[go: up one dir, main page]

WO2025051337A1 - Compositions et méthodes de traitement et de prévention du cancer buccal - Google Patents

Compositions et méthodes de traitement et de prévention du cancer buccal Download PDF

Info

Publication number
WO2025051337A1
WO2025051337A1 PCT/DK2024/050205 DK2024050205W WO2025051337A1 WO 2025051337 A1 WO2025051337 A1 WO 2025051337A1 DK 2024050205 W DK2024050205 W DK 2024050205W WO 2025051337 A1 WO2025051337 A1 WO 2025051337A1
Authority
WO
WIPO (PCT)
Prior art keywords
patch
polyvinylpyrrolidone
subject
oral
polymers
Prior art date
Application number
PCT/DK2024/050205
Other languages
English (en)
Inventor
Lars Siim Madsen
Martin Santocildes ROMERO
Ove Pedersen
Original Assignee
Afyx Development A/S
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Afyx Development A/S filed Critical Afyx Development A/S
Publication of WO2025051337A1 publication Critical patent/WO2025051337A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure relates to drug-containing patches comprising an adhesive layer and an impermeable layer.
  • the electrospun layer includes one or more polymers and chemotherapeutic agent such as a cell cycle inhibitor, e.g., a cyclin- dependent kinase (CDK) inhibitor, which is controllably released and topically delivered to the oral mucosa at a clinically effective rate.
  • chemotherapeutic agent such as a cell cycle inhibitor, e.g., a cyclin- dependent kinase (CDK) inhibitor, which is controllably released and topically delivered to the oral mucosa at a clinically effective rate.
  • CDK cyclin- dependent kinase
  • the patches disclosed herein are therefore useful for a range of applications including the treatment and prevention of precancerous oral lesions (leukoplakia, erythroplakia, and the like), oral dysplasia and cancer of the oral cavity,
  • the disclosed patches are also expected to address the challenges and limitations associated
  • Malignant transformation of oral lesions such as leukoplakia and erythroplakia can be high (0.13% to 17% for leukoplakia and 14% to 50% for erythroplakia), particularly in certain patient populations, e.g., in individuals with ahistory of smoking and/or chewing tobacco.
  • the primary objective of treating these and other precancerous oral lesions is to prevent them from becoming cancer.
  • treatment can be challenging and outcomes are often unsatisfactory. For example, even after surgical removal, there remains a 10% to 20% chance that the lesions will return, and a 3% to 12% chance of developing cancer in the treated area.
  • the present disclosure provides electrospun mucoadhesive patches with an impermeable layer that are designed for localized, unidirectional delivery of a chemotherapeutic agent such as a cell cycle inhibitor (e.g., a CDK inhibitor) to the oral mucosa of a subject in need of treatment.
  • a chemotherapeutic agent such as a cell cycle inhibitor (e.g., a CDK inhibitor)
  • the disclosed patches are expected to provide high drug-encapsulation efficiency and fast, sustainable release rates of the active agent, long residence times at the treatment site, and high patient acceptability/compliance.
  • the patches disclosed herein are useful for treating a variety diseases and conditions, including oral leukoplakia, oral dysplasia and various head and neck cancers that effect the oral mucosa.
  • the patches disclosed herein are also useful for preventing the conversion of oral precancerous lesions and oral dysplasia to cancer.
  • the present disclosure provides a drug-containing patch comprising: (a) an adhesive layer layer, wherein the adhesive layer comprises (i) one or more polymers, and (ii) a therapeutically effective amount of a chemotherapeutic agent such as a cell cycle inhibitor; and (b) an impermeable backing layer.
  • 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.
  • the adhesive layer comprises electrospun fibers.
  • the adhesive layer is a film layer.
  • the present disclosure provides a drug-containing patch comprising: (a) an electrospun fiber layer, wherein the electrospun fibers comprises (i) one or more polymers, and (ii) a therapeutically effective amount of a cell cycle inhibitor; and (b) an impermeable backing layer.
  • the present disclosure provides a drug-containing patch comprising: (a) an film layer, wherein the film comprises (i) one or more polymers, and (ii) a therapeutically effective amount of a cell cycle inhibitor; and (b) an impermeable backing layer.
  • the chemotherapeutic agent is selected among cell cycle inhibitors and other therapeutic agents known to kill or inhibit the growth on cancer cells.
  • the cell cycle inhibitor is a cyclin-dependent (CDK) inhibitor.
  • 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.
  • the CDK inhibitor is a selective CDK inhibitor.
  • the selective CDK inhibitor is a CDK4/6 inhibitor.
  • the CDK inhibitor is selected from the group consisting of palbociclib, ribociclib, abemaciclib, trilaciclib, dinaciclib, riviciclib, miliciclib, samuraciclib, fadraciclib, atuveciclib, alvociclib, roniciclib, birociclib, ebvaciclib, lerociblib, dalpiciclib, voruciclib, senexin A, purvalanol, roscovitine, cinobufagin, wogonin, flavopiridol, bohemine, alsterpaullone, kenpaullone, indirubin-3 '-monoxime, resibufogenin, indisulam, MK-8776, JNJ-7706621, BMS-265246, BAY 1251152, BPI- 1178, BPI-16350, HS-10342, PF-562271 beyslate,
  • the one or more polymers are selected from the group consisting of polyvinylpyrrolidone, an ammonio methacrylate copolymer, polyethylene glycol, polyethylene oxide, polyacrylate, sodium polyacrylate, polyvinyl alcohol, dextran and gelatin.
  • the one or more polymers are present in an amount ranging from about 20% to about 99% by weight of the electrospun fiber or film layer. In some embodiments, the one or more polymers is present in an amount ranging from about 60% to about 95% by weight of the electrospun fiber or film layer.
  • 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, ethylcellulose, poly caprolactone, carbothane or polysoftane. In some embodiments, the hydrophobic impermeable layer comprises polycaprolactone.
  • the patch further comprises an absorption enhancer disclosed herein.
  • the absorption enhancer is provided in the adhesive layer.
  • the patch further comprises a plasticizer disclosed herein.
  • the plasticizer is provided in the adhesive layer and/or impermeable backing layer.
  • the plasticizer is provided in the adhesive layer.
  • the plasticizer is provided in the impermeable backing layer.
  • the present disclosure also provides methods for preventing the malignant transformation of a precancerous (i.e., premalignant) oral lesion to oral cancer in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a drug-containing patch disclosed herein.
  • the present disclosure provides methods for preventing the malignant transformation of oral dysplasia to oral cancer in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a drugcontaining patch disclosed herein.
  • the present disclosure provides methods for preventing the malignant transformation of oral leukoplakia to oral dysplasia in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a drugcontaining patch disclosed herein.
  • the present disclosure provides methods for preventing the malignant transformation of oral leukoplakia to oral cancer in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a drugcontaining patch disclosed herein.
  • the present disclosure provides methods for preventing the malignant transformation of oral erythroplakia to oral dysplasia in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a drugcontaining patch disclosed herein.
  • the present disclosure provides methods for preventing the malignant transformation of oral erythroplakia to oral cancer in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a drugcontaining patch disclosed herein.
  • the present disclosure provides methods for treating a precancerous oral lesion in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a drug-containing patch disclosed herein.
  • the present disclosure provides methods for treating oral leukoplakia or erythroplakia in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a drug-containing patch disclosed herein.
  • the present disclosure provides methods for treating oral dysplasia in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a drug-containing patch disclosed herein.
  • the present disclosure provides methods for treating, preventing, and/or reducing the symptoms of oral cancer in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a drugcontaining patch disclosed herein.
  • the subject being treated for oral cancer has or was previously diagnosed with oral dysplasia.
  • the oral cancer is squamous cell carcinoma.
  • the oral cancer is verrucous carcinoma, minor salivary gland carcinoma, or lymphoma.
  • the minor salivary gland carcinoma is selected from the group consisting of adenoid cystic carcinoma (ACC), mucoepidermoid carcinoma, polymorphous low grade adenocarcinoma, or carcinoma ex-pleomorphic adenoma.
  • ACC adenoid cystic carcinoma
  • mucoepidermoid carcinoma mucoepidermoid carcinoma
  • polymorphous low grade adenocarcinoma polymorphous low grade adenocarcinoma
  • carcinoma ex-pleomorphic adenoma carcinoma ex-pleomorphic adenoma.
  • 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.
  • the patch provides a therapeutically effective amount of the chemotherapeutic agent such as the CDK inhibitor for at least about 2 h, at least about 4 h, at least about 6 h, at least about 8 h, at least about 12 h, at least about 18 h, or at least about 24 h, following application to the oral mucosa of a subject.
  • the chemotherapeutic agent such as the CDK inhibitor for at least about 2 h, at least about 4 h, at least about 6 h, at least about 8 h, at least about 12 h, at least about 18 h, or at least about 24 h, following application to the oral mucosa of a subject.
  • the present disclosure provides a method of preparing a patch, the process comprising (a) combining an aqueous alcoholic solvent with one or more polymers and a CDK inhibitor to provide an electrospinning mixture; (b) electrospinning the electrospinning mixture of step (a) to provide electrospun fibers; and (c) attaching an impermeable backing layer to the electrospun fibers of step (b).
  • FIG. 1 provides a flowchart outlining one possible strategy for developing and evaluating drug-containing patches of the present disclosure.
  • FIG. 2 provides a flowchart outlining one possible strategy for developing, optimizing, and evaluating drug-containing patches of the present disclosure.
  • the term “about” when immediately preceding a numerical value means a range (e.g., plus or minus 10% of that value).
  • “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.
  • “about 49, about 50, about 55, ... ” “about 50” means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 52.5.
  • the phrases “less than about” a value or “greater than about” a value should be understood in view of the definition of the term “about” provided herein.
