-b-cyclodextrin (bHPCD) or polyanhydride polyvinyl acetate alone or in combination with polyethylene glycol, etc.
  • a slow release drug delivery system such as polymers, matrices, microcapsules, nanoparticles or microspheres, microparticles of porous silicon or other delivery systems formulated from poly glycolic acid, lactic acid, combinations of glycolic and lactic acid, liposomes, silicone, as nano- or microparticles with
  • polycaprolactone can be implanted intraocularly such as abegrin cilengitide, abciximab, tirofiban, natalizumab eptifibatide or a low concentration 1 micrograms to 10 micrograms as a solution or polymeric nano-or microparticles or suspension, topically, at doses of 1 -200-micrograms per milliliter or more or injecting intraocularly, subconjunctivally, in the choroid, or the vitreous at doses of 1-20 micrograms per 0.1 milliliter or more, or as implants as a bio-erodible implant or polymeric nanoparticles or microparticles to release the medication at a non-toxic dose of a nanogram to microgram concentration or more per day for a long time at 1-6 or 12 or more months comprising integrin inhibitors or in combination with GSK inhibitors, wherein the chronic inflammation-mediated by various conditions of the eye such
  • the Wnt inhibitors such as Dickkopf (Dkk) proteins, Wnt Inhibitory Factor- 1 (WIF-l) in a non-toxic nano- to microgram concentration, Rock inhibitors or integrin inhibitors such as abegrin cilengitide, abciximab, tirofiban, natalizumab eptifibatide or a low concentration 1 microgram to 10 micrograms as a solution or GSK-3 inhibitors with or without ACPP may be injected into the eye, for example, injection under the conjunctiva or tenon capsule, intravitreal injection, or retrobulbar injection as a slow release nanoparticle.
  • Dkk Dickkopf
  • WIF-l Wnt Inhibitory Factor- 1
  • Rock inhibitors or integrin inhibitors such as abegrin cilengitide, abciximab, tirofiban, natalizumab eptifibatide or a low concentration 1 microgram to 10 micrograms as a solution or GSK-3 inhibitors
  • the agent(s) may be administered with a slow release drug delivery system, such as polymers, matrices, microcapsules, nanoparticles or microspheres, microparticles of porous silicon or other delivery systems formulated from, polyglycolic acid, lactic acid, combinations of glycolic and lactic acid, liposomes, porous silicon, as nano- or microparticles with (alpha)-cyclodextrin, or (beta)-cyclodextrin, or (gamma)-cyclodextrin, hydroxypropyl-b-cyclodextrin (bHPCD) or polyanhydride polyvinyl acetate alone or in combination with polyethylene glycol, etc.
  • a slow release drug delivery system such as polymers, matrices, microcapsules, nanoparticles or microspheres, microparticles of porous silicon or other delivery systems formulated from, polyglycolic acid, lactic acid, combinations of glycolic and lactic acid, liposomes, porous
  • a polymeric implant for slow release of medication such as porous silicon implant, polycaprolactone
  • a polymeric implant for slow release of medication such as porous silicon implant, polycaprolactone
  • post ocular surgery procedures such as corneal refractive surgery, LASIK, small incision
  • the topical application of Rock inhibitors, integrin inhibitors, GSK-3 inhibitors, Wnt inhibitors are applied to the cornea and conjunctiva as a solution or polymeric nanoparticles or an implant under the conjunctiva to release medication for 3-6 months delivering nanogram to microgram concentrations or in case of Botulinum toxin (Botox) ⁇ 1-10 international unit as an injection in 0.1-3 milliliters or topical application or spray or evaporative solution or in a evaporative semifluorinated alkane to enhance comeal nerve growth and corneal sensation to prevent dry eye or pain and scarring after the comeal surgery including comeal transplant, and cataract extraction.
  • Botulinum toxin Botox
  • biodegradable polymeric compositions are orthoesters, anhydrides, amides, calcium alginate, polysaccharides, functionalized celluloses, carboxymethylcellulose, polycaprolactone, copolymers of glycolic and lactic acid, polymers of D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid, porous silicon implant or nano- or microparticles.
  • the polymer can be of any size, but preferably for injectable compounds, it can be about 2-150 micrometers or larger in diameter and 20 microns to 4 millimeters in length or longer.
  • the polymeric implant or nano- or microparticles can be combined with antibiotics, antifungals, antivirals, antineoplastic macrolides, etc. as needed.
