Classifications

• • 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
  • A61K9/0021—Intradermal administration, e.g. through microneedle arrays or needleless injectors
• • 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
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
• • 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
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/26—Glucagons
• • 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
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/28—Insulins
• • 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
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
  • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
  • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
  • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
  • A61M2037/0023—Drug applicators using microneedles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
  • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
  • A61M2037/0046—Solid microneedles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
  • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
  • A61M2037/0061—Methods for using microneedles

Definitions

• This invention relates to the treatment of diabetes, obesity, and related conditions. Particularly, this invention relates to drug-device core-shell microneedle devices containing antidiabetes and anti-obesity medications, and transdermal delivery of said medications.
• Diabetes and its related complications continue to increase worldwide due to demographic changes, improper dietary control, and other risk factors. Uncontrolled diabetes leads to cardiovascular, renal, cognitive, and neurodegenerative disorders; peripheral and autonomic neuropathy; depression; nonalcoholic steatohepatitis (NASH); erectile dysfunction (ED); arthritis; and bone loss, among other complications.
• Some of the most effective medications for the treatment of diabetes include peptide hormones that are involved in blood glucose regulation and appetite regulation. Peptide hormones are produced in glands and in several other tissues including the stomach, the intestine, the brain, and carry information from one tissue through the blood to another.
• Peptide hormones that are involved in blood glucose regulation include insulin, secreted by pancreatic beta cells; amylin, co-secreted with insulin from pancreatic beta cells; glucagon, secreted by the pancreatic alpha cells; incretin hormones such as glucagon-like-peptide-1 (GLP- 1), secreted by the intestinal L cells; and glucose dependent insulinotropic polypeptide (GIP), secreted by the intestinal K cells.
• GLP-1 glucagon-like-peptide-1
• GIP glucose dependent insulinotropic polypeptide
• GLP-1 receptor belongs to Family B 1 of the seven transmembrane G-protein coupled receptors (GPCRs). Its natural agonist ligands are glucagon and the related peptide hormone, GLP-1, which is involved in glucose homeostasis.
• GLP-1R receptor agonists represent one the most effective FDA-approved drug classes for the treatment of diabetes and obesity, and are currently administered as injectables once daily (Liraglutide), twice daily (Exenatide), or once weekly (Semaglutide, Dulaglutide and Exenatide LAR) [4], Semaglutide is now available as the first oral GLP-1RA medication approved by the FDA for the treatment of type-2 diabetes. Other oral GLP-1RA drugs are under development.
• GLP-1RA/GIP Trirzepatide
• GLP-1 RA/Glucagon Tritadutide
• GLP-1 RA/GIP/Glucagon triple agonist combination
• an amylin analog, Cagrilintide is under development alone and in combination with Semaglutide [6, 7]
• GIP GIP alone has not been marketed as a drug to date. Despite being a potent incretin hormone and powerfully stimulating insulin secretion during meal intake, it also contributes to the development of body fat by enhancing deposition of fat in the adipose tissues [8], Furthermore, GIP loses its insulinotropic effect in diabetic individuals and may be diabetogenic because it retains a stimulatory effect on glucagon secretion [8], However, the GIP receptor (GIPR) knockout mice develop resistance toward diet induced obesity, and people with inactivating mutations of GIP receptor show reduced body weight [9], Recently, a composition comprising a monoclonal antibody directed against the human and/or the murine GIPR conjugated with GLP-1RA was shown to reduce body weight and improve metabolic parameters in mice and monkeys [70], In addition, said compositions have a long duration of action that renders them suitable for at least weekly use.
• GIPR GIP receptor
• GLP-lRAs such as once daily, high dose liraglutide (Saxenda) and once weekly high dose Semaglutide (Wegovy) have been approved for the treatment of obesity. Further, specific GLPl-RA’s such as semaglutide and dulaglutide are FDA approved for prevention of cardiovascular disease [72, 73].
