Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • 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
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
  • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• • 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
• • 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
  • A61K9/7007—Drug-containing films, membranes or sheets

Definitions

• This application relates to drug delivery systems comprising thin films configured for administration to the ocular mucosa.
• the application also relates to methods employing thin films for delivering at least one pharmaceutically active agent to ocular locations in a subject.
• Treatment of many ocular conditions or performance of ophthalmic procedures requires the topical application of drugs or other compositions to ocular tissue.
• drugs or other compositions for example, treatment of acute or chronic ocular conditions may require application of antibiotics, steroids, non-steroidal anti-inflammatory drugs (NSAIDs), or other medications to the eye.
• NSAIDs non-steroidal anti-inflammatory drugs
• ophthalmic procedures such as cataract surgery and intravitreal injections may require the delivery of anesthetics, antiseptics, emollients, mydriatics and/or other medicinal or non-medicinal agents to the eye, for example pre-procedure or postprocedure.
• the topical application of such compositions to the eye is often done using liquid drops.
• drawbacks to the conventional approach there are many drawbacks to the conventional approach.
• the need has therefore arisen for systems and methods for reliably, conveniently, and economically delivering pharmaceutically active agents to a subject’s eye in substitution for conventional drops.
• the need has particularly arisen for drug delivery systems employing thin films for reducing drug wastage, reducing wait time, increasing drug bioavailability or penetration, improving time-release of drugs, enhancing user comfort, reducing contamination risks and generally enabling more targeted delivery of optimum drug doses to the desired ocular locations.
• Some intraocular films or pellets known in the prior art are directed towards subconjunctival or episcleral drug delivery to the eye.
• a number of these prior art references comprise bioerodible devices.
• An aim of some of the prior art is to deliver pharmaceuticals to the posterior region of the eye from a subconjunctival or episcleral site, as opposed to local delivery of pharmaceuticals to a subconjunctival, episcleral or other ocular administration sites.
• the prior art is limited by the configuration, shape and colour of the drug delivery systems.
• One aspect of the invention provides a drug delivery system comprising a thin film configured for positioning at an ocular administration site of a subject for delivery of at least one pharmaceutically active agent to a target location at or near the administration site.
• the thin film is configured to comprise: (a) a first bioadhesive layer for adhering to a mucosal surface at the administration site; and (b) a second layer coupled to the first layer, wherein at least one of the first layer and the second layer comprises the at least one pharmaceutically active agent.
• Another aspect of the invention provides a method of delivering at least one pharmaceutically active agent to a target ocular location in a subject comprising providing a mucoadhesive film comprising the at least one pharmaceutically active agent; applying the film to a mucosal surface of an eye of the subject; and maintaining the film on the mucosal surface for a time period sufficient to enable delivery of the at least one pharmaceutically active agent to the ocular location.
• Another aspect of the invention relates to use of a thin film to deliver at least one pharmaceutically active agent to an ocular administration site in a subject.
• Figure 1 is a cross-sectional side view of an embodiment of a drug delivery system of the present invention comprising a multi-layer mucoadhesive film.
• Figure 2 is a perspective view of the drug delivery system of Figure 1 .
• Figure 3 is a cross-sectional side view of the drug delivery system of Figures 1 and 2 contacting a mucosal surface.
• Figure 4 is a cross-sectional view of another embodiment of a drug delivery system of the present invention comprising a multi-layer mucoadhesive film.
• Figure 5 is a perspective view of the drug delivery system of Figure 4.
• Figure 6 is a cross-sectional side view of the drug delivery system of Figures 3 and 4 contacting a mucosal surface.
• Figure 7 illustrates exemplary shapes of the mucoadhesive films of the present invention.
• Figure 8 is a perspective view of a drug delivery system comprising a packaging unit for supporting a mucoadhesive film.
• Figure 9 is a top plan view of a packaging unit for supporting a plurality of mucoadhesive films.
• Figure 10 illustrates exemplary ocular surfaces to which the drug delivery system of the present invention may be applied in regions of the eye and its substructures.
• Figure 11 is a top plan view of a packaging unit for supporting a plurality of mucoadhesive films wherein the films comprise different pharmaceutically active and/or non-medicinal agents.
