Transdermal drug delivery systems

Abstract

The present disclosure relates to formulations and methods for transdermal delivery of a drug through the skin of a subject. In some aspects, the formulation comprises a therapeutically effective amount of a drug and a penetrating moiety comprising a phospholipid, a fatty acid ester formed from a low molecular weight alcohol, and a long chain fatty acid. In some embodiments, the penetrating moiety further comprises one or more of a viscosity improving agent, a penetration enhancer, and an emulsifier.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 137,127, filed January 13, 2021, U.S. Provisional Application No. 63 / 218,983, filed July 7, 2021, U.S. Provisional Application No. 63 / 219,280, filed July 7, 2021, U.S. Provisional Application No. 63 / 227,330, filed July 29, 2021, U.S. Provisional Application No. 63 / 261,510, filed September 22, 2021, U.S. Provisional Application No. 63 / 271,014, filed October 22, 2021, and U.S. Provisional Application No. 63 / 287,492, filed December 8, 2021. The entire contents of the seven priority applications are incorporated herein by reference. [Background technology]

[0002] Topical administration refers to the application of a substance to the surface of the skin. This term is often used to describe the application of creams, foams, gels, lotions, or ointments to the skin or mucous membranes. The high degree of keratinization and density of skin cells creates an impenetrable barrier in most cases. As a result, most substances are not absorbed through the skin. There is an unmet need for formulations and methods for transdermal penetration that work with a variety of drugs and active agents, overcome the barrier posed by the stratum corneum and deeper layers of the skin, and achieve transdermal penetration that is effective for the delivery of high molecular weight drugs such as peptides, proteins, and nucleic acids, without the use of harsh solvents. [Brief explanation of the drawings]

[0003] [Figure 1] 1 is a graph showing plasma pharmacokinetics from topical administration of vancomycin-containing formulations to adult mice. [Figure 2] 1 is a graph showing plasma pharmacokinetics from topical administration of vancomycin-containing formulations to adult mice. [Figure 3]1 is a graph showing plasma pharmacokinetics from topical administration of vancomycin-containing formulations to adult mice. [Figure 4] 1 is a graph showing plasma pharmacokinetics from topical administration of vancomycin-containing formulations to adult mice. [Figure 5] 1 is a graph showing plasma pharmacokinetics from topical administration of vancomycin-containing formulations to adult mice. [Figure 6] 1 is a graph showing plasma pharmacokinetics from topical administration of neratinib-containing formulations to adult mice. [Figure 7] 1 is a graph showing plasma pharmacokinetics from topical administration of neratinib-containing formulations to adult mice. [Figure 8] 1 is a graph showing plasma pharmacokinetics from topical administration of neratinib-containing formulations to adult mice. [Figure 9] 1 is a graph showing plasma pharmacokinetics from topical administration of neratinib-containing formulations to adult mice. [Figure 10] 1 is a graph showing plasma pharmacokinetics from topical administration of neratinib-containing formulations to adult mice. [Figure 11] 1 is a graph showing plasma pharmacokinetics from topical administration of neratinib-containing formulations to adult mice. [Figure 12] 1 is a graph showing plasma pharmacokinetics from oral administration (gavage) of neratinib-containing solutions to adult mice. [Figure 13] 1 is a graph showing plasma pharmacokinetics from topical administration of doxycycline-containing formulations to adult mice. [Figure 14] 1 is a graph showing plasma pharmacokinetics from topical administration of doxycycline-containing formulations to adult mice. [Figure 15] 1 is a graph showing plasma pharmacokinetics from topical administration of doxycycline-containing formulations to adult mice. [Figure 16] 1 is a graph showing plasma pharmacokinetics from oral administration (gavage) of doxycycline-containing solutions to adult mice. [Figure 17]1 is a graph showing plasma pharmacokinetics from topical administration of doxycycline-containing formulations to adult mice. [Figure 18] 1 is a graph showing plasma pharmacokinetics from topical administration of doxycycline-containing formulations to adult mice. [Figure 19] 1 is a graph showing plasma pharmacokinetics from topical administration of cefepime-containing formulations to adult mice. [Figure 20] 1 is a graph showing plasma pharmacokinetics from topical administration of cefepime-containing formulations to adult mice. [Figure 21] 1 is a graph showing plasma pharmacokinetics from topical administration of cefepime-containing formulations to adult mice. [Figure 22] 1 is a graph showing plasma pharmacokinetics from intravenous administration of cefepime-containing solutions to adult mice. [Figure 23] 1 is a graph showing plasma pharmacokinetics from topical administration of eletriptan-containing formulations to adult mice. [Figure 24] 1 is a graph showing plasma pharmacokinetics from topical administration of eletriptan-containing formulations to adult mice. [Figure 25] 1 is a graph showing plasma pharmacokinetics from topical administration of eletriptan-containing formulations to adult mice. [Figure 26] 1 is a graph showing plasma pharmacokinetics from oral administration of eletriptan-containing solutions to adult mice. Summary of the Invention

[0004] Aspects of the present disclosure teach certain advantages in construction and use that result in exemplary advantages, which are described below.