  • the device contains a ROCK inhibitor such as Fasudil, netarsudil, etc. or ROCK inhibitor selective Rho-kinase (ROCK) inhibitor H1152 dihydrochloride, selective Rho-kinase (ROCK) inhibitor Glycyl H 1152 dihydrochloride, selective Rho-kinase (ROCK) inhibitor; more selective analogue of H1152, cell-permeable, selective Rho-kinase inhibitor OXA 06 dihydrochloride, potent ROCK inhibitor PKI1447 dihydrochloride, potent and selective ROCK inhibitor; antitumor SB 772077B, potent Rho- kinase inhibitor; vasodilator SR 3677 dihydrochloride, potent, selective Rho-kinase (ROCK) inhibitorTC-S700l, potent and highly selective ROCK inhibitor; orally active Y-27632 dihydrochloride.
  • ROCK inhibitor such as Fasudil, netarsudil, etc. or ROCK inhibitor
  • the device may also contain at least one of an anti-vascular endothelial growth factor (VEGF), such as avastin, ranizumab, afibercept,an anti-platelet derived growth factor (PDGF), an integrin inhibitor such as abegrin cilengitide, abciximab, tirofiban, natalizumab eptifibatide or a low concentration 1 microgram to 10 micrograms as a solution, a beta-blocker, an adrenergic agonist, a carbonic anhydrase inhibitor, a cholinergic agent, a prostaglandin analog, a derivative of cannabinoid receptors, and combinations thereof working synergistically as needed or GSK inhibitor 429286.
  • VEGF anti-vascular endothelial growth factor
  • PDGF anti-platelet derived growth factor
  • an integrin inhibitor such as abegrin cilengitide, abciximab, tirofiban, natalizuma
  • Rock inhibitors or integrin inhibitors such as abciximab, Eptifibatide, Tirofiban, aIPtb3 antagonists, Natalizumab, 3 mg to ⁇ 52 pg/mL, MLN-00002, Firategrast, IVL745, antagonists of anb3 and/or anb5 integrins, LM609, Vitaxin, Abegrin, CNT095, Cilengitide.
  • MLD- based disintegrins L000845704, SB273005, Volociximab, JSM6427, are administered intraocularly or topically to a patient suffering from ocular inflammatory processes caused by viral or non- viral infection or after eye surgery, such as glaucoma, retinal detachment, or cataract extraction at a concentration in the range of about 1 nanogram/ml (0.0000001%) to less than 1 microgram/ml (less than 0.0001%).
  • injectable or polymeric nanoparticle or microparticles of the Wnt inhibitors such as FH535, IWP-2, PNU-74654, IWR-lendo, IWR-exo, niclosamide or Rock inhibitors or integrin inhibitor such as abegrin cilengitide, abciximab, tirofiban, natalizumab eptifibatide or a low concentration 1 microgram to 10 micrograms as a solution or polymeric nanoparticles, GSK-3 inhibitors 429286, alone or in combination with or without ACPP may be injected into the vitreous cavity as an implant or nano- or
  • microparticles at concentration of 1 nanogram to few microgram release per day for 1-6 months in chronic inflammatory diseases, such as diabetic retinopathy, uveitis, macular edema, dry and wet macular degeneration, with or without anti VEGFs, retinal detachment, ocular tumors, multifocal choroiditis, uveitis, proliferative vitreoretinopathy (PVR), fungal or viral infections, sympathetic opthalmia, histoplasmosis, and uveal diffusion.
  • chronic inflammatory diseases such as diabetic retinopathy, uveitis, macular edema, dry and wet macular degeneration, with or without anti VEGFs, retinal detachment, ocular tumors, multifocal choroiditis, uveitis, proliferative vitreoretinopathy (PVR), fungal or viral infections, sympathetic opthalmia, histoplasmosis, and uveal diffusion.
  • proliferative vitreoretinopathy caused by recurrent retinal detachment and formation of traction bands and membrane over and under the retina, nanoparticles, e.g., dendrimer or microparticles of the Wnt inhibitors such as FH535, IWP-2, PNU-74654, IWR-lendo, IWR-exo, niclosamide or Rock inhibitors or integrin inhibitors such as abegrin cilengitide, abciximab, tirofiban, natalizumab eptifibatide or a low concentration 1 microgram to 10 micrograms as a solution or polymeric
  • Wnt inhibitors such as FH535, IWP-2, PNU-74654, IWR-lendo, IWR-exo, niclosamide or Rock inhibitors or integrin inhibitors
  • abegrin cilengitide abciximab, tirofiban, natalizumab eptifibatide or a low concentration 1
  • nanoparticles with CPP, or GSK-3 inhibitor 429286, alone or in combination with or without ACPP may be injected in the vitreous cavity, subconjunctivally, or inside the choroid to prevent the side effects of the surgery.
