Compositions and methods for treating and preventing oral cancer

Abstract

The present disclosure relates to a drug-containing patch comprising a cyclin inhibitor, a cyclin-dependent kinase (CDK) inhibitor as described herein. The patch includes an impermeable layer that acts as a barrier, for example, to prevent water penetration. When the patch is attached to the skin or mucous membranes, the compound is released to treat and / or prevent precancerous oral conditions, oral cancer, and related diseases.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to drug-containing patches comprising an adhesive layer and an impermeable layer. The electrospun layer comprises one or more polymers and a chemotherapeutic agent, such as a cell cycle inhibitor, e.g., a cyclin-dependent kinase (CDK) inhibitor, that is controllably released and locally delivered to the oral mucosa at a clinically effective rate. Thus, the patches disclosed herein are useful for a variety of applications, including the treatment and prevention of precancerous oral lesions (leukoplakia, erythroplakia, etc.), oral dysplasia, and oral cancer. The disclosed patches are also expected to address the challenges and limitations associated with surgical intervention and existing treatment regimens. 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 a history of smoking and / or chewing tobacco. The primary goal 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, there is a 10% to 20% chance of recurrence of the lesion even after surgical removal, and a 3% to 12% chance of developing cancer in the treated area.

[0003] In addition to surgical intervention (which is not practical due to high recurrence rates), treatment options are limited. Oral retinoids can help reduce lesions, but recurrence and side effects are common. Carotenoids, vitamins, and other supplements have been used, but lesions recur when supplementation is stopped. Moreover, treatment agents delivered systemically can not be particularly suitable for treating precancerous lesions that are potentially recurrent due to their high levels of toxicity.

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

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

[0006] To address the above-referenced problems, the present disclosure provides electrospun mucoadhesive patches having an impermeable layer that are designed for local, unidirectional delivery of chemotherapeutic agents, such as cell cycle inhibitors (e.g., CDK inhibitors), to the oral mucosa of a subject in need of treatment. The disclosed patches are expected to provide high drug encapsulation efficiency and a rapid, sustained release rate of active agents, long residence time at the treatment site, and high patient acceptability / compliance.

[0007] Accordingly, the patches disclosed herein can be used to treat a variety of diseases and conditions, including oral leukoplakia, oral dysplasia, and various head and neck cancers affecting the oral mucosa. The patches disclosed herein can also be used to prevent the transformation of oral precancerous lesions and oral dysplasia to cancer.

[0008] In one aspect, the disclosure provides a medicated 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, such as a cell cycle inhibitor; and (b) an impermeable backing layer.

[0009] In some embodiments, the adhesive layer comprises electrospun fibers. In some embodiments, the adhesive layer is a film layer. In another aspect, the disclosure provides a medicated patch comprising: (a) an electrospun fiber layer, wherein the electrospun fibers comprise (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 disclosure provides a medicated patch comprising: (a) a 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 from cell cycle inhibitors and other therapeutic agents known to kill or inhibit the growth of cancer cells.

[0012] In some embodiments, the cell cycle inhibitor is a cyclin-dependent kinase (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, BAY1251152, BPI-1178, BPI-16350, HS-10342, PF-562271 besylate, R547, AT7519, LDC067, NU6027, AG-024322, AZD5438, AZD4573, or PHA-793887. In some embodiments, the 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 material disclosed herein.

[0017] In some embodiments, the one or more polymers are selected from the group consisting of polyvinylpyrrolidone, 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 the film layer. In some embodiments, the one or more polymers are present in an amount ranging from about 60% to about 95% by weight of the electrospun fiber or the 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, the impermeable layer is hydrophobic. In some embodiments, the hydrophobic impermeable layer comprises polyethylene-co-vinyl acetate, ethyl cellulose, polycaprolactone, 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 the 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 malignant transformation of a precancerous (i.e., pre-malignant) 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 malignant transformation of an oral dysplasia 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.

[0024] In some aspects, the present disclosure provides methods for preventing malignant transformation of an oral leukoplakia to an 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.

[0025] In some aspects, the present disclosure provides methods for preventing malignant transformation of an oral leukoplakia 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.

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

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

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

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

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

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

[0033] In some embodiments, the oral cancer is a squamous cell carcinoma. In some embodiments, the oral cancer is a verrucous carcinoma, a salivary gland carcinoma, or a lymphoma. In some embodiments, the salivary gland carcinoma is selected from the group consisting of an adenoid cystic carcinoma (ACC), a mucoepidermoid carcinoma, a pleomorphic low-grade adenocarcinoma, or a 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 a CDK inhibitor, for at least about 2 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, at least about 12 hours, at least about 18 hours, or at least about 24 hours after application to the oral mucosa of a subject.

[0036] In one aspect, the present disclosure provides a method of making a patch, the method comprising (a) combining an aqueous alcoholic solvent with one or more polymers and a CDK inhibitor to provide an electrospinning mixture; (b) electrospinning the 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 DRAWINGS

[0037] Figure 1 A flowchart outlining one possible strategy for developing and evaluating drug- containing patches of the present disclosure is provided.

[0038] Figure 2 A flowchart outlining one possible strategy for developing, optimizing, and evaluating drug-containing patches of the present disclosure is provided. DEFINITIONS

[0039] For convenience, certain terms used herein are collectively set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning 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 cited. The disclosure content of these patents, patent applications, and publications is incorporated by reference in its entirety for all purposes to more fully describe the state of the art as known to those having ordinary skill in the art as of the date of the disclosure. In the event of any inconsistencies between the disclosure content of the cited patents, patent applications, and publications and that of the present disclosure, the present disclosure shall prevail.

[0041] The term "about," when used in reference to a numerical value, means a range (e.g., plus or minus 10% of the 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 a range extending less than half way between the preceding and succeeding values, e.g., greater than 49.5 to less than 52.5. Furthermore, in view of the definition of the term "about" provided herein, the phrases "less than about" a value or "greater than about" a value are to be understood. Similarly, the term "about" when used before a series of numerical values or a range of values (e.g., "about 10, 20, 30" or "about 10-30") refers to all the values in the series or the endpoints of the range, respectively.

[0042] As used herein in the specification and claims, the phrase "and / or" should be understood to mean "either or both" of the entities so conjoined, i.e., "one or the other or both." The use of "and / or" as used in the context of having a feature, advantage or benefit both, individually or in combination, of two or more of the listed items, should be understood as such. Conjunctive language such as "at least one of' or "one or more of' for a list of items, such as "at least one of A and B" is satisfied when any of the items in the list occur, individually or in combination with any of the items. The interpretation "one or more of' should be interpreted in the same manner as "one, two or more of' and "one, but not other" or "another," even if only one item is listed. The phrase "one, but not more than one" or "only one of, in reference to a list of two or more items, means only one of an item in the list can be present in, or in combination with other enumerated items, one or more times, whereas the phrase "one, two, or more of means that either one, two, or more of a listed item can be present in, or in combination with other enumerated items, one or more times.

[0043] "Optional" or "optionally" means that the subsequently described element, event or circumstance can or can not occur, and that the description includes instances where the event, element or circumstance occurs and instances where 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 an active ingredient (e.g., a 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 fiber that increases the ability of a cell cycle inhibitor to be absorbed by a targeted tissue or membrane (e.g., oral mucosa).