• Dulaglutide is also showing promise for the prevention of progression of chronic kidney disease [74] and erectile dysfunction [75], Furthermore, pramlintide, the analogue of peptide hormone, amylin is FDA-approved not only for the treatment of typel and type 2 diabetes but is also being investigated for weight loss, either alone or in combination with other peptide hormones such as GLP-1RA [76, 77], Preliminary efficacy data with double and triple peptide combinations such as GLP-1RA/GIP, GLP-1 RA/Glucagon, GLP- 1 RA/GIP/Glucagon combinations are very promising, and these combinations are currently under FDA review for the treatment of diabetes, obesity [18-20], and NASH [27], Type 2 diabetes has been identified as a major risk factor for the development of Alzheimer’s disease.
• Bariatric surgery is also indicated for individuals with a BMI over or equal to 35 and at least one or more obesity related co-morbid conditions such as type 2 diabetes, hypertension, hyperlipidemia, sleep apnea and other respiratory disorders, non-alcoholic fatty liver disease, debilitating arthritis or considerably impaired quality of life, GERD, venous stasis disease, and cardiovascular disorders.
• Other candidates for bariatric surgery include patients with a BMI of 30 to 34.9 with diabetes or metabolic syndrome.
• Microneedle patches incorporating small molecule drugs or biologies have advantages over conventional hypodermic needles for delivery of these medications [25], Insulin is very effective in lowering blood glucose levels, and recent advances in insulin therapy resulted in once weekly basal insulin such as Insulin ICODEC, which allows for once weekly dosing at clinically relevant doses. Further, Insulin ICODEC was shown to be safe and well -tolerated with favorable half-life of about 196 hours [26], Zhou et al. [27] provide a comprehensive review of delivery of insulin using microneedles. Many microneedle systems for insulin delivery are under clinical trials, but none thus far have been introduced into the market.
• microneedle patch system specific system for transdermal delivery of specific medication depends on many physicochemical properties of both the patch system and the medication. These properties include molecular structure, topology, charge, membrane permeability (which is related to lipophilicity of said medication), and adhesion property between of the medication and the microneedle patch. Most of the current microneedle platforms deliver drugs and biologies either via bolus or sustained release without any modulation. Other technologies employing hollow microneedles do provide a micro-infusing system, but require an external drug reservoir placed on the skin or on portable devices.
• SEAL system has been shown to create different polymeric layers that often results in the formation of a thick scum residual layer which requires a manual, inconsistent and slow removal process using scotch-tape and oxygen plasma.
• One of the earliest and most commonly used and effective treatment for diabetes is injectable insulin or insulin derivatives.
• the new microneedle patch system conceived and developed by us [28], and which are incorporated herein by reference in its entirety, overcomes the aforementioned problems, and enables the delivery of drugs and biologies in a programmable, pulsatile manner.
• microneedle patch system for the delivery of anti-diabetes and anti-obesity medications.
• We [28, 29] and others [30] have provided general method for the design and fabrication of microneedle patches. It should be emphasized, however, that the design and development of microneedle system incorporating various drugs and biologies depends on the molecular weight, size, in vitro and in vivo stability, adhesion properties, release kinetics from microneedle, pharmacokinetics, membrane permeability, and the like that are not accurately predictable from the prior art. Development of optimal microneedle delivery systems for anti-diabetes and anti-obesity medications require considerable effort and cannot be ascertained from any of the prior art disclosures without undue experimentation.
• the present invention particularly relates to a drug/device combination for a controlled, singly-administered, and therapeutically effective transdermal delivery of medications for the treatment of diabetes, obesity, and diabetes/obesity associated conditions including, but not limited to vascular disease (small and large vessel disease), NASH, hyperlipidemia, peripheral neuropathy, chronic kidney disease, erectile dysfunction, depression, or dementia.