  • Laser trabeculoplasty is a procedure in which argon laser is applied to the trabecular meshwork of the eyes outflow channels. ALT is applied to reduce the intraocular pressure in about 20-30% of cases after the one year. The disadvantages have been potential scar formation in the trabecular meshwork. Subsequent studies using selected laser trabeculoplasy (SLT) demonstrated that the thermal or coagulative energy may not have been needed for many of the patients.
  • SLT laser trabeculoplasy
  • SLT laser application using femtosecond, nanopulse or micropulse application encourages the renewal of the remaining cells, and to treat glaucoma.
  • Rock inhibitors such as fasudil hydrochloride (inhibitor of cyclic nucleotide dependent- and rho kinases); netarsudil rhpressa, GSK 429286 (a selective ROCK inhibitors); H 1152 dihydrochloride (a selective ROCK inhibitor); glycyl-H 1152 dihydrochloride (a more selective analog of H 1152 dihydrochloride); HA 1100 hydrochloride (a cell-permeable, selective ROCK inhibitor); SR 3677 hydrochloride (a potent, selective ROCK inhibitor); Y 39983 dihydrochloride (a selective ROCK inhibitor); and Y 27632 dihydrochloride a selective pl60 ROCK inhibitor or Wnt inhibitor
  • Rock inhibitors such as fasudil hydrochloride (inhibitor
  • the integrin inhibitor in addition to abegrin cilengitide, abciximab, tirofiban, natalizumab, or eptifibatide, may also be in the form of R-G-Cysteic Acid (i.e., linear form of R-G-NH— CH(CH.sub.2-SO.sub.3H)COOH or cyclic form of R-G- NH— CH(CH.sub.2-SO.sub.3H)COOH) and their a derivatives as a solution or slow release compound such as PLGA or micelles or other polymeric nanoparticle.
  • R-G-Cysteic Acid i.e., linear form of R-G-NH— CH(CH.sub.2-SO.sub.3H)COOH or cyclic form of R-G- NH— CH(CH.sub.2-SO.sub.3H)COOH
  • R-G-Cysteic Acid i.e., linear form of R-G-NH— CH(CH.sub
  • a Wnt inhibitor such as FH535, IWP-2, PNU-74654, IWR-lendo, IWR-exo, niclosamide inhibitors or Rock inhibitors or integrin inhibitor or GSK-3 inhibitors 429286
  • TRPV4 transient receptor potential vanillod isoform4
  • Pannexin-l Pannexin-l
  • p2x7 receptors that ultimately lead to the retinal ganglion cell degeneration.
  • Rock inhibitors are administered simultaneously with probenecid to inhibit pannexin-l (Panxl), and p2x7 receptors.
  • one uses Rock inhibitors, with Wnt inhibitors or Anti-integrins or GSK inhibitors given topically subconjunctivally or intravitreally as a slow release polymer that reduces the signal for cellular adhesion and proliferation to eliminate the side effects of the rise in the intraocular pressure and damage to the retinal ganglion cells.
  • the Wnt inhibitors or Rock inhibitors or integrin inhibitors such as abegrin cilengitide, abciximab, tirofiban, natalizumab eptifibatide or a low concentration 1 microgram to 10 micrograms as a solution or polymeric nanoparticles or GSK inhibitors 429286 can be in polymeric nanoparticles, micelles, solution as a topical application, delivering the medication from one nanogram to one microgram to 20 micrograms per day or more.
  • the medication can be implanted or injected in the eye as an implant in a micro nanoparticle format in dendrimers, or polylactic or polyglycolic acid or a combination or as slow drug delivery polymers using chitosan or polycaprolactone, porous silicon or coated with CPP or ACPP to reduce the inflammatory process, etc.
  • small molecule Wnt inhibitor PKF118-310 the Wnt ⁇ -catenin pathway inhibitor and Fasudil, a Rock inhibitor Fasudil (HA-1077), a selective RhoA/Rho kinase (ROCK) inhibitor, or Y-27632, small molecule inhibitor of ROCK1 and ROCK2, with CPP or ACPP, etc.