[0005] The present disclosure relates to systems and methods for transdermal delivery of drugs that provide a variety of benefits.

[0006] The present disclosure solves the above problems by providing a transdermal formulation having improved permeability. In at least one embodiment, a transdermal penetration formulation for transdermal administration of a drug is disclosed herein.

[0007] One aspect of the present disclosure is a formulation for transdermal delivery of a drug through the skin of a subject. The formulation comprises a therapeutically effective amount of the drug and a penetrating moiety. The penetrating moiety comprises a phospholipid, a fatty acid ester formed from a low molecular weight alcohol, and a long-chain fatty acid, and optionally one or more of a viscosity-improving agent, a penetration enhancer, and an emulsifier.

[0008] In embodiments, the phospholipid is selected from phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, inositol phosphatide, and sphingomyelin. In some cases, the phospholipid is a phosphatidylcholine.

[0009] In some embodiments, the penetrating moiety comprises two or more phospholipids.

[0010] In various embodiments, the phospholipid is in an amount of about 3% to about 15% by weight of the formulation.

[0011] In certain embodiments, the low molecular weight alcohol is selected from isopropanol, methanol, ethanol, butanol, glycerol, cetyl alcohol.

[0012] In embodiments, the low molecular weight alcohol is isopropanol.

[0013] In some embodiments, the fatty acid ester is selected from isopropyl palmitate, isopropyl myristate, isopropyl linoleate, isopropyl oleate, ethyl laurate, and ethyl myristate. In some cases, the fatty acid ester is isopropyl palmitate.

[0014] In various embodiments, the penetrating moiety comprises two or more fatty acid esters.

[0015] In certain embodiments, the fatty acid ester is in an amount of about 5% to about 20% by weight of the formulation.

[0016] In embodiments, the long-chain fatty acid is selected from linoleic acid, oleic acid, stearic acid, linolenic acid, palmitic acid, arachidonic acid, palmitoleic acid, myristic acid, eicosenoic acid, benehic acid, euricic acid, and lignoceric acid. In some cases, the long-chain fatty acid is linoleic acid. In other cases, the long-chain fatty acid is oleic acid. In further cases, the long-chain fatty acid is stearic acid. In some cases, the long-chain fatty acid is obtained from safflower oil or almond oil.

[0017] In some embodiments, the long chain fatty acid is in an amount of about 0.1% to about 10% by weight of the formulation.

[0018] In various embodiments, the penetrating moiety comprises two or more long chain fatty acids.

[0019] In certain embodiments, the penetrating portion comprises a viscosity improving agent.

[0020] In some embodiments, the viscosity-improving agent is a poloxamer. In some cases, the poloxamer is selected from poloxamer 407, poloxamer 188, poloxamer 184, and poloxamer 124.

[0021] In some embodiments, the viscosity improver is a surfactant. In some cases, the surfactant is selected from the group consisting of sodium lauryl sulfate (sodium dodecyl sulfate), polyoxyethylated castor oil derivatives such as HCO-60 surfactants, nonoxynol, octoxynol, phenylsulfonates, poloxamers such as Pluronic® F68, Pluronic® F127, and Pluronic® L62, polyoleates, Rewopal® HVIO, sodium laurate, sodium oleate, sorbitan dilaurate, sorbitan dioleate, sorbitan monolaurate such as Span® 20, sorbitan monooleate, sorbitan trilaurate, sorbitan trioleate, sorbitan monopalmitate such as Span® 40, and sorbitan stearate such as Span® 85. polyethylene glycol nonylphenyl ether such as Synperonic® NP; p-(1,1,3,3-tetramethylbutyl)-phenyl ether such as Triton™ X-100; and polysorbates such as polyoxyethylene (20), sorbitan monolaurate such as Tween® 20, polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate) such as Tween® 40, polysorbate 60 (polyoxyethylene (20) sorbitan monostearate) such as Tween® 60, polysorbate 80 (polyoxyethylene (20) sorbitan monooleate) such as Tween® 80, and polyoxyethylene sorbitan trioleate such as Tween® 85. In some cases, the surfactant is sodium lauryl sulfate.

