Compositions and methods for treating and preventing oral cancer

Abstract

The present disclosure relates to drug-containing patches comprising cell cycle inhibitors, such as the cyclin-dependent kinase (CDK) inhibitors described herein. The patches include an impermeable layer that functions as a barrier, e.g., to prevent to penetration of water. Upon attachment of the patch to skin or mucosa, the compound is released in order to treat and / or prevent precancerous oral conditions, oral cancer, and related diseases.

Description

COMPOSITIONS AND METHODS FOR TREATING AND PREVENTINGORAL CANCERTECHNICAL FIELD

[0001] The present disclosure relates to drug-containing patches comprising an adhesive layer and an impermeable layer. The electrospun layer includes one or more polymers and chemotherapeutic agent such as a cell cycle inhibitor, e.g., a cyclin- dependent kinase (CDK) inhibitor, which is controllably released and topically delivered to the oral mucosa at a clinically effective rate. The patches disclosed herein are therefore useful for a range of applications including the treatment and prevention of precancerous oral lesions (leukoplakia, erythroplakia, and the like), oral dysplasia and cancer of the oral cavity, The disclosed patches are also expected to address the challenges and limitations associated with surgical intervention and existing treatment options. Methods of manufacturing the patches disclosed herein are also provided.BACKGROUND

[0002] Malignant transformation of oral lesions such as leukoplakia and erythroplakia can be high (0.13% to 17% for leukoplakia and 14% to 50% for erythroplakia), particularly in certain patient populations, e.g., in individuals with ahistory of smoking and / or chewing tobacco. The primary objective of treating these and other precancerous oral lesions is to prevent them from becoming cancer. However, treatment can be challenging and outcomes are often unsatisfactory. For example, even after surgical removal, there remains a 10% to 20% chance that the lesions will return, and a 3% to 12% chance of developing cancer in the treated area.

[0003] Other than surgical intervention, which can be impractical based on the high recurrence rate, treatment options are limited. Retinoids taken orally can help reduce lesions, but relapses and side-effects are common. Carotenoids, vitamins, and other supplements have been used, but the lesions return when the supplement is stopped. Moreover, therapeutic agents delivered systemically may not be particularly suitable for treating potentially recurring precancerous lesions based on their high level of toxicity.

[0004] Accordingly, there is clearly a need in the art for new topical drug-delivery systems that provide controlled release of therapeutic agents at a targeted site (i.e., theoral mucosa) and provide sufficient exposure in order to safely and effectively treat precancerous oral lesions and related conditions, and prevent their malignant transformation to oral cancer.

[0005] The present disclosure addresses this and other unmet needs.SUMMARY

[0006] To address the aforementioned issues, the present disclosure provides electrospun mucoadhesive patches with an impermeable layer that are designed for localized, unidirectional delivery of a chemotherapeutic agent such as a cell cycle inhibitor (e.g., a CDK inhibitor) to the oral mucosa of a subject in need of treatment. The disclosed patches are expected to provide high drug-encapsulation efficiency and fast, sustainable release rates of the active agent, long residence times at the treatment site, and high patient acceptability / compliance.

[0007] Accordingly, the patches disclosed herein are useful for treating a variety diseases and conditions, including oral leukoplakia, oral dysplasia and various head and neck cancers that effect the oral mucosa. The patches disclosed herein are also useful for preventing the conversion of oral precancerous lesions and oral dysplasia to cancer.

[0008] In one aspect, the present disclosure provides a drug-containing patch comprising: (a) an adhesive layer layer, wherein the adhesive layer comprises (i) one or more polymers, and (ii) a therapeutically effective amount of a chemotherapeutic agent such as a cell cycle inhibitor; and (b) an impermeable backing layer.

[0009] In some embodiment, the adhesive layer comprises electrospun fibers. In some embodiments, the adhesive layer is a film layer. In another aspect, the present disclosure provides a drug-containing patch comprising: (a) an electrospun fiber layer, wherein the electrospun fibers comprises (i) one or more polymers, and (ii) a therapeutically effective amount of a cell cycle inhibitor; and (b) an impermeable backing layer.

[0010] In another aspect, the present disclosure provides a drug-containing patch comprising: (a) an film layer, wherein the film comprises (i) one or more polymers, and (ii) a therapeutically effective amount of a cell cycle inhibitor; and (b) an impermeable backing layer.

[0011] In some embodiments the chemotherapeutic agent is selected among cell cycle inhibitors and other therapeutic agents known to kill or inhibit the growth on cancer cells.

[0012] In some embodiments, the cell cycle inhibitor is a cyclin-dependent (CDK) inhibitor.

[0013] In some embodiments, the electrospun fiber layer comprises about 0.005% to about 20.0% (wt. / wt.%) of the CDK inhibitor. In some embodiments, the electrospun fiber layer comprises about 0.1% to about 5.0% (wt. / wt.%) of the CDK inhibitor.

[0014] In some embodiments, the CDK inhibitor is a selective CDK inhibitor. In some embodiments, the selective CDK inhibitor is a CDK4 / 6 inhibitor.

[0015] In some embodiments, the CDK inhibitor is selected from the group consisting of palbociclib, ribociclib, abemaciclib, trilaciclib, dinaciclib, riviciclib, miliciclib, samuraciclib, fadraciclib, atuveciclib, alvociclib, roniciclib, birociclib, ebvaciclib, lerociblib, dalpiciclib, voruciclib, senexin A, purvalanol, roscovitine, cinobufagin, wogonin, flavopiridol, bohemine, alsterpaullone, kenpaullone, indirubin-3 '-monoxime, resibufogenin, indisulam, MK-8776, JNJ-7706621, BMS-265246, BAY 1251152, BPI- 1178, BPI-16350, HS-10342, PF-562271 beyslate, R547, AT7519, LDC067, NU6027, AG-024322, AZD5438, AZD4573, or PHA-793887. In some embodiments, CDK inhibitor is palbociclib, ribociclib, or abemaciclib.

[0016] In some embodiments, the one or more polymers comprise one or more hydrophilic polymers disclosed herein and a bioadhesive substance disclosed herein.

[0017] In some embodiments, the one or more polymers are selected from the group consisting of polyvinylpyrrolidone, an ammonio methacrylate copolymer, polyethylene glycol, polyethylene oxide, polyacrylate, sodium polyacrylate, polyvinyl alcohol, dextran and gelatin.

[0018] In some embodiments, the one or more polymers are present in an amount ranging from about 20% to about 99% by weight of the electrospun fiber or film layer. In some embodiments, the one or more polymers is present in an amount ranging from about 60% to about 95% by weight of the electrospun fiber or film layer.

[0019] In some embodiments, the impermeable layer is an electrospun layer. In some embodiments, the impermeable layer is a film layer. In some embodiments, theimpermeable layer is hydrophobic. In some embodiments, the hydrophobic impermeable layer comprises polyethylene-co-vinyl acetate, ethylcellulose, poly caprolactone, carbothane or polysoftane. In some embodiments, the hydrophobic impermeable layer comprises polycaprolactone.

[0020] In some embodiments, the patch further comprises an absorption enhancer disclosed herein. In some embodiments the absorption enhancer is provided in the adhesive layer.

[0021] In some embodiments, the patch further comprises a plasticizer disclosed herein. In some embodiments, the plasticizer is provided in the adhesive layer and / or impermeable backing layer. In some embodiments, the plasticizer is provided in the adhesive layer. In some embodiments, the plasticizer is provided in the impermeable backing layer.

[0022] The present disclosure also provides methods for preventing the malignant transformation of a precancerous (i.e., premalignant) oral lesion to oral cancer in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a drug-containing patch disclosed herein.

[0023] In some aspects, the present disclosure provides methods for preventing the malignant transformation of oral dysplasia to oral cancer in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a drugcontaining patch disclosed herein.

[0024] In some aspects, the present disclosure provides methods for preventing the malignant transformation of oral leukoplakia to oral dysplasia in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a drugcontaining patch disclosed herein.

[0025] In some aspects, the present disclosure provides methods for preventing the malignant transformation of oral leukoplakia to oral cancer in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a drugcontaining patch disclosed herein.

[0026] In some aspects, the present disclosure provides methods for preventing the malignant transformation of oral erythroplakia to oral dysplasia in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a drugcontaining patch disclosed herein.

[0027] In some aspects, the present disclosure provides methods for preventing the malignant transformation of oral erythroplakia to oral cancer in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a drugcontaining patch disclosed herein.

[0028] In some embodiments, the present disclosure provides methods for treating a precancerous oral lesion in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a drug-containing patch disclosed herein.

[0029] In some embodiments, the present disclosure provides methods for treating oral leukoplakia or erythroplakia in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a drug-containing patch disclosed herein.

[0030] In some embodiments, the present disclosure provides methods for treating oral dysplasia in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a drug-containing patch disclosed herein.

[0031] In some embodiments, the present disclosure provides methods for treating, preventing, and / or reducing the symptoms of oral cancer in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a drugcontaining patch disclosed herein.

[0032] In some embodiments, the subject being treated for oral cancer has or was previously diagnosed with oral dysplasia.

[0033] In some embodiments, the oral cancer is squamous cell carcinoma. In some embodiments, the oral cancer is verrucous carcinoma, minor salivary gland carcinoma, or lymphoma. In some embodiments, the minor salivary gland carcinoma is selected from the group consisting of adenoid cystic carcinoma (ACC), mucoepidermoid carcinoma, polymorphous low grade adenocarcinoma, or carcinoma ex-pleomorphic adenoma.

[0034] In some embodiments, the patch is administered to the subject daily, every other day, every 3 days, every 4 days, every 5 days, every 6 days, or once a week. In some embodiments, the patch is administered daily for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, or at least 12 weeks.

[0035] In some embodiments, the patch provides a therapeutically effective amount of the chemotherapeutic agent such as the CDK inhibitor for at least about 2 h, at least about 4 h, at least about 6 h, at least about 8 h, at least about 12 h, at least about 18 h, or at least about 24 h, following application to the oral mucosa of a subject.

[0036] In one aspect, the present disclosure provides a method of preparing a patch, the process comprising (a) combining an aqueous alcoholic solvent with one or more polymers and a CDK inhibitor to provide an electrospinning mixture; (b) electrospinning the electrospinning mixture of step (a) to provide electrospun fibers; and (c) attaching an impermeable backing layer to the electrospun fibers of step (b).BRIEF DESCRIPTION OF THE DRAWINGS

[0037] FIG. 1 provides a flowchart outlining one possible strategy for developing and evaluating drug-containing patches of the present disclosure.

[0038] FIG. 2 provides a flowchart outlining one possible strategy for developing, optimizing, and evaluating drug-containing patches of the present disclosure.DEFINITIONS

[0039] For convenience, certain terms employed in the specification, examples and claims are collected here. Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0040] Throughout this disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference for all purposes in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure.

[0041] The term “about” when immediately preceding a numerical value means a range (e.g., plus or minus 10% of that value). For example, “about 50” can mean 45 to 55, “about 25,000” can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example in a list of numerical values such as “about 49, about 50, about 55, ... ” “about 50” means arange extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 52.5. Furthermore, the phrases “less than about” a value or “greater than about” a value should be understood in view of the definition of the term “about” provided herein. Similarly, the term “about” when preceding a series of numerical values or a range of values (e.g., “about 10, 20, 30” or “about 10-30”) refers, respectively to all values in the series, or the endpoints of the range.

[0042] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0043] “Optional” or “optionally” means that the subsequently described element, event or circumstances may or may not occur, and that the description includes instances where said event, element, or circumstance occurs and instances in which it does not.

[0044] As used herein, the term “impermeable layer” or “impermeable backing layer” refers to a coating or barrier layer in a layered patch configuration that prevents or substantially limits the passage of water through the layer. The impermeable layer can also prevent or substantially limit the passage of the active ingredient(s) (e.g., CDK inhibitor) through the layer.