• Figure 12 is a top plan view of a drug delivery system comprising a packaging unit for supporting a mucoadhesive film having a plurality of different portions comprising different pharmaceutically active and/or non-medicinal agents.
• Figure 13 is a top plan view depicting the film of Figure 12.
• Figure 14 is a cross-sectional side view of the drug delivery system of Figure 13.
• Figure 15 is a cross-sectional perspective view of the drug delivery system of Figure 13.
• the present invention relates to a drug delivery system comprising a dosage form suitable for in vivo administration to an administration site.
• the dosage form is a thin film positionable at the administration site for delivering at least one pharmaceutically active agent to a target location.
• the administration site is an ocular site in a subject’s eye and the target location is a location at or near the ocular site.
• the target location may be a portion of the subject’s eye in need of treatment and/or affected by an ophthalmic procedure.
• the subject may be a human being. In other embodiments the subject may be a non-human animal, for example in the case of veterinary applications.
• the film may be formulated for rapid, sustained and/or extended release of the at least one pharmaceutically active agent.
• the at least one pharmaceutically active agent may comprise a plurality of different pharmaceutical agents.
• the different pharmaceutical agents are delivered directionally, for example in a desired direction from the administration site toward a target location.
• the different pharmaceutical agents are delivered sequentially (in relation to one another) to a target location.
• the delivery of the different pharmaceutical agents is time-released.
• the at least one pharmaceutically active agent may be combined with other compounds, compositions or constituents which facilitate administration and use of the at least one pharmaceutical active agent but which do not necessarily have a medicinal effect.
• the non-medicinal agents or constituents may comprise emollients, mydriatic agents, lipid compounds, or other inactive or inert constituents, such as diluents, carriers, excipients or combinations thereof.
• the present invention encompasses systems, compositions, methods and uses for delivering non-medicinal agents or constituents to a target location, optionally in combination with at least one pharmaceutically active agent or separately therefrom.
• the thin films of the invention may be useful in other applications for treating conditions, disorders or diseases relating to, for example, urology, gastroenterology, gynecology and ENT (Ears, Nose and Throat).
• Other possible mucosal surfaces therefore include nasal, pharyngeal, oral, vaginal, urethral and anorectal mucosal surfaces.
• Bioadhesive layer 14 may comprise bioadhesive polymers selected to interact with mucosal membranes for extended periods of time by interfacial forces.
• Nonadhesive layer 16 may form a backer structure of film 12 and third layer 18 may form an intermediate layer disposed between layers 14 and 16 in a “sandwich” configuration.
• layers 14-18 may carry different pharmaceutically active agents or other non-medicinal agents or constituents.
• the outer layers 14 and 16 of film 12 may comprise emollients and/or anesthetics and intermediate layer 18 may comprise at least one pharmaceutically active agent, for example for treatment of an ocular disease or condition.
• ocular emollients may comprise artificial tears or other lanolin preparations and/or oleaginous ingredients and anesthetics may comprise one or more of tetracaine, alcaine or lidocaine.
• the pharmaceutically active or non-medicinal agents may include agents routinely included in clinical eye drops such as phenylephrine (adrenergic), mydriacyl (anti-cholinergic), lidocaine (amide anesthetic), tetracaine (ester anesthetics), CHX (aqueous chlorhexidine/antiseptics), povidone-iodine, emollients, and hyaluronic acid (artificial tears).
• agents routinely included in clinical eye drops such as phenylephrine (adrenergic), mydriacyl (anti-cholinergic), lidocaine (amide anesthetic), tetracaine (ester anesthetics), CHX (aqueous chlorhexidine/antiseptics), povidone-iodine, emollients, and hyaluronic acid (artificial tears).
• anti-inflammatories may include steroids such as one or more of difluprednate, loteprednol etabonate, prednisolone acetate, prednisolone sodium phosphate, rimexolone, fluoromethoIone acetate and fluoromethoIone alcohol, and non- steriodal anti-inflammatory drugs (NSAIDs) such as one or more of ketorolac tromethamine, bromfenac, nepafenac and diclofenac sodium.