  • the term “about” when preceding a series of numerical values or a range of values refers, respectively to all values in the series, or the endpoints of the range.
  • a reference to “A and/or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
  • impermeable layer refers to a coating or barrier layer in a layered patch configuration that prevents or substantially limits the passage of water through the layer.
  • the impermeable layer can also prevent or substantially limit the passage of the active ingredient(s) (e.g., CDK inhibitor) through the layer.
  • the term “absorption enhancer” or “permeation enhancer” refers to an additive in a patch or electrospun fibers that improves the ability of the cell cycle inhibitor to be absorbed by a targeted tissue or membrane, e.g., oral mucosa.
  • the term “treating” with regard to a subject refers to improving at least one symptom of the subject’s disorder. Treating can be curing, improving, or at least partially ameliorating a disorder.
  • the term “therapeutic effect” as used herein refers to a desired or beneficial effect provided by the method and/or the composition. For example, the method for treating a disclosed disease or condition provides a therapeutic effect when the method reduces at least one symptom of the disease or condition in a subject.
  • the term “preventing” with regard to a subject refers to reducing or eliminating the onset of the symptoms or complications of a disease, condition or disorder. In some embodiments, the symptoms or complications are reduced or eliminated in a subject that is predisposed to the disease, condition, or disorder.
  • the patches of the present disclosure are capable of preventing or treating such diseases, condition, or disorders.
  • subject include vertebrates, more specifically a mammal (e.g., a human, horse, pig, rabbit, dog, sheep, goat, non-human primate, cow, cat, guinea pig or rodent), a fish, a bird or a reptile or an amphibian.
  • the subject is a human subject.
  • the term subject does not denote a particular age or sex.
  • the subject may be a geriatric subject, a pediatric subject, a teenage subject, a young adult subject, or a middle-aged subject. In some embodiments, the subject is less than about 18 years of age.
  • the subject is at least about 18 years of age. In some embodiments, the subject is about 5-10, about 10-15, about 15-20, about 20-25, about 25-30, about SO- 35, about 35-40, about 40-45, about 45-50, about 50-55, about 55-60, about 60-65, about 65-70, about 70-75, about 75-80, about 85-90, about 90-95, or about 95-100 years of age. In some embodiments the subject is a male subject. In some embodiments the subject is a female subject. In some embodiments, the subject is diagnosed with or is considered at risk of having oral dysplasia or oral cancer. [0050] All documents cited herein are incorporated by reference in their entirety for all purposes.
  • the present disclosure provides drug-containing patches that are suitable for application to the oral mucosa.
  • the disclosed patches adhere to the oral mucosa and controllably release a chemotherapeutic agent (such as, a CDK inhibitor) in a localized manner at a clinically effective rate.
  • a chemotherapeutic agent such as, a CDK inhibitor
  • the patches disclosed herein are therefore useful for a range of applications including the treatment of precancerous oral lesions, oral dysplasia and oral cancer. Additionally, the patches disclosed herein are useful for preventing precancerous oral lesions and dysplasia from becoming oral cancer.
  • the present disclosure provides drug-containing patches comprising: (a) an adhesive layer, wherein the adhesive layer comprises (i) one or more polymers, and (ii) a therapeutically effective amount of a chemotherapeutic agent such as a cell cycle inhibitor; and (b) an impermeable backing layer.
  • 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.
  • the cell cycle inhibitor is a biological agent. Accordingly, in some embodiments, the cell cycle inhibitor is selected from the group consisting of a monoclonal antibody, a fragment antigen-binding (Fab fragment) antibody, a single-chain variable fragment (scFv), a full antigen, a fragmented antigen, a protein, a peptide, and an enzyme.
  • Fab fragment fragment antigen-binding
  • scFv single-chain variable fragment
  • the cell cycle inhibitor is a cyclin-dependent kinase (CDK) inhibitor as disclosed herein.
  • CDK cyclin-dependent kinase
  • the present disclosure provides drug-containing patches comprising: (a) an adhesive layer, wherein the adhesive layer comprises (i) one or more polymers, and (ii) a therapeutically effective amount of a chemotherapeutic agent sue as a CDK inhibitor; and (b) an impermeable backing layer.
  • the adhesive layer comprises an electrospun fiber layer or a film layer. In some embodiments, the adhesive layer comprises an electrospun fiber layer. In some embodiments, the adhesive layer comprises a film layer. In some embodiments, an electrospun layer is calendared to the adhesive layer, becoming a film once attached. In some embodiments, a film is prepared directly by calendaring a film layer to an adhesive layer. In some embodiments, the adhesive layer is a mucoadhesive layer.
  • 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.
  • the adhesive layer and the impermeable backing layer are both electrospun fiber layers.
  • the adhesive layer and the impermeable backing layer are both film layers.
  • the adhesive layer is an electrospun fiber layer and the impermeable backing layer is a film layer.
  • the adhesive layer is a film layer and the impermeable backing layer is an electrospun fiber layer.
  • the electrospun fiber layer and impermeable layer can be joined to provide a patch using methods that are known to those skilled in the art, for example, the methods disclosed in International Publication No. WO/2018/133909 or WO/2018/133910.
  • the patches of the present disclosure adhere to the targeted site (e.g., tissue, mucosa, skin, etc.) for a period of time sufficient to provide (i.e., release) an effective amount of a chemotherapeutic agent such as a CDK inhibitor.
  • a chemotherapeutic agent such as a CDK inhibitor.
  • the patch adheres to the targeted site for a period greater than 2 h, greater than 4 h, greater than 8 h, greater than 12 h, greater than 16 h, greater than 24 h, greater than 30 h, greater than 36 h, greater than 42 h, or greater than 48 h.
  • the patch adheres to the targeted site for a period of at least 2 h.
  • the patch adheres to the targeted site for a period of at least 4 h. In some embodiments, the patch adheres to the targeted site for a period of at least 6 h. In some embodiments, the patch adheres to the targeted site for a period of at least 8 h. In some embodiments, the patch adheres to the targeted site for a period of at least 12 h. In some embodiments, the patch adheres to the targeted site for a period of at least 24 h.
  • the impermeable layer e.g., a hydrophobic impermeable layer, protects the patch from saliva and other sources of moisture in order to prevent it from detaching from the application site (skin or mucosa) prematurely.
  • the impermeable layer facilitates the application of the patch to the mucosa by providing a non-adhesive surface that will not stick the fingers.
  • a patch according to the present disclosure provides a therapeutically effective amount of a chemotherapeutic agent such as a cell cycle inhibitor (e.g., a CDK inhibitor) for at least about 2 h, at least about 4 h, at least about 6 h, at least about 8 h, at least about 10 h, at least about 12 h, at least about 14 h, at least about 16 h, at least about 18 h, at least about 20 h, at least about 22 h, or at least about 24 h following application to a subject in need thereof.
  • a chemotherapeutic agent such as a cell cycle inhibitor (e.g., a CDK inhibitor) for at least about 2 h, at least about 4 h, at least about 6 h, at least about 8 h, at least about 10 h, at least about 12 h, at least about 14 h, at least about 16 h, at least about 18 h, at least about 20 h, at least about 22 h, or at least about 24 h following application
  • the patch provides a therapeutically effective amount of a cell cycle inhibitor (e.g., a CDK inhibitor) for at least about 4 h following application to a subject in need thereof. In some embodiments, the patch provides a therapeutically effective amount of a cell cycle inhibitor (e.g., a CDK inhibitor) for at least about 8 h following application to a subject in need thereof. In some embodiments, the patch provides a therapeutically effective amount of a cell cycle inhibitor (e.g., a CDK inhibitor) for at least about 12 h following application to a subject in need thereof.
  • a cell cycle inhibitor e.g., a CDK inhibitor
  • a patch according to the present disclosure is applied to a subject in need thereof (for example, the disease site of a subject) once a day, twice a day (b.i.d.), three times per day (t.i.d.), or four times a day (q.i.d.).
  • the patch is applied to a subject in need thereof (for example, the disease site of a subject) once a day.
  • the patch is applied to a subject in need thereof (for example, the disease site of a subject) twice a day.
  • the patch is applied to a subject in need thereof (for example, the disease site of a subject) three times per day.
  • the patch is applied to a subject in need thereof (for example, the disease site of a subject) four times per day. In other embodiments, the patch is applied to a subject in need thereof on an as-needed basis.
  • a patch according to the present disclosure is applied to a subject in need thereof (for example, the disease site of a subject) once a day for a period of about 1 to 52 weeks. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) twice a day for a period of about 1 to 52 weeks.
  • the patch is applied to a subject in need thereof (for example, the disease site of a subject) three times per day for a period of about 1 to 52 weeks. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) four times per day for a period of about 1 to 52 weeks. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) once a day for a period of about 12 to 52 weeks. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) twice a day for a period of about 12 to 52 weeks.
  • the patch is applied to a subject in need thereof (for example, the disease site of a subject) three times per day for a period of about 12 to 52 weeks. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) four times per day for a period of about 12 to 52 weeks. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) once a day for at least a month. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) twice a day for at least a month.
  • the patch is applied to a subject in need thereof (for example, the disease site of a subject) three times per day for a period of at least a month. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) four times per day for a period of at least a month. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) once a day for at least 3 months. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) twice a day for at least 3 months.