  • a Rock inhibitor Fasudil HA-1077
  • a selective RhoA/Rho kinase (ROCK) inhibitor or Y-27632
  • small molecule inhibitor of ROCK1 and ROCK2 with CPP or ACPP, etc.
  • a polyanhydride such as DMSO or alcohol or sterol, lanosterol, squalene, and/or squalamine, with CPP or ACCPP or containing a polyanhydride, poly(glycolic) acid, poly(lactic) acid, or as nano- or microparticles with (alpha)-cyclodextrin, or (beta)-cyclodextrin, or (gamma)-cyclodextrin, hydroxypropyl-b- cyclodextrin (bHPCD) or polycaprolactone polymer or dendrimers to release non-toxic dose of medication slowly at desired concentration to the external or internal eye at a non-toxic concentration or along with a macrolide, cyclosporine A, mycophenolic acid, ascomycin, tacrolimus or anti-integrin or GSK-3 inhibitors 429286, or such as a topical lithium or zinc preparation, bis-indole, indirubin, aminopyrimidines,
  • the Rock inhibitors, Wnt inhibitor and integrin inhibitors or GSK inhibitors429286, application to the laser treated areas reduces the unwanted side effects of laser application such as inflammation, cell migration and severe scar formation.
  • a preparation of Rock inhibitors, Wnt inhibitors, or integrin inhibitors alone or in combination can be used to reduce the inflammatory side effects and severe scar formation.
  • the Rock inhibitor is used to reduce TGF-b production after therapy and the subsequent scar formation in form of drops or combined with polymeric nanoparticles for slow release delivery after any ocular surgery such as retinal detachment, vitrectomy, retinotomy, glaucoma surgery, cataract surgery, laser trabeculoplasty by intraocular injection or as slow release nanoparticles, dendrimers, poly glycolic acid (PGA ) or polylactic acid PLA or a combination or polycaprolactone or chitosan or as liposomal preparation or micelles.
  • any ocular surgery such as retinal detachment, vitrectomy, retinotomy, glaucoma surgery, cataract surgery, laser trabeculoplasty by intraocular injection or as slow release nanoparticles, dendrimers, poly glycolic acid (PGA ) or polylactic acid PLA or a combination or polycaprolactone or chitosan or as liposomal preparation or micelles.
  • the Rock inhibitors are selected from the group consisting of Fasudil, Ripasudil, RKI-1447, Y-27632, GSK429286A, Y-30141, and combinations thereof where the device releases the ROCK inhibitor for 3 months to 3 years.
  • the Rock inhibitors are selected from the group consisting of Fasudil (HA-1077 a selective RhoA/Rho kinase (ROCK) inhibitor), Y-27632, small molecule inhibitor of ROCK1 and ROCK2 which act as an anti-inflammatory agent and Ripasudil, Netarsudil etc.
  • Fasudil HA-1077 a selective RhoA/Rho kinase (ROCK) inhibitor
  • Y-27632 selective RhoA/Rho kinase
  • small molecule inhibitor of ROCK1 and ROCK2 which act as an anti-inflammatory agent
  • Ripasudil Netarsudil etc.
  • the Rock inhibitors such as Fasudil (HA-1077 a selective RhoA/Rho kinase (ROCK) inhibitor), Y-27632, small molecule inhibitor of ROCK1 and ROCK2 which acts as an anti-inflammatory agent and Ripasudi, netarsudil, etc. in form of drops or combined with polymeric nanoparticles, dendrimers, or microparticles for slow release delivery after any ocular surgery such as retinal detachment, glaucoma, cataract and after trauma.
  • Fasudil HA-1077 a selective RhoA/Rho kinase (ROCK) inhibitor
  • Y-27632 a selective RhoA/Rho kinase (ROCK) inhibitor
  • ROCK1 and ROCK2 small molecule inhibitor of ROCK1 and ROCK2 which acts as an anti-inflammatory agent and Ripasudi, netarsudil, etc. in form of drops or combined with polymeric nanoparticles, dendrimers, or microparticles for slow release
  • the Rock inhibitor Fasudil HA- 1077
  • a selective RhoA/Rho kinase (ROCK) inhibitor a selective ROCK inhibitor such as SAR407899, Y-27632, small molecule inhibitor of ROCK1 and ROCK2 or Ripasudi
  • netarsudil are administered and released at nanogram to microgram concentrations in a polymeric drug delivery or
  • Botulinum toxin such as Botox as picogram to nanogram concentrations or 1-10 units or more concentration per day which act as an TGF beta inhibitor and as anti-inflammatory agent after retinal surgery, glaucoma surgery preventing cell proliferation and adhesion.