[0022] In embodiments, the penetrating portion comprises two or more viscosity improving agents.

[0023] In certain embodiments, the viscosity-improving agent is in an amount of about 5% to about 20% by weight of the formulation.

[0024] In embodiments, the penetration portion comprises a penetration enhancer. In some embodiments, the penetration enhancer is an alcohol or a terpene. In some cases, the alcohol penetration enhancer is selected from benzyl alcohol, ethanol, propylene glycol, and polyethylene glycol. In various cases, the penetration enhancer is benzyl alcohol. In some cases, the terpene penetration enhancer is selected from limonene, menthol, borneol, and camphor. In various embodiments, the penetration enhancer further acts as a preservative.

[0025] In some embodiments, the penetration moiety comprises two or more penetration enhancers.

[0026] In various embodiments, the penetration enhancer is in an amount of about 0.5% to about 5% by weight of the formulation.

[0027] In certain embodiments, the penetration portion comprises at least one penetration enhancer and at least one viscosity improver.

[0028] In embodiments, the penetrating portion comprises an emulsifier.

[0029] In some embodiments, the emulsifier is chosen from polyglyceryl-4-laurate, polyglyceryl-4-oleate, Span 60, cetyl alcohol, and polyglyceryl-3-oleate.

[0030] In various embodiments, the penetration moiety comprises two or more penetration enhancers.

[0031] In certain embodiments, the emulsifier is in an amount of about 0.5 to about 10% by weight of the formulation.

[0032] In an embodiment, the penetrating portion comprises at least one emulsifier and at least one viscosity improving agent.

[0033] In some embodiments, the penetration portion comprises at least one emulsifier and at least one penetration enhancer.

[0034] In various embodiments, the penetration portion comprises at least one emulsifier, at least one viscosity improving agent, and at least one penetration enhancer.

[0035] Another aspect of the present disclosure is a formulation for transdermal delivery of a drug through the skin of a subject. The formulation comprises a therapeutically effective amount of the drug and a penetrating moiety comprising a phospholipid, a fatty acid ester formed from a low molecular weight alcohol, and a long-chain fatty acid. In this aspect, the phospholipid is phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, inositol phosphatide, or sphingomyelin; the fatty acid ester is isopropyl palmitate, isopropyl myristate, isopropyl linoleate, isopropyl oleate, ethyl laurate, or ethyl myristate; and the long-chain fatty acid is linoleic acid, oleic acid, stearic acid, linolenic acid, palmitic acid, arachidonic acid, palmitoleic acid, myristic acid, eicosenoic acid, benehic acid, euric acid, or lignoceric acid, or the long-chain fatty acid is derived from safflower oil or almond oil.

[0036] A further aspect of the present disclosure is a formulation for transdermal delivery of a drug through the skin of a subject. The formulation comprises a therapeutically effective amount of the drug and a penetrating moiety, the penetrating moiety comprising one or more of a phospholipid, a fatty acid ester formed from a low molecular weight alcohol, a long-chain fatty acid, and a viscosity-improving agent, a penetration enhancer, and an emulsifier. In this aspect, the phospholipid is phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, inositol phosphatide, or sphingomyelin; the fatty acid ester is isopropyl palmitate, isopropyl myristate, isopropyl linoleate, isopropyl oleate, ethyl laurate, or ethyl myristate; and the penetrating moiety is linoleic acid, oleic acid, stearic acid, linolenic acid, palmitic acid, arachidonic acid, palmitoleic acid, myristic acid, eicosenoic acid, benehic acid, euric acid, or the like. , or lignoceric acid is the long-chain fatty acid, or the long-chain fatty acid is derived from safflower oil or almond oil; polyglyceryl-4-laurate, polyglyceryl-4-oleate, Span 60, cetyl alcohol, or polyglyceryl-3-oleate is the penetration enhancer; poloxamer (e.g., poloxamer 407, poloxamer 188, poloxamer 184, and poloxamer 124) or sodium lauryl sulfate is the viscosity improver; and benzyl alcohol, ethanol, propylene glycol, polyethylene glycol, limonene, menthol, borneol, or camphor is the penetration enhancer.

[0037] In certain embodiments, the permeating portion amounts to about 70% to about 98% by weight of the formulation.

[0038] In an embodiment, the permeate portion comprises water.

[0039] In some embodiments, the permeate portion comprises water in an amount of about 50% to about 80% by weight of the formulation.