[0046] As used herein, the term“treat” with respect to a subject refers to ameliorating at least one symptom of a condition in a subject. Treatment can be curative, ameliorative, or at least partially alleviating a condition. The term“therapeutic effect” as used herein refers to a desired or beneficial effect provided by a method and / or composition. For example, a 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“prevent” with respect to a subject refers to reducing or eliminating the onset of a symptom or complication of a disease, condition, or disorder. In some embodiments, a symptom or complication of a disease, condition, or disorder is reduced or eliminated in a subject predisposed to the disease, condition, or disorder. The patches of the present disclosure are capable of preventing or treating such diseases, conditions, or disorders.

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

[0049] As used herein, a“subject” includes a vertebrate, more particularly a mammal (e.g., a human, a horse, a pig, a rabbit, a dog, a sheep, a goat, a non-human primate, a cow, a cat, a guinea pig, or a rodent), a fish, a bird, or a reptile or amphibian. In some embodiments, the subject is a human subject. The term“subject” does not denote a particular age or gender, unless otherwise indicated. In some embodiments, the subject can be a geriatric subject, a pediatric subject, an adolescent 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 years of age, about 10-15 years of age, about 15-20 years of age, about 20-25 years of age, about 25-30 years of age, about 30-35 years of age, about 35-40 years of age, about 40-45 years of age, about 45-50 years of age, about 50-55 years of age, about 55-60 years of age, about 60-65 years of age, about 65-70 years of age, about 70-75 years of age, about 75-80 years of age, about 85-90 years of age, about 90-95 years of age, 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 for a developmental abnormality of the oral cavity 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 suitable for application to oral mucosa. As described herein, the disclosed patches adhere to oral mucosa and controllably release chemotherapeutic agents (such as CDK inhibitors) at a clinically effective rate in a local manner. Thus, the patches disclosed herein are useful for a variety of applications, including the treatment of oral precancerous lesions, oral dysplasias, and oral cancer. Additionally, the patches disclosed herein are useful for preventing oral precancerous lesions and dysplasias from becoming oral cancer.

[0052] Highly mucoadhesive oral patches that attach to mucosal surfaces and effectively deliver active agents are described in International Publication Nos. WO 2015 / 189212, WO 2017 / 085264, WO 2018 / 133910, and WO 2018 / 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 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, such as a cell cycle inhibitor; and (b) an impermeable backing layer.

[0054] In some embodiments, the cell cycle inhibitor is a biologic agent. Thus, 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), an intact 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 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, such as a CDK inhibitor; and (b) an impermeable backing layer.

[0057] In some embodiments, the adhesive layer comprises an electrospun fiber layer or a membrane layer. In some embodiments, the adhesive layer comprises an electrospun fiber layer. In some embodiments, the adhesive layer comprises a membrane layer. In some embodiments, the electrospun layer is calendered to the adhesive layer, becoming a membrane once attached. In some embodiments, the membrane is prepared directly by calendering a membrane layer to the 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] Thus, in some embodiments, both the adhesive layer and the impermeable backing layer are electrospun fiber layers. In some embodiments, both the adhesive layer and the impermeable backing layer are 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 the impermeable layer can be combined to provide a patch using methods known to those of skill in the art, for example, the methods disclosed in International Publication Nos. WO / 2018 / 133909 or WO / 2018 / 133910.

[0061] 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 the chemotherapeutic agent (e.g., CDK inhibitor). Thus, in some embodiments, the patch adheres to the targeted site for a period of greater than 2 hours, greater than 4 hours, greater than 8 hours, greater than 12 hours, greater than 16 hours, greater than 24 hours, greater than 30 hours, greater than 36 hours, greater than 42 hours, or greater than 48 hours. In some embodiments, the patch adheres to the targeted site for a period of at least 2 hours. In some embodiments, the patch adheres to the targeted site for a period of at least 4 hours. In some embodiments, the patch adheres to the targeted site for a period of at least 6 hours. In some embodiments, the patch adheres to the targeted site for a period of at least 8 hours. In some embodiments, the patch adheres to the targeted site for a period of at least 12 hours. In some embodiments, the patch adheres to the targeted site for a period of at least 24 hours.

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

[0063] In some embodiments, the 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 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, at least about 10 hours, at least about 12 hours, at least about 14 hours, at least about 16 hours, at least about 18 hours, at least about 20 hours, at least about 22 hours, or at least about 24 hours after 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 hours after 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 hours after 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 hours after application to a subject in need thereof.

[0064] In some embodiments, the patch according to the present disclosure is applied to a subject in need thereof (e.g., a disease site of a subject) once a day, twice a day (b.i.d.), three times a 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 (e.g., a disease site of a subject) once a day. In some embodiments, the patch is applied to a subject in need thereof (e.g., a disease site of a subject) twice a day. In some embodiments, the patch is applied to a subject in need thereof (e.g., a disease site of a subject) three times a day. In some embodiments, the patch is applied to a subject in need thereof (e.g., a disease site of a subject) four times a day. In other embodiments, the patch is applied to a subject in need thereof as needed.

[0065] In some embodiments, the patch according to the present disclosure is applied to a subject in need thereof (e.g., a disease site of the 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 (e.g., a disease site of the 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 (e.g., a disease site of the subject) three times a day for a period of about 1 to 52 weeks. In some embodiments, the patch is applied to a subject in need thereof (e.g., a disease site of the subject) four times a day for a period of about 1 to 52 weeks. In some embodiments, the patch is applied to a subject in need thereof (e.g., a disease site of the 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 (e.g., a disease site of the 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 (e.g., a disease site of the subject) three times a day for a period of about 12 to 52 weeks. In some embodiments, the patch is applied to a subject in need thereof (e.g., a disease site of the subject) four times a day for a period of about 12 to 52 weeks. In some embodiments, the patch is applied to a subject in need thereof (e.g., a disease site of the subject) once a day for at least one month. In some embodiments, the patch is applied to a subject in need thereof (e.g., a disease site of the subject) twice a day for at least one month. In some embodiments, the patch is applied to a subject in need thereof (e.g., a disease site of the subject) three times a day for at least one month. In some embodiments, the patch is applied to a subject in need thereof (e.g., a disease site of the subject) four times a day for at least one month. In some embodiments, the patch is applied to a subject in need thereof (e.g., a disease site of the subject) once a day for at least 3 months. In some embodiments, the patch is applied to a subject in need thereof (e.g., a disease site of the subject) twice a day for at least 3 months. In some embodiments, the patch is applied to a subject in need thereof (e.g., a disease site of the subject) three times a day for at least 3 months. In some embodiments, the patch is applied to a subject in need thereof (e.g., a disease site of the subject) four times a day for at least 3 months. In some embodiments, the patch is applied to a subject in need thereof (e.g., a disease site of the subject) once a day for at least 6 months. In some embodiments, the patch is applied to a subject in need thereof (e.g., a disease site of the subject) twice a day for at least 6 months. In some embodiments, the patch is applied to a subject in need thereof (e.g., a disease site of the subject) three times a day for at least 6 months.In some embodiments, the patch is applied to a subject in need thereof (e.g., a 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 adhesion to the oral mucosa. In some embodiments, the flexibility of the patch is adjusted by varying the thickness of the patch, which comprises an electrospun layer and an impermeable layer. In some embodiments, decreasing the thickness of the patch results in increased flexibility of the patch for patches of the same or substantially similar composition. 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 affected skin or tissue. In some embodiments, the patches of the present disclosure are circular, semi-circular, elliptical, semi-elliptical (i.e., half-moon shaped), square, or rectangular. In some embodiments, the patch is semi-circular or semi-elliptical. In some embodiments, the patch is semi-circular. In some embodiments, the patch is semi-elliptical. In some embodiments, the semi-elliptical patch has a width of about 2 cm to about 4 cm and a length of about 5 cm to about 10 cm.