[0045] As used herein, the term “absorption enhancer” or “permeation enhancer” refers to an additive in a patch or electrospun fibers that improves the ability of the cell cycle inhibitor to be absorbed by a targeted tissue or membrane, e.g., oral mucosa.

[0046] As used herein, the term “treating” with regard to a subject, refers to improving at least one symptom of the subject’s disorder. Treating can be curing, improving, or at least partially ameliorating a disorder. The term “therapeutic effect” as used herein refers to a desired or beneficial effect provided by the method and / or the composition. For example, the method for treating a disclosed disease or condition provides a therapeutic effect when the method reduces at least one symptom of the disease or condition in a subject.

[0047] As used herein, the term “preventing” with regard to a subject refers to reducing or eliminating the onset of the symptoms or complications of a disease, condition or disorder. In some embodiments, the symptoms or complications are reduced or eliminated in a subject that is predisposed to the disease, condition, or disorder. The patches of the present disclosure are capable of preventing or treating such diseases, condition, or disorders.

[0048] As used herein, the term “oral cancer” refers to cancers of the mucosal surfaces of the oral cavity (the mouth, including the lips, gums, tongue, inside lining of the cheeks, roof of the mouth and floor of the mouth) or the oropharynx (located behind the tonsils and the back of the throat). In some embodiments, the oral cancer originates from the flattened cells that make up the lining of the oral cavity, i.e., squamous cell carcinomas.

[0049] As used herein, "subject" include vertebrates, more specifically a mammal (e.g., a human, horse, pig, rabbit, dog, sheep, goat, non-human primate, cow, cat, guinea pig or rodent), a fish, a bird or a reptile or an amphibian. In some embodiments, the subject is a human subject. Unless otherwise specified, the term subject does not denote a particular age or sex. In some embodiments, the subject may be a geriatric subject, a pediatric subject, a teenage subject, a young adult subject, or a middle-aged subject. In some embodiments, the subject is less than about 18 years of age. In some embodiments, the subject is at least about 18 years of age. In some embodiments, the subject is about 5-10, about 10-15, about 15-20, about 20-25, about 25-30, about SO- 35, about 35-40, about 40-45, about 45-50, about 50-55, about 55-60, about 60-65, about 65-70, about 70-75, about 75-80, about 85-90, about 90-95, or about 95-100 years of age. In some embodiments the subject is a male subject. In some embodiments the subject is a female subject. In some embodiments, the subject is diagnosed with or is considered at risk of having oral dysplasia or oral cancer.

[0050] All documents cited herein are incorporated by reference in their entirety for all purposes.DETAILED DESCRIPTION

[0051] The present disclosure provides drug-containing patches that are suitable for application to the oral mucosa. As described herein, the disclosed patches adhere to the oral mucosa and controllably release a chemotherapeutic agent (such as, a CDK inhibitor) in a localized manner at a clinically effective rate. The patches disclosed herein are therefore useful for a range of applications including the treatment of precancerous oral lesions, oral dysplasia and oral cancer. Additionally, the patches disclosed herein are useful for preventing precancerous oral lesions and dysplasia from becoming oral cancer.

[0052] Highly mucoadhesive oral patches that attach to mucosal surfaces and effectively deliver an active agent are described in International Publication Nos. WO2015 / 189212, WO2017 / 085264, W02018 / 133910, and WO2018 / 133909; U.S. Patent No. 10,052,291; and U.S. Publication Nos. 2019 / 0254985, 2019 / 0254986, and 2019 / 0351662, which are hereby incorporated by reference in their entireties for all purposes.Drug-containing Patches of the Present Disclosure

[0053] In some embodiments, the present disclosure provides drug-containing patches comprising: (a) an adhesive layer, wherein the adhesive layer comprises (i) one or more polymers, and (ii) a therapeutically effective amount of a chemotherapeutic agent such as a cell cycle inhibitor; and (b) an impermeable backing layer.

[0054] In some embodiments, the cell cycle inhibitor is a biological agent. Accordingly, in some embodiments, the cell cycle inhibitor is selected from the group consisting of a monoclonal antibody, a fragment antigen-binding (Fab fragment) antibody, a single-chain variable fragment (scFv), a full antigen, a fragmented antigen, a protein, a peptide, and an enzyme.

[0055] In some embodiments, the cell cycle inhibitor is a cyclin-dependent kinase (CDK) inhibitor as disclosed herein.

[0056] In some embodiments, the present disclosure provides drug-containing patches comprising: (a) an adhesive layer, wherein the adhesive layer comprises (i) one or morepolymers, and (ii) a therapeutically effective amount of a chemotherapeutic agent sue as a CDK inhibitor; and (b) an impermeable backing layer.

[0057] In some embodiments, the adhesive layer comprises an electrospun fiber layer or a film layer. In some embodiments, the adhesive layer comprises an electrospun fiber layer. In some embodiments, the adhesive layer comprises a film layer. In some embodiments, an electrospun layer is calendared to the adhesive layer, becoming a film once attached. In some embodiments, a film is prepared directly by calendaring a film layer to an adhesive layer. In some embodiments, the adhesive layer is a mucoadhesive layer.

[0058] In some embodiments, the impermeable backing layer is an electrospun fiber layer or a film layer. In some embodiments, the impermeable backing layer comprises an electrospun fiber layer. In some embodiments, the impermeable backing layer comprises a film layer.

[0059] Accordingly, in some embodiments, the adhesive layer and the impermeable backing layer are both electrospun fiber layers. In some embodiments, the adhesive layer and the impermeable backing layer are both film layers. In some embodiments, the adhesive layer is an electrospun fiber layer and the impermeable backing layer is a film layer. In some embodiments, the adhesive layer is a film layer and the impermeable backing layer is an electrospun fiber layer.

[0060] As described herein, the electrospun fiber layer and impermeable layer can be joined to provide a patch using methods that are known to those skilled in the art, for example, the methods disclosed in International Publication No. WO / 2018 / 133909 or WO / 2018 / 133910.

[0061] In order to provide effective treatment, the patches of the present disclosure adhere to the targeted site (e.g., tissue, mucosa, skin, etc.) for a period of time sufficient to provide (i.e., release) an effective amount of a chemotherapeutic agent such as a CDK inhibitor. Accordingly, in some embodiments, the patch adheres to the targeted site for a period greater than 2 h, greater than 4 h, greater than 8 h, greater than 12 h, greater than 16 h, greater than 24 h, greater than 30 h, greater than 36 h, greater than 42 h, or greater than 48 h. In some embodiments, the patch adheres to the targeted site for a period of at least 2 h. In some embodiments, the patch adheres to the targeted site for a period of at least 4 h. In some embodiments, the patch adheres to the targeted site fora period of at least 6 h. In some embodiments, the patch adheres to the targeted site for a period of at least 8 h. In some embodiments, the patch adheres to the targeted site for a period of at least 12 h. In some embodiments, the patch adheres to the targeted site for a period of at least 24 h.

[0062] Without being bound by any particular theory, the impermeable layer, e.g., a hydrophobic impermeable layer, protects the patch from saliva and other sources of moisture in order to prevent it from detaching from the application site (skin or mucosa) prematurely. In addition, the impermeable layer facilitates the application of the patch to the mucosa by providing a non-adhesive surface that will not stick the fingers.

[0063] In some embodiments, a patch according to the present disclosure provides a therapeutically effective amount of a chemotherapeutic agent such as a cell cycle inhibitor (e.g., a CDK inhibitor) for at least about 2 h, at least about 4 h, at least about 6 h, at least about 8 h, at least about 10 h, at least about 12 h, at least about 14 h, at least about 16 h, at least about 18 h, at least about 20 h, at least about 22 h, or at least about 24 h following application to a subject in need thereof. In some embodiments, the patch provides a therapeutically effective amount of a cell cycle inhibitor (e.g., a CDK inhibitor) for at least about 4 h following application to a subject in need thereof. In some embodiments, the patch provides a therapeutically effective amount of a cell cycle inhibitor (e.g., a CDK inhibitor) for at least about 8 h following application to a subject in need thereof. In some embodiments, the patch provides a therapeutically effective amount of a cell cycle inhibitor (e.g., a CDK inhibitor) for at least about 12 h following application to a subject in need thereof.

[0064] In some embodiments, a patch according to the present disclosure is applied to a subject in need thereof (for example, the disease site of a subject) once a day, twice a day (b.i.d.), three times per day (t.i.d.), or four times a day (q.i.d.). In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) once a day. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) twice a day. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) three times per day. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) four times per day. In other embodiments, the patch is applied to a subject in need thereof on an as-needed basis.

[0065] In some embodiments, a patch according to the present disclosure is applied to a subject in need thereof (for example, the disease site of a subject) once a day for a period of about 1 to 52 weeks. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) twice a day for a period of about 1 to 52 weeks. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) three times per day for a period of about 1 to 52 weeks. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) four times per day for a period of about 1 to 52 weeks. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) once a day for a period of about 12 to 52 weeks. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) twice a day for a period of about 12 to 52 weeks. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) three times per day for a period of about 12 to 52 weeks. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) four times per day for a period of about 12 to 52 weeks. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) once a day for at least a month. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) twice a day for at least a month. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) three times per day for a period of at least a month. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) four times per day for a period of at least a month. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) once a day for at least 3 months. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) twice a day for at least 3 months. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) three times per day for a period of at least 3 months. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) four times per day for a period of at least 3 months. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) once a day for at least 6 months. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) twice aday for at least 6 months. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) three times per day for a period of at least 6 months. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) four times per day for a period of at least 6 months.

[0066] The flexibility of the patches disclosed herein can be adjusted to improve comfort and adherence to the oral mucosa. In some embodiments, the flexibility of the patch is adjusted by modifying the thickness of the patch, which comprises an electrospun layer and an impermeable layer. In some embodiments, for patches of the same or substantially similar composition, decreasing the thickness of the patch results in an increase in patch flexibility. In some embodiments, the average thickness of the patch prior to application is less than about 1 mm, less than about 0.8 mm, less than about 0.6 mm, or less than about 0.3 mm. In some embodiments, the average thickness of the patch prior to application is less than about 1 mm. In some embodiments, the average thickness of the patch prior to application is less than about 0.6 mm. In some embodiments, the average thickness of the patch prior to application is less than about 0.3 mm.

[0067] The patches of the present disclosure can be any shape and size suitable for effective treatment of the affected skin or tissue. In some embodiments, the patches of the present disclosure are circular, semicircular, oval, semioval (i.e., half-moon shaped), square, or rectangular. In some embodiments, the patches are semicircular or semioval. In some embodiments, the patches are semicircular. In some embodiments, the patches are semioval. In some embodiments, a semioval patch is from about 2 cm to about 4 cm in width and from about 5 cm to about 10 cm in length.

[0068] In some embodiments, the patches of the present disclosure further comprise one or more pharmaceutically acceptable excipients. In some embodiments, the patches further comprise a plasticizer disclosed herein. In some embodiments, the patches further comprise an absorption enhancer disclosed herein.

[0069] In some embodiments, the drug-containing patches of the present disclosure are layered compositions comprising two or more layers. For example, in some embodiments, the drug-containing patches comprise two layers. In some embodiments, the drug-containing patches comprise three layers. In some embodiments, the drug-containing patches comprise four layers. In some embodiments, the drug-containing patches comprise five layers. As described herein, such layered compositions comprise a drug-containing layer and a backing layer to protect the drug-containing layer(s) from moisture or saliva or to function as an occlusive layer, which may drive the penetration of the drug substance into the oral mucosa. When applied to the oral mucosa, a backing layer can protect the drug-containing layer from being washed away from the application site, which would result in swallowing of the composition, whereby the desired local therapeutic effect can be reduced or eliminated.