[0040] In various embodiments, the formulation comprises a phospholipid, an emollient / moisturizer, a fatty acid, an alcohol, an oil, a surfactant, water, and a drug.

[0041] An additional aspect of the present disclosure is a formulation for transdermal delivery of a drug through the skin of a subject. The formulation includes a phospholipid in an amount of about 5% to about 15% by weight of the formulation, an emollient / moisturizer in an amount of about 10% to about 20% by weight of the formulation, a fatty acid in an amount of about 0.5% to about 2% by weight of the formulation, an alcohol in an amount of about 0.5% to about 2% by weight of the formulation, an oil in an amount of about 1% to about 5% by weight of the formulation, a surfactant in an amount of about 0.5% to about 2% by weight of the formulation, water in an amount of about 30% to about 80% by weight of the formulation, and a therapeutically effective amount of a drug in an amount of about 0.001% to about 30% by weight of the formulation. In some cases, the drug is in an amount of about 0.001% to about 0.01% by weight of the formulation. In other cases, the drug is in an amount of about 0.011% to about 0.1% by weight of the formulation. In various cases, the drug is present in an amount of about 0.11% to about 1.0% by weight of the formulation. In further cases, the drug is present in an amount of about 1% to about 10% by weight of the formulation. In additional cases, the drug is present in an amount of about 11% to about 20% by weight of the formulation. In alternative cases, the drug is present in an amount of about 21% to about 30% by weight of the formulation.

[0042] In one aspect, the present disclosure provides a formulation for transdermal delivery of a drug through the skin of a subject.The formulation comprises phosphatidylcholine in an amount of about 7.64% by weight of the formulation, isopropyl palmitate in an amount of about 13.30% by weight of the formulation, stearic acid in an amount of about 0.62% by weight of the formulation, benzyl alcohol in an amount of about 1.39% by weight of the formulation, safflower oil in an amount of about 2.93% by weight of the formulation, oleic acid in an amount of about 0.97% by weight of the formulation, polyglyceryl-4-laurate in an amount of about 1.06% by weight of the formulation, deionized water in an amount of about 60.84% ​​by weight of the formulation, poloxamer 407 in an amount of about 9.25% by weight of the formulation, and a therapeutically effective amount of a drug in an amount of about 2% by weight of the formulation.In some cases, the amount of the drug is not about 2% by weight of the formulation, but the amount of the drug is less than about 2%, and the amount of water is increased proportionately. In other cases, rather than the amount of drug being about 2% by weight of the formulation, the amount of drug is greater than about 2% and the amount of water is reduced proportionately. In various cases, the amount of drug is less than about 30%.

[0043] In another aspect, the present disclosure provides a formulation for transdermal delivery of a drug through the skin of a subject. The formulation comprises phosphatidylcholine in an amount of about 7.66% by weight of the formulation, isopropyl palmitate in an amount of about 13.34% by weight of the formulation, benzyl alcohol in an amount of about 1.39% by weight of the formulation, stearic acid in an amount of about 0.68% by weight of the formulation, carthamus tinctorius (safflower) oil in an amount of about 2.79% by weight of the formulation, polyglyceryl-4-laurate in an amount of about 1.07% by weight of the formulation, oleic acid in an amount of about 1.06% by weight of the formulation, deionized water in an amount of about 61.73% by weight of the formulation, poloxamer 407 in an amount of about 9.28% by weight of the formulation, and a therapeutically effective amount of a drug in an amount of about 1.00% by weight of the formulation. In some cases, the amount of drug is not about 1% by weight of the formulation, but the amount of drug is less than about 1%, and the amount of water is increased proportionately. In other cases, rather than the amount of drug being about 1% by weight of the formulation, the amount of drug is greater than about 1% and the amount of water is reduced proportionately. In various cases, the amount of drug is less than about 30%.

[0044] In a further aspect, the disclosure provides a formulation for transdermal delivery of a drug through the skin of a subject, the formulation comprising a therapeutically effective amount of the drug and a penetrating moiety, the penetrating moiety comprising phosphatidylcholine in an amount of about 3% to about 15% by weight of the formulation, isopropyl palmitate in an amount of about 5% to about 20% by weight of the formulation, stearic acid in an amount of about 0.1% to about 10% by weight of the formulation, benzyl alcohol in an amount of about 0.5% to about 5% by weight of the formulation, polyglyceryl-4-laurate in an amount of about 0.5% to about 10% by weight of the formulation, and poloxamer 407 in an amount of about 5% to about 20% by weight of the formulation.