• this invention relates to a specialized, clinically acceptable biodegradable core-shell microneedle drug-device ensemble for programmable pulsatile delivery of GLP-1RA agents such as Exenatide, Semaglutide, Liraglutide, Dulaglutide, Lixisenatide, albiglutide, and the like, alone or in combination with peptide hormones such as glucagon, GIP, amylin, leptin, CCK, OXM, PYY, PP and the like.
• the present invention also relates to the transdermal, pulsatile delivery of therapeutically effective peptide hormones alone or in combination, with GLP-1RA, for the treatment of diabetes, obesity, and diabetes/obesity associated conditions.
• the phrase "therapeutically effective amount" of the compound of the invention means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
• the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated, the severity of the disorder; activity of the specific compound employed; the specific composition employed, age, body weight, general health, sex, diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed, and the duration of the treatment.
• the microneedle drug-device system of the present invention comprises following components (Figs. 1 and 2): (a) a two-dimensional array of conical bilayer (referred to a ‘coreshell’) containing an inner layer with the base diameter ranging from about 100 pm to about 500 pm and the height ranging from about 100 pm about 1200 pm capable of accommodating a known amount of anti -diabetes and/or anti -obesity medications, (b) a larger outer layer that adheres to and encapsulates the inner layer, and protects the inner layer, and (c) a two-dimensional array of cylindrical ‘cap layer’ that aligns with and adheres to the basal surface of core shell bilayer and seals the bilayer to prevent leakage of said medication(s).
• the apical (i.e., sharp) ends of the conical bilayer array inserts into the skin and are programmed to allow the said medications to effuse out of the bilayer and into the skin in a controlled fashion (Fig. 3).
• the core-shell microneedle drug-device system of the present invention would be fully inserted inside the skin and then release the anti-diabetes and/or anti-obesity medications as sharp bursts (boluses) in a predictable, programmed, and controlled manner with a single administration.
• This one-time application of the microneedle drug-device patch on skin is an easy-to-use, painless method for delivering anti-diabetes and anti-obesity medications repeatedly over a long period of time.
• the frequency of use of the microneedle patch can vary according to the medical conditions of the individual and can be increased or decreased.
• the present invention enhances patient compliance and adherence to treatment by setting a one-time dissolvable micro-needle patch administered every week or customized to be administered every 2, 3, 4, or up to 12 weeks or potentially even over 24, 36, 48 or 52 weeks and beyond.
• the programmable microneedle system eliminates repetitive and painful injections experienced with conventional administrations.
• FIG. 1 Fabrication of microneedle: hollow outer layer.
• Figure 2 Fabrication of microneedle: drug-filled inner layer.
• Figure 4 Complete exenatide microneedle patch system.
• Figure 5 Release profile of exenatide from the microneedle patch in vivo.
• Figure 6 Release profile semaglutide, from the microneedle patch in vivo.
• the present invention relates to the controlled, pulsatile, delivery of effective amounts of anti-diabetes and/or anti-obesity peptide hormones via transdermal microneedle system comprising:
• a biodegradable polymeric ‘outer layer’ fabricated as a two-dimensional array of plurality of hollow, conical microneedles with the base diameter ranging from about 100 pm to about 500 mm and the height ranging from about 100 pm about 1200 pm that adheres to and fully encapsulating an inner layer (Fig. 1), wherein said biodegradable polymer includes, but not limited to polyglycolic acid (PGA), polylactic acid (PLA), or polylactic-glycolic acid (PLGA); and wherein said outer layer protects the inner layer;
• PGA polyglycolic acid
• PLA polylactic acid
• PLGA polylactic-glycolic acid
• a biodegradable polymeric ‘inner layer’ fabricated as a two-dimensional array of plurality of conical drug-containing microneedles with the base diameter ranging from about 100 pm to about 500 mm and the height ranging from about 100 pm about 1200 pm, wherein said drugcontaining microneedles are loaded with anti-diabetes and/or anti-obesity peptide hormones (Fig. 2), and wherein said biodegradable polymer includes, but not limited to polyglycolic acid (PGA), polylactic acid (PLA), or polylactic-glycolic acid (PLGA); and
• biodegradable polymeric ‘cap layer’ fabricated as a two-dimensional array of plurality of cylindrical discs with the base diameter ranging from about 100 pm to about 500 pm and the height ranging from about 100 pm about 500 pm that aligns with and adheres to the basal surface of said inner and outer layers (Fig. 3), wherein said biodegradable polymer includes, but not limited to polyglycolic acid (PGA), polylactic acid (PLA), or polylactic-glycolic acid (PLGA).