  • the patch is applied to a subject in need thereof (for example, the disease site of a subject) three times per day for a period of at least 3 months. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) four times per day for a period of at least 3 months. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) once a day for at least 6 months. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) twice a day for at least 6 months.
  • the patch is applied to a subject in need thereof (for example, the disease site of a subject) three times per day for a period of at least 6 months. In some embodiments, the patch is applied to a subject in need thereof (for example, the disease site of a subject) four times per day for a period of at least 6 months.
  • the flexibility of the patches disclosed herein can be adjusted to improve comfort and adherence to the oral mucosa.
  • the flexibility of the patch is adjusted by modifying the thickness of the patch, which comprises an electrospun layer and an impermeable layer.
  • decreasing the thickness of the patch results in an increase in patch flexibility.
  • 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.
  • the average thickness of the patch prior to application is less than about 1 mm.
  • the average thickness of the patch prior to application is less than about 0.6 mm.
  • the average thickness of the patch prior to application is less than about 0.3 mm.
  • the patches of the present disclosure can be any shape and size suitable for effective treatment of the affected skin or tissue.
  • the patches of the present disclosure are circular, semicircular, oval, semioval (i.e., half-moon shaped), square, or rectangular.
  • the patches are semicircular or semioval.
  • the patches are semicircular.
  • the patches are semioval.
  • a semioval patch is from about 2 cm to about 4 cm in width and from about 5 cm to about 10 cm in length.
  • the patches of the present disclosure further comprise one or more pharmaceutically acceptable excipients.
  • the patches further comprise a plasticizer disclosed herein.
  • the patches further comprise an absorption enhancer disclosed herein.
  • the drug-containing patches of the present disclosure are layered compositions comprising two or more layers.
  • the drug-containing patches comprise two layers.
  • the drug-containing patches comprise three layers.
  • the drug- containing patches comprise four layers.
  • the drug-containing patches comprise five layers.
  • such layered compositions comprise a drug-containing layer and a backing layer to protect the drug-containing layer(s) from moisture or saliva or to function as an occlusive layer, which may drive the penetration of the drug substance into the oral mucosa.
  • a backing layer can protect the drug-containing layer from being washed away from the application site, which would result in swallowing of the composition, whereby the desired local therapeutic effect can be reduced or eliminated.
  • the drug-containing patch comprises: about 1-500 pg of a chemotherapeutic agent; about 30 g to 40 g of PVP; about 40 g to 50 g of ammonio methacrylate polymer B; about 65 g to 75 g of PEO; and about 15 g to 25 g of PCL.
  • the drug-containing patch comprises: about 1-500 pg of CDK inhibitor; about 30 g to 40 g of PVP; about 40 g to 50 g of ammonio methacrylate polymer B; about 65 g to 75 g of PEO; and about 15 g to 25 g of PCL.
  • the drug-containing patch comprises: about 1-500 pg of CDK inhibitor; about 35 g of PVP; about 44 g of ammonio methacrylate polymer B; about 71 g of PEO; and about 17 g of PCL.
  • the term “electrospun fibers” includes fibers that are obtained by a method that involves electrostatics.
  • the methods referred in the art as electrohydrodynamic (EHD) methods, include electrospinning, coaxial electrospinning, coaxial electrospraying, emulsion electrospinning, and the like. Any such method can be used to prepare the fibers of the present disclosure. Accordingly, the term “electrospun fibers” is not limited to fibers obtained by electrospinning, but instead refers to fibers obtained by electrohydrodynamic methods known in the art.
  • the electrospun fibers are uniaxial. In some embodiments, the electrospun fibers are not coaxial. Coaxial fibers are described, for example, in H. Qu, et al. J. Mater. Chem. A, 2013, 1, 11513-11528.
  • the electrospun fibers or the fiber layer of the patches of the present disclosure comprises about 0.005% to about 50.0% (wt./wt.%), e.g., about 0.005%, about 0.01%, about 0.1%, about 0.5%, about 1%, about 2.5%, about 5%, 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 the chemotherapeutic agent such as the cell cycle inhibitor (e.g., a CDK inhibitor), including all ranges and values therebetween.
  • the chemotherapeutic agent such as the cell cycle inhibitor (e.g., a CDK inhibitor), including all ranges and values therebetween.
  • the electrospun fiber or fiber layer comprises about 0.005% to about 10.0% (wt./wt.%) of the cell cycle inhibitor (e.g., a CDK inhibitor). In some embodiments, the electrospun fiber or fiber layer comprises about 0.005% to about 5.0% (wt./wt.%) of the cell cycle inhibitor (e.g., a CDK inhibitor). In some embodiments, the electrospun fiber or fiber layer comprises about 0.005% to about 1.0% (wt./wt.%) of the cell cycle inhibitor (e.g., a CDK inhibitor).
  • the electrospun fibers of the present disclosure are provided in a layer, which when applied to the skin, mucosa or a humid internal surface of the body adhere to the surface.
  • a cell cycle inhibitor e.g., CDK inhibitor such as abemaciclib
  • CDK inhibitor such as abemaciclib
  • the electrospun fibers of the present disclosure comprise one or more polymers, a therapeutically effective amount of cell cycle inhibitor, an optional absorption enhancer, and an optional plasticizer, each of which is described in more detail below.
  • the electrospun fiber layer and an impermeable layer can be joined by various by various processes to provide a patch that is useful in the methods of treatment and prevention disclosed herein.
  • the film layer for use in the presently disclosed patches can be prepared by any suitable method known in the art.
  • a chemotherapeutic agent such as a cell cycle inhibitor, e.g., CDK inhibitor such as abemaciclib
  • a chemotherapeutic agent can be homogeneously distributed in the film layer, whereby the concentration of drug substance per surface area of the layer is constant and a dose of the drug substance can easily be determined by using a measured area of the layer.
  • the film layer of the present disclosure comprises one or more polymers, a therapeutically effective amount of a chemotherapeutic agent such as a cell cycle inhibitor, an optional absorption enhancer, and an optional plasticizer, each of which is described in more detail below.
  • the film layer and an impermeable layer can be joined by various processes to provide a patch that is useful in the methods of treatment and prevention disclosed herein.
  • the adhesive layer comprises a plasticizer.
  • the plasticizer is selected from the group consisting of citrate esters, fatty acid esters, sebacate esters, phthalate esters, and glycol derivatives.
  • the plasticizer is selected from the group consisting of triethyl citrate, acetyl triethyl citrate, tributyl citrate, butyl stearate, glycerol monostearate, stearyl alcohol, castor oil, mineral oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, dibutyl phthalate, dioctyl phosphate, sorbitol, glycerol, triacetin, tributyrin, cellulose nitrate, polyethylene glycol, polyethylene glycol monomethyl ether, propylene glycol, or mixtures thereof.
  • the plasticizer is dibutyl serotarate
  • 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.
  • the adhesive layer of the drug-containing patch can be an electrospun fiber layer or a film layer.
  • the electrospun fiber layer or film layer comprises one or more polymers selected from the group consisting of dextran, polyethylene oxides, alginate, tragacanth, carrageenan, pectin, gelatin, guar, xanthan, gellan, fibronectin, collagen, hyaluronic acid, chitosan, cellulosic polymers such as methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose, cellulose acetates, carboxymethylcellulose and alkali salts thereof, polymers of acrylic acids (PAA derivatives), chitosan, lectins, thiolated polymers, poly ox WSR, PAA-co-PEG (PEG is polyethylene glycol), polylactic acid, polyglycolic acid, poly(butylene succinate), and mixtures thereof.
  • PEG is polyethylene glycol
  • polylactic acid polyglycolic acid
  • mixtures thereof mixtures thereof.
  • the electrospun fiber layer or film layer comprises one or more polymers selected from the group consisting of polyvinylpyrrolidone (PVP), acrylates and acrylic copolymers (e.g., Eudragit®), ethylcellulose (EC), hydroxypropylcellulose (HPC), polyvinyl alcohol, carboxymethylcellulose, and mixtures thereof.
  • the one or more polymers is selected from polyvinylpyrrolidone (PVP), hydroxypropylcellulose (HPC) and mixtures thereof.
  • the one or more polymers is polyvinyl alcohol or carboxymethylcellulose.
  • the electrospun fiber layer or film layer comprises one or more polymers selected from the group consisting of ethylcellulose, polyvinylpyrrolidone, an ammonio methacrylate copolymer, polyethylene glycol, polyethylene oxide, polyacrylate, sodium polyacrylate, polyvinyl alcohol, polycaprolactone (PCL), dextran and gelatin.
  • the electrospun fiber layer or film layer comprises one or more polymers selected from the group consisting of polyvinylpyrrolidone, an ammonio methacrylate copolymer, polyethylene glycol, polyethylene oxide, polyacrylate, sodium polyacrylate, polyvinyl alcohol, polycaprolactone (PCL), dextran and gelatin.
  • the electrospun fibers comprise one or more polymers selected from the group consisting of polyvinylpyrrolidone, an ammonio methacrylate copolymer, polyethylene glycol, polyethylene oxide, polyacrylate, sodium polyacrylate, polyvinyl alcohol, dextran and gelatin.
  • the electrospun fiber layer or film layer comprises one or more polymers selected from the group consisting of polyvinylpyrrolidone, an ammonio methacrylate copolymer, polyethylene glycol, polyethylene oxide, polyacrylate, sodium polyacrylate, polyvinyl alcohol, dextran and gelatin.
  • the one or more polymers comprises one or more hydrophilic polymers and a bioadhesive substance.
  • the one or more hydrophilic polymers is polyvinylpyrrolidone (PVP), acrylates and acrylic copolymers (e.g., Eudragit®), ethylcellulose (EC), hydroxypropylcellulose (HPC), or mixtures thereof; and the bioadhesive substance is dextran, polyethylene oxides, alginate, tragacanth, carrageenan, pectin, gelatin, guar, xanthan, gellan, fibronectin, collagen, hyaluronic acid, chitosan, cellulosic polymers (e.g., methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose, cellulose acetates, carboxymethylcellulose and alkali salts thereof), polyvinylalcohol (PVA), polymers of acrylic acids (PAAs), chitosan, lectins, thiolated polymers, polyox WSR, PAA-co