• steroids such as one or more of difluprednate, loteprednol etabonate, prednisolone acetate, prednisolone sodium phosphate, rimexolone, fluoromethoIone acetate and fluoromethoIone alcohol
• NSAIDs non- steriodal anti-inflammatory drugs
• Anti-bacterials may include one or more of besifloxacin, ciprofloxacin, moxifloxacin, ofloxacin, gatifloxacin, tobramycin, gentamicin, polymyxin B, trimethoprim, gramicidin, neomycin, bacitracin, azithromycin and erythromycin.
• Antivirals may include one or more of acyclovir, ganciclovir, trifluridine and idoxuridine.
• Antifungals may include one or more of nystatin, natamycin, and amphotericin B.
• Azoles comprise one or more of ketoconazole, miconazole, fluconazole, itraconazole, econazole, clotrimazole, and voriconazole.
• Fluorinated pyrimidines include flucytosine.
• Antimetabolites may include one or more of methotrexate, mycophenolate mofetil (MMF), and azathioprine.
• Anti-histamines may include one or more of ketorolac tromethamine, ketotifen fumarate, loteprednol etabonate, bepotastine besilate, epinastine HCL, emedastine difumarate, alcaftadine, azelastine hydrochloride, olopatadine hydrochloride, nedocromil sodium, lodoxamide tromethamine and cromolyn sodium.
• T-cell inhibitors may include one or more of cyclosporine, tacrolimus, and sirolimus.
• Alkylating agents comprise one or more of cyclophosphamide and chlorambucil.
• Biologic agents may include one or more of tumor necrosis factor (TNF) inhibitors, lymphocycte inhibitors and interleukin inhibitors.
• Adrenergics may include phenylephrine.
• Anti-cholinergics comprise mydriacyl.
• Anesthetics may include one or more of lidocaine, alcaine and tetracaine.
• Antiseptics may include one or more of aqueous chlorhexidine (CHX) and povidone-iodine.
• Alpha- adrenergics may include one more of brimonidine and apraclonidine.
• Beta blockers include one or more of timolol, levobunolol and betaxolol.
• Carbonic anhydrase inhibitors may include one or more of brinzolamide and dorzolamide.
• Prostaglandins may include one or more of latanoprost, tafluprost, bimatoprost, and travoprost.
• many other pharmaceutically active agents may be suitable for ocular or non-ocular administration in addition to the foregoing non-limiting examples.
• thin film 12 may be placed in contact with a mucosal surface 20 at an administration site.
• thin film 12 may adhere to mucosal surface 20 by bioadhesive layer 14 contacting and associating with mucosal surface 20.
• the configuration of thin film 12 enables delivery of bioabsorbable elements comprising pharmaceuticals or pharmaceutically inactive constituents associated with first layer 14 and/or second layer 16 to mucosal surface 20 before the delivery of pharmaceuticals associated with film layer 18.
• film 12 may be configured so that film layers 14 and 16 comprise anesthetics and/or emollients which are delivered to or near the administration site (e.g. to mucosal surface 20).
• the one or more pharmaceutically active agents of layer 18 may then contact the mucosal surface 20 and disperse to the target location, for example to confer a local or systemic therapeutic effect.
• the thin film 12 may also be configured to deliver pharmaceutically active agents in a directional manner, for example in a unidirectional manner toward a target location.
• the direction of flow of the one or more pharmaceutically active agents is from the layer of origin of the one or more pharmaceutically active agents (e.g. one or more layers 14-16) to the mucosal surface 20.
• the outer layer (layer 16) causes the one or more pharmaceutically active agents to move unidirectionally toward the mucosal layer 20 and/or prevents exit of the one or more pharmaceutically active agents through layer 16.
• the outer layer (layer 16) contains adhesive, one or more pharmaceutically active agents or is inert. In some embodiments, when the eyelid of the subject closes, layer 16 will come into contact with a mucosal surface opposite to or in the vicinity of mucosal surface 20, for example a mucosal surface of the subject’s eyelid.
• Figures 4 and 5 illustrate another embodiment of multi-layer film 12 comprising a first layer 22 and a second layer 24.
• first layer 22 is a bioadhesive layer similar to bioadhesive layer 14 configured for placement in contact with a mucosal surface 20 and layer 24 is a second layer coupled to first layer 22 in a manner similar to layer 16.