  • the conventional signaling receptors and integrins serve as linkers between the actin cytoskeleton and extracellular intracellular signaling matrix, stimulating the cell survival, growth, and cell proliferation.
  • the anti-integrin are used to inhibit cell proliferation and migration and scar formation in microgram concentrations, e.g., in retinal detachment surgery, vitrectomy to prevent development of proliferative vitreoretinopthy that leads to fixed fold and re-detachment of the retina or after cataract surgery or laser surgery of the retina and trabecular meshwork or laser surgery of the iris or ciliary body or laser of ciliary processes to reduce the intraocular pressure
  • the integrin inhibitors are selected from the group abegrin, cilengitide, abciximab, tirofiban, natalizumab eptifibatide at non-toxic doses of nanogram to microgram concentrations per milliliter or more.
  • the Rock inhibitors such as fasudil, netarsudil, etc. or anti- integrins such as abciximab, Eptifibatide, Tirofiban, a.II b3 antagonists, Natalizumab at microgram per milliliter, MLN-00002, Firategrast, IVL745, antagonists of anb3 and/or anb5 integrins, LM609, Vitaxin, Abegrin, CNT095, Cilengitide.
  • fasudil netarsudil, etc.
  • anti- integrins such as abciximab, Eptifibatide, Tirofiban, a.II b3 antagonists, Natalizumab at microgram per milliliter, MLN-00002, Firategrast, IVL745, antagonists of anb3 and/or anb5 integrins, LM609, Vitaxin, Abegrin, CNT095, Cilengit
  • MLD- based disintegrins L000845704, SB273005, Volociximab, JSM6427
  • the non-toxic doses of Wnt inhibitors, integrin inhibitors and/or Rock inhibitors, or Botox act as an anti-inflammatory agent.
  • the botulinum toxin or botox preparation may be administered topically to the eye or eye lid, forehead skin atl picogram to 1 nanogram concentrations, 1 pictogram to 5 nanogram or higher concentrations of microgram concentrations, for example, using drops, an ointment, a cream, a gel, a suspension of microspheres, dendrimers , micelles, etc.
  • GSK-3 Glycogen Synthase Kinase-3
  • the (GSK-3) inhibitor 269962 is administered in a slow release polymeric form or lithium or zinc preparation, bis-indole indirubin, aminopyrimidines, arylindolemaleimides SB-216763, Paullones, pyrazolo 13,4-61 quinoxalines, human kinome, tideglusib ,b-carboline alkaloids b-carboline alkaloids Palinurin and tricantin, peptide L803- mts, Axin GID-25 residues, NP-l2/Tideglusib at non-toxic concentrations.
  • the agent penetration is extended to at least one of the posterior segment of the eye or anterior segment of the eye or from the cornea to the retina.
  • a mucophilic preparation shuch as chitosan or micelles, of Rock inhibitors, integrin inhibitors, or Wnt inhibitors is administered comprising a compound selected from the group consisting of chitosan, dendrimer, coated or linked with cell penetrating peptides (CPPs), activated cell penetrating peptides (ACPPs), hyaluronic acid, and combinations thereof.
  • CPPs cell penetrating peptides
  • ACPPs activated cell penetrating peptides
  • hyaluronic acid hyaluronic acid
  • the integrin inhibitors are administered with cell penetrating peptide or ACPP coated dendrimers or nanoparticles, macrolides such as cyclosporine A, mycophenolic acid, tactolimus or ascomycin as nanoparticles or conjugated with the dendrimers or in a solution in the early stage of glaucoma as a topical medication at a concentration of Rock inhibitors of 1-5 micrograms per milliliter once or twice per day and macrolides at concentration of 0.000000001% to 0.1% in a physiological solution.
  • macrolides such as cyclosporine A, mycophenolic acid, tactolimus or ascomycin as nanoparticles or conjugated with the dendrimers or in a solution in the early stage of glaucoma as a topical medication at a concentration of Rock inhibitors of 1-5 micrograms per milliliter once or twice per day and macrolides at concentration of 0.000000001% to 0.1% in a physiological solution.