[0068] In some embodiments, the patches of the present disclosure further comprise one or more pharmaceutically acceptable excipients. In some embodiments, the patch further comprises a plasticizer disclosed herein. In some embodiments, the patch further comprises 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 patch comprises two layers. In some embodiments, the drug-containing patch comprises three layers. In some embodiments, the drug-containing patch comprises four layers. In some embodiments, the drug-containing patch comprises five layers. As described herein, such layered compositions comprise a drug-containing layer and a backing layer, which serves to protect the drug-containing layer from moisture or saliva, or acts as a barrier layer, which can facilitate penetration of the drug into the oral mucosa. The backing layer can protect the drug-containing layer from being washed away from the site of application when applied to the oral mucosa, which would result in swallowing of the composition, thereby reducing or eliminating the desired local therapeutic effect.

[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 copolymer 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 a CDK inhibitor; about 30 g to 40 g of PVP; about 40 g to 50 g of ammonio methacrylate copolymer 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 a CDK inhibitor; about 35 g of PVP; about 44 g of ammonio methacrylate copolymer B; about 71 g of PEO; and about 17 g of PCL. Adhesive layer Drug-containing electrospun fiber layer

[0073] As used in the present disclosure, the term “electrospun fiber” includes fibers obtained by methods involving electrostatics. These methods are known in the art as electrohydrodynamic (EHD) methods, including electrospinning, coaxial electrospinning, coaxial electrospray, emulsion electrospinning, and the like. Any such method can be used to make the fibers of the present disclosure. Thus, the term “electrospun fiber” is not limited to fibers obtained by electrospinning, but 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. For example, coaxial fibers are described in H. Qu et al., J. Mater. Chem. A, 2013, 1, 11513-11528.

[0075] In some embodiments, the electrospun fibers or fiber layer of the patch of the present disclosure comprise 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%, about 7.5%, 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 a chemotherapeutic agent, such as a cell cycle inhibitor (e.g., a CDK inhibitor), including all ranges and values therebetween. In some embodiments, the electrospun fibers or fiber layer comprise about 0.005% to about 10.0% (wt. / wt.) of a cell cycle inhibitor (e.g., a CDK inhibitor). In some embodiments, the electrospun fibers or fiber layer comprise about 0.005% to about 5.0% (wt. / wt.) of a cell cycle inhibitor (e.g., a CDK inhibitor). In some embodiments, the electrospun fibers or fiber layer comprise about 0.005% to about 1.0% (wt. / wt.) of a cell cycle inhibitor (e.g., a CDK inhibitor).

[0076] Generally, the electrospun fibers of the present disclosure are provided in a layer that adheres to a surface when applied to the skin, mucosa, or moist internal surface of the body. In some embodiments, the cell cycle inhibitor (e.g., a CDK inhibitor, such as abemaciclib) can be uniformly distributed in the electrospun fibers, whereby the drug concentration per unit surface area of the layer is constant and the dose of the drug substance can be easily determined by using the 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 a cell cycle inhibitor, optionally an absorption enhancer, and optionally a plasticizer, each of which will be described in greater detail below.

[0078] The electrospun fiber layer and the impermeable layer can be joined by various methods to provide a patch useful in the therapeutic and prophylactic methods disclosed herein. Membrane layer containing a drug

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

[0080] In some embodiments, the chemotherapeutic agent, such as a cell cycle inhibitor (e.g., a CDK inhibitor, such as abemaciclib) can be uniformly distributed in the membrane layer, whereby the drug concentration per unit surface area of the layer is constant and the dose of the drug substance can be easily determined by using the 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 will be described in greater detail below.

[0082] The film layer and the impermeable layer can be joined by various methods to provide a patch useful in the therapeutic and prophylactic methods 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, glyceryl triacetate, glyceryl tributyrate, 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 described 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 the film layer comprises one or more polymers selected from the group consisting of dextran, polyethylene oxide, alginate, tragacanth, carrageenan, pectin, gelatin, guar gum, xanthan gum, gellan gum, fibronectin, collagen, hyaluronic acid, chitosan, cellulosic polymers such as methylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose, cellulose acetate, carboxymethylcellulose and alkali metal salts thereof, polymers of acrylic acid (PAA derivatives), chitosan, lectins, thiolated polymers, polyox WSR, PAA-co-PEG (PEG is polyethylene glycol), polylactic acid, polyglycolic acid, poly(butylene succinate), and mixtures thereof.

[0087] In some embodiments, the electrospun fibrous layer or film layer comprises one or more polymers selected from the group consisting of polyvinylpyrrolidone (PVP), acrylate and acrylic copolymers (e.g., Eudragit®), ethyl cellulose (EC), hydroxypropyl cellulose (HPC), polyvinyl alcohol, carboxymethyl cellulose, and mixtures thereof. In some embodiments, the one or more polymers are selected from polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), and mixtures thereof. In some embodiments, the one or more polymers are polyvinyl alcohol or carboxymethyl cellulose.

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

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

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

[0091] In some embodiments, the one or more hydrophilic polymers is polyvinylpyrrolidone (PVP), an acrylic acid ester and acrylic acid copolymer (e.g., Eudragit®), ethyl cellulose (EC), hydroxypropyl cellulose (HPC), or a mixture thereof; and the bioadhesive substance is dextran, polyethylene oxide, alginate, tragacanth, carrageenan, pectin, gelatin, guar gum, xanthan gum, gellan gum, fibronectin, collagen, hyaluronic acid, chitosan, a cellulose polymer (e.g., methyl cellulose, hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose, cellulose acetate, carboxymethyl cellulose, and alkali metal salts thereof), polyvinyl alcohol (PVA), polyacrylic acid (PAA), chitosan, lectin, a thiolated polymer, polyox WSR, PAA-co-polyethylene glycol (PAA-co-PEG), polylactic acid, polyglycolic acid, poly(butylene succinate), or a mixture thereof.

[0092] In some embodiments, the one or more hydrophilic polymers is polyvinylpyrrolidone (PVP), a methacrylic acid ammonium polymer of type B, or a mixture thereof; and the bioadhesive substance is dextran, polyethylene oxide (e.g., polyox WSR), gelatin, polyvinyl alcohol (PVA), or a mixture thereof.