• layer 22 may comprise at least one pharmaceutically active agent and layer 24 may comprise an inert, slow-dissolving pharmaceutically acceptable polymer which blocks or limits the dispersion of the at least one pharmaceutically active agent.
• slow-dissolving refers to relatively slower kinetics of solubilisation, degradation or erosion of layer 24 relative to layer 22 based on parameters such as composition or thickness of the respective layers.
• layer 24 partially encapsulates layer 22 to help direct dispersion of the at least one pharmaceutically active agent toward the target location.
• This configuration thus focuses delivery of the pharmaceuticals or other constituents associated with bioadhesive layer 22 to the mucosal site of application as described above and minimizes unwanted dispersion of pharmaceuticals or other constituents to other regions of the eye, for example the tarsal conjunctiva rather than the bulbar conjunctiva. This may have the effect of enhancing drug bioavailability at the target location and reducing drug wastage and possible unwanted side effects.
• the thin film of Figures 4 and 5 may contact a mucosal surface 20 through both first bioahesive layer 22 and second layer 24.
• at least part of layer 24 e.g. end portions thereof
• Another aspect of the invention provides for one or more dyes, colourants or inspecting agents to be impregnated in or associated with any or all layers comprising thin film 12.
• Such embodiments may be directed towards temporarily marking the ocular administration site of thin film 12 and/or the in vivo location (e.g. dispersion) of pharmaceutically active agents or other constituents.
• Such dyes, colourants and inspecting agents may include, for example, fluorescein, gentian violet, trypan blue, brilliant blue, indocyanine green, and infracyanine green. These dyes, colourants and inspecting agents may assist in determining which drug or other pharmaceutically active agent is used, the location where the drug has been administered and/or the tissue(s) affected.
• short duration dyes may be used to assess if the thin film is fully absorbed.
• immediate-to long-acting dyes e.g. 24hrs temporarily stain the site where the film is administered thereby aiding in visualizing the procedural or surgical site.
• thin film 12 may be shaped and sized to conform the contour of an ocular surface at the site of administration.
• ocular surface refers to regions of the eye and its substructures ( Figure 10) including but not limited to the lid margin 100, tarsal conjunctiva 110, fornix 120, bulbar conjunctiva 130, corneoscleral limbus 140, cornea 150, or a combination thereof.
• Figure 7 illustrates various possible shapes of thin films 12 conforming to different ocular surfaces, such as square, rectangular, circular, ovular, annular and crescent shapes.
• film 12 may include a footing or other structure for bearing film 12 against or otherwise seating film 12 relative to an ocular surface.
• a circular, annular or crescent-shaped film 12 may be suitable for positioning at a corneal or corneoscleral location
• a rectangular, square or oval-shaped film 12 may be suitable for positioning at a juxta-tarsal location.
• Additional non-limiting examples include a large ring for positioning around the cornea at the limbus, and a rectangular shape that can be positioned at the fornix. Variability in the shape of the thin film and its configuration (e.g. layers, height, length, thickness) allow for the tailored administration of one or more pharmaceutically active agents in a particular procedure, examination or treatment.
• the administration of one or more pharmaceutically active agents is titratable.
• the titration meets the clinical requirements of the procedure, examination or treatment through suitable shaping and/or configuration of the thin film.
• the thin film is shaped for drug delivery to a specific location of the eye (e.g. superotemporal bulbar conjunctiva, corneal, corneoscleral, forniceal, tarsal plate and the like).
• the shape and/or configuration of the thin film improves placement and speed of delivery of the one or more pharmaceutically active agents. Unlike conventional methods where eye drops may miss the target location of the eye or the timing of repeat drop installation is lengthy, in some embodiments the shape and/or configuration of the thin film provides for targeted, quick and accurate drug delivery.
• variable dosages or durations may be modulated by varying the number and/or thickness of the layers (e.g. layers 14-16; layers 22-24) comprising thin film 12, the properties of the pharmaceutically acceptable polymers comprising the layers of film 12, and/or the concentration of the bioabsorbable elements such as the at least one pharmaceutically active agent and other non-medicinal or inactive agents associated with the layers comprising thin film 12.
• the bioabsorbable elements associated with thin film 12 are therefore titratable to treatment requirements.