[0070] In some embodiments the drug-containing patch comprises: about 1-500 pg of a chemotherapeutic agent; about 30 g to 40 g of PVP; about 40 g to 50 g of ammonio methacrylate polymer B; about 65 g to 75 g of PEO; and about 15 g to 25 g of PCL.

[0071] In some embodiments the drug-containing patch comprises: about 1-500 pg of CDK inhibitor; about 30 g to 40 g of PVP; about 40 g to 50 g of ammonio methacrylate polymer B; about 65 g to 75 g of PEO; and about 15 g to 25 g of PCL.

[0072] In some embodiments the drug-containing patch comprises: about 1-500 pg of CDK inhibitor; about 35 g of PVP; about 44 g of ammonio methacrylate polymer B; about 71 g of PEO; and about 17 g of PCL.Adhesive LayerDrug-containing Electrospun Fiber Layer

[0073] As used in the present disclosure, the term “electrospun fibers” includes fibers that are obtained by a method that involves electrostatics. The methods, referred in the art as electrohydrodynamic (EHD) methods, include electrospinning, coaxial electrospinning, coaxial electrospraying, emulsion electrospinning, and the like. Any such method can be used to prepare the fibers of the present disclosure. Accordingly, the term “electrospun fibers” is not limited to fibers obtained by electrospinning, but instead refers to fibers obtained by electrohydrodynamic methods known in the art.

[0074] In some embodiments, the electrospun fibers are uniaxial. In some embodiments, the electrospun fibers are not coaxial. Coaxial fibers are described, for example, in H. Qu, et al. J. Mater. Chem. A, 2013, 1, 11513-11528.

[0075] In some embodiments, the electrospun fibers or the fiber layer of the patches of the present disclosure comprises about 0.005% to about 50.0% (wt. / wt.%), e.g., about 0.005%, about 0.01%, about 0.1%, about 0.5%, about 1%, about 2.5%, about 5%, about7.5%, about 10%, 12.5%, about 15%, about 17.5%, about 20%, 22.5%, about 25%, about 27.5%, about 30%, 32.5%, about 35%, about 37.5%, about 40%, 42.5%, about 45%, about 47.5%, or about 50%, of the chemotherapeutic agent such as the cell cycle inhibitor (e.g., a CDK inhibitor), including all ranges and values therebetween. In some embodiments, the electrospun fiber or fiber layer comprises about 0.005% to about 10.0% (wt. / wt.%) of the cell cycle inhibitor (e.g., a CDK inhibitor). In some embodiments, the electrospun fiber or fiber layer comprises about 0.005% to about 5.0% (wt. / wt.%) of the cell cycle inhibitor (e.g., a CDK inhibitor). In some embodiments, the electrospun fiber or fiber layer comprises about 0.005% to about 1.0% (wt. / wt.%) of the cell cycle inhibitor (e.g., a CDK inhibitor).

[0076] In general, the electrospun fibers of the present disclosure are provided in a layer, which when applied to the skin, mucosa or a humid internal surface of the body adhere to the surface. In some embodiments, a cell cycle inhibitor, e.g., CDK inhibitor such as abemaciclib, can be homogeneously distributed in the electrospun fibers, whereby the concentration of drug substance per surface area of the layer is constant and a dose of the drug substance can easily be determined by using a measured area of the layer.

[0077] In some embodiments, the electrospun fibers of the present disclosure comprise one or more polymers, a therapeutically effective amount of cell cycle inhibitor, an optional absorption enhancer, and an optional plasticizer, each of which is described in more detail below.

[0078] The electrospun fiber layer and an impermeable layer can be joined by various by various processes to provide a patch that is useful in the methods of treatment and prevention disclosed herein.Drug-containing Film Layer

[0079] The film layer for use in the presently disclosed patches can be prepared by any suitable method known in the art.

[0080] In some embodiments, a chemotherapeutic agent such as a cell cycle inhibitor, e.g., CDK inhibitor such as abemaciclib, can be homogeneously distributed in the film layer, whereby the concentration of drug substance per surface area of the layer is constant and a dose of the drug substance can easily be determined by using a measured area of the layer.

[0081] In some embodiments, the film layer of the present disclosure comprises one or more polymers, a therapeutically effective amount of a chemotherapeutic agent such as a cell cycle inhibitor, an optional absorption enhancer, and an optional plasticizer, each of which is described in more detail below.

[0082] The film layer and an impermeable layer can be joined by various processes to provide a patch that is useful in the methods of treatment and prevention disclosed herein.Plasticizer

[0083] In some embodiments, the adhesive layer comprises a plasticizer. In some embodiments, the plasticizer is selected from the group consisting of citrate esters, fatty acid esters, sebacate esters, phthalate esters, and glycol derivatives. In some embodiments, the plasticizer is selected from the group consisting of triethyl citrate, acetyl triethyl citrate, tributyl citrate, butyl stearate, glycerol monostearate, stearyl alcohol, castor oil, mineral oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, dibutyl phthalate, dioctyl phosphate, sorbitol, glycerol, triacetin, tributyrin, cellulose nitrate, polyethylene glycol, polyethylene glycol monomethyl ether, propylene glycol, or mixtures thereof. In some embodiments, the plasticizer is dibutyl sebacate.

[0084] In some embodiments, the plasticizer is present in an amount ranging from about 0.1% to about 30% by weight of the adhesive layer. In some embodiments, the plasticizer is present in an amount ranging from about 5% to about 30% by weight of the adhesive layer. In some embodiments, the plasticizer is present in an amount ranging from about 1% to about 20% by weight of the adhesive layer.Polymers of the Present Disclosure

[0085] As noted above, the adhesive layer of the drug-containing patch can be an electrospun fiber layer or a film layer.

[0086] In some embodiments, the electrospun fiber layer or film layer comprises one or more polymers selected from the group consisting of dextran, polyethylene oxides, alginate, tragacanth, carrageenan, pectin, gelatin, guar, xanthan, gellan, fibronectin, collagen, hyaluronic acid, chitosan, cellulosic polymers such as methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose, cellulose acetates, carboxymethylcellulose and alkali salts thereof, polymers of acrylic acids (PAAderivatives), chitosan, lectins, thiolated polymers, poly ox WSR, PAA-co-PEG (PEG is polyethylene glycol), polylactic acid, polyglycolic acid, poly(butylene succinate), and mixtures thereof.

[0087] In some embodiments, the electrospun fiber layer or film layer comprises one or more polymers selected from the group consisting of polyvinylpyrrolidone (PVP), acrylates and acrylic copolymers (e.g., Eudragit®), ethylcellulose (EC), hydroxypropylcellulose (HPC), polyvinyl alcohol, carboxymethylcellulose, and mixtures thereof. In some embodiments, the one or more polymers is selected from polyvinylpyrrolidone (PVP), hydroxypropylcellulose (HPC) and mixtures thereof. In some embodiments, the one or more polymers is polyvinyl alcohol or carboxymethylcellulose.

[0088] In some embodiments, the electrospun fiber layer or film layer comprises one or more polymers selected from the group consisting of ethylcellulose, polyvinylpyrrolidone, an ammonio methacrylate copolymer, polyethylene glycol, polyethylene oxide, polyacrylate, sodium polyacrylate, polyvinyl alcohol, polycaprolactone (PCL), dextran and gelatin. In some embodiments, the electrospun fiber layer or film layer comprises one or more polymers selected from the group consisting of polyvinylpyrrolidone, an ammonio methacrylate copolymer, polyethylene glycol, polyethylene oxide, polyacrylate, sodium polyacrylate, polyvinyl alcohol, polycaprolactone (PCL), dextran and gelatin. In some embodiments, the electrospun fibers comprise one or more polymers selected from the group consisting of polyvinylpyrrolidone, an ammonio methacrylate copolymer, polyethylene glycol, polyethylene oxide, polyacrylate, sodium polyacrylate, polyvinyl alcohol, dextran and gelatin.

[0089] In some embodiments, the electrospun fiber layer or film layer comprises one or more polymers selected from the group consisting of polyvinylpyrrolidone, an ammonio methacrylate copolymer, polyethylene glycol, polyethylene oxide, polyacrylate, sodium polyacrylate, polyvinyl alcohol, dextran and gelatin.

[0090] In some embodiments, the one or more polymers comprises one or more hydrophilic polymers and a bioadhesive substance.

[0091] In some embodiments, the one or more hydrophilic polymers is polyvinylpyrrolidone (PVP), acrylates and acrylic copolymers (e.g., Eudragit®),ethylcellulose (EC), hydroxypropylcellulose (HPC), or mixtures thereof; and the bioadhesive substance is dextran, polyethylene oxides, alginate, tragacanth, carrageenan, pectin, gelatin, guar, xanthan, gellan, fibronectin, collagen, hyaluronic acid, chitosan, cellulosic polymers (e.g., methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose, cellulose acetates, carboxymethylcellulose and alkali salts thereof), polyvinylalcohol (PVA), polymers of acrylic acids (PAAs), chitosan, lectins, thiolated polymers, polyox WSR, PAA-co- polyethylene glycol (PAA-co-PEG), polylactic acid, polyglycolic acid, poly(butylene succinate), or mixtures thereof.

[0092] In some embodiments, the one or more hydrophilic polymers is polyvinylpyrrolidone (PVP), ammonio methacrylate polymer type B, or mixtures thereof; and the bioadhesive substance is dextran, polyethylene oxides (e.g., poly ox WSR), gelatin, polyvinylalcohol (PVA), or mixtures thereof.

[0093] In some embodiments, the one or more polymers comprise: (a) polyvinylpyrrolidone and an ammonio methacrylate copolymer; (b) polyvinylpyrrolidone and polyethylene glycol; (c) polyvinylpyrrolidone and polyethylene oxide; (d) polyvinylpyrrolidone and dextran; (e) polyvinylpyrrolidone and gelatin; (f) polyvinylpyrrolidone and polyvinyl alcohol; (g) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyethylene glycol; (h) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyethylene oxide; (i) polyvinylpyrrolidone, an ammonio methacrylate copolymer and dextran; (j) polyvinylpyrrolidone, an ammonio methacrylate copolymer and gelatin; (k) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyvinyl alcohol; (1) polyvinylpyrrolidone and an ethylcellulose; (m) polyvinylpyrrolidone, an ethylcellulose and polyethylene glycol; (n) polyvinylpyrrolidone, an ethylcellulose and polyethylene oxide; (o) polyvinylpyrrolidone, an ethylcellulose and dextran; (p) polyvinylpyrrolidone, an ethylcellulose and gelatin; or (q) polyvinylpyrrolidone, an ethylcellulose and polyvinyl alcohol.

[0094] In some embodiments, the one or more polymers comprise: (a) polyvinylpyrrolidone and an ammonio methacrylate copolymer; (b) polyvinylpyrrolidone and polyethylene glycol; (c) polyvinylpyrrolidone and polyethylene oxide; (d) polyvinylpyrrolidone and dextran; (e) polyvinylpyrrolidone and gelatin; (f) polyvinylpyrrolidone and polyvinyl alcohol; (g) polyvinylpyrrolidone, anammonio methacrylate copolymer and polyethylene glycol; (h) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyethylene oxide; (i) polyvinylpyrrolidone, an ammonio methacrylate copolymer and dextran; j) polyvinylpyrrolidone, an ammonio methacrylate copolymer and gelatin; or (k) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyvinyl alcohol.

[0095] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone and ammonio methacrylate copolymer. In some embodiments, the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer in the electrospun fibers is about 0.1 to about 10, including, about 0.1, about 0.25, about 0.5, about 0.75, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10, including all ranges and values therebetween. In some embodiments, the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer is about 0.5 to about 5. In some embodiments, the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer is about 0.5 to about 2.