  • a porous tubular implant further contains stem cells, or genetically modified stem cells, for slow release where the stem cells are selected from the group consisting of cultured stem cells, genetically modified stem cells, embryonic stem cells, mesenchymal stem cells, neuronal stem cells, pluripotent stem cells, glial stem cells, stem cells or genetically modified stem cells having complement receptor 35, and combinations thereof to treat loss of cells in the retina, retinal pigment epithelium, corneal genetic diseases or loss of ganglion cells or choroid or cells in trabecular meshwork.
  • stem cells are selected from the group consisting of cultured stem cells, genetically modified stem cells, embryonic stem cells, mesenchymal stem cells, neuronal stem cells, pluripotent stem cells, glial stem cells, stem cells or genetically modified stem cells having complement receptor 35, and combinations thereof to treat loss of cells in the retina, retinal pigment epithelium, corneal genetic diseases or loss of ganglion cells or choroid or cells in trabecular meshwork.
  • the Rock inhibitors are administered with macrolides such as cyclosporine A, mycophenolic acid, tacrolimus or ascomycin in the early stage of glaucoma as topical medication at a concentration of Rock inhibitors 1-5 microgram/ml once or twice per day and macrolides at concentration of 0.000000001% to 0.1% in a physiological solution for topical application or injection in the eye.
  • macrolides such as cyclosporine A, mycophenolic acid, tacrolimus or ascomycin
  • the slow release preparation of Rock inhibitors or integrin inhibitors or combination thereof are administered inside the eye as a polymeric implant in the lens capsule after cataract surgery, or implanted in the vitreous or in the anterior chamber or in the suprachoroidal space or under the conjunctiva to deliver medication for 3-6 months to release medication at microgram concentrations in a non-toxic dose daily after cataract surgery, glaucoma surgery, to prevent encapsulation of a glaucoma stent or bleb scarring or membrane formation after retinal surgery, or cell proliferation after retinal surgery, or retinal laser surgery.
  • TRPV4 transient receptor potential vanillod isoform4
  • Panxl pannexin-l
  • p2x7 receptors are activated leading to glial cell activation and inflammatory response involving Toll-like receptors, complement molecules, tumor necrosis factor-a (TNFa), and interleukin- 1.
  • the laser surgery is also often associated with inflammation that causes cell proliferation on the retina, producing traction on the retina or pre-retinal and sub-retinal scar formation, inducing re-detachment of the retina due to cell proliferation in proliferative vitreoretinopathy.
  • GSK-3 Glycogen Synthase Kinase-3
  • the GSK-3 inhibitor such as 429286
  • CPP cell penetrating peptides
  • ACPP coated-den dri m ers or nanoparticles or macrolides such as cyclosporine A, mycophenolic acid, tacrolimus or ascomycin as nanoparticles or conjugated with the dendrimers or in a solution in the early stage of glaucoma as a topical medication at concentration of Rock inhibitor
  • the stems cells of a patient when the stem cells of a patient also carry the genetic defect that they have inherited, the stems cells of the patient are modified in cell culture prior to the administration to the eye.
  • the stem cells may be cultured stem cells, genetically modified stem cells, embryonic stem cells, mesenchymal stem cells, neuronal stem cells, pluripotent stem cells, glial stem cells, etc.
  • stem cells can be genetically modified using the technology known as non-homologous end joining (NHEJ) or homologous directed repair (HDR) in which the gene modification is done along with CRISPR cas9 or Cpf 1 using nanoparticles as a vector to deliver the gene(s) inside the cells, or to cut out the mutated gene, eliminating the side effects of immune activation, as observed with the viral vector gene delivery.
  • NHEJ non-homologous end joining
  • HDR homologous directed repair
  • CRISPR-conjugated to the desired nanoparticles via thiol to create a strong electrostatic bound.
  • CRISPR-NP are then conjugated with Cas 9 and gRNA to be used in non-homologous end joining NHEJ or the NP-DNA conjugate is hybridized with the donor DNA, thus creating NP-donor DNA suspended in sodium silicate, generating NP-Donor-Cas9 RNP- silicate, which is re suspended in a cationic polymer such as cyclodextrin or calixarene-based polycationic amphiphiles polymer as gene delivery systems or PAsp(DET) to be used in Homology Directed repair (HDR) after administration to the stem cells with appropriate gene(s).
  • a cationic polymer such as cyclodextrin or calixarene-based polycationic amphiphiles polymer as gene delivery systems or PAsp(DET) to be used in Homology Directed repair (HDR) after
  • the nanoparticles can be metallic, such as gold or ferric oxide, combination of silica/gold, QDs, polymeric organic, cationic polymeric NP, PAsp(DET), piezoelectric, such as perovskites, quartz, or other vectors such as Naked DNA, etc. with the size of 5-50 nanometers.