• thin film 12 may be configured to rapidly dissolve to allow for focused and localized delivery of an associated bioabsorbable element (e.g. to minimize dispersion), or configured to dissolve slowly to allow for release of a bioabsorbable element in a diffuse manner and over a longer duration.
• an associated bioabsorbable element e.g. to minimize dispersion
• Thin films of the present invention can be prepared by numerous methods known in the art. The selection and use of suitable film-forming mucoadhesive polymers would be readily apparent to a person skilled in the art having regard to prior publications in this field and common general knowledge: e.g.
• thin films for controlled drug delivery may be prepared using a polymer or combination of polymers, such as hydroxypropyl methycellulose (HPMC), polyvinyl pyrrolidone (PVP), sodium carboxymethylcellulose (CMC), polyvinyl alcohol (PVA) and hyaluronic acid (HA).
• HPMC hydroxypropyl methycellulose
• PVP polyvinyl pyrrolidone
• CMC sodium carboxymethylcellulose
• PVA polyvinyl alcohol
• HA hyaluronic acid
• the film forming technique may, for example, be solvent casting or electrospinning.
• the ratio of the polymers may be selected to optimize mucoadhesive, residence time, flexibility or other properties of the films.
• the durability of the films may be enhanced by post-casting modifications, such as crosslinking.
• the flexibility of the films may be optimized by adding plasticizers, such as glycerol and polyethylene glycol.
• the release profile of the active ingredients may also be optimized.
• drug delivery system 10 may further comprise structures for supporting, storing and/or administering films 12.
• such structures may comprise packaging units 30 for receiving one or more films 12 prior to administration.
• thin film 12 may be attached to or associated with a packaging unit 30 comprising a substrate 32.
• substrate 32 may comprise an inert paper or non-medicated mucoadhesive strip and a thin film 12 may be positioned at an end portion thereof (medicated tip) to form a composite medicated strip 34.
• drug delivery system 10 is configured in this embodiment to facilitate storage of thin film 12 and/or deployment of film 12 at an administration site when desired.
• a user can manually handle and deploy drug delivery system 10 by holding or otherwise engaging substrate 32 of medicated strip 34 and applying film 12 to a mucosal surface 20.
• thin film 12 separates from substrate 32 when placed on a mucosal surface, thereby applying film 12 without direct handling or manipulation thereof.
• film 12 and substrate 32 may be packaged as an individual strip 34 or as multiple strips 34, and may be packaged in a sterile or semi-sterile format.
• the drug delivery system and/or its packaging is in a sterile or semi- sterile format.
• the drug delivery system and/or its packaging has improved storage.
• the drug delivery system and/or packaging for example, is easier to store than conventional treatments (e.g.
• the drug delivery system and/or its packaging is stored without the need for refrigeration (e.g. at room temperature). Unlike conventional methods (e.g. eye drops) where repeated use of containers may introduce microbes, in some embodiments, the drug delivery system and/or its packaging of the invention is not susceptible to contamination. This provides for a reduction or elimination of preservatives and decontaminants in the drug delivery system and/or its packaging. It also reduces the costs of discarding product in the case where an applicator (e.g. eye dropper bottle) comes in contact with a patient’s ocular surface or eyelash. In some embodiments, the drug delivery system and/or its packaging is light weight (e.g. containing little water) compared to conventional treatments (e.g. eye drops) and is therefore easier and less costly to transport.
• drug delivery system 10 may comprise a series of medicated strips 34, each comprising a thin film 12 and substrate 32, applied to an inert backer sheet 36.
• medicated strip 34 comprising thin films 12 may be arranged on backer sheet 36 in a stacked or parallel array.
• each medicated strip 34 is separated from adjacent strips 34 by perforations.
• individual medicated strips 34 are removed from backer sheet 36 by manually holding or otherwise engaging a substrate 32 and separating the selected medicated strip 34 from adjacent strips 34 along the perforation lines and removing the selected medicated strip 34 from the backer sheet 36.
• the selected medicated strip 34 can then be used as described above to apply thin film 12 at an administration site.
• the medicated strips 34 may be packaged in a sterile or semi-sterile format to avoid or limit risk of contamination of film 12.