  • the one or more hydrophilic polymers is polyvinylpyrrolidone (PVP), ammonio methacrylate polymer type B, or mixtures thereof; and the bioadhesive substance is dextran, polyethylene oxides (e.g., poly ox WSR), gelatin, polyvinylalcohol (PVA), or mixtures thereof.
  • PVP polyvinylpyrrolidone
  • PVA polyvinylalcohol
  • the one or more polymers comprise: (a) polyvinylpyrrolidone and an ammonio methacrylate copolymer; (b) polyvinylpyrrolidone and polyethylene glycol; (c) polyvinylpyrrolidone and polyethylene oxide; (d) polyvinylpyrrolidone and dextran; (e) polyvinylpyrrolidone and gelatin; (f) polyvinylpyrrolidone and polyvinyl alcohol; (g) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyethylene glycol; (h) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyethylene oxide; (i) polyvinylpyrrolidone, an ammonio methacrylate copolymer and dextran; (j) polyvinylpyrrolidone, an ammonio methacrylate copolymer and gelatin; (k) polyvin
  • the one or more polymers comprise: (a) polyvinylpyrrolidone and an ammonio methacrylate copolymer; (b) polyvinylpyrrolidone and polyethylene glycol; (c) polyvinylpyrrolidone and polyethylene oxide; (d) polyvinylpyrrolidone and dextran; (e) polyvinylpyrrolidone and gelatin; (f) polyvinylpyrrolidone and polyvinyl alcohol; (g) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyethylene glycol; (h) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyethylene oxide; (i) polyvinylpyrrolidone, an ammonio methacrylate copolymer and dextran; j) polyvinylpyrrolidone, an ammonio methacrylate copolymer and gelatin; or (k) polyvinylpyrrolidone
  • the one or more polymers comprise polyvinylpyrrolidone and ammonio methacrylate copolymer.
  • the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer in the electrospun fibers is about 0.1 to about 10, including, about 0.1, about 0.25, about 0.5, about 0.75, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about
  • 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.
  • the one or more polymers comprise polyvinylpyrrolidone and polyethylene glycol.
  • the weight ratio of polyvinylpyrrolidone to polyethylene glycol in the electrospun fibers is about 0.15 to about 10, e.g., including 0.15, about 0.5, about 0.75, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10, including all ranges and values therebetween.
  • the weight ratio of polyvinylpyrrolidone to polyethylene glycol is about 0.25 to about 5.
  • the weight ratio of polyvinylpyrrolidone to polyethylene glycol is about 0.5 to about 2.
  • the one or more polymers comprise polyvinylpyrrolidone and polyethylene oxide.
  • the weight ratio of polyvinylpyrrolidone to polyethylene oxide in the electrospun fibers is about 0.3 to about 10, including, about 0.3, about 0.5, about 0.75, about 1, about 1.5, about 2, about
  • 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.
  • the one or more polymers comprise polyvinylpyrrolidone and dextran.
  • the weight ratio of polyvinylpyrrolidone to dextran in the electrospun fibers is about 0.3 to about 10, including about 0.3, about 0.5, about 0.75, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about
  • 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.
  • the one or more polymers comprise polyvinylpyrrolidone and gelatin.
  • the weight ratio of polyvinylpyrrolidone to gelatin in the electrospun fibers is about 0.6 to about 10, including about 0.6, about 0.8, about 1, about 1.5, about 2, about 2.5, about 3, about
  • 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.
  • the one or more polymers comprise polyvinylpyrrolidone and polyvinyl alcohol.
  • the weight ratio of polyvinylpyrrolidone to polyvinyl alcohol in the electrospun fibers is about 0.5 to about 10, including about 0.5, about 0.75, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10, including all ranges and values therebetween.
  • the weight ratio of polyvinylpyrrolidone to polyvinyl alcohol is about 0.5 to about 5.
  • the weight ratio of polyvinylpyrrolidone to polyvinyl alcohol is about 1 to about 3.
  • the one or more polymers comprise polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyethylene glycol.
  • the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer to polyethylene glycol in the electrospun fibers is about 1 : 0.5 : 0.1 to about 1 : 2 : 6, including all ranges and values therebetween.
  • the one or more polymers comprise polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyethylene oxide.
  • the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer to polyethylene oxide in the electrospun fibers is about 1 : 0.5 : 0.1 to about 1 : 2 : 3, including all ranges and values therebetween.
  • the one or more polymers comprise polyvinylpyrrolidone, an ammonio methacrylate copolymer and dextran.
  • the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer to dextran in the electrospun fibers is about 1 : 0.5 : 0.1 to about 1 : 2 : 3, including all ranges and values therebetween.
  • the one or more polymers comprise polyvinylpyrrolidone, an ammonio methacrylate copolymer and gelatin.
  • the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer to gelatin in the electrospun fibers is about 1 : 0.5 : 0.1 to about 1 : 2 : 1.5, including all ranges and values therebetween.
  • the one or more polymers comprise polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyvinyl alcohol.
  • the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer to polyvinyl alcohol in the electrospun fibers is about 1 : 0.5 : 0.1 to about 1 : 2 : 2, including all ranges and values therebetween.
  • the electrospun fibers of the present disclosure comprise one or more polymers (as described herein), typically including hydrophilic polymers, which provide various desirable properties, e.g., providing for rheological properties suitable for electrospinning, physical properties (e.g., strength, flexibility, etc.) to provide a patch that is sufficiently durable for handling during manufacturing and use and sufficiently flexible such that it can conform to a mucosal surface, and a suitable degree of hydrophilicity for application to mucosal surfaces.
  • Such polymers can provide bioadhesive properties to aid in adhesion to a mucosal surface.
  • one or more additional polymers can be added to improve bioadhesion.
  • the electrospun fibers of the present disclosure comprise polyvinylpyrrolidone and acrylic copolymers (e.g., Eudragit® copolymers), in combination with polyethylene oxide polymers.
  • acrylic copolymers e.g., Eudragit® copolymers
  • Such electrospun fiber compositions are described, for example, in US Patent No. 10,052,291, US Patent Publication Nos. 2019/0254985, and 2019/0254986, 2019/0351662.
  • polyvinylpyrrolidone When used as a polymer in the electrospun fibers, it can be used in a grade having an approximate molecular weight of from 2,500 Da to 3,000,000 Da.
  • PVP can be purchased as Kollidon® having a variety of molecular weight ranges as shown below.
  • Ethylcellulose is sold under the trademark ETHOCELTM (Dow Chemical Company) and is available in different grades. Dependent on its ethoxyl content, ethylcellulose may have different softening point and melting point temperatures. Ethylcellulose is also produced in a number of different viscosities (see Table below).
  • Acrylates and acrylic acid derivatives include polymethacrylates, methacrylate copolymers, acrylic copolymers and methacrylate polymers, and include acrylates sold as EUDRAGIT as well as acrylates/octaacrylamide sold as DERMACRYL 79.
  • Nonlimiting example of such acrylates are EUDRAGIT®E 12,5 (amino methacrylate copolymer), EUDRAGIT® El 00 (amino methacrylate copolymer; basic butylated methacrylate copolymer), EUDRAGIT®E PO ((amino methacrylate copolymer), EUDRAGIT®L 100-55, EUDRAGIT®L 100 (methacrylic acid - methyl methacrylate copolymer 1:1), EUDRAGIT®S 100 (methacrylic acid-methyl methacrylate copolymer 1:2), EUDRAGIT®RL 100, EUDRAGIT®RL 100 (ammonio methacrylate copolymer type A), EUDRAGIT®RL PO, EUDRAGIT®RS 100 (ammonio methacrylate copolymer type B), EUDRAGIT®RS PO.
  • EUDRAGIT®E is a cationic polymer based on dimethylaminoethyl methacrylate and other neutral methacrylic acid esters: EUDRAGIT®L and S are methacrylic acid copolymers and are cationic copolymerization products of methacrylic acid and methyl methacrylate. EUDRAGIT®RL or RS is ammonio methacrylate copolymers synthesized from acrylic acid and methacrylic acid.
  • Carboxymethylcellulose is available in a broad selection of viscosity grades.
  • the viscosity of carboxymethylcellulose in the electrospun fibers ranges from 10 to 100,000 mPa*s.
  • the carboxymethylcellulose is a sodium salt.
  • Methylcellulose is sold under the name METHOCELTM (Dow Chemical Company) and is available in a wide range of viscosity grades.
  • the viscosity grade of methylcellulose in the electrospun fibers is from less than about 3 to greater than about 100,000 mPA*s.
  • HPMC is sold under the names Methocel® and Klucel®.
  • HPMC of the electrospun fibers has an average molecular weight of from about 80,000 to about 140,000.
  • polyvinyl alcohol has a molecular weight ranging from about 20,000 Da to about 200,000. In some embodiments, polyvinyl alcohol has a molecular weight ranging from about 100,000 Da to about 200,000.
  • polyethylene oxide (PEO) which is sold commercial under the name POLYOXTM (Dow Chemical Company), has average molecular weights ranging from about 100,000 Da to about 4,000,000 Da. In some embodiments, the average molecular weight of the PEO is from about 100,000 Da to about 4,000,000 Da. In some embodiments, the average molecular weight of the PEO is from about 100,000 Da to about 2,000,000 Da. In some embodiments, the PEO has an average molecular weight of from about 100,000 Da to about 1,000,000 Da.
  • the PEO has an average molecular weight of from about 100,000 Da to about 700,000 Da. In some embodiments, the PEO has an average molecular weight of from about 100,000 Da to about 500,000 Da. In some embodiments, the PEO has an average molecular weight of from about 100,000 Da to about 400,000 Da. In some embodiments, the PEO has an average molecular weight of about 100,000 Da. In some embodiments, the PEO has an average molecular weight of about 200,000 Da. In some embodiments, the PEO has an average molecular weight of about 300,000 Da. In some embodiments, the PEO has an average molecular weight of about 400,000 Da.
  • dextran is used in grade having a molecular weight of from about 400,000 Da to about 2,000,000 Da. In some embodiments, dextran has a molecular weight of from about 500,000 Da to about 2,000,000 Da, e.g., about 700,000 Da to about 800,000 Da or from about 1,000,000 Da to about 2,000,000 Da. In some embodiments, dextran has a molecular weight of from about 100,000 Da to about 1,000,000 Da. In some embodiments, dextran has a molecular weight of from about 100,000 Da to about 700,000 Da. . In some embodiments, dextran has a molecular weight of from about 100,000 Da to about 500,000 Da. In some embodiments, dextran has a molecular weight of from about 400,000 Da to about 1,000,000 Da. In some embodiments, dextran has a molecular weight of from about 400,000 Da to about 700,000 Da.