[0096] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone and polyethylene glycol. In some embodiments, the weight ratio of polyvinylpyrrolidone to polyethylene glycol in the electrospun fibers is about 0.15 to about 10, e.g., including 0.15, about 0.5, about 0.75, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10, including all ranges and values therebetween. In some embodiments, the weight ratio of polyvinylpyrrolidone to polyethylene glycol is about 0.25 to about 5. In some embodiments, the weight ratio of polyvinylpyrrolidone to polyethylene glycol is about 0.5 to about 2.

[0097] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone and polyethylene oxide. In some embodiments, the weight ratio of polyvinylpyrrolidone to polyethylene oxide in the electrospun fibers is about 0.3 to about 10, including, about 0.3, about 0.5, about 0.75, about 1, about 1.5, about 2, about2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10, including all ranges and values therebetween. In some embodiments, the weight ratio of polyvinylpyrrolidone to polyethylene oxide is about 0.3 to about 5. In someembodiments, the weight ratio of polyvinylpyrrolidone to polyethylene oxide is about 0.5 to about 2.

[0098] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone and dextran. In some embodiments, the weight ratio of polyvinylpyrrolidone to dextran in the electrospun fibers is about 0.3 to about 10, including about 0.3, about 0.5, about 0.75, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about7.5, about 8, about 8.5, about 9, about 9.5, or about 10, including all ranges and values therebetween. In some embodiments, the weight ratio of polyvinylpyrrolidone to dextran is about 0.3 to about 5. In some embodiments, the weight ratio of polyvinylpyrrolidone to dextran is about 0.5 to about 2.

[0099] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone and gelatin. In some embodiments, the weight ratio of polyvinylpyrrolidone to gelatin in the electrospun fibers is about 0.6 to about 10, including about 0.6, about 0.8, about 1, about 1.5, about 2, about 2.5, about 3, about3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10, including all ranges and values therebetween. In some embodiments, the weight ratio of polyvinylpyrrolidone to gelatin is about 0.6 to about 5. In some embodiments, the weight ratio of polyvinylpyrrolidone to gelatin is about 1 to about 3.

[0100] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone and polyvinyl alcohol. In some embodiments, the weight ratio of polyvinylpyrrolidone to polyvinyl alcohol in the electrospun fibers is about 0.5 to about 10, including about 0.5, about 0.75, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10, including all ranges and values therebetween. In some embodiments, the weight ratio of polyvinylpyrrolidone to polyvinyl alcohol is about 0.5 to about 5. In some embodiments, the weight ratio of polyvinylpyrrolidone to polyvinyl alcohol is about 1 to about 3.

[0101] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyethylene glycol. In some embodiments, the weight ratio of polyvinylpyrrolidone to ammoniomethacrylate copolymer to polyethylene glycol in the electrospun fibers is about 1 : 0.5 : 0.1 to about 1 : 2 : 6, including all ranges and values therebetween.

[0102] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyethylene oxide. In some embodiments, the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer to polyethylene oxide in the electrospun fibers is about 1 : 0.5 : 0.1 to about 1 : 2 : 3, including all ranges and values therebetween.

[0103] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone, an ammonio methacrylate copolymer and dextran. In some embodiments, the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer to dextran in the electrospun fibers is about 1 : 0.5 : 0.1 to about 1 : 2 : 3, including all ranges and values therebetween.

[0104] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone, an ammonio methacrylate copolymer and gelatin. In some embodiments, the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer to gelatin in the electrospun fibers is about 1 : 0.5 : 0.1 to about 1 : 2 : 1.5, including all ranges and values therebetween.

[0105] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyvinyl alcohol. In some embodiments, the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer to polyvinyl alcohol in the electrospun fibers is about 1 : 0.5 : 0.1 to about 1 : 2 : 2, including all ranges and values therebetween.

[0106] In some embodiments, the electrospun fibers of the present disclosure comprise one or more polymers (as described herein), typically including hydrophilic polymers, which provide various desirable properties, e.g., providing for rheological properties suitable for electrospinning, physical properties (e.g., strength, flexibility, etc.) to provide a patch that is sufficiently durable for handling during manufacturing and use and sufficiently flexible such that it can conform to a mucosal surface, and a suitable degree of hydrophilicity for application to mucosal surfaces. Such polymers can provide bioadhesive properties to aid in adhesion to a mucosal surface. As desired, one or more additional polymers can be added to improve bioadhesion. In particular embodiments, the electrospun fibers of the present disclosure comprisepolyvinylpyrrolidone and acrylic copolymers (e.g., Eudragit® copolymers), in combination with polyethylene oxide polymers. Such electrospun fiber compositions are described, for example, in US Patent No. 10,052,291, US Patent Publication Nos. 2019 / 0254985, and 2019 / 0254986, 2019 / 0351662.

[0107] When polyvinylpyrrolidone is used as a polymer in the electrospun fibers, it can be used in a grade having an approximate molecular weight of from 2,500 Da to 3,000,000 Da. PVP can be purchased as Kollidon® having a variety of molecular weight ranges as shown below.

[0108] Ethylcellulose is sold under the trademark ETHOCEL™ (Dow Chemical Company) and is available in different grades. Dependent on its ethoxyl content, ethylcellulose may have different softening point and melting point temperatures. Ethylcellulose is also produced in a number of different viscosities (see Table below).

[0109] Acrylates and acrylic acid derivatives include polymethacrylates, methacrylate copolymers, acrylic copolymers and methacrylate polymers, and include acrylates sold as EUDRAGIT as well as acrylates / octaacrylamide sold as DERMACRYL 79. Nonlimiting example of such acrylates are EUDRAGIT®E 12,5 (amino methacrylate copolymer), EUDRAGIT® El 00 (amino methacrylate copolymer; basic butylated methacrylate copolymer), EUDRAGIT®E PO ((amino methacrylate copolymer), EUDRAGIT®L 100-55, EUDRAGIT®L 100 (methacrylic acid - methyl methacrylate copolymer 1:1), EUDRAGIT®S 100 (methacrylic acid-methyl methacrylate copolymer 1:2), EUDRAGIT®RL 100, EUDRAGIT®RL 100 (ammonio methacrylate copolymer type A), EUDRAGIT®RL PO, EUDRAGIT®RS 100 (ammonio methacrylate copolymer type B), EUDRAGIT®RS PO. EUDRAGIT®E is a cationic polymer based on dimethylaminoethyl methacrylate and other neutral methacrylic acid esters: EUDRAGIT®L and S are methacrylic acid copolymers and are cationic copolymerization products of methacrylic acid and methyl methacrylate. EUDRAGIT®RL or RS is ammonio methacrylate copolymers synthesized from acrylic acid and methacrylic acid.

[0110] Carboxymethylcellulose is available in a broad selection of viscosity grades. In some embodiments, the viscosity of carboxymethylcellulose in the electrospun fibers ranges from 10 to 100,000 mPa*s. In some embodiments, the carboxymethylcellulose is a sodium salt.

[0111] Methylcellulose is sold under the name METHOCEL™ (Dow Chemical Company) and is available in a wide range of viscosity grades. In some embodiments, the viscosity grade of methylcellulose in the electrospun fibers is from less than about 3 to greater than about 100,000 mPA*s.

[0112] HPMC is sold under the names Methocel® and Klucel®. In some embodiments, HPMC of the electrospun fibers has an average molecular weight of from about 80,000 to about 140,000.

[0113] In some embodiments, polyvinyl alcohol has a molecular weight ranging from about 20,000 Da to about 200,000. In some embodiments, polyvinyl alcohol has a molecular weight ranging from about 100,000 Da to about 200,000.

[0114] In some embodiments, polyethylene oxide (PEO), which is sold commercial under the name POLYOX™ (Dow Chemical Company), has average molecular weights ranging from about 100,000 Da to about 4,000,000 Da. In some embodiments, the average molecular weight of the PEO is from about 100,000 Da to about 4,000,000 Da. In some embodiments, the average molecular weight of the PEO is from about 100,000 Da to about 2,000,000 Da. In some embodiments, the PEO has an average molecular weight of from about 100,000 Da to about 1,000,000 Da. In some embodiments, the PEO has an average molecular weight of from about 100,000 Da to about 700,000 Da. In some embodiments, the PEO has an average molecular weight of from about 100,000 Da to about 500,000 Da. In some embodiments, the PEO has an average molecular weight of from about 100,000 Da to about 400,000 Da. In some embodiments, the PEO has an average molecular weight of about 100,000 Da. In some embodiments, the PEO has an average molecular weight of about 200,000 Da. In some embodiments, the PEO has an average molecular weight of about 300,000 Da. In some embodiments, the PEO has an average molecular weight of about 400,000 Da.

[0115] In some embodiments, dextran is used in grade having a molecular weight of from about 400,000 Da to about 2,000,000 Da. In some embodiments, dextran has a molecular weight of from about 500,000 Da to about 2,000,000 Da, e.g., about 700,000 Da to about 800,000 Da or from about 1,000,000 Da to about 2,000,000 Da. In some embodiments, dextran has a molecular weight of from about 100,000 Da to about 1,000,000 Da. In some embodiments, dextran has a molecular weight of from about 100,000 Da to about 700,000 Da. . In some embodiments, dextran has a molecular weight of from about 100,000 Da to about 500,000 Da. In some embodiments, dextran has a molecular weight of from about 400,000 Da to about 1,000,000 Da. In some embodiments, dextran has a molecular weight of from about 400,000 Da to about 700,000 Da.

[0116] In some embodiments, the one or more polymers is present in an amount ranging from about 20% to about 99% by weight of the electrospun fibers, including about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99%, including all ranges and values therebetween. In some embodiments, the one or more polymers is present in an amount ranging from about 50% to about 99% by weight of the electrospun fibers. In some embodiments,the one or more polymers is present in an amount ranging from about 60% to about 99% by weight of the electrospun fibers. In some embodiments, the one or more polymers is present in an amount ranging from about 75% to about 99% by weight of the electrospun fibers. In some embodiments, the one or more polymers is present in an amount ranging from about 50% to about 95% by weight of the electrospun fibers. In some embodiments, the one or more polymers is present in an amount ranging from about 60% to about 95% by weight of the electrospun fibers. In some embodiments, the one or more polymers is present in an amount ranging from about 75% to about 95% by weight of the electrospun fibers. In some embodiments, the one or more polymers is present in an amount ranging from about 50% to about 90% by weight of the electrospun fibers. In some embodiments, the one or more polymers is present in an amount ranging from about 60% to about 30% by weight of the electrospun fibers. In some embodiments, the one or more polymers is present in an amount ranging from about 75% to about 90% by weight of the electrospun fibers. In some embodiments, the one or more polymers is present in an amount ranging from about 50% to about 90% by weight of the electrospun fibers. In some embodiments, the one or more polymers is present in an amount ranging from about 20% to about 60% by weight of the electrospun fibers. In some embodiments, the one or more polymers is present in an amount ranging from about 20% to about 50% by weight of the electrospun fibers. In some embodiments, the one or more polymers is present in an amount ranging from about 20% to about 40% by weight of the electrospun fibers.Chemotherapeutic agents

[0117] The chemotherapeutic agents may in principle be any drug or agent capable of killing or inhibiting growth or cancer cells or any agent that is capable of inhibiting the transformation of precancerous cells to cancer cells.

[0118] The chemotherapeutic agents preferably selected among cell cycle inhibitors and chemotherapeutic drugs as known in the art as well as combinations thereof.

[0119] In some embodiments the chemotherapeutic agents are selected among therapeutically active chemical or biological agents. Examples of preferred chemotherapeutic agents includes cell cycle inhibitors.