• drug delivery system 10 comprises a plurality of medicated strips 34 arranged in an array
• at least some strips 34 of the array may comprise different pharmaceutically active agents (e.g. medications) or non-medicinal agents than other strips 34 of the array. This may enable easy administration of multiple pharmaceutically active agents or other preparations in sequence or in combination.
• drug delivery system 10 may comprise a stacked array of multiple medicated strips 34 comprising (1 ) an anesthetic (e.g. lidocaine); (2) a mydriatic agent (pupil dilator); and (3) fluorescein/emollient.
• drug delivery system 10 may comprise a packaging unit 30 for supporting a plurality of films 12 wherein the films 12 may comprise different pharmaceutically active and/or non-medicinal agents.
• the films 12 are arranged in a side- by-side array in this example.
• the strips 34 could be removed from the packaging unit sequentially and the respective films 12 could be administered sequentially as discussed above as part of a clinical or surgical procedure and/or ocular treatment.
• a packaging unit 30 may be configured so that strips 34 and the respective films 12 relate to a particular procedure and/or therapy.
• a packaging unit 30 could comprise a one thin film 12 for use before an ophthalmic procedure (pre-procedure) and one thin film 12 for use after an ophthalmic procedure (post-procedure).
• Figure 12 illustrates an example embodiment of a drug delivery system 10 comprising a packaging unit 30 comprising a single medicated strip 34 supporting a thin film 12.
• film 12 may comprise a plurality of portions or sub-films 12A, 12B and 12C each optionally comprising different pharmaceutically active and/or non-medicinal agents.
• the portions 12A, 12B and 12C may be arranged side-by-side ( Figures 12 - 15). In other embodiments portions 12A, 12B and 12C may partially or entirely overlap.
• film 12 may be configured so that one or more layers 14-18 comprise a plurality of portions or sub-layers.
• third layer 18 may comprise a plurality of portions or sub-layers 18A, 18B and 18C each optionally comprising different pharmaceutically active and/or non-medicinal agents.
• portions 18A, 18B and 18C are arranged side- by-side.
• portions 18A, 18B and 18C may partially or entirely overlap, for example to form a tiered layer 18.
• each portion 18A, 18B and 18C may comprise different pharmaceutically active and/or non-medicinal agents configured for combined or sequential release at the site of administration.
• a drug delivery system 10 may comprise a plurality of stacked films 12 wherein the films 12 may each optionally comprise different pharmaceutically active and/or non-medicinal agents.
• each film 12 may comprise a respective third layer 18 comprising a different portion 18A, 18B or 18C having a different size and/or make-up.
• each thin film 12, including respective layers 18A, 18B and 18C, in the stacked array is of a different length and may comprise a correspondingly different amount of a pharmaceutically active and/or non-medicinal agent.
• some or all of the films 12 in the stacked array may be the same length.
• layers 18A, 18B and 18C are separated by intervening layers 14 but other configurations are possible.
• a drug delivery system 10 for example in the form of a thin film 12 or a medicated strip 34 comprising a film 12, may be deployed at the administration site with a separate instrument, such as a hand-held applicator.
• a separate instrument such as a hand-held applicator.
• a disposable, moistened “Dabb” applicator could be used to engage film 12 and position it at the administration site.
• a forceps-like instrument could be employed to engage a portion of a strip 34 (e.g. a non-medicated portion of substrate 32) and position film 12 at an administration site.
• a method comprising the application of a thin film drug delivery system to an ocular surface for treatment of ocular conditions or as part of ophthalmic procedures, including pre-operatively and post- operatively.
• the thin film is shaped to conform to an ocular surface to facilitate treatment of an ocular condition or as part of or to facilitate an ophthalmic procedure.
• the invention relates to a method of delivering at least one pharmaceutically active agent to a target ocular location in a subject comprising providing a mucoadhesive film comprising the at least one pharmaceutically active agent as described herein; applying the film to a mucosal surface of an eye of the subject; and maintaining the film on the mucosal surface for a time period sufficient to enable delivery of the at least one pharmaceutically active agent to the ocular location.
• the thin film may be removed from the mucosal surface after the sufficient time period.
• the sufficient time period may be between approximately one minute and one hour.
• having a dye, colourant or inspecting agent may assist in removing the thin film when desired.
• the thin film and use thereof comprises particular methods of delivery of one or more pharmaceutically active agents.