  • the one or more polymers is present in an amount ranging from about 20% to about 99% by weight of the electrospun fibers, including about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99%, including all ranges and values therebetween.
  • the one or more polymers is present in an amount ranging from about 50% to about 99% by weight of the electrospun fibers.
  • the one or more polymers is present in an amount ranging from about 60% to about 99% by weight of the electrospun fibers.
  • the one or more polymers is present in an amount ranging from about 75% to about 99% by weight of the electrospun fibers. In some embodiments, the one or more polymers is present in an amount ranging from about 50% to about 95% by weight of the electrospun fibers. In some embodiments, the one or more polymers is present in an amount ranging from about 60% to about 95% by weight of the electrospun fibers. In some embodiments, the one or more polymers is present in an amount ranging from about 75% to about 95% by weight of the electrospun fibers. In some embodiments, the one or more polymers is present in an amount ranging from about 50% to about 90% by weight of the electrospun fibers.
  • the one or more polymers is present in an amount ranging from about 60% to about 30% by weight of the electrospun fibers. In some embodiments, the one or more polymers is present in an amount ranging from about 75% to about 90% by weight of the electrospun fibers. In some embodiments, the one or more polymers is present in an amount ranging from about 50% to about 90% by weight of the electrospun fibers. In some embodiments, the one or more polymers is present in an amount ranging from about 20% to about 60% by weight of the electrospun fibers. In some embodiments, the one or more polymers is present in an amount ranging from about 20% to about 50% by weight of the electrospun fibers. In some embodiments, the one or more polymers is present in an amount ranging from about 20% to about 40% by weight of the electrospun fibers.
  • the chemotherapeutic agents may in principle be any drug or agent capable of killing or inhibiting growth or cancer cells or any agent that is capable of inhibiting the transformation of precancerous cells to cancer cells.
  • chemotherapeutic agents preferably selected among cell cycle inhibitors and chemotherapeutic drugs as known in the art as well as combinations thereof.
  • the chemotherapeutic agents are selected among therapeutically active chemical or biological agents. Examples of preferred chemotherapeutic agents includes cell cycle inhibitors.
  • the chemotherapy drug is imiquimod, cisplatin, carboplatin, 5 -fluorouracil (5-FU), paclitaxel, docetaxel, hydroxyurea, methotrexate, capecitabine, or mixtures thereof.
  • the chemotherapy drug is imiquimod, 5 -fluorouracil (5-FU), or a combination thereof.
  • the therapeutic agent is a targeted therapeutic, e.g., a drug that targets epidermal growth factor receptor (EFGR).
  • EFGR epidermal growth factor receptor
  • the targeted therapeutic is cetuximab.
  • the therapeutic agent is an immune checkpoint inhibitor.
  • the immune checkpoint inhibitor is pembrolizumab or nivolumab.
  • the adhesive layer of the drug-containing patch can include a therapeutically effective amount of a cell cycle inhibitor.
  • the cell cycle inhibitor is a cyclin-dependent kinase (CDK) inhibitor.
  • the CDK inhibitor is a pan CDK inhibitor.
  • the compound is a selective CDK inhibitor.
  • the selective CDK inhibitor is a CDK2/4/6 inhibitor.
  • the selective CDK inhibitor is a CDK4/6 inhibitor.
  • the selective CDK inhibitor is a CDK4 inhibitor.
  • the selective CDK inhibitor is a CDK1/4/6 inhibitor.
  • the selective CDK inhibitor is a CDK2/4/7 inhibitor.
  • the selective CDK inhibitor is a CDK4/6/9 inhibitor.
  • the selective CDK inhibitor is a CDK6/9 inhibitor.
  • the selective CDK inhibitor is a CDK9 inhibitor.
  • the CDK inhibitor is palbociclib, ribociclib, abemaciclib, trilaciclib, dinaciclib, riviciclib, miliciclib, samuraciclib, fadraciclib, atuveciclib, alvociclib, roniciclib, birociclib, ebvaciclib, lerociblib, dalpiciclib, voruciclib, senexin A, purvalanol, roscovitine, cinobufagin, wogonin, flavopiridol, bohemine, alsterpaullone, kenpaullone, indirubin-3 '-monoxime, resibufogenin, indisulam, MK- 8776, JNJ-7706621, BMS-265246, BAY 1251152, BPI-1178, BPI-16350, HS-10342, PF-562271 beyslate, R547, AT7519
  • the CDK inhibitor is palbociclib, ribociclib, abemaciclib, trilaciclib, dinaciclib, riviciclib, milciclib, samuraciclib, fadraciclib, atuveciclib, ebvaciclib, birociclib, lerociclib, voruciclib, or auceliciclib.
  • the CDK inhibitor is palbociclib, ribociclib, or abemaciclib.
  • the CDK inhibitor is abemaciclib.
  • the CDK inhibitor is ribociclib.
  • the CDK inhibitor is palbociclib.
  • Abemaciclib [5-(4-ethyl-piperazin-l-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7- fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-amine
  • Verzenio® is a CDK inhibitor selective for CDK4 and CDK6 that has the structure: , or a pharmaceutically acceptable salt thereof.
  • Selective benzimidazolyl CDK inhibitors including abemaciclib and crystalline forms thereof, their methods of use in treating cancer, and methods of preparation are disclosed in U.S. Patent No. 7,855,211, which is incorporated herein by reference in its entirety.
  • Palbociclib (6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(l-piperazinyl)-2- pyridinyl]amino]-pyrido[2,3-d]pyrimidin-7(8H)-one), sold under the brand name Ibrance®, is a CDK inhibitor selective for CDK4 and CDK6 that has the structure:
  • Kisqali® is a CDK inhibitor selective for CDK4 and CDK6 that has the structure: pharmaceutically acceptable salt thereof, e.g. a succinate salt.
  • pharmaceutically acceptable salt thereof e.g. a succinate salt.
  • Selective pyrrolopyrimidine CDK inhibitors, including riboci clib, their methods of use in treating cancer, and methods of preparation are disclosed in
  • the CDK inhibitor is present in the electrospun fibers in an amount ranging from about 0.005% to about 50.0% (wt./wt.%). In some embodiments, the CDK inhibitor is present in the electrospun fibers in an amount ranging from about 0.01% to about 50.0% (wt./wt.%). In some embodiments, the CDK inhibitor is present in the electrospun fibers in an amount ranging from about 0.01% to about 40.0% (wt./wt.%) . In some embodiments, the CDK inhibitor is present in the electrospun fibers in an amount ranging from about 0.005% to about 30.0% (wt./wt.%).
  • the CDK inhibitor is present in the electrospun fibers in an amount ranging from about 0.005% to about 20.0% (wt./wt.%). In some embodiments, the CDK inhibitor is present in the electrospun fibers in an amount ranging from about 0.005% to about 10.0% (wt./wt.%). In some embodiments, the CDK inhibitor is present in the electrospun fibers in an amount ranging from about 0.005% to about 5.0% (wt./wt.%). In some embodiments, the CDK inhibitor is present in the electrospun fibers in an amount ranging from about 0.005% to about 2.5% (wt./wt.%).
  • the CDK inhibitor is present in the electrospun fibers in an amount ranging from about 0.005% to about 1.0% (wt./wt.%). In some embodiments, the CDK inhibitor is present in the electrospun fibers in an amount ranging from about 0.01% to about 5.0% (wt./wt.%).In some embodiments, the CDK inhibitor is present in the electrospun fibers in an amount ranging from about 0.01% to about 2.5% (wt./wt.%). In some embodiments, the CDK inhibitor is present in the electrospun fibers in an amount ranging from about 0.01% to about 1% (wt./wt.%).
  • the cell cycle inhibitor included in the drug-containing patch is a biological agent.
  • the biological agent is selected from the group consisting of a monoclonal antibody, a fragment antigen-binding (Fab fragment) antibody, a single-chain variable fragment (scFv), a full antigen, a fragmented antigen, a protein, a peptide, and an enzyme.
  • the biological agent is present in the electrospun fibers in an amount ranging from about 0.005% to about 50.0% (wt./wt.%). In some embodiments, the biological agent is present in the electrospun fibers in an amount ranging from about 0.01% to about 50.0% (wt./wt.%). In some embodiments, the biological agent is present in the electrospun fibers in an amount ranging from about 0.01% to about 40.0% (wt./wt.%) . In some embodiments, the biological agent is present in the electrospun fibers in an amount ranging from about 0.005% to about 30.0% (wt./wt.%).
  • the biological agent is present in the electrospun fibers in an amount ranging from about 0.005% to about 20.0% (wt./wt.%). In some embodiments, the biological agent is present in the electrospun fibers in an amount ranging from about 0.005% to about 10.0% (wt./wt.%). In some embodiments, the biological agent is present in the electrospun fibers in an amount ranging from about 0.005% to about 5.0% (wt./wt.%). In some embodiments, the biological agent is present in the electrospun fibers in an amount ranging from about 0.005% to about 2.5% (wt./wt.%).
  • the biological agent is present in the electrospun fibers in an amount ranging from about 0.005% to about 1.0% (wt./wt.%). In some embodiments, the biological agent is present in the electrospun fibers in an amount ranging from about 0.01% to about 5.0% (wt./wt.%).In some embodiments, the biological agent is present in the electrospun fibers in an amount ranging from about 0.01% to about 2.5% (wt./wt.%). In some embodiments, the biological agent is present in the electrospun fibers in an amount ranging from about 0.01% to about 1% (wt./wt.%).
  • the electrospun fibers of the drug-containing patches of the present disclosure in addition to a cell cycle inhibitor comprise an effective amount of an additional therapeutic agent.
  • the additional therapeutic agent is a chemotherapy drug.
  • the chemotherapy drug is imiquimod, cisplatin, carboplatin, 5- fluorouracil (5-FU), paclitaxel, docetaxel, hydroxyurea, methotrexate, capecitabine, or mixtures thereof.
  • the chemotherapy drug is imiquimod, 5- fluorouracil (5-FU), or a combination thereof.
  • the additional therapeutic agent is a targeted therapeutic, e.g., a drug that targets epidermal growth factor receptor (EFGR).
  • EFGR epidermal growth factor receptor
  • the targeted therapeutic is cetuximab.
  • the additional therapeutic agent is an immune checkpoint inhibitor.
  • the immune checkpoint inhibitor is pembrolizumab or nivolumab.
  • the patches of the present disclosure comprise an impermeable layer.
  • the impermeable layer is provided as a coating disposed on a drug-containing layer.
  • the impermeable layer is co-spun with the drug-containing, and is therefore integrated into the electrospun fibers.
  • the impermeable layer is a backing layer.
  • the backing layer is a film layer. In some embodiments, the backing layer is an electrospun layer.