[0045] In certain embodiments, the formulation has a pH of about 7 to about 10.5.

[0046] In embodiments, the formulation has a pH of about 9 to about 11.

[0047] In embodiments, the transdermal formulations of the present disclosure deliver drugs of various sizes, including drugs with molecular weights of less than about 500 Da, such as nicotine (162.2 Da), diphenhydramine hydrochloride (291.8 Da), and hydrocortisone (362.5 Da); drugs with molecular weights of about 500 Da to about 1000 Da, such as sildenafil citrate (666.7 Da), neratinib (557 Da), and doxycycline hyclate (512.9 Da); and drugs with molecular weights of more than about 1000 Da, such as cyclosporine A (1202.6 Da), vancomycin hydrochloride (1485.70 Da), and RBD protein (10,000+ Da).

[0048] In various embodiments, the agent is (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine; (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide; 2-fluoro-N-methyl-4-[7-quinolin-6-yl-methyl)-imidazo[1,2-B][1,2,4]triazin-2yl]benzamide; 4 -(3-Amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide;4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile;Abacavir;Abiraterone acetate;Abiratone acetate;Abobotulinumtoxin A;Acalabrutinib;Acarbose;Acetaminophen;Acetazolamide;Acetylsalicylic acid;Acitretin;Acitretin Clovir; Adalimumab; Adapalene; Adapalene; Afoxolaner; Agalsidase beta; Albendazole; Alectinib; Alectinib; Alendronate sodium; Alglucosidase alfa; Alitretinoin; Alogliptin; Alpelisib; Aluminum hydroxide; Ambrisentan; Amiodarone; Amitriptyline; Amlodipine; Amlodipine; Amlodipine besylate; Amlodopine besylate; Amorolfine hydrochloride; Amoxicillin; Amphotericin B; Amphotericin B liposomal; Ampicillin; Amprenavir; Antithrombotic Anti-inflammatory factors, Fc fusion proteins; apalutamide; apatinib; apixaban; apremilast; aprepitant; aripiprazole; artemether; aspirin; atazanavir; atenolol; atomoxetine; atorvastatin; avapritinib; axitinib (Inritin); azacitidine; azathioprine; azelaic acid; azilsartan medoxomil; azithromycin; baclofen; baricitinib; basiliximab; batimastat (BB-94); becaplermin; belmosudil; bendamustine; benzoyl peroxide;Benzoyl peroxide; betamethasone dipropionate; betamethasone valerate; bexarotene; bictegravir; bimatoprost; binimetinib (Mektobi); bortezomib; bortezomib (Velcade); bosentan; bosutinib (Bosurif); botulinum toxin A; branched-chain amino acids; brexpiprazole; brimonidine; brimonidine tartrate; brodalumab; buproprion; cabazitaxel; cabozantinib; cabozantinib (Cometriz); Calcifediol; Calcipotriene; Calcipotriene; Calcipotriol; Calcitonin; Calcitriol; Calcium carbonate; Canagliflozin; Canakinumab; Capecitabine; Capmatinib; Capsaicin; Carbamazepine; Carbidopa; Carfilzomib; Carfilzomib (Cyprolis); Cariprazine; Carvedilol; CD-12681; CEE-321; Cefazolin; Cefepime; Cefoperazone; Cefotaxime sodium Celecoxib; Celecoxib; Cemiplimab; Ceritinib; Chlorothiazide; Chlorpromazine; Chlorthalidone; Cinacalcet; Ciprofloxacin; Cisapride; Citalopram; Citric acid; Clarithromycin; Clavulanate; Clindamycin phosphate; Clobazam; Clobetasol propionate; Clofazimine; Clomiphene; Clonidine; Clopidogrel; Clopidogrel bisulfate; Cobicistat; Cobicistat; Colcosine ; colistin; corticotropin; crisaborole; crizanlizumab; crizotinib (xalkori); cyclobenzaprine; cyclosporine; dabigatran etexilate; dabrafenib; dabrafenib; dabrafenib; dacomitinib (visimpro); dalbavancin; dalfopristin; danazol; dapagliflozin; dapsone; daptomycin; darunavir; dasatinib; decitabine; defatted peanuts (Arachis hypogaea) powder; deferasirox; delgocitinib; deoxycholic acid; desipramine; desonide; dexlansoprazole; dexmethylphenidate; dextroamphetamine / amphetamine salts; diclofenac; diclofenac sodium; diflucortolone; diflucortolone; difinisal; digoxin; diloxanide; dimethyl fumarate; diphenhydramine hydrochloride; diphtheria vaccine;Docetaxel; Dolutegravir; Dolutegravir; Donepezil; Doxercalciferol; Doxycycline; Doxycycline ER; Doxycycline hyclate (B); Doxycycline monohydrate (A); Dronabinol; Dronedarone; Drospirenone; Dukoral / ShanChol cholera vaccine; Duloxetine; Dupilumab; Durvalumab; Dutasteride; Duvelisib; Ecallantide; Edoxaban; Efavirenz; Efavirenz; Elafibranol; Elagolix sodium; Elbasvir; Eletriptan; El Thrombopag; Elvitegravir; Empagliflozin; Emtricitabine; Entricitabine; Entricitabine; Entricitabine; Encorafenib (Braftovi); Enfuviritide; Enoxaparin sodium; Entecavir; Entrectinib; Enzalutamide; Epinephrine; Erdafitinib; Erenumab; Eribulin; Erlotinib; Erlotinib hydrochloride (Tarceva); Ertapenem; Erythromycin; Escitalopram; Esketamine (Ketamine); Esome Prazol; Esopremazole; Estradiol; Estrogen-conjugated; Etanercept; Ethinyl estradiol; Ethinyl estradiol; Ethinyl estradiol; Etonogestrel; Etonogestrel; Etravirine; Etretinate; Everolimus; Everolimus (Afinitor); Everolimus (Votuvia, Zotres / Certican); Ezetimibe; Ezetimibe; Ezetimibe; Famotidine; Fasinumab; Febuxostat; Fedratinib; Fenofibrate; Ferric carboxymaltose; Fexofenadine Hydrochloride; Filgotinib; Filgrastim; Fingolimod; Fluocinolone acetonide; Fluocinolone acetonide; Fluoxetine; Flurbiprofen; Folic acid; Forskolin; Fostamatinib; Fulvestrant; Furosemide; Fusidic acid; Fusidic acid; Gabapentin; Ganetespib; Gefitinib (Iressa); Gilteritinib; Glasdedib (Daurismo) or Glasdedib maleate; Glecaprevir; Glibenclamide; Glimepiride; Glipizide; Glucagon; Glucosamine; Glutaric anhydride; Glycopyrrolate; Goserelin;Goserelin LA; Granisetron; Grazoprevir; Griseofulvin; Halobetasol