[0093] In some embodiments, the one or more polymers comprises: (a) polyvinylpyrrolidone and a methacrylic acid ammonium 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, a methacrylic acid ammonium copolymer, and polyethylene glycol; (h) polyvinylpyrrolidone, a methacrylic acid ammonium copolymer, and polyethylene oxide; (i) polyvinylpyrrolidone, a methacrylic acid ammonium copolymer, and dextran; (j) polyvinylpyrrolidone, a methacrylic acid ammonium copolymer, and gelatin; (k) polyvinylpyrrolidone, a methacrylic acid ammonium copolymer, and polyvinyl alcohol; (l) polyvinylpyrrolidone and ethyl cellulose; (m) polyvinylpyrrolidone, ethyl cellulose, and polyethylene glycol; (n) polyvinylpyrrolidone, ethyl cellulose, and polyethylene oxide; (o) polyvinylpyrrolidone, ethyl cellulose, and dextran; (p) polyvinylpyrrolidone, ethyl cellulose, and gelatin; or (q) polyvinylpyrrolidone, ethyl cellulose, and polyvinyl alcohol.

[0094] In some embodiments, the one or more polymers comprise: (a) polyvinylpyrrolidone and 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, ammonio methacrylate copolymer, and polyethylene glycol; (h) polyvinylpyrrolidone, ammonio methacrylate copolymer, and polyethylene oxide; (i) polyvinylpyrrolidone, ammonio methacrylate copolymer, and dextran; (j) polyvinylpyrrolidone, ammonio methacrylate copolymer, and gelatin; or (k) polyvinylpyrrolidone, 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 fiber 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, 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 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 fiber is about 0.15 to about 10, including for example 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 fiber 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, 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 some embodiments, 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 fiber 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, 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 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 fiber 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, 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 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 fiber 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, ammonio methacrylate copolymer, and polyethylene glycol. In some embodiments, the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer to polyethylene glycol in the electrospun fiber 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, ammonio methacrylate copolymer, and polyethylene glycol. In some embodiments, the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer to polyethylene glycol in the electrospun fiber is about 1:0.5:0.1 to about 1:2:6, including all ranges and values therebetween.

[0103] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone, ammonio methacrylate copolymer, and polyethylene glycol. In some embodiments, the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer to polyethylene glycol in the electrospun fiber is about 1:0.5:0.1 to about 1:2:6, including all ranges and values therebetween.

[0104] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone, ammonio methacrylate copolymer, and polyethylene glycol. In some embodiments, the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer to polyethylene glycol in the electrospun fiber is about 1:0.5:0.1 to about 1:2:6, including all ranges and values therebetween.

[0105] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone, ammonio methacrylate copolymer, and polyethylene glycol. In some embodiments, the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer to polyethylene glycol in the electrospun fiber is about 1:0.5:0.1 to about 1:2:6, including all ranges and values therebetween.

[0106] In some embodiments, the electrospun fibers of this disclosure comprise one or more polymers (as described herein), typically including hydrophilic polymers that provide a variety of desired properties, such as rheological properties suitable for electrospinning, physical properties (e.g., strength, flexibility, etc.) to provide a patch that is sufficiently durable and flexible to be conformable to mucosal surfaces during manufacturing and use, and an appropriate degree of hydrophilicity suitable for mucosal surfaces. Such polymers can provide bioadhesive properties to aid adhesion to mucosal surfaces. One or more additional polymers may be added as needed to improve bioadhesiveness. In specific embodiments, the electrospun fibers of this disclosure comprise a combination of polyvinylpyrrolidone and acrylic copolymers (e.g., Eudragit® copolymers) with polyethylene oxide polymers. Such electrospun fiber compositions are described, for example, in U.S. Patent Nos. 10,052,291, 2019 / 0254985 and 2019 / 0254986, and 2019 / 0351662.

[0107] When polyvinylpyrrolidone (PVP) is used as a polymer in electrospun fibers, it can be used in grades with molecular weights ranging from approximately 2,500 Da to 3,000,000 Da. PVP is available as Kollidon® in various molecular weight ranges as shown below.

[0108] Ethyl cellulose is marketed under the trademark ETHOCEL TM Ethyl cellulose is sold by Dow Chemical Company and is available in different grades. Depending on its ethoxy content, ethyl cellulose can have different softening points and melting temperatures. Ethyl cellulose is also produced in a variety of different viscosities (see table below).

[0109] Acrylates and acrylic derivatives include polymethacrylates, methacrylate copolymers, acrylic copolymers, and methacrylate polymers, and include acrylates sold under the name EUDRAGIT and acrylate / octacrylamide sold under the name DERMACRYL 79. Non-limiting examples of such acrylates are EUDRAGIT® E 12,5 (ammonio methacrylate copolymer), EUDRAGIT® E100 (ammonio methacrylate copolymer; basic butyl methacrylate copolymer), EUDRAGIT® E PO (ammonio 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 methacrylates: EUDRAGIT® L and S are methacrylic acid copolymers and are cationic copolymer products of methacrylic acid and methyl methacrylate. EUDRAGIT® RL or RS are ammonio methacrylate copolymers synthesized from acrylic acid and methacrylic acid.

[0110] Carboxymethyl cellulose is available in a variety of viscosity grades. In some embodiments, the viscosity of the carboxymethyl cellulose in the electrospun fiber is in the range of 10 to 100,000 In some embodiments, the carboxymethyl cellulose is a sodium salt.

[0111] Methyl cellulose is sold under the name METHOCEL TM (Dow Chemical Company) and is available in a variety of viscosity grades. In some embodiments, the viscosity grade of the methyl cellulose in the electrospun fiber is less than about 3 to greater than about 100,000 .

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

[0113] In some embodiments, the polyvinyl alcohol has a molecular weight in the range of about 20,000 Da to about 200,000. In some embodiments, the polyvinyl alcohol has a molecular weight in the range of about 100,000 Da to about 200,000.

[0114] In some embodiments, the polyethylene oxide (PEO) commercially available under the trade name TM The average molecular weight of the PEO commercially available under the trade name POLYOX (Dow Chemical Company) is in the range of about 100,000 Da to about 4,000,000 Da. In some embodiments, the average molecular weight of the PEO is about 100,000 Da to about 4,000,000 Da. In some embodiments, the average molecular weight of the PEO is about 100,000 Da to about 2,000,000 Da. In some embodiments, the average molecular weight of the PEO is about 100,000 Da to about 1,000,000 Da. In some embodiments, the average molecular weight of the PEO is about 100,000 Da to about 700,000 Da. In some embodiments, the average molecular weight of the PEO is about 100,000 Da to about 500,000 Da. In some embodiments, the average molecular weight of the PEO is about 100,000 Da to about 400,000 Da. In some embodiments, the average molecular weight of the PEO is about 100,000 Da. In some embodiments, the average molecular weight of the PEO is about 200,000 Da. In some embodiments, the average molecular weight of the PEO is about 300,000 Da. In some embodiments, the average molecular weight of the PEO is about 400,000 Da.