  • the impermeable backing layer comprises a plasticizer.
  • the plasticizer is selected from the group consisting of citrate esters, fatty acid esters, sebacate esters, phthalate esters, and glycol derivatives.
  • the plasticizer is selected from the group consisting of triethyl citrate, acetyl triethyl citrate, tributyl citrate, butyl stearate, glycerol monostearate, stearyl alcohol, castor oil, mineral oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, dibutyl phthalate, dioctyl phosphate, sorbitol, glycerol, triacetin, tributyrin, cellulose nitrate, polyethylene glycol, polyethylene glycol monomethyl ether, propylene glycol, or mixtures thereof.
  • the plasticizer is dibutyl sebacate.
  • 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.
  • the impermeable layer is a hydrophobic impermeable layer.
  • the impermeable hydrophobic layer protects the drugcontaining layer(s) from moisture or saliva. In some embodiments, the impermeable layer protects the drug-layer from being washed away from the application site, which results in the desired local therapeutic effect being reduced or eliminated. In some embodiments, the impermeable layer functions as an occlusive layer, which drives the penetration of drug substance into the skin or mucosa.
  • the impermeable layer comprises one or more biodegradable polyesters.
  • the biodegradable polyester is an aliphatic polyester.
  • the biodegradable polyester is an aromatic polyester.
  • the impermeable layer comprises one or more polymers selected from the group consisting of poly(caprolactone), poly(gly colic acid), poly(lactic acid), poly(lactide-co-glycolide), poly(butylene succinate), poly(butylene succinate-co-adipate), poly(/?-dioxanone). and poly(trimethylene carbonate).
  • the impermeable layer comprises one or more polymers selected from the group consisting of poly(caprolactone), poly(glycolic acid), poly(lactic acid), and poly(lactide-co-glycolide). In some embodiments, the impermeable layer comprises poly(caprolactone). In some embodiments, the hydrophobic backing layer comprises polycaprolactone or ethyl cellulose plasticized with dibutyl sebacate. In some embodiments, the hydrophobic backing layer comprises polycaprolactone. In some embodiments, the hydrophobic backing layer comprises ethyl cellulose plasticized with dibutyl sebacate.
  • the impermeable layer comprises polyethylene-co-vinyl acetate, ethylcellulose, poly(caprolactone), carbothane or polysoftane.
  • the impermeable layer comprises acrylates/octylacrylamide copolymer (sold under the name DERMACRL® 79), amino methacrylate copolymer (EUDRAGIT®), dimethylaminoethyl methacrylate, methacrylate, methyl methacrylate (e.g. EUDRAGIT ®E 100), or other acrylates.
  • the impermeable layer comprises about 5-70% by weight of the patch, including about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, including all values and ranges therebetween, by weight of the patch.
  • the impermeable layer comprises about 5-50% by weight of the patch.
  • the impermeable layer comprises about 10-30% by weight of the patch.
  • the present disclosure provides methods of treating or preventing an oral disease or disorder in a subject in need thereof by administering a drug-containing patch as disclosed herein to the oral cavity (e.g., the oral mucosa) of the subject.
  • the disease or disorder is an oral precancerous condition (e.g., a precancerous lesion, dysplasia, etc.), oral cancer, or a related condition.
  • the present disclosure provides methods of treating a precancerous oral lesion in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a drug-containing patch disclosed herein.
  • the present disclosure provides methods of preventing the malignant transformation of a precancerous oral lesion to oral cancer in a subject in need thereof, the method comprising administering to the oral mucosa of the subject a drug-containing patch disclosed herein.
  • the present disclosure provides methods of treating a precancerous oral lesion in a subject in need thereof, the method comprising administering to the subject an effective amount of a chemotherapeutic agent such as a CDK inhibitor, wherein the CDK inhibitor is administered topically via a drugcontaining patch disclosed herein.
  • a chemotherapeutic agent such as a CDK inhibitor
  • the precancerous oral lesion comprises leukoplakia, and/or erythroplakia. In some embodiments, the precancerous oral lesion comprises leukoplakia. In some embodiments, the precancerous oral lesion comprises erythroplakia. In some embodiments, the leukoplakia is dysplastic leukoplakia. In some embodiments, the erythroplakia is dysplastic erythroplakia.
  • the present disclosure provides methods of treating oral dysplasia in a subject in need thereof, the method comprising administering a patch disclosed herein to the oral mucosa of the subject.
  • the present disclosure provides methods of preventing the malignant transformation of oral dysplasia to oral cancer in a subj ect in need thereof, the method comprising administering to the oral mucosa of the subject a drugcontaining patch disclosed herein.
  • the oral dysplasia comprises leukoplakia, and/or erythroplakia.
  • the leukoplakia is dysplastic leukoplakia.
  • the erythroplakia is dysplastic erythroplakia.
  • the leukoplakia and/or erythroplakia are homogenous.
  • the leukoplakia and/or erythroplakia are irregular shaped patches that may be flat, nodular, or verrucous.
  • Such leukoplakia referred to as non-homogenous, is seven times more likely to become cancerous than homogenous leukoplakia are characterized as being evenly colored thin patches with a smooth, wrinkled or rigid surface that is consistent throughout.
  • the present disclosure provides methods of treating oral leukoplakia in a subject in need thereof, the method comprising administering a patch disclosed herein to the oral mucosa of the subject.
  • the present disclosure provides methods of preventing the malignant transformation of oral leukoplakia to oral cancer in a subject in need thereof, the method comprising administering a patch disclosed herein to the oral mucosa of the subject.
  • the present disclosure provides methods of treating or preventing oral cancer in a subject in need thereof, the method comprising administering a patch disclosed herein to the oral mucosa of the subject.
  • the present disclosure provides methods of treating or preventing oral cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of chemotherapeutic agent such as a CDK inhibitor, wherein the chemotherapeutic agent such as the CDK inhibitor is administered topically via a drug-containing patch disclosed herein.
  • chemotherapeutic agent such as a CDK inhibitor
  • the oral cancer is squamous cell carcinoma.
  • the oral cancer is verrucous carcinoma, minor salivary gland carcinoma, or lymphoma.
  • the minor salivary gland carcinoma is selected from the group consisting of adenoid cystic carcinoma (ACC), mucoepidermoid carcinoma, polymorphous low grade adenocarcinoma, or carcinoma ex-pleomorphic adenoma.
  • the oral dysplasia or cancer comprises leukoplakia and/or erythroplakia.
  • the leukoplakia is dysplastic leukoplakia.
  • the erythroplakia is dysplastic erythroplakia.
  • the leukoplakia is proliferative leukoplakia.
  • the erythroplakia is proliferative erythroplakia.
  • the subject in need of treatment previously had surgical intervention to remove dysplastic precancerous oral lesions.
  • the subject in need of treatment by the present methods experienced a recurrence of precancerous oral lesions (e.g., leukoplakia and/or erythroplakia).
  • the recurrence occurred after surgical intervention to remove one or more dysplastic precancerous oral lesions.
  • a subject being treated for cancer according to the present methods was previously treated with cisplatin, carboplatin, 5 -fluorouracil, paclitaxel, docetaxel, hydroxyurea, methotrexate, capecitabine, or a combination thereof.
  • a subject being treated for cancer according to the present methods is undergoing concurrent treatment with cisplatin, carboplatin, 5- fluorouracil, paclitaxel, docetaxel, hydroxyurea, methotrexate, capecitabine, or a combination thereof.
  • treatment comprises one or more of: reducing an area of leukoplakia, eliminating leukoplakia, alleviating abnormal hyperplasia of leukoplakia, reversing to simple hyperplasia, and transforming leukoplakia to normal mucosa.
  • a patch of the present disclosure is administered once a day. In some embodiments, the patch is administered twice a day. In some embodiments, the patch is administered three times a day. In some embodiments, the patch is administered four times a day. In some embodiments, the patch is administered once a day for a period of about 1-52 weeks. In some embodiments, the patch is administered twice a day for a period of about 1-52 weeks. In some embodiments, the patch is administered three times a day for a period of about 1-52 weeks. In some embodiments, the patch is administered four times a day for a period of about 1-52 weeks. In some embodiments, the patch is administered once a day for a period of about 12-52 weeks.
  • the patch is administered twice a day for a period of about 12-52 weeks. In some embodiments, the patch is administered three times a day for a period of about 12-52 weeks. In some embodiments, the patch is administered four times a day for a period of about 12-52 weeks. In some embodiments, the patch is administered once a day for at least a month. In some embodiments, the patch is administered twice a day for at least a month. In some embodiments, the patch is administered three times a day for at least a month. In some embodiments, the patch is administered four times a day for at least a month. In some embodiments, the patch is administered once a day for at least 3 months. In some embodiments, the patch is administered twice a day for at least 3 months.
  • 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.
  • the patches of the present disclosure upon administration to the oral mucosa, provide a daily dose of about 1 mg to 500 mg of the cell cycle inhibitor (e.g., a CDK inhibitor such as abemaciclib). In some embodiments, upon administration to the oral mucosa, the patches of the present disclosure provide a daily dose of about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg of the cell cycle inhibitor.
  • the cell cycle inhibitor e.g., a CDK inhibitor such as abemaciclib
  • the patches of the present disclosure upon administration to the oral mucosa, provide a daily dose of about 1 mg, about 5 mg, about 10 mg,
  • the patches of the present disclosure upon administration to the oral mucosa, provide a daily dose of about 5 mg of the cell cycle inhibitor. In some embodiments, upon administration to the oral mucosa, the patches of the present disclosure provide a daily dose of about 10 mg of the cell cycle inhibitor. In some embodiments, upon administration to the oral mucosa, the patches of the present disclosure provide a daily dose of about 25 mg of the cell cycle inhibitor. In some embodiments, upon administration to the oral mucosa, the patches of the present disclosure provide a daily dose of about 50 mg of the cell cycle inhibitor. In some embodiments, upon administration to the oral mucosa, the patches of the present disclosure provide a daily dose of about 75 mg of the cell cycle inhibitor.