propionate; Haloperidol; Heparin sodium; Heplisub B vaccine; Hyaluronic acid; Hydrochlorothiazide; Hydrochlorothiazide; Hydrochlorothiazide; Hydrocortisone; Hydrocortisone acetate; Hydroquinone; Hydroxychloroquine; Hydroxyprogesterone; Ibrutinib; Ibrutinib (Imbruvica); Ibuprofen; Icatibant acetate; Idelalisib; Imatinib; Imatinib (Gleevec); Imatinib mesylate; Imiglucerase; Inclisiran; Indinavir; Indomethacin; Infliximab; Ingenol mebuate; Inotersen; Insulin A; Insulin glargine; Interferon beta-1b; Iopanoic acid; Irbesartan; Isoconazole; Isoconazole; Isotretinoin; Itraconazole; Ivacaftor; Ivermectin; Ixazomib; Ketoconazole; Ketone bodies; Ketoprofen; Keilvir; Lacosamide; Lamictal; Lamivudine; Lansoprazole; Lapatinib; Lapatinib (Tycar) ib); larotrectinib; ledipasvir; leflunomide; lenalidomide; lenvatinib; LEO-138559; LEO-152020; leuprolide; levetiracetam; levodopa; levodopa / benserazide; levonorgestrel; levothyroxine; linagliptin; linezolid; lisinopril; L-lysine free base; lofexidine; lopinavir; loratadine; lorlatinib (Lorviqua); losartan; lovastatin; lubiprostone; lumacaftor / ivacaftor; lumefantrine; lurasidone; ruspatercept; rimecycline methicone; macitentan; magnesium; magnesium lactate; marimastat (BB-2516); marizomib (NPI-0052); mebendazole; mefloquine; melatonin; meloxicam; memantine hydrochloride; meningococcal [serotype b] vaccine; mesalazine; metformin; metformin; methotrexate; methyl aminolevulinate hydrochloride; methylphenidate; methylprednisolone; metoprolol succinate; metronidazole; midostaurin; minoxidil; mirabegron; mizolastine MR; montelukast;Mycophenolate mofetil;N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)-isonicotinamide;N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)-pyrimidin-4-yl Zin-3-carboxamide hydrochloride; Nalidixic acid (quinolone antibiotic); Naloxone; Naproxen; Navitoclax (ABT-263); Nebivolol; Nelfinavir; Nemolizumab; Neomycin; Neovastat (AE-941); Neratinib free base; Neratinib (Nerlynx); Neratinib maleate; Nevirapine; Niclosamide; Nifedipine; Nilotinib; Nilotinib; Nilotinib (Tasigna); Nintedanib; Niratimib; Nitric oxide; Nitrofurantoin; Norethindrone acetate; Nusinersen; NVP-AUY922; Na Istatin; Obatoclax (GX15-070); Octreotide acetate; Ofatumumab; Ofloxacin; Olanzapine; Olaparib; Olmesartan medoxomil; Ormacostat; Omalizumab; Oseltamivir; Osimertinib; Osimertinib mesylate; Oxaprozin; Ozanimod; Paclitaxel; Paclitaxel protein-bound; Palbociclib (Ibrance); Paliperidone palmitate; Pantoprazole; Parathyroid hormone; Paricalcitol; Patisiran; Pazopanib; Pazopanib (Votrient); Pazopanib hydrochloride; Peficitinib; pegfilgrastim; pembrolizumab (Keytruda); pemetrexed; pemigatinib; perifosine; pexidartinib; phenazopyridine; phenytoin; pibrentasvir; piperacillin; pirfenidone; piroxicam; pomalidomide; ponatinib; ponatinib (lclusig); posaconazole; pralsetinib; pravastatin; prednicarbate; prednisone; pregabalin; prinomastat (AG-3340); progesterone; propanolol; protamine sulfate; psilocybin; pyrantel;Pyrimethamine; quetiapine; quinupristin; raloxifene; raltegravir; ranibizumab; ranitidine; ranolazine; levimastat (BMS-275291); regorafenib; regorafenib (Stivarga); relugolix (Orgovix); remibrutinib; resiquimod; retinal; retino; Ribociclib; Ribociclib succinate; Rifampin; Rilpivirine; Rilpivirine; Rimegepant; Riociguat; Risdipram; Risperidone; Ritonavir; Rivaroxaban; Rosuvastatin; Rosuvastatin calcium; Rotigotine; Roxadustat; Rucaparib camsylate (Rubraca); Ruxolitinib; Ruxolitinib (Jafaki); Sacubitril, valsartan; Salicylic acid; Sapropterin; Saquinavir; Sarilumab; Saxagliptin, metformin; Secukinumab; Selexipag; Serine Xar; Selpercatinib; Selpercatinib (LOXO-292); Selumetinib; Semaglutide; Sertraline; Sevoflurane; Sildenafil; Sildenafil citrate; Simvastatin; Siponimod; Siremadrine; Sirolimus; Sitagliptin; Sitagliptin phosphate monohydrate; Sodium bicarbonate or sodium carbonate; Sodium deoxycholate; Sodium nitrate; Sofosbuvir; Sofosbuvir; Solifenacin; Somatropin; Sonidegib phosphate; Sorafenib; Sorafenib (Nexavar); Spartalizumab Spironolactone; Sufentanil citrate; Sugammadex; Sulbactam; Sulbactam; Sulfadiazine; Sulfamethoxazole; Sulfasalazine; Sumatriptan; Sunitinib; Sunitinib; Sunitinib (Sutent); Sunitinib malate (Sutent); Tacrolimus; TAF; TAF; TAF; TAF; Talazoparib - Talzenna; Talinolol; Tamoxifen; Tamsulosin; Tazarotene; Tazobactam; TDF; TDF; Temsirolimus (CCl-779, Torisel); Teneligliptin; Tenofovir alafenamide; Te Nofovir disoproxil fumarate; tepotinib; terbinafine; terfenadine; teriflunomide; testosterone; tezacaftor; THC; ticagrelor; tigecycline; timolol; timolol maleate; tipranavir; tisagenlecleucel; tisagenlecleucel (Kymriah); tivozanib; tofacitinib citrate; tolvaptan; tralokinumab; tramadol; trametinib; trametinib; trametinib; trametinib (Mekinist); tranexamic acid; travoprost; trazodone; tretinoin;At least one of the following is considered to be an effective antiviral: tretinoin; triamcinolone; triclabendazole; trifalotene; trimethoprim; triptorelin; Tris; tucatinib; ubrogepant; umbralisib; upadacitinib; valproic acid; valsartan; vancomycin; vancomycin hydrochloride (A); vancomycin hydrochloride (B); vandetanib; vandetanib (Caprelsa); varenicline; vasopressin; velpatasvir; velpatasvir; vemurafenib; venetoclax; verapamil hydrochloride; vilazodone; vildagliptin; vismodegib; vitamin B6; vitamin D; vonoprazan; voriconazole; vortioxetine; voxilaprevir; warfarin sodium; zanubrutinib; zinc; zoledronic acid; and zolpidem.