• PGA polyglycolic acid
• PLA polylactic acid
• PLGA polylactic-glycolic acid
• One embodiment of the present invention is related to the drug-device microneedle patch system wherein said inner layer is filled with a peptide hormone related to diabetes, obesity, and associated comorbidity.
• Another embodiment of the present invention is related to the drug-device microneedle patch system wherein said inner layer is filled with anti-diabetes medication.
• Another embodiment of the present invention is related to the drug-device microneedle patch system wherein said inner layer is filled with anti-obesity medication.
• Another embodiment of the present invention is related to the drug-device microneedle patch system wherein said inner layer is filled with GLP-1RA ligands.
• Another embodiment of the present invention is related to the drug-device microneedle patch system wherein said inner layer is filled with GLP-1RA ligands, including but not limited to exenatide, liraglutide, semaglutide, dulaglutide, lixisenatide, or albiglutide.
• GLP-1RA ligands including but not limited to exenatide, liraglutide, semaglutide, dulaglutide, lixisenatide, or albiglutide.
• Another embodiment of the present invention is related to the drug-device microneedle patch system wherein said inner layer is filled with anti-obesity medication.
• Another embodiment of the present invention is related to the drug-device microneedle patch system wherein said inner layer is filled with GIP, amylin, leptin, ghrelin, CCK, OXM, PYY, or PP.
• Another embodiment of the present invention is related to the drug-device microneedle patch system wherein said inner layer is filled with GIPR antibody alone or in combination with GLP-1RA ligands.
• Another embodiment of the present invention is related to the drug-device microneedle patch system wherein said inner layer is filled with antihyperlipidemic molecule GLP- 1RA/PCSK9 inhibitor.
• Another embodiment of the present invention is related to the drug-device microneedle patch system wherein said inner layer is filled with any combinations of the peptide hormones listed in paragraphs [0024] and [0026],
• GLP-1RA/GIP and other related combinations which are single dose injectables, have been shown effective for the treatment of diabetes and obesity.
• the microneedle patch of the present invention is purported to release these medications not only on a weekly basis up to 4 weeks (fig.6).
• Said patch is applied to the skin resulting in a weekly or monthly GLP-1RA drug release, and potentially over 12-weeks and beyond resulting in glycemic control and weight loss.
• the patch is also useful for the treatment of obesity even in non-diabetic individuals as several GLP-lRAs such as semaglutide and liraglutide were approved by the FDA for that purpose.
• the drug delivery system according to the present invention provides a one-time administration of several dosages which are programmed to release at predictable time points.
• the core-shell microneedle drug/device ensemble of the present invention overcomes the aforementioned SEAL limitations in fabrication, provides a minimally invasive approach, and allows for self-administration. Microneedles are, therefore, an appealing delivery approach to enable one-time, painless, and effective administration of anti-diabetes/anti-obesity medications to replace multiple injections in the conventional process.
• the microneedles are fabricated from FDA approved materials (e.g., Poly(D,L-lactide-co-glycolide) (PLGA), poly-lactide acid (PLA) that are commonly used for drug delivery, medical devices, etc.
• FDA approved materials e.g., Poly(D,L-lactide-co-glycolide) (PLGA), poly-lactide acid (PLA) that are commonly used for drug delivery, medical devices, etc.
• a biodegradable two-dimensional polymer film made PGA, PLA, PLGA, and the like is compression-molded into a pre-fabricated negative mold containing an array of conical cavities.
