Mucoadhesive drug delivery systems and methods of use

Abstract

The present application relates to a drug delivery system including a thin film configured for administration to an ocular mucosa. In some embodiments, the drug delivery system includes a multilayer thin film having a first bioadhesive layer for adhering to a mucosal surface at an administration site and a second non-adhesive layer bonded to the first layer, wherein at least one of the first and second layers comprises at least one pharmacologically active agent. In some embodiments, the second layer limits the diffusion of the at least one pharmacologically active agent, thereby allowing a majority of the at least one pharmacologically active agent to be delivered to a targeted location. In some embodiments, the multilayer film may include a third layer bonded to the second layer, wherein the first and third layers form outer layers of the thin film and the second layer forms an inner layer of the thin film containing at least one pharmacologically active agent. In some embodiments, the drug delivery system may include packaging for storing the thin film in a sterile or semi-sterile state until administration to the eye. The present application also relates to methods of using the thin film to deliver at least one pharmacologically active agent to a site in the eye of a subject. In some embodiments, the mucoadhesive film is applied to the mucosal surface of the eye using an applicator.

Description

[Technical Field]

[0001]

[0002] This application relates to a drug delivery system including a thin film configured for administration to the ocular mucosa. This application also relates to a method of using the thin film to deliver at least one pharmacologically active agent to an ocular location of a subject. [Background technology]

[0002]

[0003] All publications referenced herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description contains information that may be helpful in understanding the present invention. No admission is made that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

[0003]

[0004] Treatment of many ocular conditions and the performance of ophthalmic procedures requires the topical application of drugs or other compositions to ocular tissues. For example, treatment of acute or chronic ocular conditions may require the application of antibiotics, steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or other medications to the eye. Additionally, ophthalmic procedures such as cataract surgery and intravitreal injections may require the delivery of anesthetics, disinfectants, emollients, mydriatics, and / or other medicated or non-medicated agents to the eye, for example, before or after the procedure. Topical application of such compositions to the eye is often accomplished using liquid drops. However, traditional approaches have many drawbacks. In many cases, the liquid drops do not remain at the ocular administration site but instead drip onto the subject's cheek or drain into the subject's nasolacrimal duct, resulting in a significant waste of the drug or other active ingredient. Such drainage can also potentially cause unwanted systemic side effects. Eye drops often present other challenges, including insufficient tissue contact time, contamination risks, storage requirements and the need for preservatives, and relatively high shipping costs.

[0004]

[0005] Ophthalmic procedures and examinations often require the application of a series of eye drops (of different medications) in a specific order. These repeated administrations are usually separated by long waiting periods. These multiple administrations of separate medications significantly increase the cost, effort, and complexity of ophthalmic procedures. Patient compliance and the need for healthcare professionals to administer the eye drops are major drawbacks of traditional approaches.

[0005]

[0006] Therefore, there is a need for systems and methods for reliably, conveniently, and economically delivering pharmacologically active agents to a subject's eye as an alternative to traditional eye drops. In particular, there is a growing need for drug delivery systems that employ thin films to reduce drug waste, shorten waiting times, increase drug bioavailability or permeability, improve drug sustained release, increase user comfort, reduce the risk of contamination, and generally enable more precise delivery of optimal drug doses to desired locations in the eye.

[0006]

[0007] Some intraocular films or pellets known in the prior art are intended for subconjunctival or episcleral drug delivery. Many of these prior art documents involve biodegradable devices. The goal of some of these prior art designs is to deliver drugs from the subconjunctival or episcleral site to the posterior region of the eye, rather than locally delivering drugs to the subconjunctival, episcleral, or other ocular administration site. Furthermore, the prior art designs are limited by the configuration, shape, and color of the drug delivery systems.

[0007]

[0008] The foregoing examples of the related art and limitations associated therewith are intended to be illustrative and not exhaustive. Other limitations of the related art will become apparent to those skilled in the art upon reading this specification and studying the drawings. Summary of the Invention

[0008]

[0009] The following embodiments and aspects thereof are described and illustrated in conjunction with systems, tools, and methods that are intended to be exemplary and illustrative, not limiting in scope. In various embodiments, one or more of the problems discussed above are reduced or eliminated, while other embodiments are directed to other improvements.

[0009]

[0010] One aspect of the present invention provides a drug delivery system comprising a thin film configured to be positioned at an administration site in a subject's eye to deliver at least one pharmacologically active agent to a target location at or near the administration site. In some embodiments, the thin film is configured to include (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 pharmacologically active agent.

[0010]

[0011] Another aspect of the present invention provides a method for delivering at least one pharmacologically active agent to a target ocular location in a subject, the method comprising: providing a mucoadhesive film comprising the at least one pharmacologically active agent; applying the film to a mucosal surface of an eye of a subject; and maintaining the film on the mucosal surface for a period of time sufficient to deliver the at least one pharmacologically active agent to the ocular location.

[0011]

[0012] Another aspect of the present invention relates to the use of a thin film to deliver at least one pharmacologically active agent to an administration site in the eye of a subject.

[0013] In addition to the exemplary aspects and embodiments described above, further aspects and embodiments will become apparent by reference to the drawings and by study of the following detailed descriptions. [Brief explanation of the drawings]

[0012]

[0014] Exemplary embodiments are shown in the referenced figures of the drawings. It is intended that the embodiments and figures disclosed herein be considered illustrative and not restrictive. [Figure 1]

[0015] FIG. 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]

[0016] FIG. 2 is a perspective view of the drug delivery system of FIG. [Figure 3]

[0017] FIG. 3 is a cross-sectional side view of the drug delivery system of FIGS. 1 and 2 in contact with a mucosal surface. [Figure 4]

[0018] FIG. 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]

[0019] FIG. 5 is a perspective view of the drug delivery system of FIG. [Figure 6]

[0020] FIG. 6 is a cross-sectional side view of the drug delivery system of FIGS. 3 and 4 in contact with a mucosal surface. [Figure 7]

[0021] FIG. 7 shows an exemplary configuration of the mucoadhesive film of the present invention. [Figure 8]

[0022] FIG. 8 is a perspective view of a drug delivery system including a packaging unit for supporting a mucoadhesive film. [Figure 9]

[0023] FIG. 9 is a top view of a packaging unit for supporting a plurality of mucoadhesive films. [Figure 10]

[0024] FIG. 10 illustrates an exemplary ocular surface, region of the eye and its substructures to which the drug delivery system of the present invention may be applied. [Figure 11]

[0025] FIG. 11 is a top view of a packaging unit for supporting multiple mucoadhesive films, each film containing a different pharmacologically active agent and / or non-medicated agent. [Figure 12]

[0026] FIG. 12 is a top view of a drug delivery system including a packaging unit for supporting a mucoadhesive film having multiple distinct portions containing different pharmacologically active agents and / or non-medicated agents. [Figure 13]

[0027] FIG. 13 is a top view of the film of FIG. [Figure 14]

[0028] 14 is a side cross-sectional view of the drug delivery system of FIG. [Figure 15]

[0029] FIG. 15 is a cross-sectional perspective view of the drug delivery system of FIG. [Figure 16]

[0030] FIG. 16 is a cross-sectional side view of a drug delivery system comprising multiple stacked, partially overlapping films. [Figure 17]

[0031] 17 is a cross-sectional perspective view of the drug delivery system of FIG. DETAILED DESCRIPTION OF THE INVENTION

[0013]

[0032] Throughout the following description, specific details are set forth to provide a more thorough understanding to those skilled in the art. However, well-known elements may not be shown or described in detail to avoid unnecessarily obscuring the disclosure. Accordingly, the description and drawings should be regarded in an illustrative sense, rather than a restrictive sense.

[0014]

[0033] In some embodiments, the present invention relates to a drug delivery system comprising a dosage form suitable for in vivo administration to an administration site. In some embodiments, the dosage form is a thin film that can be placed at the administration site to deliver at least one pharmacologically active agent to the target location. In some embodiments, the administration site is a site in a subject's eye, and the target location is a location at or near the site in the eye. For example, the target location can be a portion of the subject's eye in need of treatment and / or affected by an ophthalmic procedure. In some embodiments, the subject can be a human. In other embodiments, the subject can be a non-human animal, for example, for veterinary use. In some embodiments, the thin film can be configured to adhere to a mucosal surface at the administration site. In some embodiments, the drug delivery system can comprise either a single-layer film or a multi-layer film. In one embodiment, the thin film can comprise a single-layer structure comprising one or more pharmacologically active agents. In another embodiment, the film can comprise a multi-layer structure comprising multiple layers (i.e., two, three, four, five, or more layers). In some embodiments, the multilayer film may comprise a first bioadhesive layer for adhering to the mucosal surface at the site of administration and second and / or third non-adhesive layers bonded to the first layer, at least one of said layers comprising at least one pharmacologically active agent.