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

[0116] In some embodiments, the one or more polymers are present in an amount in the range of about 20% to about 99% by weight of the electrospun fiber, 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 are present in an amount in the range of about 50% to about 99% by weight of the electrospun fiber. In some embodiments, the one or more polymers are present in an amount in the range of about 60% to about 99% by weight of the electrospun fiber. In some embodiments, the one or more polymers are present in an amount in the range of about 75% to about 99% by weight of the electrospun fiber. In some embodiments, the one or more polymers are present in an amount in the range of about 50% to about 95% by weight of the electrospun fiber. In some embodiments, the one or more polymers are present in an amount in the range of about 60% to about 95% by weight of the electrospun fiber. In some embodiments, the one or more polymers are present in an amount in the range of about 75% to about 95% by weight of the electrospun fiber. In some embodiments, the one or more polymers are present in an amount in the range of about 50% to about 90% by weight of the electrospun fiber. In some embodiments, the one or more polymers are present in an amount in the range of about 60% to about 30% by weight of the electrospun fiber. In some embodiments, the one or more polymers are present in an amount in the range of about 75% to about 90% by weight of the electrospun fiber. In some embodiments, the one or more polymers are present in an amount in the range of about 50% to about 90% by weight of the electrospun fiber. In some embodiments, the one or more polymers are present in an amount in the range of about 20% to about 60% by weight of the electrospun fiber. In some embodiments, the one or more polymers are present in an amount in the range of about 20% to about 50% by weight of the electrospun fiber. In some embodiments, the one or more polymers are present in an amount in the range of about 20% to about 40% by weight of the electrospun fiber. chemotherapeutic agent

[0117] The chemotherapeutic agent can in principle be any drug or agent capable of killing or inhibiting the growth of cancer cells, or any agent capable of inhibiting the transformation of a precancerous cell into a cancer cell.

[0118] The chemotherapeutic agent is preferably selected from the group consisting of cell cycle inhibitors and chemotherapeutic drugs known in the art and combinations thereof.

[0119] In some embodiments, the chemotherapeutic agent is selected from a chemically or biologically active agent having therapeutic activity. Examples of preferred chemotherapeutic agents include cell cycle inhibitors.

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

[0121] In some embodiments, the therapeutic agent is a targeted therapeutic agent, for example, a drug that targets the epidermal growth factor receptor (EFGR). In some embodiments, the targeted therapeutic agent 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, repotrectinib, miliciclib, samuraciclib, fangatimib, aviciclib, eviciclib, pyroctinib, reloxaliib, 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.

[0126] In some embodiments, the CDK inhibitor is palbociclib, ribociclib, abemaciclib, trilaciclib, dinaciclib, repotrectinib, miliciclib, samuraciclib, fangatimib, aviciclib, eviciclib, pyroctinib, reloxaliib, 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] under the trade name Verzenio ® Abemaciclib, sold under the trade name [5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzimidazol-5-yl)-pyrimidin-2-yl]-amine, is a selective CDK inhibitor for CDK4 and CDK6, which has the structure: or a pharmaceutically acceptable salt thereof. U.S. Patent No. 7,855,211, which is incorporated by reference herein in its entirety, discloses selective benzimidazolyl CDK inhibitors, including abemaciclib and crystalline forms thereof, methods of their use in treating cancer, and methods of preparation.

[0128] under the trade name Ibrance ® Palbociclib, sold under the trade name 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(1- piperazinyl)-2-pyridinyl]amino]-pyrido[2,3-d]pyrimidin-7(8H)-one, is a selective CDK inhibitor for CDK4 and CDK6, which has the structure: or pharmaceutically acceptable salts thereof. U.S. Patent Nos. 6,936,612, 10,723,730, and RE47739 disclose selective pyrrolopyrimidine CDK inhibitors, including palbociclib and crystalline forms thereof, methods of their use in treating cancer, and methods of preparation, which are incorporated by reference in their entirety.

[0129] sold under the trade name Kisqali ® Ribociclib (7-cyclopentyl-N,N-dimethyl-2-[[5-(1-piperazinyl)-2-pyridinyl]- amino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide), which is a selective CDK inhibitor against CDK4 and CDK6, is sold under the trade name Kisqali or pharmaceutically acceptable salts thereof, such as the succinate salt. U.S. Patent Nos. 8,324,225, 8,415,355, 8,685,980, 8,962,630, and 9,193,732 disclose selective pyrrolopyrimidine CDK inhibitors, including ribociclib, methods of their use in treating cancer, and methods of preparation, which are incorporated by reference in their entirety.

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

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

[0132] In some embodiments, the biopharmaceutical agent is present in the electrospun fibers in an amount in the range of about 0.005% to about 50.0% (wt. / wt.%). In some embodiments, the biopharmaceutical agent is present in the electrospun fibers in an amount in the range of about 0.01% to about 50.0% (wt. / wt.%). In some embodiments, the biopharmaceutical agent is present in the electrospun fibers in an amount in the range of about 0.01% to about 40.0% (wt. / wt.%). In some embodiments, the biopharmaceutical agent is present in the electrospun fibers in an amount in the range of about 0.005% to about 30.0% (wt. / wt.%). In some embodiments, the biopharmaceutical agent is present in the electrospun fibers in an amount in the range of about 0.005% to about 20.0% (wt. / wt.%). In some embodiments, the biopharmaceutical agent is present in the electrospun fibers in an amount in the range of about 0.005% to about 10.0% (wt. / wt.%). In some embodiments, the biopharmaceutical agent is present in the electrospun fibers in an amount in the range of about 0.005% to about 5.0% (wt. / wt.%). In some embodiments, the biopharmaceutical agent is present in the electrospun fibers in an amount in the range of about 0.005% to about 2.5% (wt. / wt.%). In some embodiments, the biopharmaceutical agent is present in the electrospun fibers in an amount in the range of about 0.005% to about 1.0% (wt. / wt.%). In some embodiments, the biopharmaceutical agent is present in the electrospun fibers in an amount in the range of about 0.01% to about 5.0% (wt. / wt.%). In some embodiments, the biopharmaceutical agent is present in the electrospun fibers in an amount in the range of about 0.01% to about 2.5% (wt. / wt.%). In some embodiments, the biopharmaceutical agent is present in the electrospun fibers in an amount in the range of about 0.01% to about 1% (wt. / wt.%). Combination of cell cycle inhibitors and therapeutically active agents

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

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

[0135] In some embodiments, the additional therapeutic agent is a targeted therapeutic agent, e.g., a drug that targets the epidermal growth factor receptor (EFGR). In some embodiments, the targeted therapeutic agent 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, among 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 the drug-containing layer. In some embodiments, the impermeable layer is co-spun with the drug-containing layer and thus 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, glyceryl triacetate, glyceryl tributyrate, 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 layer containing the substance from moisture or saliva. In some embodiments, the impermeable layer protects the drug layer from being washed away from the site of application, which results in a reduced or eliminated desired local therapeutic effect. In some embodiments, the impermeable layer acts as a barrier layer, which facilitates the penetration of the drug 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 aromatic polyester. 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), poly(lactide-co-glycolide), poly(butylene succinate), poly(butylene succinate-co-adipate), poly(p-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 poly(caprolactone) plasticized with dibutyl sebacate or ethyl cellulose. In some embodiments, the hydrophobic backing layer comprises poly(caprolactone). In some embodiments, the hydrophobic backing layer comprises ethyl cellulose plasticized with dibutyl sebacate.

[0145] In some embodiments, the impermeable layer comprises poly(ethylene-co-vinyl acetate), ethyl cellulose, poly(caprolactone), carbothane, or polysoftane. In some embodiments, the impermeable layer comprises acrylate / octyl acrylamide copolymer (sold under the name DERMACRL® 79), methacrylate amine copolymer (EUDRAGIT®), dimethylaminoethyl methacrylate, methacrylic acid ester, methyl methacrylate (e.g., EUDRAGIT® E 100), or other methacrylates.