• a separate positive two-dimensional hydrophobic PLA mold with a smaller conical dimension but with an identical array than the negative mold is aligned by a custom-built alignment system and impinged into the microneedles entrapped inside the negative PDMS mold at elevated temperature, typically about 50-100 °C.
• This subtractive process creates conical dimple-like structures which serve as the microneedle.
• the shell with empty outer layer of the present invention containing two-dimensional array of microneedle is obtained and is trapped inside the negative PDMS mold.
• a second negative two-dimensional PDMS mold having the same structure and spacing as the outer layer, but slightly smaller cone dimensions, is prepared in the similar manner as first negative PDMS mold. Thereafter, a solution of drug or biomolecules of interest in a solution of aqueous polyvinylpyrrolidone (PVP) prepared, and the entire mixture is solution-casted (i.e. not filled into each micro-well of the mold) onto to the second PDMS mold and allowed to dry to obtain the drug-filled microneedle inner layer.
• PVP polyvinylpyrrolidone
• the drugs can also be dissolved inside just a water based solution containing excipients such as trehalose or sucrose which can stabilize the drug and form a solid matrix drug-core after molding process.
• micro-molded drug array cores are then aligned and loaded into arrays of empty microneedle outer layer.
• This single-step and high- throughput loading allows drugs to fill the entire volume of the microneedle cores, thereby significantly increasing the loading consistency and efficiency.
• this method also does not use any organic solvents or high temperature, thereby providing a gentle process to avoid potential damage to the drug bioactivity.
• this fabrication process introduces a new method for scum removal (i.e. residual layer after each molding) by rapidly spinning PDMS molds while gently adding appropriate solvents on top of the molds to remove hydrophobic polymers or water to remove hydrophilic drugs.
• the two-dimensional cap layer was fabricated in the similar manner of compression molding and scum removal described for the outer and inner layers, except that the cavities in negative PDMS mold are cylindrically-shaped.
• a polymer film of PLGA or PLA was compression molded into PDMS mold of the caps and supporting array, respectively.
• the supporting array was transferred to a glass substrate and further coated with a water-soluble polymer solution of PVP K30 in ethanol (0.2 g/ml), then air-dried for 24 hours.
• the cap layer is then aligned with the drug- filled inner layer encapsulated by the outer layer and sintered using heat.
• the core-shell microneedles are capped and transferred onto a PVP coated PLA supporting array.
• the supporting array is pre-coated with a water-soluble polymer (PVP) which can be dissolved by local bodily fluid at the site of insertion to release the drugs/vaccines into the skin.
• PVP water-soluble polymer
• the mold entrapping the core-shell microneedles is then peeled off to yield free-standing core-shell microneedles on the supporting array.
• core-shell microneedle drug-device system for anti-diabetes or anti-obesity medications are described below. It is to be understood, however, that the invention is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the drawings. As would be apparent to skilled artisans, various modifications in the composition, operation, and method are possible, and are contemplated herein without departing from the concept and scope of the invention as defined in the claims.
• Example 1 Exenatide core-shell microneedle patch system
• Step 1 Fabrication of microneedle outer layer.
• Poly(D,L-lactide-co-glycolide) (PLGA) (MilliporeSigma and Polysciences, Inc., USA) was dissolved in acetone (20% w/v) and casted as a film on a Teflon-coated petri dish. The film was then lyophilized for complete removal of the organic solvent. A sufficient amount of PLGA film was placed between the PDMS mold and a Teflon film which sat on two glass slides. Then the polymer was compression molded under a binder clip in the vacuum oven at 60 °C for 1-2 hours depending on the polymer properties.
• PLGA Poly(D,L-lactide-co-glycolide)
• a positive mold made from Poly-lactide acid (PLA) (NatureWorks, USA) was fabricated by compression molding PLA pellets into the PDMS mold at 180 C under vacuum for 2 hours. The PLA mold was then transferred onto a glass slide. This second mold, which has smaller dimensions and the same relative spacing, was aligned using a custom-built alignment device, then pressed into the needles which had been heated prior to this process. At an elevated temperature, the second mold would penetrate into the polymer, creating dimple-like structures. After peeling off the second mold, a two-dimensional array of hollow conical microneedle outer layer embedded inside the PDMS mold was obtained.