  • the nanoparticle is gold or ferromagnetic covered with gold before conjugated with the CRISPR‘gRNA- cationic polymer and or gold NP- Donor DNA and suspended in silicate and a cationic polymer.
  • the nanoparticle is PAsp(DET) or gold to which CRISPR or donor DNA is attached via thiol, before suspending the complex in sodium silicate to be followed by another cationic polymer to enhance cell penetration and endosomal escape and gene(s) delivery to the nucleus after their administration to the stem cell culture.
  • the device further contains stem cells, where the stem cells are selected from the group consisting of cultured stem cells or modified genetically modified stem cells, genetically modified stem cells, embryonic stem cells, or modified genetically modified embryonic stem cells, mesenchymal stem cells, or genetically modified
  • mesenchymal stem cells neuronal stem cells, or genetically modified stem cells, neuronal pluripotent stem cells, glial stem cells, or genetically modified stem cells, neuronal stem cells having complement receptor 35, and combinations thereof.
  • the method comprising injecting stem cells or genetically modified stem cells to replace the loss of endothelial cells and normalize the function of the perifoveal capillaries in patients with diabetic macular edema associated with vascular leakage, demonstrable deep retinal vascular deformation or loss, age related macular degeneration, glaucoma, and retinal ischemia either centrally or peripherally.
  • the stem cells or genetically modified stem cell are administered at a concentration of about 5,000 to 100,000 stem cells or genetically modified stem cells having complement receptor 35 (CD 35) in combination with ROCK inhibitors.
  • the method comprising injecting stem cells or genetically modified stem cells to replace the loss of endothelial cells and normalize the function of the perifoveal capillaries in patients with diabetic macular edema associated with vascular leakage, demonstrable deep retinal vascular deformation or loss, age related macular degeneration, glaucoma, and retinal ischemia either centrally or peripherally.
  • the stem cells or genetically modified stem cell are administered at a concentration of about 5,000 to 100,000 stem cells or genetically modified stem cells having complement receptor 35 (CD 35) in combination with Rock inhibitors.

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Abstract

L'invention concerne une méthode de traitement, de réduction ou d'atténuation d'une pathologie chez un patient. La méthode comprend l'administration d'un implant d'administration de médicament à un patient en ayant besoin, l'implant d'administration de médicament comprenant un ou plusieurs inhibiteurs de Rock, un ou plusieurs inhibiteurs de Wnt, un ou plusieurs inhibiteurs d'intégrine, et/ou un ou plusieurs inhibiteurs de la glycogène synthase kinase-3 (GSK-3), le patient ayant une pathologie choisie dans le groupe constitué par la sécheresse oculaire, le glaucome, le lichen plan, l'arthrite, le psoriasis, la fasciite plantaire, la pars planite, la sclérite, la kératite, l'inflammation de la glande de meibomius chronique, la névrite du nerf optique, l'uvéite, la papillite, la douleur neuronale diabétique, la rétinopathie diabétique, la cataracte, une inflammation postopératoire, un effet secondaire survenant après une chirurgie réfractive, un effet secondaire survenant après une greffe cornéenne, un effet secondaire survenant après une chirurgie de décollement rétinien, et des combinaisons de ceux-ci. L'administration de médicament traite la pathologie, réduit les symptômes de la pathologie, améliore la régénération nerveuse, empêche la formation de cicatrice, et/ou atténue la pathologie.