[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% by weight of the patch, including all values and ranges therebetween. 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 a method of treating or preventing a disease or disorder of the oral cavity in a subject in need thereof by administering to the oral cavity (e.g., oral mucosa) of the subject a drug-in-adhesive patch as disclosed herein. In some embodiments, the disease or disorder is a precancerous condition of the oral cavity (e.g., a precancerous lesion, a dysplasia, etc.), oral cancer, or a related condition.

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

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

[0150] In some embodiments, the present disclosure provides a method of treating a precancerous lesion of the oral cavity 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 locally via a drug-in-adhesive patch as disclosed herein.

[0151] In some embodiments, the precancerous lesion of the oral cavity comprises leukoplakia and / or erythroplakia. In some embodiments, the precancerous lesion of the oral cavity comprises leukoplakia. In some embodiments, the precancerous lesion of the oral cavity 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 a method of treating a dysplasia of the oral cavity in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a patch as disclosed herein.

[0153] In some embodiments, the present disclosure provides a method of preventing malignant transformation of a dysplasia of the oral cavity to oral cancer in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a drug-in-adhesive patch as disclosed herein.

[0154] In some embodiments, the dysplasia of the oral cavity 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 the erythroplakia is homogeneous. In some embodiments, the leukoplakia and / or erythroplakia is a patch of irregular shape, which can be flat, nodular, or warty. Such leukoplakia, which is referred to as nonhomogeneous, has a seven-fold higher likelihood of cancerization than homogeneous leukoplakia. Homogeneous leukoplakia is characterized by a thin patch of uniform color, smooth, wrinkled, or hard surface, and uniformity.

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

[0156] In some embodiments, the present disclosure provides a method of preventing 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 patch disclosed herein.

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

[0158] In some embodiments, the present disclosure provides a method of treating or preventing oral cancer 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 chemotherapeutic agent, such as the CDK inhibitor, is administered locally 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, small salivary gland carcinoma, or lymphoma. In some embodiments, the small salivary gland carcinoma is selected from the group consisting of adenoid cystic carcinoma (ACC), mucoepidermoid carcinoma, pleomorphic low-grade adenocarcinoma, or carcinoma in pleomorphic adenoma.

[0160] In some embodiments, the oral dysplasia or oral 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 hyperplastic leukoplakia. In some embodiments, the erythroplakia is hyperplastic erythroplakia.

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

[0162] In some embodiments, the subject receiving cancer treatment according to the methods of the present application has previously been treated with cisplatin, carboplatin, 5-fluorouracil, paclitaxel, docetaxel, hydroxyurea, methotrexate, capecitabine, or a combination thereof. In some embodiments, the subject receiving cancer treatment according to the methods of the present application has experienced treatment with cisplatin, carboplatin, 5-fluorouracil, paclitaxel, docetaxel, hydroxyurea, methotrexate, capecitabine, or a combination thereof concurrently.

[0163] In some embodiments, the treatment comprises one or more of the following: reducing the area of the white spot, eliminating the white spot, reducing the abnormal proliferation of the white spot, reversing to simple hyperplasia, and converting the white spot to normal mucosa.

[0164] In some embodiments, the 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 about 1-52 weeks. In some embodiments, the patch is administered twice a day for about 1-52 weeks. In some embodiments, the patch is administered three times a day for about 1-52 weeks. In some embodiments, the patch is administered four times a day for about 1-52 weeks. In some embodiments, the patch is administered once a day for about 12-52 weeks. In some embodiments, the patch is administered twice a day for about 12-52 weeks. In some embodiments, the patch is administered three times a day for about 12-52 weeks. In some embodiments, the patch is administered four times a day for about 12-52 weeks. In some embodiments, the patch is administered once a day for at least one month. In some embodiments, the patch is administered twice a day for at least one month. In some embodiments, the patch is administered three times a day for at least one month. In some embodiments, the patch is administered four times a day for at least one 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 some embodiments, 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, the patches of the present disclosure provide a daily dose of about 1 mg to 500 mg of a cell cycle inhibitor (e.g., a CDK inhibitor, such as abemaciclib) after administration to the oral mucosa. In some embodiments, 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 a cell cycle inhibitor after administration to the oral mucosa. In some embodiments, the patches of the present disclosure provide a daily dose of about 5 mg of a cell cycle inhibitor after administration to the oral mucosa. In some embodiments, the patches of the present disclosure provide a daily dose of about 10 mg of a cell cycle inhibitor after administration to the oral mucosa. In some embodiments, the patches of the present disclosure provide a daily dose of about 25 mg of a cell cycle inhibitor after administration to the oral mucosa. In some embodiments, the patches of the present disclosure provide a daily dose of about 50 mg of a cell cycle inhibitor after administration to the oral mucosa. In some embodiments, the patches of the present disclosure provide a daily dose of about 75 mg of a cell cycle inhibitor after administration to the oral mucosa. In some embodiments, the patches of the present disclosure provide a daily dose of about 100 mg of a cell cycle inhibitor after administration to the oral mucosa. In some embodiments, the patches of the present disclosure provide a daily dose of about 200 mg of a cell cycle inhibitor after administration to the oral mucosa. In some embodiments, the patches of the present disclosure provide a daily dose of about 300 mg of a cell cycle inhibitor after administration to the oral mucosa. In some embodiments, the patches of the present disclosure provide a daily dose of about 400 mg of a cell cycle inhibitor after administration to the oral mucosa. In some embodiments, the patches of the present disclosure provide a daily dose of about 400 mg of a cell cycle inhibitor after administration to the oral mucosa.

[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 minutes. 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 hours. 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 hours.

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

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

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

[0170] In one aspect, the present disclosure provides a method of making a patch as described herein, the method comprising (a) combining a solvent with one or more polymers of the present disclosure and a chemotherapeutic agent, such as a CDK inhibitor, to provide an electrospinning mixture; (b) electrospinning the 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 electrospun mixture in step (a) is from about 150 µS / cm to about 600 µS / cm, for example, about 150 µS / cm, 175 µS / cm, 200 µS / cm, about 225 µS / cm, about 250 µS / cm, about 275 µS / cm, about 300 µS / cm, about 325 µS / cm, about 350 µS / cm, about 375 µS / cm, about 400 µS / cm, about 425 µS / cm, about 450 µS / cm, about 475 µS / cm, about 500 µS / cm, about 525 µS / cm, about 550 µS / cm, about 575 µS / cm, or about 600 µS / cm, including all ranges and values ​​therein. In some embodiments, the conductivity of the electrospun mixture in step (a) is from about 150 µS / cm to about 300 µS / cm.

[0172] In some embodiments, the solvent in step (a) is an aqueous alcohol 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 alcohol 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% acetic acid as a residue in phosphate-buffered saline (PBS). In some embodiments, the aqueous solvent comprises about 80% ethanol and about 20% 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 n-butanol. In some embodiments, the alcohol is n-butanol. In some embodiments, the solvent of step (a) is a mixture of n-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 n-butanol and chloroform.