[0120] In some embodiments, the chemotherapy drug is imiquimod, cisplatin, carboplatin, 5 -fluorouracil (5-FU), paclitaxel, docetaxel, hydroxyurea, methotrexate, capecitabine, or mixtures thereof. In some embodiments, the chemotherapy drug is imiquimod, 5 -fluorouracil (5-FU), or a combination thereof.

[0121] In some embodiments, the therapeutic agent is a targeted therapeutic, e.g., a drug that targets epidermal growth factor receptor (EFGR). In some embodiments, the targeted therapeutic is cetuximab.

[0122] In some embodiments, the therapeutic agent is an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is pembrolizumab or nivolumab.Cell Cycle Inhibitors

[0123] As disclosed herein, the adhesive layer of the drug-containing patch can include a therapeutically effective amount of a cell cycle inhibitor.

[0124] In some embodiments, the cell cycle inhibitor is a cyclin-dependent kinase (CDK) inhibitor. In some embodiments, the CDK inhibitor is a pan CDK inhibitor. In some embodiments, the compound is a selective CDK inhibitor. In some embodiments, the selective CDK inhibitor is a CDK2 / 4 / 6 inhibitor. In some embodiments, the selective CDK inhibitor is a CDK4 / 6 inhibitor. In some embodiments, the selective CDK inhibitor is a CDK4 inhibitor. In some embodiments, the selective CDK inhibitor is a CDK1 / 4 / 6 inhibitor. In some embodiments, the selective CDK inhibitor is a CDK2 / 4 / 7 inhibitor. In some embodiments, the selective CDK inhibitor is a CDK4 / 6 / 9 inhibitor. In some embodiments, the selective CDK inhibitor is a CDK6 / 9 inhibitor. In some embodiments, the selective CDK inhibitor is a CDK9 inhibitor.

[0125] In some embodiments, the CDK inhibitor is palbociclib, ribociclib, abemaciclib, trilaciclib, dinaciclib, riviciclib, miliciclib, samuraciclib, fadraciclib, atuveciclib, alvociclib, roniciclib, birociclib, ebvaciclib, lerociblib, dalpiciclib, voruciclib, senexin A, purvalanol, roscovitine, cinobufagin, wogonin, flavopiridol, bohemine, alsterpaullone, kenpaullone, indirubin-3 '-monoxime, resibufogenin, indisulam, MK- 8776, JNJ-7706621, BMS-265246, BAY 1251152, BPI-1178, BPI-16350, HS-10342, PF-562271 beyslate, R547, AT7519, LDC067, NU6027, AG-024322, AZD5438, AZD4573, or PHA-793887.

[0126] In some embodiments, the CDK inhibitor is palbociclib, ribociclib, abemaciclib, trilaciclib, dinaciclib, riviciclib, milciclib, samuraciclib, fadraciclib, atuveciclib, ebvaciclib, birociclib, lerociclib, voruciclib, or auceliciclib. In some embodiments, the CDK inhibitor is palbociclib, ribociclib, or abemaciclib. In some embodiments, the CDK inhibitor is abemaciclib. In some embodiments, the CDK inhibitor is ribociclib. In some embodiments, the CDK inhibitor is palbociclib.

[0127] Abemaciclib ([5-(4-ethyl-piperazin-l-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7- fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-amine), sold under the brand name Verzenio®, is a CDK inhibitor selective for CDK4 and CDK6 that has the structure:, or a pharmaceutically acceptable salt thereof. Selective benzimidazolyl CDK inhibitors, including abemaciclib and crystalline forms thereof, their methods of use in treating cancer, and methods of preparation are disclosed in U.S. Patent No. 7,855,211, which is incorporated herein by reference in its entirety.

[0128] Palbociclib (6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(l-piperazinyl)-2- pyridinyl]amino]-pyrido[2,3-d]pyrimidin-7(8H)-one), sold under the brand name Ibrance®, is a CDK inhibitor selective for CDK4 and CDK6 that has the structure:, or a pharmaceutically acceptable salt thereof.Selective pyrrolopyrimidine CDK inhibitors, including palbociclib and crystalline forms thereof, their methods of use in treating cancer, and methods of preparation are disclosed in U.S. Patent Nos. 6,936,612, 10,723,730 and RE47739, which are incorporated herein by reference in their entirety.

[0129] Ribociclib (7-cyclopentyl- V, V-dimethyl-2-[[5-(l-piperazinyl)-2-pyridinyl]- amino]-7 7-pyrrolo[2,3-<7]pyrimidine-6-carboxamide), sold under the brand nameKisqali®, is a CDK inhibitor selective for CDK4 and CDK6 that has the structure:pharmaceutically acceptable salt thereof, e.g. a succinate salt. Selective pyrrolopyrimidine CDK inhibitors, including riboci clib, their methods of use in treating cancer, and methods of preparation are disclosed inU.S. Patent Nos. 8,324,225, 8,415,355, 8,685,980, 8,962,630, and 9,193,732, which are incorporated herein by reference in their entirety.

[0130] In some embodiments, the CDK inhibitor is present in the electrospun fibers in an amount ranging from about 0.005% to about 50.0% (wt. / wt.%). In someembodiments, the CDK inhibitor is present in the electrospun fibers in an amount ranging from about 0.01% to about 50.0% (wt. / wt.%). In some embodiments, the CDK inhibitor is present in the electrospun fibers in an amount ranging from about 0.01% to about 40.0% (wt. / wt.%) . In some embodiments, the CDK inhibitor is present in the electrospun fibers in an amount ranging from about 0.005% to about 30.0% (wt. / wt.%). In some embodiments, the CDK inhibitor is present in the electrospun fibers in an amount ranging from about 0.005% to about 20.0% (wt. / wt.%). In some embodiments, the CDK inhibitor is present in the electrospun fibers in an amount ranging from about 0.005% to about 10.0% (wt. / wt.%). In some embodiments, the CDK inhibitor is present in the electrospun fibers in an amount ranging from about 0.005% to about 5.0% (wt. / wt.%). In some embodiments, the CDK inhibitor is present in the electrospun fibers in an amount ranging from about 0.005% to about 2.5% (wt. / wt.%). In some embodiments, the CDK inhibitor is present in the electrospun fibers in an amount ranging from about 0.005% to about 1.0% (wt. / wt.%). In some embodiments, the CDK inhibitor is present in the electrospun fibers in an amount ranging from about 0.01% to about 5.0% (wt. / wt.%).In some embodiments, the CDK inhibitor is present in the electrospun fibers in an amount ranging from about 0.01% to about 2.5% (wt. / wt.%). In some embodiments, the CDK inhibitor is present in the electrospun fibers in an amount ranging from about 0.01% to about 1% (wt. / wt.%).

[0131] In some embodiments, the cell cycle inhibitor included in the drug-containing patch is a biological agent. In some embodiments, the biological agent is selected from the group consisting of a monoclonal antibody, a fragment antigen-binding (Fab fragment) antibody, a single-chain variable fragment (scFv), a full antigen, a fragmented antigen, a protein, a peptide, and an enzyme.

[0132] In some embodiments, the biological agent is present in the electrospun fibers in an amount ranging from about 0.005% to about 50.0% (wt. / wt.%). In some embodiments, the biological agent is present in the electrospun fibers in an amount ranging from about 0.01% to about 50.0% (wt. / wt.%). In some embodiments, the biological agent is present in the electrospun fibers in an amount ranging from about 0.01% to about 40.0% (wt. / wt.%) . In some embodiments, the biological agent is present in the electrospun fibers in an amount ranging from about 0.005% to about 30.0% (wt. / wt.%). In some embodiments, the biological agent is present in the electrospun fibers in an amount ranging from about 0.005% to about 20.0% (wt. / wt.%).In some embodiments, the biological agent is present in the electrospun fibers in an amount ranging from about 0.005% to about 10.0% (wt. / wt.%). In some embodiments, the biological agent is present in the electrospun fibers in an amount ranging from about 0.005% to about 5.0% (wt. / wt.%). In some embodiments, the biological agent is present in the electrospun fibers in an amount ranging from about 0.005% to about 2.5% (wt. / wt.%). In some embodiments, the biological agent is present in the electrospun fibers in an amount ranging from about 0.005% to about 1.0% (wt. / wt.%). In some embodiments, the biological agent is present in the electrospun fibers in an amount ranging from about 0.01% to about 5.0% (wt. / wt.%).In some embodiments, the biological agent is present in the electrospun fibers in an amount ranging from about 0.01% to about 2.5% (wt. / wt.%). In some embodiments, the biological agent is present in the electrospun fibers in an amount ranging from about 0.01% to about 1% (wt. / wt.%).Combination of Cell cycle inhibitors and a Therapeutically Active Agents

[0133] In some embodiments, the electrospun fibers of the drug-containing patches of the present disclosure in addition to a cell cycle inhibitor comprise an effective amount of an additional therapeutic agent.

[0134] In some embodiments, the additional therapeutic agent is a chemotherapy drug. In some embodiments, the chemotherapy drug is imiquimod, cisplatin, carboplatin, 5- fluorouracil (5-FU), paclitaxel, docetaxel, hydroxyurea, methotrexate, capecitabine, or mixtures thereof. In some embodiments, the chemotherapy drug is imiquimod, 5- fluorouracil (5-FU), or a combination thereof.

[0135] In some embodiments, the additional therapeutic agent is a targeted therapeutic, e.g., a drug that targets epidermal growth factor receptor (EFGR). In some embodiments, the targeted therapeutic is cetuximab.

[0136] In some embodiments, the additional therapeutic agent is an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is pembrolizumab or nivolumab.Impermeable Layer

[0137] To prevent premature detachment from the skin or mucosal surface as well as other therapeutic benefits, the patches of the present disclosure comprise an impermeable layer.

[0138] In some embodiments, the impermeable layer is provided as a coating disposed on a drug-containing layer. In some embodiments, the impermeable layer is co-spun with the drug-containing, and is therefore integrated into the electrospun fibers. In some embodiments, the impermeable layer is a backing layer.

[0139] In some embodiments, the backing layer is a film layer. In some embodiments, the backing layer is an electrospun layer.

[0140] In some embodiments, the impermeable backing layer comprises a plasticizer. In some embodiments, the plasticizer is selected from the group consisting of citrate esters, fatty acid esters, sebacate esters, phthalate esters, and glycol derivatives. In some embodiments, the plasticizer is selected from the group consisting of triethyl citrate, acetyl triethyl citrate, tributyl citrate, butyl stearate, glycerol monostearate, stearyl alcohol, castor oil, mineral oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, dibutyl phthalate, dioctyl phosphate, sorbitol, glycerol, triacetin, tributyrin, cellulose nitrate, polyethylene glycol, polyethylene glycol monomethyl ether, propylene glycol, or mixtures thereof. In some embodiments, the plasticizer is dibutyl sebacate.

[0141] In some embodiments, the plasticizer is present in an amount ranging from about 0.1% to about 30% by weight of the backing layer. In some embodiments, the plasticizer is present in an amount ranging from about 5% to about 30% by weight of the backing layer. In some embodiments, the plasticizer is present in an amount ranging from about 1% to about 20% by weight of the backing layer.

[0142] In some embodiments, the impermeable layer is a hydrophobic impermeable layer.

[0143] In some embodiments, the impermeable hydrophobic layer protects the drugcontaining layer(s) from moisture or saliva. In some embodiments, the impermeable layer protects the drug-layer from being washed away from the application site, which results in the desired local therapeutic effect being reduced or eliminated. In some embodiments, the impermeable layer functions as an occlusive layer, which drives the penetration of drug substance into the skin or mucosa.