[0015]

[0034] The film may be formulated to release at least one pharmacologically active agent in a rapid, sustained, and / or timed manner. In some embodiments, the at least one pharmacologically active agent may comprise multiple different medicinal agents. In some embodiments, the different medicinal agents are delivered directionally, e.g., in a desired direction from the administration site toward the target location. In some embodiments, the different medicinal agents are delivered sequentially (relative to one another) to the target location. In some embodiments, the delivery of the different medicinal agents is sustained. The at least one pharmacologically active agent may be combined with other compounds, compositions, or ingredients that facilitate administration and use of the at least one pharmacologically active agent but do not necessarily have a medicinal effect. For example, non-medicinal agents or ingredients may include emollients, mydriatics, lipid compounds, or other inactive ingredients, such as diluents, carriers, excipients, or combinations thereof. In some embodiments, the present invention encompasses systems, compositions, methods, and uses for delivering non-medicinal agents or ingredients to a target location, optionally in combination with or separate from at least one pharmacologically active agent.

[0016]

[0035] In some embodiments, the dosage form can be formulated from one or more pharmaceutically acceptable, water-soluble, film-forming polymers. As described herein, the polymers can be formed into thin, flexible films, for example, using solvent casting or electrospinning. In some embodiments, the polymer can be selected so that at least one pharmacologically active agent is bioabsorbable at the target location. For example, in some embodiments, the polymer can form a bioabsorbable substrate impregnated with or bonded to at least one pharmacologically active agent and / or other non-medicinal agents or components formulated for delivery at the administration site. In some embodiments, the film is dissolvable. In some embodiments, the dosage form comprises a hydrogel, including a hydrogel film.

[0017]

[0036] The system may also include a packaging unit configured to store one or more thin films in a sterile or semi-sterile state until administration. In some embodiments, the packaging unit allows for rapid removal and administration of the thin films. In some embodiments, the packaging unit may include multiple thin films arranged in a stack or side-by-side configuration. In some embodiments, the thin films may be removed from the packaging unit and deployed at the administration site using a separate device, such as a handheld applicator.

[0018]

[0037] Referring to Figures 1 and 2, in one embodiment, a drug delivery system 10 includes a multilayer thin film 12. In this embodiment, the film 12 includes a first bioadhesive layer 14, a second non-adhesive layer 16, and a third layer 18 disposed between layers 14 and 16. Each of layers 14-18 may be formed from one or more water-soluble, film-forming, pharmaceutically acceptable polymers. The bioadhesive layer 14 may be configured to be placed in contact with a mucosal surface, such as an ocular mucosal surface. In addition to ophthalmic applications, the thin films of the present invention may also be useful for other applications, such as treating symptoms, disorders, or diseases associated with urology, gastroenterology, gynecology, and ENT (ear, nose, and throat). Accordingly, other potential mucosal surfaces include those of the nose, pharynx, mouth, vagina, urethra, and anorectum. The bioadhesive layer 14 may include a bioadhesive polymer selected to interact with the mucosa over an extended period of time via interfacial tension. Non-adhesive layer 16 forms the backing structure of film 12, and third layer 18 may form an intermediate layer disposed between layers 14 and 16 in a "sandwich" configuration. At least one of these layers may include at least one pharmacologically active agent. Optionally, some or all of the layers of the multilayer film may include a pharmacologically active agent. For example, in some embodiments, bioadhesive layer 14 may include a pharmacologically active agent. In some embodiments, layers 16 and / or 18 may be adhesive layers, may contain one or more pharmacologically active agents, or may be inert.

[0019]

[0038] In some embodiments, layers 14-18 may carry different pharmacologically active agents or other non-medicinal agents or components. For example, in some embodiments, outer layers 14 and 16 of film 12 may include an emollient and / or anesthetic, while middle layer 18 may include at least one pharmacologically active agent, e.g., for treating an ocular disease or condition. By way of example, the emollient may include artificial tears or other lanolin preparations and / or oil-based components, and the anesthetic may include one or more of tetracaine, alcaine, or lidocaine. By way of further example, the at least one pharmacologically active agent may include one or more of glaucoma medications, anti-inflammatory agents, antihistamines, antibacterial agents, antivirals, antifungals, antimetabolites, T-cell inhibitors, alkylating agents, biologics, azoles, fluoropyrimidines, adrenergic agonists, anticholinergics, anesthetics, disinfectants, prostaglandins, carbonic anhydrase inhibitors, beta-blockers, alpha-adrenergic agonists, and combinations thereof. In some specific embodiments, the pharmacologically active or non-medicinal agents may include agents routinely found in clinical eye drops, such as phenylephrine (adrenergic agonist), mydriacyl (anticholinergic), lidocaine (amide anesthetic), tetracaine (ester anesthetic), CHX (chlorhexidine aqueous solution / antiseptic), povidone-iodine, emollients, and hyaluronic acid (artificial tears).

[0020]

[0039] As will be appreciated by those skilled in the art, a wide variety of pharmacologically active agents can be used alone or in combination for ophthalmic or non-ophthalmic applications. Various non-limiting examples of pharmacologically active agents are described herein. For example, anti-inflammatory drugs can include steroids such as one or more of difluprednate, loteprednol etabonate, prednisolone acetate, prednisolone sodium phosphate, rimexolone, fluorometholone acetate, and fluorometholone alcohol, and nonsteroidal anti-inflammatory drugs (NSAIDs) such as one or more of ketorolac tromethamine, bromfenac, nepafenac, and diclofenac sodium. Antibacterial agents may include one or more of besifloxacin, ciprofloxacin, moxifloxacin, ofloxacin, gatifloxacin, tobramycin, gentamicin, polymyxin B, trimethoprim, gramicidin, neomycin, bacitracin, azithromycin, and erythromycin. Antiviral agents may include one or more of acyclovir, ganciclovir, trifluridine, and idoxuridine. Antifungal agents may include one or more of nystatin, natamycin, and amphotericin B. Azoles include 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. Antihistamines may include one or more of ketorolac tromethamine, ketotifen fumarate, loteprednol etabonate, bepotastine besilate, epinastine hydrochloride, emedastine fumarate, 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 may include one or more of cyclophosphamide and chlorambucil.Biologics may include one or more of tumor necrosis factor (TNF) inhibitors, lymphocyte inhibitors, and interleukin inhibitors. Adrenergic agonists may include phenylephrine. Anticholinergic agents may include 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 adrenergic agonists may include one or more of brimonidine and apraclonidine. Beta blockers may 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. As will be appreciated by those skilled in the art, in addition to the non-limiting examples above, many other pharmacologically active agents may be suitable for ocular or non-ocular administration.

[0021]

[0040] As shown in FIG. 3 , the thin film 12 can be positioned to contact the mucosal surface 20 at the administration site. In particular, the thin film 12 can adhere to the mucosal surface 20 via a bioadhesive layer 14 that contacts and bonds to the mucosal surface 20. As discussed above, in some embodiments, the configuration of the thin film 12 allows for delivery of a bioabsorbable element containing a drug or pharmaceutically inactive component bound to the first layer 14 and / or the second layer 16 to the mucosal surface 20 prior to delivery of the drug bound to the film layer 18. For example, the film 12 can be configured such that the film layers 14 and 16 contain an anesthetic and / or emollient that is delivered to or near the administration site (e.g., the mucosal surface 20). After layers 14 and 16 solubilize, dissolve, degrade, and / or erode at the administration site, the one or more pharmacologically active agents in layer 18 can contact the mucosal surface 20 and diffuse to the target location, thereby providing, for example, a local or systemic therapeutic effect.

[0022]

[0041] In some embodiments, thin film 12 may be configured to deliver pharmacologically active agents in a directional manner, e.g., unidirectionally toward a target location. In some embodiments, the direction of flow of one or more pharmacologically active agents is from the layer (e.g., one or more layers 14-16) through which the one or more pharmacologically active agents are released toward mucosal surface 20. In some embodiments, an outer layer (layer 16) allows the one or more pharmacologically active agents to migrate unidirectionally toward mucosal layer 20 and / or prevents the one or more pharmacologically active agents from passing through layer 16. In some embodiments, outer layer (layer 16) comprises an adhesive, one or more pharmacologically active agents, or is inert. In some embodiments, when the subject's eyelids are closed, layer 16 contacts a mucosal surface opposite or adjacent to mucosal surface 20, e.g., the mucosal surface of the subject's eyelid.

[0023]

[0042] 4 and 5 illustrate another embodiment of a multilayer film 12 including a first layer 22 and a second layer 24. In this embodiment, first layer 22 is a bioadhesive layer similar to bioadhesive layer 14 configured to be placed in contact with mucosal surface 20, and layer 24 is a second layer bonded to first layer 22 in a manner similar to layer 16. In this embodiment, layer 22 includes at least one pharmacologically active agent, and layer 24 may include an inert, slowly dissolving, pharmaceutically acceptable polymer that blocks or limits the diffusion of the at least one pharmacologically active agent. As used herein, "slowly dissolving" refers to a relatively slower rate of solubilization, degradation, or erosion of layer 24 compared to layer 22, based on parameters such as the composition and thickness of each layer. In this embodiment, layer 24 partially encapsulates layer 22, thereby assisting in the directed diffusion of the at least one pharmacologically active agent toward the target location. This configuration therefore focuses the delivery of medicinal agents or other components bound to the bioadhesive layer 22 to the mucosal site of application as described above, minimizing unwanted diffusion of the medicinal agents or other components to other areas of the eye, such as the palpebral conjunctiva rather than the bulbar conjunctiva, which may increase the bioavailability of the drug at the target location and reduce drug wastage and potential unwanted side effects.