[0049] In certain embodiments, the formulation further comprises at least a second pharmaceutical agent.In some cases, the first agent and at least the second agent are selected from the group consisting of abacavir, dolutegravir, and lamivudine; adapalene and benzoyl peroxide; amlodipine and valsartan; amlodipine besylate and valsartan; amoxicillin and clavulanate; ampicillin and sulbactam; artemether and lumefantrine; betamethasone valerate and fusidic acid; bictegravir, emtricitabine, and TAF; bimatoprost and timolol maleate; brimonidine and timolol; calcipotriene and betamethasone dipropionate. Methasone; canagliflozin and metformin; carbidopa and levodopa; cefoperazone and sulbactam; dabrafenib and trametinib; darunavir, cobicistat, emtricitabine, and tenofovir alafenamide; diflucortolone and isoconazole; drospirenone and ethinyl estradiol; efavirenz, emtricitabine, and TDF; elbasvir and grazoprevir; elvitegravir, cobicistat, emtricitabine, and TAF; emtricitabine, rilpivirine, and TAF ;Emtricitabine and TAF;Emtricitabine and tenofovir disoproxil fumarate;Ethinyl estradiol and etonogestrel;Ezetimibe and atorvastatin;Ezetimibe and simvastatin;Fluocinolone acetonide, hydroquinone, and tretinoin;Fusidic acid and hydrocortisone acetate;Glecaprevir and pibrentasvir;Hydrochlorothiazide and valsartan;Irbesartan and hydrochlorothiazide;Ledipasvir and sofosbuvir;Linagliptin and metformin;Losartan and hydrocortisone Selected from the group consisting of chlorothiazide; metformin and sitagliptin; norethindrone acetate and ethinyl estradiol; piperacillin and tazobactam; pregabalin and celecoxib; quinupristin and dalfopristin; rilpivirine and emtricitabine and TDF; sofosbuvir and velpatasvir; sofosbuvir, velpatasvir and voxilaprevir; tezacaftor and ivacaftor; trametinib and dabrafenib; trametinib and dabrafenib; and zinc, magnesium, and vitamin B6.