[0144] In some embodiments, the impermeable layer comprises one or more biodegradable polyesters. In some embodiments, the biodegradable polyester is an aliphatic polyester. In some embodiments, the biodegradable polyester is an aromaticpolyester. In some embodiments, the impermeable layer comprises one or more polymers selected from the group consisting of poly(caprolactone), poly(gly colic acid), poly(lactic acid), poly(lactide-co-glycolide), poly(butylene succinate), poly(butylene succinate-co-adipate), poly( / ?-dioxanone). and poly(trimethylene carbonate). In some embodiments, the impermeable layer comprises one or more polymers selected from the group consisting of poly(caprolactone), poly(glycolic acid), poly(lactic acid), and poly(lactide-co-glycolide). In some embodiments, the impermeable layer comprises poly(caprolactone). In some embodiments, the hydrophobic backing layer comprises polycaprolactone or ethyl cellulose plasticized with dibutyl sebacate. In some embodiments, the hydrophobic backing layer comprises polycaprolactone. In some embodiments, the hydrophobic backing layer comprises ethyl cellulose plasticized with dibutyl sebacate.

[0145] In some embodiments, the impermeable layer comprises polyethylene-co-vinyl acetate, ethylcellulose, poly(caprolactone), carbothane or polysoftane. In some embodiments, the impermeable layer comprises acrylates / octylacrylamide copolymer (sold under the name DERMACRL® 79), amino methacrylate copolymer (EUDRAGIT®), dimethylaminoethyl methacrylate, methacrylate, methyl methacrylate (e.g. EUDRAGIT ®E 100), or other acrylates.

[0146] In some embodiments, the impermeable layer comprises about 5-70% by weight of the patch, including about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, including all values and ranges therebetween, by weight of the patch. In some embodiments, the impermeable layer comprises about 5-50% by weight of the patch. In some embodiments, the impermeable layer comprises about 10-30% by weight of the patch.Methods of Treatment

[0147] In some embodiments, the present disclosure provides methods of treating or preventing an oral disease or disorder in a subject in need thereof by administering a drug-containing patch as disclosed herein to the oral cavity (e.g., the oral mucosa) of the subject. In some embodiments, the disease or disorder is an oral precancerous condition (e.g., a precancerous lesion, dysplasia, etc.), oral cancer, or a related condition.

[0148] In some embodiments, the present disclosure provides methods of treating a precancerous oral lesion in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a drug-containing patch disclosed herein.

[0149] In some embodiments, the present disclosure provides methods of preventing the malignant transformation of a precancerous oral lesion to oral cancer in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a drug-containing patch disclosed herein.

[0150] In some embodiments, the present disclosure provides methods of treating a precancerous oral lesion in a subject in need thereof, the method comprising administering to the subject an effective amount of a chemotherapeutic agent such as a CDK inhibitor, wherein the CDK inhibitor is administered topically via a drugcontaining patch disclosed herein.

[0151] In some embodiments, the precancerous oral lesion comprises leukoplakia, and / or erythroplakia. In some embodiments, the precancerous oral lesion comprises leukoplakia. In some embodiments, the precancerous oral lesion comprises erythroplakia. In some embodiments, the leukoplakia is dysplastic leukoplakia. In some embodiments, the erythroplakia is dysplastic erythroplakia.

[0152] In some embodiments, the present disclosure provides methods of treating oral dysplasia in a subject in need thereof, the method comprising administering a patch disclosed herein to the oral mucosa of the subject.

[0153] In some embodiments, the present disclosure provides methods of preventing the malignant transformation of oral dysplasia to oral cancer in a subj ect in need thereof, the method comprising administering to the oral mucosa of the subject a drugcontaining patch disclosed herein.

[0154] In some embodiments, the oral dysplasia comprises leukoplakia, and / or erythroplakia. In some embodiments, the leukoplakia is dysplastic leukoplakia. In some embodiments, the erythroplakia is dysplastic erythroplakia. In some embodiments, the leukoplakia and / or erythroplakia are homogenous. In some embodiments, the leukoplakia and / or erythroplakia are irregular shaped patches that may be flat, nodular, or verrucous. Such leukoplakia, referred to as non-homogenous, is seven times more likely to become cancerous than homogenous leukoplakia arecharacterized as being evenly colored thin patches with a smooth, wrinkled or rigid surface that is consistent throughout.

[0155] In some embodiments, the present disclosure provides methods of treating oral leukoplakia in a subject in need thereof, the method comprising administering a patch disclosed herein to the oral mucosa of the subject.

[0156] In some embodiments, the present disclosure provides methods of preventing the malignant transformation of oral leukoplakia to oral cancer in a subject in need thereof, the method comprising administering a patch disclosed herein to the oral mucosa of the subject.

[0157] In some embodiments, the present disclosure provides methods of treating or preventing oral cancer in a subject in need thereof, the method comprising administering a patch disclosed herein to the oral mucosa of the subject.

[0158] In some embodiments, the present disclosure provides methods of treating or preventing oral cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of chemotherapeutic agent such as a CDK inhibitor, wherein the chemotherapeutic agent such as the CDK inhibitor is administered topically via a drug-containing patch disclosed herein.

[0159] In some embodiments, the oral cancer is squamous cell carcinoma. In some embodiments, the oral cancer is verrucous carcinoma, minor salivary gland carcinoma, or lymphoma. In some embodiments, the minor salivary gland carcinoma is selected from the group consisting of adenoid cystic carcinoma (ACC), mucoepidermoid carcinoma, polymorphous low grade adenocarcinoma, or carcinoma ex-pleomorphic adenoma.

[0160] In some embodiments, the oral dysplasia or cancer comprises leukoplakia and / or erythroplakia. In some embodiments, the leukoplakia is dysplastic leukoplakia. In some embodiments, the erythroplakia is dysplastic erythroplakia. In some embodiments, the leukoplakia is proliferative leukoplakia. In some embodiments, the erythroplakia is proliferative erythroplakia.

[0161] In some embodiments, the subject in need of treatment previously had surgical intervention to remove dysplastic precancerous oral lesions. In some embodiments, the subject in need of treatment by the present methods experienced a recurrence of precancerous oral lesions (e.g., leukoplakia and / or erythroplakia). In someembodiments, the recurrence occurred after surgical intervention to remove one or more dysplastic precancerous oral lesions.

[0162] In some embodiments, a subject being treated for cancer according to the present methods was previously treated with cisplatin, carboplatin, 5 -fluorouracil, paclitaxel, docetaxel, hydroxyurea, methotrexate, capecitabine, or a combination thereof. In some embodiments, a subject being treated for cancer according to the present methods is undergoing concurrent treatment with cisplatin, carboplatin, 5- fluorouracil, paclitaxel, docetaxel, hydroxyurea, methotrexate, capecitabine, or a combination thereof.

[0163] In some embodiments, treatment comprises one or more of: reducing an area of leukoplakia, eliminating leukoplakia, alleviating abnormal hyperplasia of leukoplakia, reversing to simple hyperplasia, and transforming leukoplakia to normal mucosa.

[0164] In some embodiments, a patch of the present disclosure is administered once a day. In some embodiments, the patch is administered twice a day. In some embodiments, the patch is administered three times a day. In some embodiments, the patch is administered four times a day. In some embodiments, the patch is administered once a day for a period of about 1-52 weeks. In some embodiments, the patch is administered twice a day for a period of about 1-52 weeks. In some embodiments, the patch is administered three times a day for a period of about 1-52 weeks. In some embodiments, the patch is administered four times a day for a period of about 1-52 weeks. In some embodiments, the patch is administered once a day for a period of about 12-52 weeks. In some embodiments, the patch is administered twice a day for a period of about 12-52 weeks. In some embodiments, the patch is administered three times a day for a period of about 12-52 weeks. In some embodiments, the patch is administered four times a day for a period of about 12-52 weeks. In some embodiments, the patch is administered once a day for at least a month. In some embodiments, the patch is administered twice a day for at least a month. In some embodiments, the patch is administered three times a day for at least a month. In some embodiments, the patch is administered four times a day for at least a month. In some embodiments, the patch is administered once a day for at least 3 months. In some embodiments, the patch is administered twice a day for at least 3 months. In some embodiments, the patch is administered three times a day for at least 3 months. In some embodiments, the patch is administered four times a day for at least 3 months. In someembodiments, the patch is administered once a day for at least 6 months. In some embodiments, the patch is administered twice a day for at least 6 months. In some embodiments, the patch is administered three times a day for at least 6 months. In some embodiments, the patch is administered four times a day for at least 6 months. In some embodiments, the patch is administered to the subject as needed.

[0165] In some embodiments, upon administration to the oral mucosa, the patches of the present disclosure provide a daily dose of about 1 mg to 500 mg of the cell cycle inhibitor (e.g., a CDK inhibitor such as abemaciclib). In some embodiments, upon administration to the oral mucosa, the patches of the present disclosure provide a daily dose of about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg of the cell cycle inhibitor. In some embodiments, upon administration to the oral mucosa, the patches of the present disclosure provide a daily dose of about 5 mg of the cell cycle inhibitor. In some embodiments, upon administration to the oral mucosa, the patches of the present disclosure provide a daily dose of about 10 mg of the cell cycle inhibitor. In some embodiments, upon administration to the oral mucosa, the patches of the present disclosure provide a daily dose of about 25 mg of the cell cycle inhibitor. In some embodiments, upon administration to the oral mucosa, the patches of the present disclosure provide a daily dose of about 50 mg of the cell cycle inhibitor. In some embodiments, upon administration to the oral mucosa, the patches of the present disclosure provide a daily dose of about 75 mg of the cell cycle inhibitor. In some embodiments, upon administration to the oral mucosa, the patches of the present disclosure provide a daily dose of about 100 mg of the cell cycle inhibitor. In some embodiments, upon administration to the oral mucosa, the patches of the present disclosure provide a daily dose of about 200 mg of the cell cycle inhibitor. In some embodiments, upon administration to the oral mucosa, the patches of the present disclosure provide a daily dose of about 300 mg of the cell cycle inhibitor. In some embodiments, upon administration to the oral mucosa, the patches of the present disclosure provide a daily dose of about 400 mg of the cell cycle inhibitor. In some embodiments, uponadministration to the oral mucosa, the patches of the present disclosure provide a daily dose of about 400 mg of the cell cycle inhibitor.

[0166] In some embodiments, the patches of the present disclosure provide immediate release of the cell cycle inhibitor. In some embodiments, to provide immediate release, greater than about 50%, greater than about 60%, greater than about 80%, or greater than about 90% of the compound is released within 30 min. In some embodiments, to provide immediate release, greater than about 50%, greater than about 60%, greater than about 80%, or greater than about 90% of the compound is released within 1-3 h. In some embodiments, to provide immediate release, greater than about 50%, greater than about 60%, greater than about 80%, or greater than about 90% of the compound is released within 1-2 h.

[0167] In some embodiments, the patches of the present disclosure provide sustained release of the cell cycle inhibitor, e.g., over a period of 2 h or more, 4 h or more, 8 h or more, 12 h or more, 16 h or more, 20 h or more, or 24 h or more. In some embodiments, the patches of the present disclosure release an effective dosage of the cell cycle inhibitor over a period of about 1 h, about 2 h, about 3 h, about 4 h, about 5 h, about 6 h, about 7 h, about 8 h, about 9 h, about 10 h, about 11 h, about 12 h, about 13 h, about 14 h, about 15 h, about 16 h, about 17 h, about 18 h, about 19 h, about 20 h, about 21 h, about 22 h, about 23 h, or about 24 h or longer.

[0168] In some embodiments, the patch releases at least about 10% of the cell cycle inhibitor between about 2-4. In some embodiments, the patch releases at least about 50% of the cell cycle inhibitor between about 2-8. In some embodiments, the patch releases at least about 75% of the cell cycle inhibitor between about 8-12. In some embodiments, the patch releases at least about 90% of the cell cycle inhibitor after about 12 h or more.