[0024]

[0043] 6, in some embodiments, the thin films of Figures 4 and 5 can contact the mucosal surface 20 through both the first bioadhesive layer 22 and the second layer 24. In this embodiment, at least a portion of layer 24 (e.g., its edges) may optionally be bioadhesive.

[0025]

[0044] Another aspect of the present invention allows for one or more dyes, colorants, or diagnostic agents to be impregnated into or attached to any or all of the layers comprising the thin film 12. Such embodiments are intended to temporarily mark the intraocular administration site of the thin film 12 and / or the in vivo location (e.g., diffusion) of a pharmacologically active agent or other component. Such dyes, colorants, and diagnostic agents may include, for example, fluorescein, gentian violet, trypan blue, brilliant blue, indocyanine green, and infracyanine green. These dyes, colorants, and diagnostic agents may help identify which drug or other pharmacologically active agent is being used, where it has been administered, and / or the affected tissue. In some embodiments, short-acting dyes may be used to assess whether the thin film has been fully absorbed. In some embodiments, fast-acting to long-acting (e.g., 24 hours) dyes temporarily stain the site of film administration, thereby aiding in visualization of the treatment or surgical site. In some embodiments, different colors are used to indicate administration of different pharmacologically active agents (e.g., red=mydriatic, blue=disinfecting, etc.).

[0026]

[0045] To facilitate placement and use of the drug delivery system 10, the thin film 12 can be shaped and sized to conform to the contours of the ocular surface at the site of administration. As will be appreciated by those skilled in the art, "ocular surface" refers to regions of the eye and their underlying structures ( FIG. 10 ), including, but not limited to, the eyelid margin 100, palpebral conjunctiva 110, fornix 120, bulbar conjunctiva 130, corneoscleral limbus 140, cornea 150, or combinations thereof. By way of non-limiting example, FIG. 7 illustrates various possible shapes of the thin film 12 to conform to various ocular surfaces, such as square, rectangular, circular, oval, annular, and crescent shapes. Additional shapes similar to the shape shown in FIG. 7 are also contemplated herein. In other embodiments, the film 12 may include a scaffold or other structure to support or otherwise secure the film 12 to the ocular surface. By way of non-limiting example, a circular, annular, or crescent-shaped film 12 may be suitable for placement in a corneal or corneoscleral location, while a rectangular, square, or oval-shaped film 12 may be suitable for placement in a proximal tarsal location. Additional non-limiting examples include a large annular shape for placement in the limbus and a rectangular shape that can be placed in the fornix. The variety of shapes and configurations (e.g., layers, heights, lengths, thicknesses) of the thin film allows for customized administration of one or more pharmacologically active agents for a particular procedure, examination, or therapy.

[0027]

[0046] In some embodiments, the administration of one or more pharmacologically active agents is titrable. In some embodiments, through appropriate shaping and / or configuration of the thin film, the titration meets the clinical requirements of the procedure, examination, or treatment. In other embodiments, the thin film is shaped for drug delivery to specific locations in the eye (e.g., the superotemporal bulbar conjunctiva, cornea, corneosclera, fornix, tarsal plate, etc.). In some embodiments, the shape and / or configuration of the thin film improves the placement and delivery rate of one or more pharmacologically active agents. Unlike conventional methods that result in missed eye drops or lengthy timing of repeated eye drop administration, in some embodiments, the shape and / or configuration of the thin film provides rapid, targeted, and precise drug delivery.

[0028]

[0047] Another aspect of the present invention is that thin film 12 can deliver various doses and durations of bioabsorbable elements contained therein. For example, various doses or durations can be achieved 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 concentrations of bioabsorbable elements, such as at least one pharmacologically active agent and other non-medicinal or inactive agents, bound to the layers comprising thin film 12. With regard to dose variation, the bioabsorbable elements bound to thin film 12 can be titrated to meet therapeutic requirements. For example, thin film 12 can be configured to dissolve rapidly, enabling targeted, localized delivery of the bound bioabsorbable elements (e.g., minimizing diffusion), or to dissolve slowly, allowing the bioabsorbable elements to be released diffusively over a longer period of time.

[0029]

[0048] The thin films of the present invention can be prepared by a number of methods known in the art. The selection and use of suitable film-forming mucoadhesive polymers is well understood through prior art and common general knowledge in the field, e.g., Karki et al., Thin films as an emerging platform for drug delivery , Asian Journal of Pharmaceutical Sciences, Volume 11, Issue 5, October 2016, pages 559-574; Park et al., Layer-by-layer assembled polymeric thin films as prospective drug delivery carriers: design and applications , Biomaterials Research, Volume 22, Article number: 29 (2018); Zelikin, Drug Releasing Polymer Thin Films: New Era of Surface-Mediated Drug Delivery, ACS Nano 2010, 4, 5, 2494-2509; Mucoadhesive Polymers: Strategies, Achievements and Future Challenges, Advanced Drug Delivery Reviews, Volume 57, Issue 11, 3 November 2005, pages 1553-1730; The use of mucoadhesive polymers in ocular drug delivery, ibid, pages 1595-1639; Bibliometric and visualized analysis of ocular drug delivery from 2001 to 2020, Journal of Controlled Release, Volume 345, May 2022, pages 625-645, will be readily apparent to those skilled in the art.

[0030]

[0049] As an example, thin films for controlled drug delivery can be prepared using polymers or combinations of polymers such as hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), sodium carboxymethylcellulose (CMC), polyvinyl alcohol (PVA), and hyaluronic acid (HA). Film formation techniques can be, for example, solvent casting or electrospinning. The ratio of polymers can be selected to optimize the film's mucoadhesion, residence time, flexibility, or other properties. Post-casting modifications, such as crosslinking, may improve film durability. The addition of plasticizers, such as glycerol or polyethylene glycol, can optimize film flexibility. The release profile of the active ingredient can also be optimized. In some embodiments, multilayer films can be formulated.

[0031]

[0050] 8 and 9, the drug delivery system 10 may further include a structure for supporting, storing, and / or administering the film 12. In some embodiments, such a structure may include a packaging unit 30 for housing one or more films 12 until administration. For example, as shown in FIG. 8, the thin film 12 may be attached to or coupled to a packaging unit 30 that includes a substrate 32. For example, the substrate 32 may include an inert paper or a non-medicated mucoadhesive strip, onto whose end (medicated tip) the thin film 12 is disposed to form a composite medicated strip 34. Thus, in this embodiment, the drug delivery system 10 is configured to facilitate storage of the thin film 12 and / or deployment of the film 12 at the administration site when needed. For example, a user can manually handle and deploy the drug delivery system 10 by holding or engaging the substrate 32 of the medicated strip 34 and applying the film 12 to the mucosal surface 20. In this example, the thin film 12 separates from the substrate 32 upon placement on the mucosal surface, thereby allowing application without direct handling or manipulation of the film 12. In various embodiments, the film 12 and substrate 32 may be packaged as individual strips 34 or as multiple strips 34, and may be packaged in a sterile or semi-sterile format. Accordingly, in some embodiments, the drug delivery system and / or its packaging is sterile or semi-sterile. In some embodiments, the drug delivery system and / or its packaging has improved shelf life. For example, the drug delivery system and / or its packaging is easier to store than conventional therapeutic agents (e.g., eye drops). In some embodiments, 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), which can introduce microbial contamination with repeated use of the container, in some embodiments, the drug delivery system and / or its packaging of the present invention is less susceptible to contamination. This allows for the reduction or elimination of preservatives and decontaminating agents in the drug delivery system and / or its packaging. It also reduces the cost of disposing of the product if the applicator (eg, eye dropper) comes into contact with the patient's ocular surface or eyelashes.In some embodiments, the drug delivery system and / or its packaging is lightweight (e.g., contains little water) compared to conventional therapeutic agents (e.g., eye drops), and therefore easier and less costly to transport.

[0032]

[0051] 9, in another exemplary embodiment of the present invention, a drug delivery system 10 can include a series of medicated strips 34, each including a thin film 12 and a substrate 32 attached to an inert backing sheet 36. In some embodiments, the medicated strips 34, including the thin film 12, can be arranged on the backing sheet 36 in a stacked or side-by-side manner. In some embodiments, each medicated strip 34 is separated from adjacent strips 34 by perforations. During use, an individual medicated strip 34 is removed from the backing sheet 36 by manually grasping or otherwise engaging the substrate 32, separating the selected medicated strip 34 from adjacent strips 34 along the perforations, and removing the selected medicated strip 34 from the backing sheet 36. The selected medicated strip 34 can then be used as described above to apply the thin film 12 to the administration site. As with the previous embodiment, in the example of FIG. 9, the medicated strip 34 can be packaged in a sterile or semi-sterile format to avoid or limit the risk of contamination of the film 12.

[0033]

[0052] In embodiments in which the drug delivery system 10 includes multiple medicated strips 34 arranged side by side, at least some of the strips 34 in the row may include a different pharmacologically active agent (e.g., a medicated agent) or non-medicated agent than the other strips 34 in the row. This facilitates sequential or combined administration of multiple pharmacologically active agents or other formulations. In one exemplary embodiment, the drug delivery system 10 may include a stack of multiple medicated strips 34 including (1) an anesthetic (e.g., lidocaine), (2) a mydriatic (pupil dilator), and (3) a fluorescein / emollient.