• PLA Poly-lactide acid
• Step 2 Fabrication of exenatide-filled microneedle inner layer.
• a second negative PDMS mold having identical two-dimensional array of conical cavities, but with a smaller cone dimensions than the first negative mole in Step 1, was prepared by the same procedure described in Step 1.
• a two-dimensional PLGA film was then compression molded and impinged with a positive mold to give a two-dimensional array of conical hollow microneedles.
• the scum layer was then removed by high velocity spinning accompanied with addition of water or organic solvent such as acetone.
• Acetyl-Exenatide trifluoroacetate 0.5 mg was dissolved into 1 mL of purified water with the desired final concentration, and the entire mixture is solution-casted onto to the PDMS mold and allowed to dry.
• the scum layer was removed spinning and addition of distilled water.
• the scum- free drug-filled inner layer was then transferred onto a sacrificial layer comprising a solid polymer film of PLGA, placed on top of the mold, and compressed at the glass transition temperature under vacuum.
• the entire drug-filled inner layer was delaminated onto a solid substrate, such as a glass slide, using heat-assisted micro-transfer molding.
• the exenatide-filled inner layer was then aligned with and immersed into the outer layer in Step 1 resulting in the attachment of the two layers.
• Step 3 Fabrication and attachment of the cap-layer to the core-shell.
• the cap layer and supporting array for the core-shell microneedles were fabricated using the same procedure in Step 1 .
• a polymer film of PLGA or PLA was compression molded into PDMS mold of the caps and supporting array, respectively.
• the supporting array was transferred to a glass substrate and further coated with a water-soluble polymer solution of PVP K30 in ethanol (0.2 g/ml), then air-dried for 24 hours.
• the two-dimensional cap layer and the supporting layer were aligned with the inner and outer layers in Step 2 and sintered using heat.
• the entire exenatide-microneedle drug-devices system (patch) is detached (peeled off) from the mold.
• the resulting system is then used as the patch for transdermal delivery of exenatide.
• Example 3 Semaglutide core-shell microneedle patch system
• Step 1 Fabrication of PDMS mold.
• the Semaglutide powder was purchased form the Adipogen Pharmaceutical, USA.
• Poly lactic-co-glycolic acid (PLGA) was purchased from the Polysciences inc., USA.
• PVP was purchased from the Thermo Fisher Scientific Inc., USA.
• Semaglutide Elisa assay kit was purchased from Creative Diagnostic Inc., USA. All other utilized chemical were analytical grades.
• the master structures of core, shell, array, and cap were replicated by curing PDMS on wafers.
• the mixture of the PDMS base and curing agent (Sylgard 184, Dow Coming) at a ratio of 7: 1 was poured onto the wafers and then degassed under a vacuum for at least 1 h before curing in the room temperature for overnight. The PDMS molds were then gently peeled off from the silicon wafers and used for later fabrication process.
• Step 3 Fabrication of shell microneedles.
• the shell of the MNs was fabricated by using different kind of PLGA into 700 pm Shell molds and superficial layer of PLGA was removed by using acetone. PVP core were aligned into Shell by heating method.
• Step 4 Fabrication of microneedle caps and supporting array.
• the supporting array for the coreshell microneedles were fabricated following similar procedures of compression molding and scum removal.
• the supporting array was fabricated from water-soluble polymer solution of PVP K30 in ethanol (0.2 g/mL), sodium bicarbonate, and citric acid mixture.
• PLA was used as a backing layer for array.
• the caps that were made from PLGA and trapped inside the PDMS mold were aligned with the P VP-coated PLA supporting array and sintered using heat. These MNs were further processed for various other analysis.
• effervescent rray were attached to coreshell to form the complete MNs patch.