  • the patches of the present disclosure upon administration to the oral mucosa, provide a daily dose of about 100 mg of the cell cycle inhibitor. In some embodiments, upon administration to the oral mucosa, the patches of the present disclosure provide a daily dose of about 200 mg of the cell cycle inhibitor. In some embodiments, upon administration to the oral mucosa, the patches of the present disclosure provide a daily dose of about 300 mg of the cell cycle inhibitor. In some embodiments, upon administration to the oral mucosa, the patches of the present disclosure provide a daily dose of about 400 mg of the cell cycle inhibitor. In some embodiments, upon administration to the oral mucosa, the patches of the present disclosure provide a daily dose of about 400 mg of the cell cycle inhibitor.
  • the patches of the present disclosure provide immediate release of the cell cycle inhibitor.
  • to provide immediate release greater than about 50%, greater than about 60%, greater than about 80%, or greater than about 90% of the compound is released within 30 min.
  • to provide immediate release greater than about 50%, greater than about 60%, greater than about 80%, or greater than about 90% of the compound is released within 1-3 h.
  • to provide immediate release greater than about 50%, greater than about 60%, greater than about 80%, or greater than about 90% of the compound is released within 1-2 h.
  • the patches of the present disclosure provide sustained release of the cell cycle inhibitor, e.g., over a period of 2 h or more, 4 h or more, 8 h or more, 12 h or more, 16 h or more, 20 h or more, or 24 h or more.
  • the patches of the present disclosure release an effective dosage of the cell cycle inhibitor over a period of about 1 h, about 2 h, about 3 h, about 4 h, about 5 h, about 6 h, about 7 h, about 8 h, about 9 h, about 10 h, about 11 h, about 12 h, about 13 h, about 14 h, about 15 h, about 16 h, about 17 h, about 18 h, about 19 h, about 20 h, about 21 h, about 22 h, about 23 h, or about 24 h or longer.
  • the patch releases at least about 10% of the cell cycle inhibitor between about 2-4. In some embodiments, the patch releases at least about 50% of the cell cycle inhibitor between about 2-8. In some embodiments, the patch releases at least about 75% of the cell cycle inhibitor between about 8-12. In some embodiments, the patch releases at least about 90% of the cell cycle inhibitor after about 12 h or more.
  • the patch releases at least about 10% of the cell cycle inhibitor after about 2 h. In some embodiments, the patch releases at least about 50% of the cell cycle inhibitor after about 4 h. In some embodiments, the patch releases at least about 75% of the cell cycle inhibitor after about 8 h. In some embodiments, the patch releases at least about 90% of the cell cycle inhibitor after about 12 h.
  • the present disclosure provides a method of preparing a patch as described herein, the process comprising (a) combining a solvent with one or more polymers and chemotherapeutic agent such as a CDK inhibitor of the present disclosure to provide an electrospinning mixture; (b) electrospinning the electrospinning mixture of step (a) to provide electrospun fibers; and (c) attaching an impermeable backing layer to the electrospun fibers of step (b).
  • the conductivity of the electrospinning mixture of step (a) is from about 150 pS/cm to about 600 pS/cm, e.g., about 150 pS/cm, 175 pS/cm, 200 pS/cm, about 225 pS/cm, about 250 pS/cm, about 275 pS/cm, about 300 pS/cm, about 325 pS/cm, about 350 pS/cm, about 375 pS/cm, about 400 pS/cm, about 425 pS/cm, about 450 pS/cm, about 475 pS/cm, about 500 pS/cm, about 525 pS/cm, about 550 pS/cm, about 575 pS/cm, or about 600 pS/cm, including all ranges and values therebetween.
  • the conductivity of the electrospinning mixture is from about 150 pS/cm to
  • the solvent of Step (a) is an aqueous alcoholic solvent.
  • the aqueous alcohol solvent comprises ethanol and water.
  • the aqueous alcohol solvent comprises about 20% to about 97% (vol. /vol. %) of ethanol.
  • the aqueous alcohol solvent comprises about 40% to about 97% (vol. /vol. %) of ethanol.
  • the aqueous alcohol solvent comprises about 80% to about 97% (vol. /vol. %) of ethanol.
  • the aqueous alcohol solvent comprises about 50% to about 80% (vol. /vol. %) of ethanol.
  • 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.
  • the aqueous alcoholic solvent comprises a mixture of ethanol and 2% acetic acid in phosphate-buffered saline. In some embodiments, the aqueous solvent comprises about 40% to about 80% ethanol and 20% of 2% acetic acid in phosphate-buffered saline (PBS) as the remainder. In some embodiments, the aqueous solvent comprises about 80% ethanol and about 20% of 2% acetic acid in phosphate-buffered saline (PBS). [0174] In some embodiments, the solvent of Step (a) comprises a mixture of an alcohol and dichloromethane or chloroform.
  • the alcohol is ethanol, n- propanol, or w-butanol. In some embodiments, the alcohol is w-butanol. In some embodiments, the solvent of Step (a) is a mixture of w-butanol and chloroform. In some embodiments, the alkyl chloride is chloroform. In some embodiments, the solvent of Step (a) comprises a mixture of two solvents selected from the group consisting of dichloromethane, ethanol, isopropanol, and butanone. In some embodiments, the solvent of Step (a) comprises w-butanol and chloroform.
  • the electrospun fibers comprise one or more polymers selected from the group consisting of polyvinylpyrrolidone, an ammonio methacrylate copolymer, polyethylene glycol, polyethylene oxide, polyacrylate, sodium polyacrylate, polyvinyl alcohol, dextran and gelatin.
  • the one or more polymers comprise: (a) polyvinylpyrrolidone and an ammonio methacrylate copolymer; (b) polyvinylpyrrolidone and polyethylene glycol; (c) polyvinylpyrrolidone and polyethylene oxide; (d) polyvinylpyrrolidone and dextran; (e) polyvinylpyrrolidone and gelatin; (I) polyvinylpyrrolidone and polyvinyl alcohol; (g) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyethylene glycol; (h) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyethylene oxide; (i) polyvinylpyrrolidone, an ammonio methacrylate copolymer and dextran; j) polyvinylpyrrolidone, an ammonio methacrylate copolymer and gelatin; or (k) polyvinylpyrrolidone
  • the electrospinning mixture of Step (a) further comprises an absorption enhancer, as disclosed herein.
  • Polymeric mixtures containing 4 wt% PVP, 5 wt% Eudragit RS 100 and 8 wt% PEO were prepared by adding the required amounts of the polymers to an ethanol/water mixture and mixed at room temperature using a magnetic stirrer until fully dissolved.
  • the CDK inhibitor was added to the ethanol/water mixture prior to the addition of the polymers and stirred until fully dissolved, and the target was producing electrospun fibers with a content of 0.05 wt% of CDK inhibitor.
  • Electrospun fibers were fabricated using a system composed of a PHD2000 syringe pump (Havard Apparatus, Cambridge, UK) and an Alpha IV Brandenburg power source (Brandenburg, Worthing, UK). Plastic syringes (1 mL volume; Henke Sass Wolf, Tuttlingen, Germany) were used to drive the solutions into a 20-gauge blunt metallic needle (Fisnar Europe, Glasgow, UK). Electrospinning was performed at room temperature with a potential difference of 19 kV, a flow rate of 2 mL/h, and a flight path of 14 cm.
  • Example 2 In vitro Activity of CDK Inhibitors against Oral Cancer Cell Lines [0180] The in vitro activity of AG-024322, ebvaciclib, palbociclib, R547, and staurosporine was evaluated in multiple cancer cell lines.
  • Cells were grown in RPMI 1640, 10% FBS, 2 mM L-alanyl-L-glutamine, 1 mM Na pyruvate, or a special medium. Cells were seeded into 384-well plates and incubated in a humidified atmosphere of 5% CO2 at 37oC. Compounds were added the day following cell seeding. At the same time, a time zero untreated cell plate was generated. After a 5-day incubation period, cells were fixed and stained with fluorescently-labeled antibodies and nuclear dye to allow imaging of nuclei, apoptotic cells and mitotic cells.
  • Cell count IC50 is the test compound concentration at 50% of maximal possible response.
  • EC50 is the test compound concentration at the curve inflection point or half the effective response (parameter C of the fitted curve solution).
  • GI50 is the concentration needed to reduce the observed growth by half (midway between the curve maximum and the time zero value).
  • Activity area is an estimate of the integrated area above the curve2. Activity area values range from 0-10, where a value of zero indicates no inhibition of proliferation at all concentrations, and a value of 10 indicates complete inhibition of proliferation at all concentrations. In rare instances, values ⁇ 0 or >10 may be observed. In these instances, values ⁇ 0 should be considered as equivalent to 0, whereas values >10 should be considered equivalent to 10.
  • Results suggested that all compounds showed substantial inhibitory effects on the proliferation of all the cancer cell lines studied, as shown by the measured cell count activity area values ranging from 3 to 7. An activity area value of zero indicates no inhibition of proliferation at all concentrations, and a value of 10 indicates complete inhibition of proliferation at all concentrations.
  • Example 3 Evaluation of Antiproliferation Activity of Drug-Containing Patches
  • Drug-containing patches comprising AG-024322, ebvaciclib, palbociclib, R547, staurosporine, and potentially other CDK inhibitors are prepared according to the methods disclosed herein, the methods disclosed in International Publication No. WO/2018/133909 or WO/2018/133910, which are incorporated by reference in their entirely, and/or other previously reported method.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Nutrition Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Physiology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente divulgation concerne des timbres contenant un médicament et comprenant des inhibiteurs de cycle cellulaire, tels que les inhibiteurs de kinase cycline-dépendante (CDK) décrits ici. Les timbres comprennent une couche imperméable qui fonctionne comme une barrière, par exemple, pour empêcher la pénétration de l'eau. Lors de la pose du timbre sur la peau ou les muqueuses, le composé est libéré afin de traiter et/ou de prévenir des affections buccales précancéreuses, le cancer buccal et des maladies associées.
PCT/DK2024/050205 2023-09-06 2024-09-05 Compositions et méthodes de traitement et de prévention du cancer buccal WO2025051337A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363536783P 2023-09-06 2023-09-06
US63/536,783 2023-09-06