[0034]

[0053] Referring to FIG. 11 , a drug delivery system 10 may include a packaging unit 30 for supporting multiple films 12, each of which may contain a different pharmacologically active agent and / or non-medicated agent. In this example, the films 12 are arranged side-by-side. In this embodiment, strips 34 are sequentially removed from the packaging unit, and each film 12 can be administered sequentially as described above as part of a clinical or surgical procedure and / or ophthalmic treatment. The packaging unit 30 may be configured such that the strips 34 and each film 12 are associated with a particular treatment and / or therapy. For example, the packaging unit 30 may include one thin film 12 for use before (pre-treatment) an ophthalmic treatment and one thin film 12 for use after (post-treatment) an ophthalmic treatment.

[0035]

[0054] 12 shows an exemplary embodiment of a drug delivery system 10 including a packaging unit 30 containing a single medicated strip 34 supporting a thin film 12. In this embodiment, film 12 may include multiple portions or sub-films 12A, 12B, and 12C, each optionally containing different pharmacologically active agents and / or non-medicated agents. Portions 12A, 12B, and 12C may be positioned side-by-side (FIGS. 12-15). In other embodiments, portions 12A, 12B, and 12C may overlap, either partially or entirely.

[0036]

[0055] In some embodiments, film 12 can be configured such that one or more layers 14-18 include multiple portions or sublayers. For example, as shown in FIGS. 14 and 15, third layer 18 can include multiple portions or sublayers 18A, 18B, and 18C, each optionally including a different pharmacologically active agent and / or non-medicated agent. In the embodiment shown in FIGS. 14 and 15, portions 18A, 18B, and 18C are arranged side by side. In other embodiments, portions 18A, 18B, and 18C can overlap, partially or entirely, to form, for example, layered layer 18. In some embodiments, portions 18A, 18B, and 18C can include different pharmacologically active agents and / or non-medicated agents configured for combined or sequential release at the site of administration.

[0037]

[0056] In some embodiments, the drug delivery system 10 may include multiple laminated films 12, each of which may optionally contain a different pharmacologically active agent and / or non-medicated agent. For example, as shown in FIGS. 16 and 17, each film 12 may include a respective third layer 18 including different portions 18A, 18B, or 18C having different sizes and / or configurations. In the embodiment of FIGS. 16 and 17, each laminated film 12 including each of the stacked layers 18A, 18B, and 18C may have different lengths and, accordingly, may contain different amounts of pharmacologically active agent and / or non-medicated agent. In other embodiments, some or all of the stacked films 12 may be the same length. In the illustrated embodiment of FIGS. 16 and 17, the layers 18A, 18B, and 18C are separated by an intervening layer 14, although other configurations are possible.

[0038]

[0057] In some embodiments, the drug delivery system 10, for example, in the form of a thin film 12 or a medicated strip 34 including the film 12, may be deployed at the administration site using another instrument, such as a handheld applicator. In some embodiments, a disposable, moistened "Dabb" applicator can be used to engage and position the film 12 at the administration site. In another embodiment, an instrument such as forceps can be used to engage a portion of the strip 34 (e.g., a non-medicated portion of the substrate 32) and position the film 12 at the administration site.

[0039]

[0058] In one embodiment of the present invention, a method is provided that includes applying a thin film drug delivery system to the ocular surface for the treatment of an ocular condition or as part of an ophthalmic procedure, including pre- and post-surgical procedures. As described above, in some embodiments, the thin film is shaped to conform to the ocular surface to facilitate the treatment of an ocular condition or as part of or to facilitate an ophthalmic procedure. In some embodiments, the present invention relates to a method for delivering at least one pharmacologically active agent to a target location in a subject's eye, comprising providing a mucoadhesive film comprising at least one pharmacologically active agent described herein; applying the film to a mucosal surface of a subject's eye; and maintaining the film on the mucosal surface for a sufficient time to allow delivery of the at least one pharmacologically active agent to the ocular location. In some cases, the thin film may be removed from the mucosal surface after the sufficient time has elapsed. In some instances, the sufficient time may be between about 1 minute and 1 hour. As described above, a dye, colorant, or inspection agent may be present to aid in the removal of the thin film when necessary.

[0040]

[0059] In other embodiments, the thin film and its use include specific methods for delivering one or more pharmacologically active agents. In some embodiments, one or more agents are delivered directionally from the thin film to a target location. In some embodiments, one or more pharmacologically active agents are delivered sequentially (relative to one another) to a target location prior to a clinical or surgical procedure. An example of agents delivered sequentially prior to a clinical procedure includes delivery of an anesthetic followed by delivery of a mydriatic. An example of agents delivered sequentially prior to a surgical procedure includes delivery of an anesthetic followed by delivery of an antiseptic. In some embodiments, one or more pharmacologically active agents are delivered for the treatment of an ocular condition. Examples of agents delivered sequentially in the treatment of an ocular condition include delivery of an anesthetic followed by delivery of an antibiotic, an ocular hypotensive, and / or an emollient. In some embodiments, the shape and configuration of the thin film provide controlled delivery of the agents. In some embodiments, the delivery of the one or more agents is sustained release. In one embodiment, at least one pharmacologically active agent is rapidly released. In one embodiment, at least one of the pharmacologically active agents is sustained release. In one embodiment, at least one of the pharmacologically active agents is slowly released. In one embodiment, at least one of the pharmacologically active agents is rapidly released and sustained-release. In some embodiments, the shape and configuration of the thin film allows for rapid dissolution for targeted delivery of one or more pharmacologically active agents to a specific location. In some embodiments, the thin film provides improved permeability of one or more pharmacologically active agents compared to conventional methods (e.g., eye drops). In some embodiments, the thin film allows for the administration of lower concentrations of one or more pharmacologically active agents compared to conventional methods. Due to the improved permeability and / or reduced concentration of the pharmacologically active agents, in some embodiments, patients may benefit from reduced side effects, such as reduced tear drainage from the nasolacrimal duct, which can lead to systemic side effects.

[0041]

[0060] In some embodiments, the thin films and methods of use include ophthalmic applications, including uses related to ophthalmic conditions and ophthalmic treatments. As used herein, "ophthalmic conditions" 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. Chronic diseases and conditions include, but are not limited to, blepharitis, atopic conjunctivitis, vernal conjunctivitis, phlyctenular disease, neurotrophic corneal ulcer, persistent corneal epithelial defect, chronic uveitis, and glaucoma. As used herein, "ophthalmic procedures" refer to procedures including, but not limited to, intravitreal injections, intracameral injections or paracentesis, cataract surgery, pterygium surgery, and corneal procedures. Preoperative application of the thin film 12 in ophthalmic procedures may include delivery of anesthetics or disinfectants to the eye. Postoperative application of the thin film 12 in ophthalmic procedures may include delivery of antibiotics, anti-inflammatory drugs (e.g., nonsteroidal anti-inflammatory drugs or steroids), intraocular pressure-lowering agents, emollients, and mydriatics to the eye. In some embodiments, the thin film may be used for topical ophthalmic procedures such as measuring intraocular pressure, gonioscopy, contact lens insertion, removal of corneal and conjunctival foreign bodies, removal of conjunctival cysts, and intravitreal or intracameral injections. In some embodiments, the thin film is administered to the superior temporal bulbar conjunctiva. In other embodiments, the thin film is administered to the cornea, corneosclera, fornix, tarsal plate, etc.

[0042]

[0061] In some embodiments, the thin film is administered in a specific size. In some embodiments, the thin film is 2 x 2 mm in size. In some embodiments, the thin film is 4 x 4 mm in size. Other suitable sizes are contemplated herein.

[0043]

[0062] In some embodiments, the thin film contains at least one pharmacologically active agent for administration, such as an anesthetic. In some embodiments, the active agent is lidocaine. In some embodiments, lidocaine is present in the thin film in an amount of about 0.10 mg to about 0.50 mg, e.g., about 0.12 mg to about 0.48 mg. Other suitable dosages are also contemplated herein.

[0044]

[0063] In some embodiments, the thin film provides a drug effect (e.g., anesthesia). In some embodiments, the drug effect of the thin film has a longer duration of effect compared to eye drops. In some embodiments, the drug effect delivered by the thin film is longer than the drug effect delivered by droplets containing the same drug at the same dose. In some embodiments, the drug effect delivered by the thin film is longer than the drug effect delivered by droplets containing a higher dose of the same drug. In some embodiments, the thin film can deliver a drug effect (e.g., anesthesia) for at least 1, 2, 3, 4, 5, 10, 20, 30, or 60 minutes. In some embodiments, administration of the thin film to a subject achieves a drug effect superior to that of droplets containing the same or a larger amount of pharmacologically active agent. In some embodiments, administration of the thin film provides a more localized drug effect, resulting in more precise dosing and fewer side effects than administration by droplets. In some embodiments, the thin film dissolves within 1 to 60 seconds after application to the ocular location. In some embodiments, the thin film dissolves within 5 to 50 seconds after application to the ocular location. In some embodiments, the thin film dissolves within 10-40 seconds after application to the ocular location. In some embodiments, the thin film dissolves within 15-25 seconds after application to the ocular location. In some embodiments, the thin film dissolves within 15-20 seconds after application to the ocular location.