PCT/US2019/030931 2018-05-16 2019-05-06 Méthode de traitement, de réduction ou de soulagement d'une pathologie chez un patient Ceased WO2019221959A1 (fr)

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US201862672161P 2018-05-16 2018-05-16
US62/672,161 2018-05-16
US201862724769P 2018-08-30 2018-08-30
US62/724,769 2018-08-30
US201862780404P 2018-12-17 2018-12-17
US62/780,404 2018-12-17
US16/246,618 2019-01-14
US16/246,618 US11045352B2 (en) 2014-05-12 2019-01-14 Methods for treatment of dry eye and other acute or chronic inflammatory processes
US201962839738P 2019-04-28 2019-04-28
US62/839,738 2019-04-28

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CN112915090A (zh) * 2019-12-07 2021-06-08 王明武 用于治疗眼表疾病的一类化合物及其相关制剂和应用方法
US20210275624A1 (en) * 2020-03-06 2021-09-09 Allegro Pharmaceuticals, LLC Treatments for improving or lessening impairment of mitochondrial function
WO2022051728A1 (fr) * 2020-09-06 2022-03-10 The Schepens Eye Research Institute, Inc. Inhibition de la rho kinase pour le traitement de la vitréorétinopathie proliférative et d'états pathologiques associés à une transition épithélio-mésenchymateuse
ES2914617A1 (es) * 2020-12-11 2022-06-14 Univ Santiago Compostela Composición farmacéutica para su uso en el tratamiento de enfermedades inflamatorias
CN115867264A (zh) * 2020-06-01 2023-03-28 Ads医疗有限责任公司 局部眼科组合物和治疗异常血管新生的方法
CN115955965A (zh) * 2020-04-24 2023-04-11 拓比利亚欧斯特有限公司 用于治疗、改善或预防微生物感染的制造产品和方法
JP2023516932A (ja) * 2020-02-26 2023-04-21 ザ スクリプス リサーチ インスティテュート 抗炎症活性を有する低分子ｓｃｌ１５ａ４阻害剤
US11739326B2 (en) 2017-11-14 2023-08-29 Massachusetts Eye And Ear Infirmary RUNX1 inhibition for treatment of proliferative vitreoretinopathy and conditions associated with epithelial to mesenchymal transition
WO2024033640A1 (fr) * 2022-08-09 2024-02-15 Cambridge Enterprise Limited Dispositif médical
WO2025135087A1 (fr) * 2023-12-19 2025-06-26 株式会社デ・ウエスタン・セラピテクス研究所 Composition pharmaceutique pour prévenir/traiter une complication oculaire dans la maladie chronique du greffon contre l'hôte

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11739326B2 (en) 2017-11-14 2023-08-29 Massachusetts Eye And Ear Infirmary RUNX1 inhibition for treatment of proliferative vitreoretinopathy and conditions associated with epithelial to mesenchymal transition
CN112915090A (zh) * 2019-12-07 2021-06-08 王明武 用于治疗眼表疾病的一类化合物及其相关制剂和应用方法
JP7760513B2 (ja) 2020-02-26 2025-10-27 ザ スクリプス リサーチ インスティテュート 抗炎症活性を有する低分子ｓｌｃ１５ａ４阻害剤
JP2023516932A (ja) * 2020-02-26 2023-04-21 ザ スクリプス リサーチ インスティテュート 抗炎症活性を有する低分子ｓｃｌ１５ａ４阻害剤
US20210275624A1 (en) * 2020-03-06 2021-09-09 Allegro Pharmaceuticals, LLC Treatments for improving or lessening impairment of mitochondrial function
CN115605215A (zh) * 2020-03-06 2023-01-13 急速制药有限责任公司（Us） 改善或减轻线粒体功能损伤的治疗
CN115955965A (zh) * 2020-04-24 2023-04-11 拓比利亚欧斯特有限公司 用于治疗、改善或预防微生物感染的制造产品和方法
CN115867264A (zh) * 2020-06-01 2023-03-28 Ads医疗有限责任公司 局部眼科组合物和治疗异常血管新生的方法
US20230310446A1 (en) * 2020-09-06 2023-10-05 The Schepens Eye Research Institute, Inc. Rho kinase inhibition for treatment of proliferative vitreoretinopathy and conditions associated with epithelial to mesenchymal transition
WO2022051728A1 (fr) * 2020-09-06 2022-03-10 The Schepens Eye Research Institute, Inc. Inhibition de la rho kinase pour le traitement de la vitréorétinopathie proliférative et d'états pathologiques associés à une transition épithélio-mésenchymateuse
WO2022123102A1 (fr) * 2020-12-11 2022-06-16 Universidade De Santiago De Compostela Composition pharmaceutique destinée à être utilisée dans le traitement de maladies inflammatoires
ES2914617A1 (es) * 2020-12-11 2022-06-14 Univ Santiago Compostela Composición farmacéutica para su uso en el tratamiento de enfermedades inflamatorias
WO2024033640A1 (fr) * 2022-08-09 2024-02-15 Cambridge Enterprise Limited Dispositif médical
WO2025135087A1 (fr) * 2023-12-19 2025-06-26 株式会社デ・ウエスタン・セラピテクス研究所 Composition pharmaceutique pour prévenir/traiter une complication oculaire dans la maladie chronique du greffon contre l'hôte

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