Publications (1)

Publication Number Publication Date
WO2025051337A1 true WO2025051337A1 (fr) 2025-03-13

Family

ID=92801315

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK2024/050205 WO2025051337A1 (fr) 2023-09-06 2024-09-05 Compositions et méthodes de traitement et de prévention du cancer buccal

Country Status (1)

Country Link
WO (1) WO2025051337A1 (fr)

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6936612B2 (en) 2002-01-22 2005-08-30 Warner-Lambert Company 2-(Pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones
US7855211B2 (en) 2008-12-22 2010-12-21 Eli Lilly And Company Protein kinase inhibitors
US8324225B2 (en) 2006-05-26 2012-12-04 Novartis Ag Pyrrolopyrimidine compounds and their uses
US8415355B2 (en) 2008-08-22 2013-04-09 Novartis Ag Pyrrolopyrimidine compounds and their uses
US9193732B2 (en) 2010-11-10 2015-11-24 Novartis Ag Salt(s) of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-D]pyrimidine-6-carboxylic acid dimethylamide and processes of making thereof
WO2015189212A1 (fr) 2014-06-10 2015-12-17 Dermtreat Aps Compositions renfermant des fibres obtenues par voie électrohydrodynamique pour l'administration de doses spécifiques d'une substance active à la peau ou à une muqueuse
WO2016079246A1 (fr) * 2014-11-20 2016-05-26 Dermtreat Aps Films bioadhésifs
WO2017085264A1 (fr) 2015-11-19 2017-05-26 Dermtreat Aps Composition pharmaceutique comprenant des fibres obtenues par un procédé électrohydrodynamique, présentant un temps de séjour amélioré sur le site d'application
WO2018133910A1 (fr) 2017-01-23 2018-07-26 Dermtreat Aps Procédé de préparation de fibres électrofilées ayant une teneur élevée en substance bioadhésive
WO2018133909A1 (fr) 2017-01-23 2018-07-26 Dermtreat Aps Procédé de fabrication d'un produit à deux couches à base de fibres électrofilées
WO2020103922A1 (fr) * 2018-11-23 2020-05-28 Ascentage Pharma (Suzhou) Co., Ltd. Nouvelle composition pharmaceutique et son utilisation
US10723730B2 (en) 2013-02-21 2020-07-28 Pfizer Inc. Solid forms of a selective CDK4/6 inhibitor
WO2021072113A1 (fr) * 2019-10-08 2021-04-15 Afyx Therapeutics A/S Compositions destinée à l'administration de protéines

Patent Citations (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6936612B2 (en) 2002-01-22 2005-08-30 Warner-Lambert Company 2-(Pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones
USRE47739E1 (en) 2002-01-22 2019-11-26 Warner-Lambert Company Llc 2-(pyridin-2-ylamino)-pyrido[2,3-D]pyrimidin-7-ones
US8324225B2 (en) 2006-05-26 2012-12-04 Novartis Ag Pyrrolopyrimidine compounds and their uses
US8415355B2 (en) 2008-08-22 2013-04-09 Novartis Ag Pyrrolopyrimidine compounds and their uses
US8685980B2 (en) 2008-08-22 2014-04-01 Novartis Ag Pyrrolopyrimidine compounds and their uses
US8962630B2 (en) 2008-08-22 2015-02-24 Novartis Ag Pyrrolopyrimidine compounds and their uses
US7855211B2 (en) 2008-12-22 2010-12-21 Eli Lilly And Company Protein kinase inhibitors
US9193732B2 (en) 2010-11-10 2015-11-24 Novartis Ag Salt(s) of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-D]pyrimidine-6-carboxylic acid dimethylamide and processes of making thereof
US10723730B2 (en) 2013-02-21 2020-07-28 Pfizer Inc. Solid forms of a selective CDK4/6 inhibitor
WO2015189212A1 (fr) 2014-06-10 2015-12-17 Dermtreat Aps Compositions renfermant des fibres obtenues par voie électrohydrodynamique pour l'administration de doses spécifiques d'une substance active à la peau ou à une muqueuse
US10052291B2 (en) 2014-06-10 2018-08-21 Dermtreat Aps Compositions comprising electrohydrodynamically obtained fibres for administration of specific doses of an active substance to skin or mucosa
WO2016079246A1 (fr) * 2014-11-20 2016-05-26 Dermtreat Aps Films bioadhésifs
WO2017085264A1 (fr) 2015-11-19 2017-05-26 Dermtreat Aps Composition pharmaceutique comprenant des fibres obtenues par un procédé électrohydrodynamique, présentant un temps de séjour amélioré sur le site d'application
US20190254985A1 (en) 2015-11-19 2019-08-22 Afyx Therapeutics A/S Pharmaceutical composition comprising electrohydrodynamically obtained fibres, the composition having improved residence time on the application site
WO2018133910A1 (fr) 2017-01-23 2018-07-26 Dermtreat Aps Procédé de préparation de fibres électrofilées ayant une teneur élevée en substance bioadhésive
US20190351662A1 (en) 2017-01-23 2019-11-21 Afyx Therapeutics A/S Method for fabrication of a two-layered product based on electrospun fibres
US20190254986A1 (en) 2017-01-23 2019-08-22 Afyx Therapeutics A/S Method for preparing electrospun fibers with a high content of a bioadhesive substance
WO2018133909A1 (fr) 2017-01-23 2018-07-26 Dermtreat Aps Procédé de fabrication d'un produit à deux couches à base de fibres électrofilées
WO2020103922A1 (fr) * 2018-11-23 2020-05-28 Ascentage Pharma (Suzhou) Co., Ltd. Nouvelle composition pharmaceutique et son utilisation
WO2021072113A1 (fr) * 2019-10-08 2021-04-15 Afyx Therapeutics A/S Compositions destinée à l'administration de protéines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
H. QU ET AL., J. MATER. CHEM., vol. 4, no. 1, 2013, pages 11513 - 11528

Similar Documents

Publication Publication Date Title
JP6770157B2 (ja) 特定の投薬量の活性物質を皮膚又は粘膜に投与するための電気流体力学的に得られた繊維を含む組成物
Cunha-Reis et al. Nanoparticles-in-film for the combined vaginal delivery of anti-HIV microbicide drugs
AU2013256130B2 (en) Pharmaceutical nanoparticles showing improved mucosal transport
KR102001163B1 (ko) 전기수력학적으로 수득된 섬유를 포함하는 약학적 조성물, 적용 부위에서 향상된 체류 시간을 갖는 조성물
AU2012250862B2 (en) Rapid dissolve tablet compositions for vaginal administration
CN103889508B (zh) 用于传递丁丙诺啡的防滥用性粘膜粘附剂装置
US20180147152A1 (en) Rapid dissolve tablet compositions for vaginal administration
WO2015127389A1 (fr) Formulations de lavement hypotonique et méthodes d'utilisation
Lim et al. Current status and advances in esophageal drug delivery technology: influence of physiological, pathophysiological and pharmaceutical factors
Osmałek et al. Gadzi nski
US20180015074A1 (en) Use of mtor inhibitors to prevent and regress edhesions and fibrosis
WO2025051337A1 (fr) Compositions et méthodes de traitement et de prévention du cancer buccal
CN111601588A (zh) 用于增强粘膜表面处活性剂运输的低渗水凝胶配制物
Keerthana et al. BUCCAL PATCHES: THE GATEWAY OF MUCOADHESIVE DRUG DELIVERY–A REVIEW
KR20240154050A (ko) 마크로라이드 면역억제제를 함유하는 경점막 치료 시스템
HK40016288A (en) Compositions comprising electrohydrodynamically obtained fibres for administration of specific dosages of an active substance to skin or mucosa
HK1235690B (en) Compositions comprising electrohydrodynamically obtained fibres for administration of specific dosages of an active substance to skin or mucosa
HK1235690A1 (en) Compositions comprising electrohydrodynamically obtained fibres for administration of specific dosages of an active substance to skin or mucosa

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24772563

Country of ref document: EP

Kind code of ref document: A1