[0045]

[0064] As described above, uses and methods of use of the thin films for ocular conditions and ophthalmic treatments include clinical and surgical uses. Non-limiting examples of clinical uses include ophthalmic examinations and / or injections, which may include the administration of anesthetics, disinfectants, and / or mydriatics. In some embodiments, the thin films and methods of use are for surgical use. Non-limiting examples of surgical uses include: 1) pre-operative use, which may include the administration of anesthetics and disinfectants and / or mydriatics, such as intravitreal injections (air pressure, drug injections), intracameral injections (injections, paracentesis), cataract surgery, pterygium surgery, corneal procedures, etc.; and 2) post-operative use, which may include the administration of antibiotics, anti-inflammatory drugs (NSAIDS / steroids), intraocular pressure-reducing agents, emollients / tear supplements, and / or mydriatics. In some embodiments, the thin films and methods of use are for treating a condition, disorder, or disease. In some embodiments, the symptom, disorder, or disease is exacerbation of blepharitis, seasonal allergic conjunctivitis, conjunctivitis (e.g., viral, bacterial, atypical: gonococcal, chlamydial), episcleritis / scleritis, corneal abrasion / recurrent corneal erosion syndrome, corneal ulcer, keratitis, acute anterior uveitis, iridocyclitis, intermediate uveitis, acute glaucoma (open angle and angle closure), cystoid macular edema, blepharitis - altered microbiota, atopic conjunctivitis / vernal conjunctivitis, phlyctenular disease, neurotrophic corneal ulcer, persistent corneal epithelial defect, chronic uveitis: anti-inflammatory and primary open angle glaucoma / chronic angle closure glaucoma. A non-exhaustive list of pharmacologically active agents for use in the thin films and methods of the present invention includes: 1) conventional clinical eye drops containing a pharmacologically active agent (optionally in combination with a non-medicinal agent), such as phenylephrine (adrenergic agonist), tropicamide (anticholinergic), cyclopentolate (antimuscarinic agonist), lidocaine (amide anesthetic), tetracaine (ester anesthetic), CHX (chlorhexidine aqueous solution / disinfectant), povidone-iodine, emollients, hyaluronic acid (artificial tears);2) glaucoma medications, such as alpha adrenergic agonists (brimonidine, apraclonidine), specific and nonspecific beta blockers (timolol, levobunolol, betaxalol), carbonic anhydrase inhibitors (brinzolamide, dorzolamide), prostaglandins (latanoprost, tafluprost, bimatoprost, travoprost); 3) anti-inflammatory drugs, such as steroids (difluprednate, loteprednol etabonate, prednisolone acetate or sodium, phosphate, rimexolone, fluoromethorphan acetate). 4) antihistamines, e.g., ketorolac tromethamine, ketotifen fumarate, loteprednol etabonate, bepotastine besilate, epinastine hydrochloride, emedastine difumarate, alcaftadine, azelastine hydrochloride, olopatadine hydrochloride, nedocromil sodium, lodoxamide tromethamine, cromolyn sodium; 5) antibacterials, e.g., besifloxacin, ciprofloxacin 5) antimetabolites, e.g., methotrexate, mycophenolate mofetil, azathioprine; 6) T-cell inhibitors, e.g., cyclosporine, tacrolimus, sirolimus, gentamicin, polymyxin B / trimethoprim, polymyxin B / bacitracin, polymyxin B / neomycin / gramicidin, polymyxin B / neomycin / bacitracin, azithromycin, erythromycin, bacitracin; 7) antimetabolites, e.g., methotrexate, mycophenolate mofetil, azathioprine; 8) T-cell inhibitors, e.g., cyclosporine, tacrolimus, sirolimus 8) alkylating agents, for example, cyclophosphamide, chlorambucil; 9) biological agents, for example, TNF inhibitors, lymphocyte inhibitors, interleukin inhibitors; 10) antiviral agents, for example, acyclovir, ganciclovir, TFT (topical trifluridine), topical idoxuridine; 11) antifungal agents, for example, nystatin, natamycin, amphotericin B; 12) azoles, for example, ketoconazole, miconazole, fluconazole, itraconazole, econazole, clotrimazole, voriconazole;and 13) Fluorinated pyrimidines, such as flucytosine. In certain embodiments, pharmacologically active agents include anti-VEGF agents (bevacizumab, ranibizumab, aflibercept, brolucizumab, faricimab), angiopoietin-2, and pilocarpine compounds.

[0046] Example

[0065] The following examples are intended to illustrate exemplary embodiments of the present invention and are not intended to limit the scope of the invention in any way.

[0047] Example 1 - Use of mucoadhesive thin films for targeted intraocular delivery of anesthetic agents

[0066] Mucoadhesive single-layer thin films were used for targeted intraocular delivery of the anesthetic lidocaine. The thin films were compared with conventional eye drops containing lidocaine. The thin films contained a 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 a plastic ampule (Polyamp® Duofit™), and administered as a single drop topically.

[0048] method

[0067] The thin films were applied as 2 x 2 mm square strips containing 0.12 mg of lidocaine. The thin films were placed on the superior temporal bulbar conjunctiva of four subjects. One drop of 2% lidocaine was placed in the contralateral eye. Each drop contained, on average, approximately 50 μL of lidocaine solution, or a dose of approximately 1 mg.

[0049]

[0068] All thin films remained on the superior temporal bulbar conjunctiva until dissolved. The anesthetic effect in the quadrant of the thin film application site was assessed at 15-second, 1-minute, and 5-minute intervals, compared with the quadrants of the other eye (supernasal, inferonasal, and inferotemporal). Cotton swabs were used to compare sensation in each quadrant. Sensation was measured as normal (N), decreased (R), or absent (A).

[0050] Observations

[0069] The sensations shown in Table 1 were observed 15 seconds after placing the thin film on the subject's eye.

[0051] [Table 1]

[0052]

[0070] One minute after placing the thin film on the subject's eye, the sensations noted in Table 2 were observed.

[0053] [Table 2]

[0054]

[0071] Five minutes after placing the thin film on the subject's eye, the sensations observed were as shown in Table 3.

[0055] [Table 3]

[0056]

[0072] In comparison, lidocaine eye drops administered to the contralateral eye induced anesthesia at all time points and abolished responses in all four quadrants (A). Two of the four subjects experienced spillover of the drug onto the cheek.

[0057]

[0073] For the subject's eye in which the thin film was placed, qualitative anesthesia occurred most rapidly at the superotemporal area, where the film was applied, followed by the inferotemporal, inferonasal, and superonasal quadrants. This demonstrates the ability to localize the effects of the active ingredient (in this case, lidocaine) using a mucoadhesive thin film. This also demonstrates that the mucoadhesive thin film provides a more efficient drug delivery system for targeted delivery of the active ingredient (in this case, lidocaine) compared to eye drops, requiring less active ingredient to adequately anesthetize the ocular surface for the procedure. Furthermore, the thin film allows for more precise dosing of the active ingredient. The volume of topical eye drops typically varies (20–70 μL). As noted in paragraph

[0004] above, topical eye drops often overdose on the ocular surface, leaking onto the face (wasting the medication) and allowing excess eye drops to enter the nasolacrimal drainage system (risking systemic side effects). Reducing the overall active drug dose can reduce the risk of systemic drug side effects.

[0058] Example 2 - Comparative study of the use of thin films in targeted intraocular delivery of anesthetics with extended duration of action

[0074] The monolayer thin film described in Example 1 above was used for targeted intraocular delivery of the anesthetic lidocaine. The mucoadhesive thin film was compared with conventional eye drops. In this example, the conventional eye drops were preservative-free lidocaine 4% (Minims Lignocaine 4%, Bausch & Lomb, Macquarie Park, New South Wales 2113, Australia) administered as a single drop topically. The comparative study was designed to evaluate the safety, efficacy, onset, duration, and preference of the thin film compared to the current standard eye drops. The conventional eye drops contained, on average, approximately 50 μL of lidocaine solution, or a dose of approximately 2 mg. One drop of conventional eye drops containing approximately 2 mg of lidocaine was instilled into the right eye of each subject, while a small 4 x 4 mm square mucoadhesive thin film containing 0.48 mg of lidocaine was placed on the inferior nasal bulbar conjunctiva of the contralateral left eye of each subject.

[0059] method

[0075] Ten subjects participated in the study, and each subject received a lidocaine preparation in either a thin film or eye drops in each eye. Subjects were then asked to rate their initial discomfort level, the time it took for the discomfort to resolve, their assessment of the quality of anesthesia, and any additional comments. Clinical observations and measurements of the film and eye were also performed. The study was conducted in a room with a temperature of 23°C and a humidity level of 35% to 45%.

[0060]

[0076] Thin film strips were carefully cut into 4 x 4 mm squares (0.48 mg) and immediately applied to the conjunctival surface of each subject. Application was performed by a specialist physician on the inferior bulbar and palpebral conjunctiva. Simultaneously, one drop of 4% lidocaine was instilled into the contralateral eye as described above. Each subject was monitored for 30 minutes after lidocaine administration.

[0061]

[0077] Qualitative anesthesia testing was performed at scheduled intervals (baseline, 1, 3, 5, 10, and 30 minutes) using a cotton swab at the corneal limbus. Sensation was assessed by gently palpating the inferior temporal corneal scleral limbus of each eye with a cotton swab to assess sensation and symmetry. Patients were asked whether they felt any discomfort when the swab was applied to each eye and whether there was a difference between the two lidocaine formulations. Examinations by the examiner included recording the time it took for the film to dissolve and disappear, testing each eye for anesthesia at scheduled intervals, and examining the local ocular surface for any irritation or reaction. Slit lamp examinations of each subject's eye were also performed at baseline, before each test, and at 30 minutes. In addition, the conjunctiva was examined for hyperemia or abnormalities after application of the mucoadhesive film and eye drops throughout the study period.