[0175] In some embodiments, the electrospun fibers comprise one or more polymers selected from the group consisting of polyvinylpyrrolidone, 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 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, ammonio methacrylate copolymer, and polyethylene glycol; (h) polyvinylpyrrolidone, ammonio methacrylate copolymer, and polyethylene oxide; (i) polyvinylpyrrolidone, ammonio methacrylate copolymer, and dextran; (j) polyvinylpyrrolidone, ammonio methacrylate copolymer, and gelatin; or (k) polyvinylpyrrolidone, ammonio methacrylate copolymer, and polyvinyl alcohol.

[0177] In some embodiments, the electrospinning mixture of step (a) further comprises an absorption enhancer, as disclosed herein. Examples Example 1 Preparation of polymer solutions and manufacture of bioadhesive fibers

[0178] A polymer mixture containing 4 wt% PVP, 5 wt% Eudragit RS100, and 8 wt% PEO was prepared by adding the required amounts of polymers to an ethanol / water mixture and mixing at room temperature using a magnetic stirrer until completely dissolved. Prior to the addition of the polymers, a CDK inhibitor was added to the ethanol / water mixture and stirred until completely dissolved, and the goal was to produce electrospun fibers with a CDK inhibitor content of 0.05 wt%.

[0179] Electrospun fibres were manufactured using a system consisting of a PHD2000 syringe pump (Havard Apparatus, Cambridge, UK) and an Alpha IV Brandenburg power supply (Brandenburg, Worthing, UK). The solution was injected into a 20 gauge blunt metal needle (Fisnar Europe, Glasgow, UK) using a plastic syringe (1 mL volume; Henke Sass Wolf, Tuttlingen, Germany). Electrospinning was performed at a potential difference of 19 kV, a flow rate of 2 mL / h and a flight path of 14 cm at room temperature. Example 2: In vitro activity of CDK inhibitors on oral cancer cell lines

[0180] The in vitro activity of AG-024322, evorbucil, palbociclib, R547 and staurosporine was assessed in a range of cancer cell lines.

[0181] Multiplex cytotoxicity assay

[0182] Cells were grown in RPMI 1640, 10% FBS, 2 mM L-alanyl-L-glutamine, 1 mM sodium pyruvate or special media. Cells were seeded into 384 well plates and incubated at 37°C in 5% C02humidified air. Compounds were added the day after cell seeding. Simultaneously, time zero untreated cell plates were generated. Following a 5 day incubation period, cells were fixed and stained with fluorescently labelled antibodies and a nuclear dye to image nuclei, apoptotic and mitotic cells.

[0183] Compounds were serially diluted in half log steps starting from the highest test concentration specified in the table above and assayed over 10 concentrations with a maximum assay concentration of 0.1% DMSO. Automated fluorescent microscopy was performed using an ImageXpress Micro XL High Content Imager by Molecular Devices and images were collected with a 4X objective. 16 bit TIFF images were obtained and analysed using MetaXpress 5.1.0.41 software.

[0184] Data analysis

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

[0186] The cell count IC50 is the concentration of test compound at 50% of the maximum possible response. The EC50 is the concentration of test compound at the inflection point of the curve or half the effective response (the parameter C of the fitted curve solution). The GI50 is the concentration required to halve the observed growth (the mid-point between the maximum value of the curve and the time zero value). The active area is an estimate of the area under the curve above 2. The active area value is in the range 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 cases, values < 0 or > 10 can be observed. In these cases, values < 0 should be considered equal to 0, and values > 10 should be considered equal to 10.

[0187] Antibodies to activated caspase-3 were used to label cells undergoing apoptosis from early to late stages3. The output is shown as the fold increase in the apoptotic signal over the vehicle background, normalized to the relative cell count in each well. The concentration of test compound that caused a 5-fold induction of the caspase-3 signal was reported, indicating significant induction of apoptosis.

[0188] Antibodies to phosphorylated histone H3 were used to label mitotic cells4. The output is shown as the fold induction of the mitotic signal over the 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 was reported. > 2-fold increase indicates that the test agent induced cell accumulation in the G2 / M phase of the cell cycle. > 2-fold decrease indicates a G1 / S arrest, but only if the level of cytotoxicity is lower than the cell count IC95 measured. When such a decrease is observed at concentrations higher than the cell count IC95, the loss of mitotic cells is likely due to a more general cytotoxic effect, rather than a true G1 / S phase arrest. As shown in the data in the table below, the compounds studied had anti-proliferative activity in the A-253, Detroit 562, FaDu, OE19, OE21, OE33, Cal 27, SCC-25, SCC-4, and SCC-9 cancer cell lines.

[0189] The results show that all compounds showed significant inhibition of proliferation of all cancer cell lines studied, as indicated by measured cell count active area values in the range of 3 to 7. An active 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 the antiproliferative activity of drug-in-adhesive patches

[0190] Drug-in-adhesive patches containing AG-024322, evofem, palbociclib, R547, staurosporine, and potentially other CDK inhibitors were prepared according to the methods disclosed herein, the methods disclosed in International Publication Nos. WO / 2018 / 133909 or WO / 2018 / 133910, and / or other previously reported methods, which are incorporated by reference in their entirety.

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

[0192] For each model, the antiproliferative effect of the drug-in-adhesive patches was determined.

Claims

1. A medicated 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) Impermeable backing layer.

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

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

4. The patch according to any one of claims 1 to 3, wherein the one or more polymers are selected from the group consisting of: dextran, polyethylene oxide, alginate, tragacanth gum, carrageenan, pectin, gelatin, guar gum, xanthan gum, gellan gum, fibronectin, collagen, hyaluronic acid, chitosan, cellulose polymers (e.g., methylcellulose, hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose, cellulose acetate, carboxymethylcellulose and their alkali metal salts), polyvinyl alcohol, acrylic polymers (PAA), chitosan, lectins, thiolated polymers, polyox WSR, PAA-co-polyethylene glycol (PAA-co-PEG), polylactic acid, polyglycolic acid, poly(butylene succinate), polyvinylpyrrolidone (PVP), acrylates and acrylic copolymers (e.g., Eudragit®), ethyl cellulose (EC) and mixtures thereof.

5. The patch according to any one of claims 1 to 4, wherein the one or more polymers are selected from the group consisting of: ethyl cellulose, polyvinylpyrrolidone, ammonium methacrylate copolymer, polyethylene glycol, polyethylene oxide, polyacrylate, sodium polyacrylate, polyvinyl alcohol, dextran, and gelatin.

6. The patch according to any one of claims 1 to 5, wherein the one or more polymers comprise one or more hydrophilic polymers and bioadhesive substances.

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

8. The patch according to any one of claims 1 to 7, wherein the one or more polymers comprise: (a) Polyvinylpyrrolidone and ammonium 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, ammonium methacrylate copolymer and polyethylene glycol; (h) Polyvinylpyrrolidone, ammonium methacrylate copolymer and polyethylene oxide; (i) Polyvinylpyrrolidone, ammonium methacrylate copolymer and dextran; (j) polyvinylpyrrolidone, ammonium methacrylate copolymer and gelatin; or (k) Polyvinylpyrrolidone, ammonium methacrylate copolymer and polyvinyl alcohol.

9. The patch according to any one of claims 4 to 8, wherein the molecular weight of the dextran is in the range of about 100,000 Da to about 1,000,000 Da.