[0169] In some embodiments, the patch releases at least about 10% of the cell cycle inhibitor after about 2 h. In some embodiments, the patch releases at least about 50% of the cell cycle inhibitor after about 4 h. In some embodiments, the patch releases at least about 75% of the cell cycle inhibitor after about 8 h. In some embodiments, the patch releases at least about 90% of the cell cycle inhibitor after about 12 h.Method of Preparation

[0170] In one aspect, the present disclosure provides a method of preparing a patch as described herein, the process comprising (a) combining a solvent with one or more polymers and chemotherapeutic agent such as a CDK inhibitor of the present disclosure to provide an electrospinning mixture; (b) electrospinning the electrospinning mixture of step (a) to provide electrospun fibers; and (c) attaching an impermeable backing layer to the electrospun fibers of step (b).

[0171] In some embodiments, the conductivity of the electrospinning mixture of step (a) is from about 150 pS / cm to about 600 pS / cm, e.g., about 150 pS / cm, 175 pS / cm, 200 pS / cm, about 225 pS / cm, about 250 pS / cm, about 275 pS / cm, about 300 pS / cm, about 325 pS / cm, about 350 pS / cm, about 375 pS / cm, about 400 pS / cm, about 425 pS / cm, about 450 pS / cm, about 475 pS / cm, about 500 pS / cm, about 525 pS / cm, about 550 pS / cm, about 575 pS / cm, or about 600 pS / cm, including all ranges and values therebetween. In some embodiments, the conductivity of the electrospinning mixture of step (a) is from about 150 pS / cm to about 300 pS / cm.

[0172] In some embodiments, the solvent of Step (a) is an aqueous alcoholic solvent. In some embodiments, the aqueous alcohol solvent comprises ethanol and water. In some embodiments, the aqueous alcohol solvent comprises about 20% to about 97% (vol. / vol. %) of ethanol. In some embodiments, the aqueous alcohol solvent comprises about 40% to about 97% (vol. / vol. %) of ethanol. In some embodiments, the aqueous alcohol solvent comprises about 80% to about 97% (vol. / vol. %) of ethanol. In some embodiments, the aqueous alcohol solvent comprises about 50% to about 80% (vol. / vol. %) of ethanol. In some embodiments, the aqueous alcohol solvent comprises about 50% (vol. / vol. %) of ethanol. In some embodiments, the aqueous alcohol solvent comprises about 80% (vol. / vol. %) of ethanol. In some embodiments, the aqueous alcohol solvent comprises about 97% (vol. / vol. %) of ethanol.

[0173] In some embodiments, the aqueous alcoholic solvent comprises a mixture of ethanol and 2% acetic acid in phosphate-buffered saline. In some embodiments, the aqueous solvent comprises about 40% to about 80% ethanol and 20% of 2% acetic acid in phosphate-buffered saline (PBS) as the remainder. In some embodiments, the aqueous solvent comprises about 80% ethanol and about 20% of 2% acetic acid in phosphate-buffered saline (PBS).

[0174] In some embodiments, the solvent of Step (a) comprises a mixture of an alcohol and dichloromethane or chloroform. In some embodiments, the alcohol is ethanol, n- propanol, or w-butanol. In some embodiments, the alcohol is w-butanol. In some embodiments, the solvent of Step (a) is a mixture of w-butanol and chloroform. In some embodiments, the alkyl chloride is chloroform. In some embodiments, the solvent of Step (a) comprises a mixture of two solvents selected from the group consisting of dichloromethane, ethanol, isopropanol, and butanone. In some embodiments, the solvent of Step (a) comprises w-butanol and chloroform.

[0175] In some embodiments, the electrospun fibers comprise one or more polymers selected from the group consisting of polyvinylpyrrolidone, an ammonio methacrylate copolymer, polyethylene glycol, polyethylene oxide, polyacrylate, sodium polyacrylate, polyvinyl alcohol, dextran and gelatin.

[0176] In some embodiments, the one or more polymers comprise: (a) polyvinylpyrrolidone and an ammonio methacrylate copolymer; (b) polyvinylpyrrolidone and polyethylene glycol; (c) polyvinylpyrrolidone and polyethylene oxide; (d) polyvinylpyrrolidone and dextran; (e) polyvinylpyrrolidone and gelatin; (I) polyvinylpyrrolidone and polyvinyl alcohol; (g) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyethylene glycol; (h) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyethylene oxide; (i) polyvinylpyrrolidone, an ammonio methacrylate copolymer and dextran; j) polyvinylpyrrolidone, an ammonio methacrylate copolymer and gelatin; or (k) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyvinyl alcohol.

[0177] In some embodiments, the electrospinning mixture of Step (a) further comprises an absorption enhancer, as disclosed herein.EXAMPLESExample 1Preparation of Polymer Solutions and Fabrication of Bioadhesive Fibers

[0178] Polymeric mixtures containing 4 wt% PVP, 5 wt% Eudragit RS 100 and 8 wt% PEO were prepared by adding the required amounts of the polymers to an ethanol / water mixture and mixed at room temperature using a magnetic stirrer until fully dissolved. The CDK inhibitor was added to the ethanol / water mixture prior to the addition of thepolymers and stirred until fully dissolved, and the target was producing electrospun fibers with a content of 0.05 wt% of CDK inhibitor.

[0179] Electrospun fibers were fabricated using a system composed of a PHD2000 syringe pump (Havard Apparatus, Cambridge, UK) and an Alpha IV Brandenburg power source (Brandenburg, Worthing, UK). Plastic syringes (1 mL volume; Henke Sass Wolf, Tuttlingen, Germany) were used to drive the solutions into a 20-gauge blunt metallic needle (Fisnar Europe, Glasgow, UK). Electrospinning was performed at room temperature with a potential difference of 19 kV, a flow rate of 2 mL / h, and a flight path of 14 cm.Example 2: In vitro Activity of CDK Inhibitors Against Oral Cancer Cell Lines

[0180] The in vitro activity of AG-024322, ebvaciclib, palbociclib, R547, and staurosporine was evaluated in multiple cancer cell lines.

[0181] Multiplexed Cytotoxicity Assay

[0182] Cells were grown in RPMI 1640, 10% FBS, 2 mM L-alanyl-L-glutamine, 1 mM Na pyruvate, or a special medium. Cells were seeded into 384-well plates and incubated in a humidified atmosphere of 5% CO2 at 37oC. Compounds were added the day following cell seeding. At the same time, a time zero untreated cell plate was generated. After a 5-day incubation period, cells were fixed and stained with fluorescently-labeled antibodies and nuclear dye to allow imaging of nuclei, apoptotic cells and mitotic cells.

[0183] Compounds were serially diluted in half-log steps from the highest test concentration specified in the above table, and assayed over 10 concentrations with a maximum assay concentration of 0.1% DMSO. Automated fluorescence microscopy was carried out using a Molecular Devices ImageXpress Micro XL high-content imager, and images were collected with a 4X objective. 16-bit TIFF images were acquired and analyzed with MetaXpress 5.1.0.41 software.

[0184] Data Analysis

[0185] Cell proliferation was measured by the fluorescence intensity of an incorporated nuclear dye. The output is referred to as the relative cell count, where the measured nuclear intensity is transformed to percent of control (POC)

[0186] Cell count IC50 is the test compound concentration at 50% of maximal possible response. EC50 is the test compound concentration at the curve inflection point or half the effective response (parameter C of the fitted curve solution). GI50 is the concentration needed to reduce the observed growth by half (midway between the curvemaximum and the time zero value). Activity area is an estimate of the integrated area above the curve2. Activity area values range from 0-10, where a value of zero indicates no inhibition of proliferation at all concentrations, and a value of 10 indicates complete inhibition of proliferation at all concentrations. In rare instances, values <0 or >10 may be observed. In these instances, values <0 should be considered as equivalent to 0, whereas values >10 should be considered equivalent to 10.

[0187] An antibody to activated caspase-3 was used to label cells from early to late stage apoptosis3. The output is shown as a fold increase of apoptotic signal over vehicle background normalized to the relative cell count in each well. The concentration of test compound that caused a 5-fold induction in the caspase-3 signal is reported, indicating a significant apoptosis induction.

[0188] An antibody to phosphorylated histoneH3 was used to label mitotic cells4. The output is shown as a fold induction of mitotic signal over vehicle background normalized to the relative cell count in each well. The concentration of test compound that caused a 2-fold increase or decrease in the phospho-histone H3 signal is reported. A >2 -fold increase indicates the test agent induced an accumulation of cells in the G2 / M phase of the cell cycle. A >2-fold decrease indicates Gl / S block, but only when cytotoxicity levels are below the measured cell count IC95. When this decrease is observed at concentrations higher than the cell count IC95, the loss in mitotic cells is most likely due to amore general cytotoxicity effect rather than atrue Gl / S phase block. As shown by the data in the tables below, the compounds under investigation antiproliferative activity in A-253, Detroit 562, FaDu, OE19, OE21, OE33, Cal 27, SCC-25, SCC-4, and SCC-9 cancer cell lines.

[0189] Results suggested that all compounds showed substantial inhibitory effects on the proliferation of all the cancer cell lines studied, as shown by the measured cell count activity area values ranging from 3 to 7. An activity area value of zero indicates no inhibition of proliferation at all concentrations, and a value of 10 indicates complete inhibition of proliferation at all concentrations.Example 3: Evaluation of Antiproliferation Activity of Drug-Containing Patches

[0190] Drug-containing patches comprising AG-024322, ebvaciclib, palbociclib, R547, staurosporine, and potentially other CDK inhibitors are prepared according to the methods disclosed herein, the methods disclosed in International Publication No. WO / 2018 / 133909 or WO / 2018 / 133910, which are incorporated by reference in their entirely, and / or other previously reported method.

[0191] The effectiveness of these drug-containing patches is evaluated against A-253, Detroit 562, FaDu, OE19, OE21, OE33, Cal 27, SCC-25, SCC-4, and SCC-9 cell lines in tissue-engineered models of oral mucosa.

[0192] Antiproliferative effects of the drug-containing patches are determined for each of the models.

Claims

CLAIMSWhat is claimed is:

1. A drug-containing patch comprising:(a) an adhesive layer, wherein the adhesive layer comprises:(i) one or more polymers, and(ii) a therapeutically effective amount of a chemotherapeutic agent; and(b) an impermeable backing layer.

2. The patch of claim 1, wherein the adhesive layer comprises an electrospun fiber layer.

3. The patch of claim 1, wherein the adhesive layer comprises a film layer.

4. The patch of any one of claims 1-3, wherein the one or more polymers is selected from the group consisting of dextran, polyethylene oxides, alginate, tragacanth, carrageenan, pectin, gelatin, guar, xanthan, gellan, fibronectin, collagen, hyaluronic acid, chitosan, cellulosic polymers (e.g., methylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose, cellulose acetates, carboxymethylcellulose and alkali salts thereof), polyvinyl alcohol, polymers of acrylic acids (PAAs), chitosan, lectins, thiolated polymers, poly ox WSR, PAA-co-poly ethylene glycol (PAA-co-PEG), polylactic acid, polygly colic acid, poly(butylene succinate), polyvinylpyrrolidone (PVP), acrylates and acrylic copolymers (e.g., Eudragit®), ethylcellulose (EC), and mixtures thereof.

5. The patch of any one of claims 1-4, wherein the one or more polymers is selected from the group consisting of ethylcellulose, polyvinylpyrrolidone, an ammonio methacrylate copolymer, polyethylene glycol, polyethylene oxide, polyacrylate, sodium polyacrylate, polyvinyl alcohol, dextran, and gelatin.

6. The patch of any one of claims 1-5, wherein the one or more polymers comprises one or more hydrophilic polymers and a bioadhesive substance.