[0062] Observations

[0078] The following observations, shown in Table 4, were made regarding discomfort.

[0063] [Table 4]

[0064]

[0079] The following observations, shown in Table 5, were made regarding anesthesia at different time intervals.

[0065] [Table 5]

[0066]

[0080] The following additional observations, shown in Table 6, were made regarding discomfort, ocular appearance at the administration site, and user preference.

[0067] [Table 6]

[0068] result

[0081] No safety concerns were raised by any of the subjects participating in this example study. In all 10 subjects, the thin film had a significantly longer duration of action than the eye drops. The extended duration of action of the film was surprising, given the lower dose of lidocaine active ingredient. Initial discomfort and stinging sensation upon drug administration were subjectively comparable in four cases, while the remaining six cases preferred the eye drops for initial application comfort due to less stinging sensation. Furthermore, while six subjects experienced longer discomfort with the film, this was minimal across the entire cohort, averaging approximately 9 additional seconds of duration.

[0069]

[0082] Although the thin film reported additional initial discomfort, there was no evidence of conjunctival hyperemia, which could be evidence of hypersensitivity or irritation. Subjects who noted that discomfort took longer to resolve also noted a preference for lidocaine eye drops. This may be due to the longer time it took for the film to resolve. However, by 3 minutes, the film provided comparable subjective anesthetic efficacy in all cases. By 10 minutes, the film replaced the eye drops, with 7 of 10 subjects reporting the film as providing superior anesthetic efficacy. By 30 minutes, the film provided continued anesthetic activity in all 10 subjects, whereas the eye drops had worn off. Furthermore, some patients reported periorbital and adnexal numbness, including the eyelids, for periods exceeding 60 minutes.

[0070]

[0083] The results of this example demonstrate that the qualitative anesthetic efficacy of the thin film is comparable to that of lidocaine 4% eye drops over 3 minutes, and in all cases lasts longer than the eye drops for over 30 minutes.

[0071]

[0084] Although the initial discomfort of the film lasted approximately 9 seconds longer on average, all patients noted that they tolerated the discomfort of the film and had no issues with local or systemic adverse consequences.When asked which anesthetic agent they preferred for ophthalmic procedures involving intraocular injections, all subjects in the cohort preferred film because it provided comparable anesthetic efficacy but with a longer duration of action.

[0072]

[0085] This example demonstrates that thin films containing lidocaine can safely and effectively provide potent local anesthesia with a long duration of action, and therefore may be used in topical ophthalmic procedures such as intraocular pressure measurement, gonioscopy, contact lens insertion, removal of corneal and conjunctival foreign bodies, removal of conjunctival cysts, and intravitreal or intracameral injections.

[0073] Interpretation of terms

[0086] Throughout the specification and claims, unless the context clearly requires otherwise:

[0074] "include", "including" and the like shall be construed in an inclusive sense, i.e., meaning "including but not limited to", as opposed to an exclusive or exhaustive sense.

[0075] "Coupled," "coupled," or variations thereof, means any direct or indirect connection or coupling between two or more elements. The connection or coupling between the elements may be physical, logical, or a combination thereof.

[0076] The words "herein," "above," "below," and words of similar import, when used to describe this specification, shall refer to this specification as a whole and not to any particular portions of this specification.

[0077] "Or", in relation to a list of two or more items, covers all of the following interpretations of the word: any item in the list, all items in the list, and any combination of items in the list.

[0078] · The singular forms "one", "the" and "said" include the appropriate plural forms.

[0087] As used in this specification and the appended claims (if any), directional terms such as "vertical," "lateral," "horizontal," "upward," "downward," "forward," "rearward," "inward," "outward," "left," "right," "front," "rear," "top," "bottom," "lower," "above," "below," and the like, depend on the particular orientation of the device being described and illustrated. The subject matter described herein can assume various alternative orientations. Accordingly, these directional terms are not precisely defined and should not be narrowly construed.

[0079]

[0088] For example, while processes or blocks are presented in a particular order, alternative examples may perform routines including steps in a different order or use systems including blocks in a different order. Also, some processes or blocks may be deleted, moved, added, subdivided, combined, and / or modified to provide alternative combinations or subcombinations. Each of these processes or blocks may be implemented in a variety of ways. Also, while processes or blocks may be shown to be performed in series, these processes or blocks may be performed in parallel or at different times.

[0080]

[0089] Moreover, while elements may be shown to be performed sequentially, they may also be performed simultaneously or in a different order. It is therefore intended that the following claims be interpreted to include all such variations that are within their intended scope.

[0081]

[0090] For purposes of explanation, specific examples of systems, methods, and devices have been described herein. These are examples only. The techniques provided herein may be applied to systems other than the exemplary systems described above. Many changes, modifications, additions, omissions, and permutations are possible in the practice of the present invention. The present invention includes variations of the described embodiments that will be apparent to those skilled in the art, including variations obtained by replacing features, elements, and / or acts with equivalent features, elements, and / or acts; incorporating and matching features, elements, and / or acts from different embodiments; combining features, elements, and / or acts of the embodiments described herein with features, elements, and / or acts of other technologies; and / or omitting features, elements, and / or acts that are combined from the described embodiments.

[0082]

[0091] Various features are described herein as being present in "some embodiments." Such features are not required and may not be present in all embodiments. Embodiments of the invention may include none, any one, or any combination of two or more of such features. This is limited only to the extent that a particular one of such features is not incompatible with another one of such features (in the sense that one of ordinary skill in the art would be unable to construct a working embodiment combining such incompatible features). Thus, a statement that "some embodiments" have feature A and that "some embodiments" have feature B should be interpreted as explicitly indicating that the inventors also contemplate embodiments combining feature A and feature B (unless the description states otherwise and unless feature A and feature B are fundamentally incompatible).

[0083]

[0092] Accordingly, it is intended that the following appended claims and any claims hereafter introduced be interpreted to include all modifications, permutations, additions, omissions, and subcombinations that can reasonably be inferred. The scope of the claims should not be limited by the preferred embodiments set forth in the examples, but should be accorded the broadest interpretation consistent with the description of the entire specification.

Claims

1. The use of a mucoadhesive film formulated to deliver at least one pharmacologically active agent to a target location in the eye of a subject.

2. 10. The use of claim 1, wherein the film is formulated to adhere to the mucosal surface of the eye of a subject.

3. 3. The use of claim 2, wherein the film is formulated to contact the mucosal surface for a period of time sufficient to allow delivery of the at least one pharmacologically active agent to a target location in the eye.

4. The use according to any one of claims 1 to 3, comprising providing a packaging unit containing said mucoadhesive film and removing said mucoadhesive film from said packaging unit.

5. 4. The use of claim 2 or 3, wherein the film is formulated to be applied to the mucosal surface at or proximal to a target location in the eye.

6. 4. The use of claim 2 or 3, wherein the film is formulated to be applied to the mucosal surface distal to the target location in the eye, and the at least one pharmacologically active agent is formulated to diffuse to the target location in the eye.

7. The use according to any one of claims 1 to 6, wherein the mucoadhesive film is adapted to be applied to the mucosal surface of the eye using an applicator.

8. The use according to claim 7, wherein the applicator is disposable after use.

9. 5. The use according to claim 4, wherein the packaging unit is tearable to expose the mucoadhesive film.

10. 10. The use according to claim 4 or 9, wherein the film is sealed inside the packaging unit.

11. 11. The use according to claim 10, wherein the packaging unit maintains the mucoadhesive film in a sterile or semi-sterile form.

12. The use according to claim 4, wherein the packaging unit is configured for single use.

13. 5. The use according to claim 4, wherein the packaging unit comprises a plurality of mucoadhesive films, each of which is individually removable from the packaging unit.

14. The use according to any one of claims 1 to 13, wherein the film comprises a bioabsorbable or bioerodible element for controllably diffusing the at least one pharmacologically active agent at the target location.

15. The use according to any one of claims 1 to 14, wherein the at least one pharmacologically active agent comprises a plurality of pharmacologically active agents.

16. 3. The use of claim 2, wherein the film is shaped to conform to the shape of the ocular mucosal surface at or near the eye.

17. 17. The use of claim 16, wherein the mucosal surface of the eye is a surface located on one or more of the eyelid margin, palpebral conjunctiva, fornix, bulbar conjunctiva, corneoscleral limbus, or cornea of ​​the eye.

18. 18. The use according to any one of claims 1 to 17, wherein the at least one pharmacologically active agent is selected from the group consisting of antiglaucoma drugs, anti-inflammatory drugs, antihistamines, antibacterial drugs, antiviral drugs, antifungal drugs, antimetabolites, antihistamines, T-cell inhibitors, alkylating agents, biologics, azoles, fluoropyrimidines, adrenergic drugs, anticholinergic drugs, anesthetics, antiseptics, prostaglandins, carbonic anhydrase inhibitors, beta-blockers, alpha-adrenergic drugs, and combinations thereof.