• Example 3 The semaglutide microneedle patch in Example 3 was placed in phosphate-buffered saline (PBS) (0.1 M) solution at pH 7.3 and the effusion of drug was monitored by HPLC. The result shown in Fig. 6 indicates that Semaglutide can be programmed to be released over a 27-day period.
• PBS phosphate-buffered saline
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is filled with liraglutide.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is fdled with dulaglutide.
• Microneedle patch is fabricated in a nearly identical manner as described in Example
• Step 3 the inner layer is fdled with Amylin.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is fdled with GIP.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is fdled with leptin.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is fdled with ghrelin.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is fdled with CCK.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is fdled with OXM.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is fdled with PYY.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is fdled with PP.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is fdled with exenatide and GIP.
• Example 16 (Prophetic) Exenatide-amylin core-shell microneedle patch system.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is filled with exenatide and amylin.
• Example 17 (Prophetic) Exenatide-1 eptin core-shell microneedle patch system.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is filled with exenatide and leptin.
• Example 18 Liraglutide-GIP core-shell microneedle patch system.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is filled with liraglutide and GIP.
• Example 19 Liraglutide-amylin core-shell microneedle patch system.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is filled with liraglutide and amylin.
• Example 20 Liraglutide-leptin core-shell microneedle patch system.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is filled with liraglutide and leptin.
• Example 21 Semaglutide-GIP core-shell microneedle patch system.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is filled with semaglutide and GIP.
• Example 22 Semaglutide-amylin core-shell microneedle patch system.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is filled with semaglutide and amylin.
• Example 23 Semaglutide-leptin core-shell microneedle patch system.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is filled with semaglutide and leptin.
• Example 24 Dulaglutide-GIP core-shell microneedle patch system.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is filled with dulaglutide and GIP.
• Example 25 Dulaglutide-amylin core-shell microneedle patch system.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is fdled with dulaglutide and amylin.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is fdled with dulaglutide and leptin.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is fdled with exenatide and ghrelin.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is fdled with exenatide and CCK.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is fdled with exenatide and OXM.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is fdled with exenatide and PYY.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is fdled with exenatide and PP.
• Semaglutide-ghrelin core-shell microneedle patch system Semaglutide-ghrelin core-shell microneedle patch system.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is fdled with semaglutide and ghrelin.
• Semaglutide-CCK core-shell microneedle patch system Semaglutide-CCK core-shell microneedle patch system.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is fdled with semaglutide and CCK.
• Semaglutide-OXM core-shell microneedle patch system Semaglutide-OXM core-shell microneedle patch system.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is fdled with semaglutide and OXM.
• Example 35 Prophetic
• Microneedle patch is fabricated in a nearly identical manner as described in Example
• Step 3 the inner layer is fdled with semaglutide and PYY.
• Semaglutide-PP core-shell microneedle patch system Semaglutide-PP core-shell microneedle patch system.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is fdled with semaglutide and PP.
• Microneedle patch is fabricated in a nearly identical manner as described in Example
• Step 3 the inner layer is fdled with liraglutide and ghrelin.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is fdled with liraglutide and CCK.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is fdled with liraglutide and OXM.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is fdled with liraglutide and PYY.
• Microneedle patch is fabricated in a nearly identical manner as described in Example
• Step 3 the inner layer is fdled with liraglutide and PP.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is fdled with dulaglutide and ghrelin.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is fdled with dulaglutide and CCK.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is fdled with dulaglutide and OXM.
• Microneedle patch is fabricated in a nearly identical manner as described in Example
• Step 3 the inner layer is fdled with dulaglutide and PYY.
• Microneedle patch is fabricated in a nearly identical manner as described in Example 1, except that in Step 3, the inner layer is fdled with dulaglutide and PP.
• Lu et al. GIPR antagonist antibodies conjugated to GLP-1 peptide are bispecific molecules that decrease weight in obese mice and monkeys. Cell Rep. Med. 2021, 2, 100263-1-100263-17.

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