7. The patch of any one of claims 1-6, wherein the one or more polymers comprise:(i) a hydrophilic polymer selected from the group consisting of polyvinylpyrrolidone (PVP), hydroxypropylcellulose, ethylcellulose, acrylates, acrylic copolymers (Eudragit®), and mixtures thereof; and(ii) a bioadhesive substance selected from the group consisting of dextran, polyethylene glycol, polyethylene oxide, gelatin, polyvinyl alcohol, and mixtures thereof.

8. The patch of any one of claims 1-7, wherein the one or more polymers comprise:(a) polyvinylpyrrolidone and an ammonio methacrylate copolymer;(b) polyvinylpyrrolidone and polyethylene glycol;(c) polyvinylpyrrolidone and polyethylene oxide;(d) polyvinylpyrrolidone and dextran;(e) polyvinylpyrrolidone and gelatin;(f) polyvinylpyrrolidone and polyvinyl alcohol;(g) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyethylene glycol;(h) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyethylene oxide;(i) polyvinylpyrrolidone, an ammonio methacrylate copolymer and dextran;(j) polyvinylpyrrolidone, an ammonio methacrylate copolymer and gelatin; or(k) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyvinyl alcohol.

9. The patch of any one of claims 4-8, wherein the dextran has a molecular weight ranging from about 100,000 Da to about 1,000,000 Da.

10. The patch of any one of claims 4-8, wherein the PEO has a molecular weight ranging from about 100,000 Da to about 1,000,000 Da.

11. The patch of any one of claims 1-10, wherein the backing layer is hydrophobic.

12. The patch of claim 11, wherein the hydrophobic backing layer comprises poly caprolactone.

13. The patch of any one of claims 1-12, wherein the backing layer is a film layer.

14. The patch of any one of claims 1-12, wherein the backing layer is an electrospun layer.

15. The patch of any one of claims 1-14, wherein the chemotherapeutic agent is a chemotherapeutic drug, a cell cycle inhibitor or a combination thereof.

16. The patch of claim 15, wherein the cell cycle inhibitor is a cyclin-dependent kinase (CDK) inhibitor.

17. The patch of claim 16, wherein the CDK inhibitor is a selective CDK inhibitor.

18. The patch of claim 16 or 17, wherein the CDK inhibitor is palbociclib, ribociclib, abemaciclib, trilaciclib, dinaciclib, riviciclib, miliciclib, samuraciclib, fadraciclib, atuveciclib, alvociclib, roniciclib, birociclib, ebvaciclib, lerociblib, dalpiciclib, voruciclib, senexin A, purvalanol, roscovitine, cinobufagin, wogonin, flavopiridol, bohemine, alsterpaullone, kenpaullone, indirubin-3 '-monoxime, resibufogenin, indisulam, MK-8776, JNJ-7706621, BMS-265246, BAY 1251152, BPI-1178, BPI-16350, HS-10342, PF-562271 beyslate, R547, AT7519, LDC067, NU6027, AG-024322, AZD5438, AZD4573, or PHA-793887.

19. The patch of any one of claims 16-18, wherein the CDK inhibitor is palbociclib, ribociclib, abemaciclib, trilaciclib, dinaciclib, riviciclib, miliciclib, samuraciclib, fadraciclib, or atuveciclib.

20. The patch of any one of claims 16-18, wherein the CDK inhibitor is palbociclib, ribociclib, or abemaciclib.

21. The patch of any one of claims 16-18, wherein the CDK inhibitor is abemaciclib.

22. The patch of any one of claims 16-18, wherein the CDK inhibitor is palbociclib.

23. The patch of any one of claims 16-18, wherein the CDK inhibitor is ribociclib.

24. The patch of any one of claims 16-23, wherein the adhesive layer comprises about 0.005% to about 20.0% (wt. / wt.%) of the cell cycle inhibitor.

25. The patch of any one of claims 16-24, wherein the adhesive layer comprises about 0.01% to about 5.0% (wt. / wt.%) of the cell cycle inhibitor.

26. The patch of any one of claims 16-25, wherein the patch provides a therapeutically effective amount of the cell cycle inhibitor for at least about 2 h, at least about 4 h, at least about 6 h, at least about 8 h, at least 12 h, at least 18 h, or at least 24 h, following application to a mucosal surface.

27. The patch of claim 15, wherein the chemotherapeutic drug is a chemical or biological agent.

28. The patch of claim 27, wherein the chemical agent is selected among imiquimod, cisplatin, carboplatin, 5 -fluorouracil (5-FU), paclitaxel, docetaxel, hydroxyurea, methotrexate, capecitabine, or mixtures thereof.

29. The patch of claim 27, wherein the biological agent is selected among cetuximab, perbroluzumab and nivolumab.

30. The patch of any one of claims 1-29, wherein the electrospun fibers further comprise an absorption enhancer.

31. The patch of claim 30, wherein the absorption enhancer is selected from the group consisting of a fatty acid, a non-ionic surfactant, a poly cation, a thiolated polymer, a cyclodextrin, and a cell-penetrating peptide.

32. The patch of claim 31, wherein the fatty acid is selected from the group consisting of caproic acid, caprylic acid, capric acid, sodium caprate, lauric acid, stearic acid, oleic acid, linoleic acid, and linolenic acid.

33. The patch of claim 31, the non-ionic surfactant is selected from the group consisting of polysorbate, polyethylene glycol hexadecyl ether, polyoxyethylene alkyl ethers, nonylphenoxypolyoxyethylene (NPPOE), laurate sucrose ester (SE), and sodium glycocholate.

34. The patch of claim 31, wherein the poly cation is selected from the group consisting of a chitosan and its quaternary ammonium derivatives, a poly-L-arginine, an aminated gelatin, and cetylpyridinium chloride.

35. The patch of claim 31, wherein the thiolated polymer is selected from the group consisting of carboxymethyl cellulose-cysteine, polycarbophil (PCP)-cysteine, chitosan-thiobutylamidine, chitosan-thioglycolic acid, chitosan-thioethylamidine, chitosan iminothiolane, chitosan-glutathione conjugates, polyacrylic acid-cysteine, polymethacrylic acid-cysteine, and hyaluronicacid-L-cysteine.

36. The patch of claim 31, wherein the cyclodextrin is selected from the group consisting of a methylated P-cyclodextrin, hydroxypropyl-P-cyclodextrin, and sulphobutylether-P-cyclodextrin.

37. The patch of claim 31, wherein the cell-penetrating peptide is selected from the group consisting of penetratin, Tat (Y GRKKKRRQRRR), R6, R8, R9, pVEC (LLIILRRRIRKQAH AHSK), RRL helix (RRLRRLLRRLRRLLRRLR), shuffle (RWFKIQMQIRRWKNKK), and penetramax (KWFKIQMQIRRWKNKR).

38. The patch of any one of claims 1-37, wherein the adhesive layer and / or the backing layer comprises a plasticizer.

39. The patch of claim 38, wherein the plasticizer is selected from the group consisting of triethyl citrate, acetyl triethyl citrate, tributyl citrate, butyl stearate, glycerol monostearate, stearyl alcohol, castor oil, mineral oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, dibutyl phthalate, dioctyl phosphate, sorbitol, glycerol, triacetin, tributyrin, cellulose nitrate, polyethylene glycol, polyethylene glycol monomethyl ether, propylene glycol, or mixtures thereof.

40. A method for preventing the malignant transformation of a precancerous oral lesion to oral cancer in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a patch of any one of claims 1-39.

41. A method for treating a precancerous oral lesion in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a patch of any one of claims 1-39.

42. The method of claim 40 or 41, wherein the precancerous oral lesion comprises leukoplakia, erythroplakia, and / or dysplasia.

43. The method of claim 42, wherein the leukoplakia and erythroplakia are dysplastic.

44. A method for preventing the malignant transformation of oral leukoplakia to oral dysplasia in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a patch of any one of claims 1-39.

45. A method for preventing the malignant transformation of oral dysplasia to oral cancer in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a patch of any one of claims 1-39.

46. A method for treating, preventing, and / or reducing the symptoms of oral cancer in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a patch of any one of claims 1-39.

47. The method of claim 45 or 46, wherein the oral cancer is head and neck cancer.

48. The method of any one of claims 45-47, wherein the oral cancer is squamous cell carcinoma.

49. The method of any one of claims 45-48, wherein the oral cancer is verrucous carcinoma, minor salivary gland carcinoma, or lymphoma.

50. The method of claim 49, wherein the minor salivary gland carcinoma is selected from the group consisting of adenoid cystic carcinoma (ACC), mucoepidermoid carcinoma, polymorphous low grade adenocarcinoma, or carcinoma ex-pleomorphic adenoma.

51. The method of any one of claims 42-45, wherein the oral dysplasia comprises leukoplakia and / or erythroplakia.

52. The method of any one of claims 40-51, wherein the patch is administered daily, every other day, every 3 days, every 4 days, every 5 days, every 6 days, or once a week.

53. The method of claim 52, wherein the patch is administered daily to the subject.

54. The method of claim 53, wherein the patch is administered twice a week to the subject.

55. The method of claim 53, wherein the patch is administered once a week to the subject.

56. The method of any one of claims 40-55, wherein the patch is administered for at least a week, at least a month, at least 3 months, or at least 6 months.

57. The method of any one of claims 40-56, wherein the patch is administered for about 2-4 weeks.

58. The method of any one claims 40-56, wherein the patch is administered for at least a month.

59. The method of any one of claims 40-58, wherein the patch releases at least about 10% of the cell cycle inhibitor after about 2 h.

60. The method of any one of claims 40-59, wherein the patch releases at least about 50% of the cell cycle inhibitor after about 4 h.

61. The method of any one of claims 40-60, wherein the patch releases at least about 75% of the cell cycle inhibitor after about 8 h.

62. The method of any one of claims 40-61, wherein the patch releases about 90% of the cell cycle inhibitor after about 12 h.

63. A process for preparing a patch of any one of claims 1-62, the process comprising:(a) combining an aqueous alcoholic solvent with one or more polymers and a chemotherapeutic agent to provide an electrospinning mixture;(b) electrospinning the Step (a) mixture to provide electrospun fibers; and(c) attaching an impermeable backing layer to the Step (b) electrospun fibers.

64. The process of claim 63, wherein the conductivity of the electrospinning mixture of Step (a) is from about 150 pS / cm to about 600 pS / cm.

65. The process of claim 64, wherein the conductivity of the electrospinning mixture of Step (a) is from about 150 pS / cm to about 300 pS / cm.

66. The process of any one of claims 63-65, wherein the aqueous alcoholic solvent comprises ethanol and water.

67. The process of claim 66, wherein the solvent comprises about 40% to about 97% (vol. / vol. %) of ethanol.

68. The process of claim 67, wherein the solvent comprises about 80% to about 97% (vol. / vol. %) of ethanol.

69. The process of any one of claims 63-68, wherein the one or more polymers is selected from the group consisting of ethylcellulose, polyvinylpyrrolidone, an ammonio methacrylate copolymer, polyethylene glycol, polyethylene oxide, polyacrylate, sodium polyacrylate, polyvinyl alcohol, dextran and gelatin.

70. The process of claim 69, wherein the one or more polymers comprise:(a) polyvinylpyrrolidone and an ammonio methacrylate copolymer;(b) polyvinylpyrrolidone and polyethylene glycol;(c) polyvinylpyrrolidone and polyethylene oxide;(d) polyvinylpyrrolidone and dextran;(e) polyvinylpyrrolidone and gelatin;(f) polyvinylpyrrolidone and polyvinyl alcohol;(g) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyethylene glycol;(h) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyethylene oxide;(i) polyvinylpyrrolidone, an ammonio methacrylate copolymer and dextran;(j) polyvinylpyrrolidone, an ammonio methacrylate copolymer and gelatin; or(k) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyvinyl alcohol.

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