• the one or more pharmaceutical agents are delivered directionally from the thin film to the target location.
• the one or more pharmaceutically active agents are delivered in sequence (in relation to one another) to the target location prior to a clinical or surgical procedure. Examples of drugs that may be delivered in sequence prior to a clinical procedure include delivery of an anesthetic agent followed by delivery of a mydriatic agent or agents. Examples of drugs that may be delivered in sequence prior to a surgical procedure include delivery of an anesthetic agent followed by an antiseptic agent.
• the one or more pharmaceutically active agents are delivered in the treatment of an eye condition.
• Examples of drugs that may be delivered in sequence in the treatment of an eye condition include delivery of an anesthetic agent followed by delivery of an antibiotic, ocular antihypertensive and/or emollient.
• the shape and configuration of the thin film provides controlled drug delivery.
• the delivery of the one or more pharmaceutical agents is time-released.
• at least one of the pharmaceutically active agents is rapidly released.
• at least one of the pharmaceutically active agents is sustained released.
• at least one of the pharmaceutically active agents is slow released.
• at least one of the pharmaceutically active agents is rapidly released and sustained released.
• the thin films and methods of use include use for ophthalmic applications, including use in respect of ocular conditions and ophthalmic procedures.
• ocular condition refers to acute and chronic diseases and conditions of the eye.
• Acute diseases and conditions include, but are not limited to blepharitis, allergic conjunctivitis, conjunctivitis (viral, bacterial, gonococcal, chlamydial), episcleritis, scleritis, corneal abrasion, recurrent corneal erosion syndrome, corneal ulcer, keratitis, acute anterior uveitis, iridocyclitis, intermediate uveitis, acute glaucoma and cystoid macular edema.
• the thin films may be used for local ocular procedures including measurements of intraocular pressures, gonioscopy, contact lens insertions, removal of corneal and conjunctival foreign bodies, removal of conjunctival cysts and intravitreal or intracameral injections.
• the thin film is administered to the superotemporal bulbar conjunctiva.
• the thin film is administered to the corneal, corneoscleral, forniceal, tarsal plate and the like.
• the thin film is administered in a particular size.
• the thin film is 2x2 mm in size.
• the thin film is 4x4 mm in size.
• Other suitable sizes are also herein contemplated.
• the thin film contains at least one pharmaceutically active agent for administration, such as an anesthetic drug.
• the active agent is lidocaine.
• the lidocaine is present in the thin film in an amount of about 0.10 mg to about 0.50 mg, for example in an amount of about 0.12 mg to about 0.48 mg. Other suitable doses are also herein contemplated.
• the thin film provides a drug effect (e.g. anesthesia).
• the drug effect of the thin film has a longer duration of effect as compared to eye drops.
• the drug effect as delivered by thin film is longer than the drug effect as delivered by drops containing the same dose of the same drug.
• the drug effect as delivered by thin film is longer than the drug effect as delivered by drops containing a higher dose of the same drug.
• the thin film is capable of delivering at least 1 , 2, 3, 4, 5, 10, 20, 30 or 60 minutes of drug effect (e.g. anesthesia).
• administration of the thin film to a subject achieves better drug effect than drops containing the same or more amount of the pharmaceutically active agent.
• administration of the thin film provides localised drug effect resulting in more accurate dosing and less side effects than administration with drops.
• the thin film dissolves within 1 to 60 seconds following application to the ocular location. In some embodiments, the thin film dissolves within 5 to 50 seconds following application to the ocular location.
• the thin film dissolves within 10 to 40 seconds following application to the ocular location. In some embodiments, the thin film dissolves within 15 to 25 seconds following application to the ocular location. In some embodiments, the thin film dissolves within 15 to 20 seconds following application to the ocular location.
• use of the thin films and methods of use in respect of ocular conditions and ophthalmic procedures includes clinical and surgical use.
• clinical use include eye examination and/or injections which may include administration of anesthesia, antiseptics, and/or mydriatics.
• the thin film and methods of use are for surgical use.