19. 19. The use of any one of claims 1 to 18, wherein the at least one pharmacologically active agent is formulated to treat an ophthalmic condition, and the ophthalmic condition is one or more of blepharitis, conjunctivitis, episcleritis, scleritis, corneal abrasion, recurrent corneal erosion syndrome, corneal ulcer, keratitis, acute anterior uveitis, iridocyclitis, uveitis, glaucoma, cystoid macular edema, phlyctenular disease, neurotrophic corneal ulcer, persistent corneal epithelial defect.

20. 20. The use according to any one of claims 1 to 19, wherein the at least one pharmacologically active agent is formulated to facilitate an ophthalmic procedure, the procedure being one or more of intravitreal injection (air pressure, drug injection), intracameral (injection, paracentesis), cataract surgery, pterygium surgery, pre-operative administration of anaesthetics, antiseptics and / or mydriatics to facilitate corneal procedures, and / or the treatment being one or more of antibiotics, anti-inflammatory drugs (NSAIDS / steroids), intraocular pressure lowering agents, emollients / tear supplements and / or mydriatics.

21. The use of any one of claims 1 to 20, wherein the film is formulated to remain on the mucosal surface for a period in the range of about 1 minute to 1 hour.

22. 22. The use of any one of claims 1 to 21, wherein the film comprises a multilayer film comprising a first bioadhesive layer for adhering to a mucosal surface at an administration site and a second layer bonded to the first layer, wherein at least one of the first layer and the second layer comprises the at least one pharmacologically active agent.

23. 23. The use of claim 22, wherein the second layer is not bioadhesive.

24. 23. The use of claim 21 or claim 22, wherein the second layer limits the diffusion of the at least one pharmacologically active agent, thereby enabling a focused delivery of a majority of the at least one pharmacologically active agent to the target location.

25. 25. The use of claim 24, wherein the second layer comprises an inert, slowly dissolvable polymer.

26. The use according to any one of claims 22 to 26, wherein the first layer comprises a readily dissolvable polymer containing the at least one pharmacologically active agent.

27. 23. The use of claim 21 or claim 22, further comprising a third layer attached to the second layer, wherein the first layer and the third layer form outer layers of the thin film, and the second layer forms an inner layer of the thin film between the outer layers and comprises the at least one pharmacologically active agent.

28. 28. The use of claim 27, wherein at least one of the first layer and the third layer comprises the at least one pharmacologically active agent and / or a non-medicinal agent selected from the group consisting of an emollient, a lubricant, a lipid, and combinations thereof.

29. The use according to any one of claims 1 to 28, wherein the at least one pharmacologically active agent is lidocaine.

30. 1. A method for delivering at least one pharmacologically active agent to a target location in an eye of a subject, comprising: (a) providing a mucoadhesive film comprising said at least one pharmacologically active agent; (b) applying the film to a mucosal surface of the eye of the subject; and (c) maintaining the film on the mucosal surface for a period of time sufficient to allow delivery of the at least one pharmacologically active agent to a target location in the eye.

31. 31. The method of claim 30, further comprising removing the film from the mucosal surface after the period of time.

32. 32. The method of claim 30 or 31, wherein providing a mucoadhesive film comprises providing a packaging unit containing the mucoadhesive film and removing the mucoadhesive film from the packaging unit.

33. 33. The method of any one of claims 30 to 32, wherein the film is applied to a mucosal surface at or proximal to a target location in the eye.

34. 33. The method of any one of claims 30 to 32, wherein the film is applied to the mucosal surface distal to the target ocular location and the at least one pharmacologically active agent diffuses to the target ocular location.

35. 35. The method of any one of claims 30 to 34, wherein the mucoadhesive film is applied to the mucosal surface of the eye using an applicator.

36. 36. The method of claim 35, wherein the applicator is disposable after use.

37. 33. The method of claim 32, wherein the packaging unit is tearable to expose the mucoadhesive film.

38. 33. The method of claim 32, wherein the film is sealed inside the packaging unit.

39. 39. The method of claim 38, wherein the packaging unit maintains the mucoadhesive film in a sterile or semi-sterile format.

40. 33. The method of claim 32, wherein the packaging unit is configured for single use.

41. 33. The method of claim 32, wherein the packaging unit comprises a plurality of mucoadhesive films, each mucoadhesive film being individually removable from the packaging unit.

42. 42. The method of any one of claims 30 to 41, wherein the film comprises a bioabsorbable or bioerodible element for controllably diffusing the at least one pharmacologically active agent at the target location.

43. 43. The method of any one of claims 30 to 42, wherein the at least one pharmacologically active agent comprises a plurality of pharmacologically active agents.

44. 44. The method of any one of claims 30 to 43, wherein the film is shaped to conform to the shape of the ocular mucosal surface at or near the eye.

45. 45. The method of claim 44, wherein the mucosal surface of the eye is a surface located on one or more of the eyelid margin, palpebral conjunctiva, fornix, bulbar conjunctiva, corneoscleral limbus, or cornea of ​​the eye.

46. 46. ​​The method of any one of claims 30-45, wherein the at least one pharmacologically active agent is selected from the group consisting of antiglaucoma medications, anti-inflammatory agents, antihistamines, antibacterial agents, antivirals, antifungals, antimetabolites, antihistamines, T-cell inhibitors, alkylating agents, biologics, azoles, fluorinated pyrimidines, adrenergic agonists, anticholinergics, anesthetics, antiseptics, prostaglandins, carbonic anhydrase inhibitors, beta-blockers, alpha-adrenergic agonists, and combinations thereof.

47. 47. The method of any one of claims 30 to 46, wherein the at least one pharmacologically active agent is formulated to treat an ophthalmic condition, wherein the ophthalmic condition is one or more of blepharitis, conjunctivitis, episcleritis, scleritis, corneal abrasion, recurrent corneal erosion syndrome, corneal ulcer, keratitis, acute anterior uveitis, iridocyclitis, uveitis, glaucoma, cystoid macular edema, phlyctenular disease, neurotrophic corneal ulcer, and persistent corneal epithelial defect.

48. 48. The method of any one of claims 30 to 47, wherein the at least one pharmacologically active agent is formulated to facilitate an ophthalmic procedure, the procedure being one or more of intravitreal injection (air pressure, drug injection), intracameral (injection, paracentesis), cataract surgery, pterygium surgery, pre-operative administration of an anesthetic, antiseptic, and / or mydriatic to facilitate a corneal procedure, and / or the treatment being one or more of antibiotics, anti-inflammatory drugs (NSAIDS / steroids), intraocular pressure lowering agents, emollients / tear supplements, and / or mydriatics.

49. 49. The method of any one of claims 30 to 48, wherein the film is maintained on the mucosal surface for a period in the range of about 1 minute to 1 hour.

50. 50. The method of any one of claims 30-49, wherein the film comprises a multilayer film including a first bioadhesive layer for adhering to a mucosal surface at an administration site and a second layer bonded to the first layer, wherein at least one of the first layer and the second layer comprises the at least one pharmacologically active agent.

51. 51. The method of claim 50, wherein the second layer is not bioadhesive.

52. 52. The method of claim 50 or claim 51, wherein the second layer limits the diffusion of the at least one pharmacologically active agent, thereby enabling a majority of the at least one pharmacologically active agent to be delivered to the target location.

53. 53. The method of claim 52, wherein the second layer comprises an inert, slowly dissolvable polymer.

54. 54. The method of any one of claims 50 to 53, wherein the first layer comprises a readily dissolvable polymer containing the at least one pharmacologically active agent.

55. 52. The method of claim 50 or claim 51, further comprising a third layer attached to the second layer, wherein the first layer and the third layer form outer layers of the thin film, and the second layer forms an inner layer of the thin film between the outer layers and comprises the at least one pharmacologically active agent.

56. 56. The method of claim 55, wherein at least one of the first layer and the third layer comprises the at least one pharmacologically active agent and / or a non-medicinal agent selected from the group consisting of an emollient, a lubricant, a lipid, and combinations thereof.

57. 57. The method of any one of claims 30 to 56, wherein the at least one pharmacologically active agent is lidocaine.

58. 58. The method of claim 57, wherein the lidocaine is present in the thin film in a dose of about 0.1 mg to about 0.50 mg.

59. 59. The method of any one of claims 30 to 58, wherein the mucosal surface of the eye comprises the superior temporal bulbar conjunctiva.

60. A drug delivery system comprising a thin film configured to be placed at an administration site in a subject's eye to administer at least one pharmacologically active agent to a target location at or near the administration site.

61. (a) a bioadhesive first layer for adhering to the mucosal surface at the administration site; (b) a second layer bonded to the first layer; and 61. The system of claim 60, comprising:

62. 62. The system of claim 61, wherein the second layer is not bioadhesive.

63. 63. The system of claim 61 or claim 62, wherein the second layer limits the diffusion of the at least one pharmacologically active agent, thereby enabling a majority of the at least one pharmacologically active agent to be delivered to the target location.

64. 64. The system of claim 63, wherein the second layer comprises an inert, slowly dissolvable polymer.

65. 65. The system of any one of claims 60 to 64, wherein the first layer comprises a readily dissolvable polymer containing the at least one pharmacologically active agent.