10. The patch according to any one of claims 4 to 8, wherein the molecular weight of the PEO is in the range of about 100,000 Da to about 1,000,000 Da.

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

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

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

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

15. The patch according to any one of claims 1 to 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 according to claim 16 or 17, wherein the CDK inhibitor is palbociclib, ribociclib, abemaciclib, trilaciclib, dinaciclib, riviciclib, miliciclib, samuraciclib, fadraciclib, atuveciclib, avociclib, roniciclib, birociclib, ebvaciclib, lerociblib, dalpiciclib, voruciclib, or senexin A. A) purvalanol, roscovitine, cinobufagin, wogonin, flavopiridol, bohemine, alsterpaullone, kenpaullone, indirubin-3'-monoxime, resibufogen (in), indomethacin, MK-8776, JNJ-7706621, BMS-265246, BAY1251152, BPI-1178, BPI-16350, HS-10342, PF-562271 benzenesulfonate, R547, AT7519, LDC067, NU6027, AG-024322, AZD5438, AZD4573 or PHA-793887.

19. The patch according to any one of claims 16 to 18, wherein the CDK inhibitor is palbociclib, ribociclib, abeciclib, trilasiclib, dinasiclib, ribociclib, mirciclib, samracilib, limethicone, or avecilib.

20. The patch according to any one of claims 16 to 18, wherein the CDK inhibitor is palbociclib, ribociclib, or abeciclib.

21. The patch according to any one of claims 16 to 18, wherein the CDK inhibitor is abecine.

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

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

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

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

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

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

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

29. The patch according to claim 27, wherein the biological agent is selected from cetuximab, perbroluzumab, and nivolumab.

30. The patch according to any one of claims 1 to 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 fatty acids, nonionic surfactants, polycationic substances, thiolated polymers, cyclodextrins, and cell-penetrating peptides.

32. The patch according to claim 31, wherein the fatty acid is selected from the group consisting of: caproic acid, caprylic acid, decanoic acid, sodium decanoate, lauric acid, stearic acid, oleic acid, linoleic acid and linolenic acid.

33. The patch according to claim 31, wherein the nonionic surfactant is selected from the group consisting of: polysorbate, polyethylene glycol hexadecyl ether, polyoxyethylene alkyl ether, nonylphenoxy polyoxyethylene (NPPOE), sucrose laurate (SE), and sodium glycocholate.

34. The patch according to claim 31, wherein the polycation is selected from the group consisting of: chitosan and its quaternary ammonium derivatives, poly-L-arginine, amination gelatin and hexadecylpyridine chloride.

35. The patch according to claim 31, wherein the thiolized polymer is selected from the group consisting of: carboxymethyl cellulose-cysteine, polycarbofil (PCP)-cysteine, chitosan-thiobutylamidine, chitosan-thioglycolic acid, chitosan-thioethylamine, chitosan iminothione, chitosan-glutathione conjugate, polyacrylic acid-cysteine, polymethacrylic acid-cysteine, and hyaluronic acid-L-cysteine.

36. The patch of claim 31, wherein the cyclodextrin is selected from the group consisting of methylated β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and sulfobutyl ether-β-cyclodextrin.

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

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

39. The patch according to claim 38, wherein the plasticizer is selected from the group consisting of: triethyl citrate, acetylated triethyl citrate, tributyl citrate, butyl stearate, glyceryl monostearate, stearyl alcohol, castor oil, mineral oil, diacetylated glyceryl monostearate, dibutyl sebacate, diethyl phthalate, dibutyl phthalate, dioctyl phosphate, sorbitol, glycerin, triacetyl glyceride, glyceryl tartrate, nitrocellulose, polyethylene glycol, polyethylene glycol monomethyl ether, propylene glycol, or mixtures thereof.

40. A method for preventing the malignant transformation of precancerous oral lesions into oral cancer in a subject of need, the method comprising applying a patch according to any one of claims 1 to 39 to the oral mucosa of the subject.

41. A method for treating precancerous oral lesions in a subject in need, the method comprising applying a patch according to any one of claims 1 to 39 to the oral mucosa of the subject.

42. The method of claim 40 or 41, wherein the precancerous oral lesion comprises leukoplakia, erythema and / or developmental abnormalities.

43. The method of claim 42, wherein the white patches and the erythema are developmentally abnormal.

44. A method for preventing the malignant transformation of oral leukoplakia into oral developmental abnormalities in a subject of need, the method comprising applying a patch according to any one of claims 1 to 39 to the oral mucosa of the subject.

45. A method for preventing the malignant transformation of oral developmental abnormalities into oral cancer in a subject of need, the method comprising applying a patch according to any one of claims 1 to 39 to the oral mucosa of the subject.

46. ​​A method for treating, preventing, and / or alleviating symptoms of oral cancer in a subject of need, the method comprising applying a patch according to any one of claims 1 to 39 to the oral mucosa of the subject.

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

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

49. The method according to any one of claims 45 to 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, low-grade pleomorphic adenocarcinoma, or carcinoma ex-pleomorphic adenoma.

51. The method according to any one of claims 42 to 45, wherein the oral developmental abnormality comprises leukoplakia and / or erythema.

52. The method according to any one of claims 40 to 51, wherein the patch is applied daily, every other day, every 3 days, every 4 days, every 5 days, every 6 days, or weekly.

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

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

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

56. The method according to any one of claims 40 to 55, wherein the patch is applied for at least one week, at least one month, at least three months, or at least six months.

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

58. The method according to any one of claims 40 to 56, wherein the patch is applied for at least one month.

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

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

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

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

63. A method for preparing a patch according to any one of claims 1 to 62, the method comprising: (a) Combining an aqueous alcohol solvent with one or more polymers and a chemical therapeutic agent to provide an electrospun mixture; (b) Electrospinning the mixture from step (a) to provide electrospun fibers; and (c) Attach an impermeable backing layer to the electrospun fibers of step (b).

64. The method of claim 63, wherein the conductivity of the electrospun mixture in step (a) is from about 150 µS / cm to about 600 µS / cm.

65. The method of claim 64, wherein the conductivity of the electrospun mixture in step (a) is from about 150 µS / cm to about 300 µS / cm.

66. The method according to any one of claims 63 to 65, wherein the aqueous alcohol solvent comprises ethanol and water.

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

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

69. The method according to any one of claims 63 to 68, wherein the one or more polymers are selected from the group consisting of: ethyl cellulose, polyvinylpyrrolidone, ammonium methacrylate copolymer, polyethylene glycol, polyethylene oxide, polyacrylate, sodium polyacrylate, polyvinyl alcohol, dextran, and gelatin.

70. The method of claim 69, wherein the one or more polymers comprise: (a) Polyvinylpyrrolidone and ammonium 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, ammonium methacrylate copolymer and polyethylene glycol; (h) Polyvinylpyrrolidone, ammonium methacrylate copolymer and polyethylene oxide; (i) Polyvinylpyrrolidone, ammonium methacrylate copolymer and dextran; (j) polyvinylpyrrolidone, ammonium methacrylate copolymer and gelatin; or (k) Polyvinylpyrrolidone, ammonium methacrylate copolymer and polyvinyl alcohol.

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