• Non-limiting examples of surgical use include 1 ) preoperative use which may include the administration of anesthesia and antiseptics and/or mydriatics, for example, in procedures such as intravitreal injections (pneumatic, medication injections), intracameral (injection, paracentesis), cataract surgery, pterygium surgery, corneal procedures, and 2) postoperative use which may include the administration of antibiotics, anti-inflammatories (NSAIDS/steroids), ocular hypotensives, emollients/tear replacements, and/or mydriatics.
• the thin film and methods of use are for treating a condition, disorder, or disease.
• a non-exhaustive list of pharmaceutically active agents for use in the thin film and methods of the invention include: 1 ) routine clinical eye drops comprising pharmaceutically active agents (optionally in combination with non-medicinal agents) such as phenylephrine (adrenergic), tropicamide (anti-cholinergic), cyclopentolate (anti- muscarinic), lidocaine (amide anesthetic), tetracaine (ester anesthetics), CHX (aqueous chlorhexidine/antiseptics), povidone-iodine, emollients, hyaluronic acid (artificial tears);, 2) glaucoma drugs such as alpha-adrenergic (brimonidine, apraclonidine), beta-blockers specific and non-specific (timolol, levobunolol, betaxalol), carbonic anhydrase inhibitors (brinzolamide, dorzolamide), prostaglandins (latanoprost
• Example 1 Use of mucoadhesive thin films for targeted ocular delivery of anesthetic
• Mucoadhesive single layer thin films were used for targeted ocular delivery of the anesthetic lidocaine.
• the thin films were compared to conventional eye drops comprising lidocaine.
• the thin films comprised water-soluble polysaccharide polymer, glycerol, lidocaine hydrochloride, and sodium bicarbonate.
• the conventional eye drops used in this example were Xylocaine 2% parenteral solution (AstraZeneca) available in plastic ampules (Polyamp® Duofit®) and administered as a single topical drop.
• the thin films were formed in 2 x 2 mm square strips containing 0.12 mg lidocaine.
• the thin films were placed on the superotemporal bulbar conjunctiva in four subjects.
• a drop of 2% lidocaine was placed in the contralateral eye.
• the average drop contained approximately 50 uL lidocaine solution or a dose of approximately 1 mg.
• topical drops frequently overwhelm the ocular surface with leakage onto the face (wasted drug) with excess drops entering the nasolacrimal drainage system (risk for systemic side effects).
• An overall reduction in active drug dose would reduce the risks of systemic drug side effects.
• Example 2 Comparison study of use of thin films for targeted ocular delivery of anesthetic having extended duration of action
• Example 1 Single layer thin films as described in Example 1 above were used for targeted ocular delivery of the anesthetic lidocaine.
• the mucoadhesive thin films were compared to conventional eye drops.
• the conventional eye drops used were lidocaine 4% preservative free (Minims Lignocaine 4%, Bausch & Lomb, Macquarie Park NSW 2113, Australia) administered as a single topical drop.
• the comparison studies were designed to assess the safety, efficacy, onset, duration and preferences of the thin film against the current eye drop standard.
• the average conventional eye drop contained approximately 50 uL lidocaine solution or a dose of approximately 2 mg.
• a single drop of the conventional eye drops containing approximately 2 mg of lidocaine was instilled in the right eye of each subject while a small 4 x 4 mm square of mucoadhesive thin film containing 0.48 mg of lidocaine was placed in the inferonasal bulbar conjunctiva of each subject’s contralateral left eye.
• thin films comprising lidocaine are safe and effective in providing strong local anesthesia with extended duration of action. Accordingly, thin films may be considered for local ocular procedures including measurements of intraocular pressures, gonioscopy, contact lens insertions, removal of corneal and conjunctival foreign bodies, removal of conjunctival cysts and intravitreal or intracameral injections.
• connection means any connection or coupling, either direct or indirect, between two or more elements; the coupling or connection between the elements can be physical, logical, or a combination thereof;
• processes or blocks are presented in a given order, alternative examples may perform routines having steps, or employ systems having blocks, in a different order, and some processes or blocks may be deleted, moved, added, subdivided, combined, and/or modified to provide alternative or subcombinations.
• Each of these processes or blocks may be implemented in a variety of different ways.
• processes or blocks are at times shown as being performed in series, these processes or blocks may instead be performed in parallel, or may be performed at different times

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• 2023
  • 2023-09-22 EP EP23866770.3A patent/EP4590283A1/de active Pending
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