66. 63. The system of claim 61 or claim 62, further comprising a third layer attached to the second layer, wherein the first layer and the third layer form outer layers of the thin film, and the second layer forms an inner layer of the thin film between the outer layers and comprises the at least one pharmacologically active agent.

67. 67. The system of claim 66, wherein at least one of the first layer and the third layer comprises the at least one pharmacologically active agent and / or a non-medicinal agent selected from the group consisting of an emollient, a lubricant, a lipid, and combinations thereof.

68. 68. The system of any one of claims 60-67, wherein the at least one pharmacologically active agent is selected from the group consisting of antiglaucoma medications, anti-inflammatory agents, antihistamines, antibacterial agents, antivirals, antifungals, antihistamines, T-cell inhibitors, alkylating agents, biologics, azoles, fluorinated pyrimidines, adrenergic agonists, anticholinergics, anesthetics, antiseptics, prostaglandins, carbonic anhydrase inhibitors, beta-blockers, alpha-adrenergic agonists, and combinations thereof.

69. 69. The system of claim 68, wherein the anti-inflammatory medication comprises one or more of steroids and NSAIDs.

70. 70. The system of claim 69, wherein the steroid comprises one or more of difluprednate, loteprednol etabonate, prednisolone acetate, prednisolone sodium phosphate, rimexolone, fluorometholone acetate, and fluorometholone alcohol.

71. 71. The system of claim 69 or claim 70, wherein the NSAIDs include one or more of ketorolac tromethamine, bromfenac, nepafenac, and diclofenac.

72. 72. The system of any one of claims 68-71, wherein the antibacterial agent comprises one or more of besifloxacin, ciprofloxacin, moxifloxacin, ofloxacin, gatifloxacin, tobramycin, gentamicin, polymyxin B, trimethoprim, gramicidin, neomycin, bacitracin, azithromycin, and erythromycin.

73. 73. The system of any one of claims 68 to 72, wherein the antiviral drug comprises one or more of acyclovir, ganciclovir, trifluridine, and idoxuridine.

74. 74. The system of any one of claims 68 to 73, wherein the antifungal agent comprises one or more of nystatin, natamycin, and amphotericin B.

75. 76. The system of any one of claims 68 to 75, wherein the azole comprises one or more of ketoconazole, miconazole, fluconazole, itraconazole, econazole, clotrimazole, and voriconazole.

76. The system of any one of claims 68 to 75, wherein the fluorinated pyrimidine comprises flucytosine.

77. 77. The system of any one of claims 68 to 76, wherein the antimetabolite comprises one or more of methotrexate, mycophenolate mofetil (MMF), and azathioprine.

78. 78. The system of any one of claims 68-77, wherein the antihistamine comprises one or more of ketorolac tromethamine, ketotifen fumarate, loteprednol etabonate, bepotastine besylate, epinastine hydrochloride, emedastine fumarate, alcaftadine, azelastine hydrochloride, olopatadine hydrochloride, nedocromil sodium, lodoxamide tromethamine, and cromolyn sodium.

79. 79. The system of any one of claims 68 to 78, wherein the T cell inhibitor comprises one or more of cyclosporine, tacrolimus, and sirolimus.

80. 80. The system of any one of claims 68 to 79, wherein the alkylating agent comprises one or more of cyclophosphamide and chlorambucil.

81. The system of any one of claims 68 to 80, wherein the biological agent comprises one or more of a tumor necrosis factor (TNF) inhibitor, a lymphocyte inhibitor, and an interleukin inhibitor.

82. 82. The system of any one of claims 68 to 81, wherein the adrenergic agent comprises phenylephrine.

83. The system of any one of claims 68 to 82, wherein the anticholinergic drug comprises mydriacyl.

84. 84. The system of any one of claims 68 to 83, wherein the anesthetic agent comprises one or more of lidocaine and tetracaine.

85. 85. The system of any one of claims 68 to 84, wherein the antiseptic comprises one or more of an aqueous chlorhexidine (CHX) solution and povidone-iodine.

86. 87. The system of any one of claims 68 to 86, wherein the alpha adrenergic agonist comprises one or more of brimonidine and apraclonidine.

87. 87. The system of any one of claims 68 to 86, wherein the beta blocker comprises one or more of timolol, levobunolol, and betaxolol.

88. 88. The system of any one of claims 68 to 87, wherein the carbonic anhydrase inhibitor comprises one or more of brinzolamide and dorzolamide.

89. 89. The system of any one of claims 68 to 88, wherein the prostaglandin comprises one or more of latanoprost, tafluprost, bimatoprost, and travoprost.

90. 90. The system of any one of claims 60 to 89, wherein at least the first layer is configured to conform to the shape of an ocular structure at the administration site.

91. The system of any one of claims 60 to 90, wherein the system includes a scaffold for support against an ocular structure at the administration site.

92. 92. The system of any one of claims 60 to 91, wherein the system includes a colorant for identifying the location of the at least one pharmacologically active agent after placement of the film at the administration site.

93. 93. The system of any one of claims 60 to 92, wherein the thin film comprises a pharmaceutically acceptable, water-soluble, film-forming polymer selected from the group consisting of hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), sodium carboxymethylcellulose (CMC), polyvinyl alcohol (PVA), and hyaluronic acid (HA).

94. 94. The system of any one of claims 60 to 93, wherein the film comprises a bioabsorbable or bioerodible element for controllably diffusing the at least one pharmacologically active agent at the target location.

95. 36. The system according to any one of claims 1 to 35, comprising a packaging unit for supporting said thin film prior to deployment at said administration site.

96. 96. The system of claim 95, wherein the packaging unit maintains the pre-deployed thin film in a sterile or semi-sterile format.

97. 97. The system of claim 95 or 96, wherein the packaging unit supports a plurality of thin films.

98. 98. The system of claim 97, wherein at least a portion of the plurality of thin films are supported in a stacked state.

99. 98. The system of claim 97, wherein at least a portion of the plurality of thin films are supported in a side-by-side configuration.

100. 100. The system of claim 99, wherein at least some of the side-by-side removable strips comprising the thin film are separated from adjacent strips by perforations.

101. 101. The system of any one of claims 95 to 100, wherein the packaging unit comprises a backing layer and a plurality of separate strips removable from the backing layer, each of the strips comprising a non-medicated portion for handling and manipulation and a medicated portion comprising the thin film, the medicated portion being separable from the non-medicated portion before the thin film is deployed at the administration site.

102. 102. The system of claim 101, wherein the plurality of separate strips are manually peelable from the backing layer.

103. 103. The system of claim 101 or 102, wherein the separate strips are removable from the backing layer by a handheld applicator.

104. 104. The system of any one of claims 97 to 103, wherein at least some of the plurality of thin films comprise different pharmacologically active agents.

105. 101. The system of any one of claims 95 to 100, wherein the packaging unit comprises a backing layer and at least one strip removable from the backing layer, the at least one strip comprising a non-medicated portion for handling and manipulation, and a medicated portion comprising the thin film, the medicated portion being separable from the non-medicated portion before the thin film is deployed at the administration site.

106. 106. The system of any one of claims 60 to 105, wherein the at least one pharmacologically active agent comprises a plurality of different pharmacologically active agents.

107. 107. The system of any one of claims 60 to 106, wherein the thin film comprises a plurality of portions, the portions being aligned in a side-by-side or stacked configuration.

108. 108. The system of claim 107, wherein at least some of said portions include said at least one pharmacologically active agent.

109. 109. The system of any one of claims 60 to 108, wherein the at least one pharmacologically active agent comprises lidocaine.

110. 110. A system according to any one of claims 60 to 109 for facilitating an ophthalmic procedure and / or for treating an ophthalmic condition.

111. Use of a thin film to deliver at least one pharmacologically active agent to an administration site in the eye of a subject.

112. A drug delivery system comprising a dosage form configured to be placed at an administration site in a subject to deliver at least one pharmacologically active agent to a target location at or near the administration site.

113. The drug delivery system of claim 112, wherein the dosage form is a thin film and the administration site is the eye of the subject.

114. (a) a bioadhesive layer for adhering to the mucosal surface at the site of administration; (b) at least one other layer attached to said bioadhesive layer; and 61. The system of claim 60, comprising:

115. 115. The system of claim 114, wherein the at least one other layer comprises a plurality of other layers.

116. 21. The use of any one of claims 1 to 20, wherein the thin film is formulated to dissolve within about 1 to 60 seconds after delivery to the target ocular location, optionally within about 5 to 50 seconds after delivery to the target ocular location, optionally within about 10 to 40 seconds after delivery to the target ocular location, optionally within about 15 to 25 seconds after delivery to the target ocular location, optionally within about 15 to 20 seconds after delivery to the target ocular location.

117. 49. The method of any one of claims 30-48, wherein the film is formulated to dissolve within about 1 to 60 seconds after delivery to the target ocular location, optionally within about 5 to 50 seconds after delivery to the target ocular location, optionally within about 10 to 40 seconds after delivery to the target ocular location, optionally within about 15 to 25 seconds after delivery to the target ocular location, optionally within about 15 to 20 seconds after delivery to the target ocular location.

118. A composition, dosage form, and / or drug delivery system having any new and original feature, combination of features, or subcombination of features described herein.

119. A method having any new and original step, action, combination of steps and / or actions, or subcombination of steps and / or actions described herein.

120. Uses having any new and original feature, combination of features, or subcombination of features described in the specification.

Images