[0050] In embodiments, transdermal delivery provides systemic administration of the agent.

[0051] In yet another aspect, the present disclosure provides a method for transdermally delivering at least one agent, the method comprising applying to the skin of a subject an effective amount of any of the formulations disclosed herein.

[0052] One aspect of the present disclosure is a method for treating or alleviating the symptoms of a disease or disorder. The method includes administering any of the transdermal formulations disclosed herein to a subject in need thereof and administering to the subject in need thereof a composition comprising one or more agents selected from Table 1. In some cases, the transdermal formulation is administered before, simultaneously with, or after administration of the composition. In various cases, the amount of the one or more agents is an effective dose of the agent listed in Table 1. In some cases, the composition is administered by a standard route for the agent. In some cases, the standard route is oral, topical, enteral, parenteral, intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection. In various cases, the composition is a liquid, suspension, gel, geltab, semisolid, tablet, sachet, troche, pill, or capsule.

[0053] Another aspect of the present disclosure is the use of any of the transdermal formulations disclosed herein in a method for treating or alleviating a symptom of a disease or disorder.

[0054] A further aspect of the present disclosure is a method for manufacturing a medicament for treating or alleviating a symptom of a disease or disorder, comprising combining a penetrating moiety listed in any of the formulations disclosed herein with one or more agents listed in Table 1.

[0055] Any aspect or embodiment described herein may be combined with any other aspect or embodiment disclosed herein. DETAILED DESCRIPTION OF THE INVENTION

[0056] preface The term transdermal administration refers to applying a substance to the skin and allowing it to be absorbed into the body for local or systemic distribution. A transdermal solution (e.g., cream, ointment, or lotion) or transdermal patch is typically placed on the skin. The solution or patch contains a drug that is released into the skin. Once the skin layers absorb the solution, the drug is absorbed into the bloodstream through the blood vessels. From there, the substance can circulate throughout the body.

[0057] There are clear advantages to administering drugs transdermally. The consumer does not need to schedule and remember to consume a pill dose. Furthermore, transdermal administration is not affected by stomach or gastrointestinal problems. Administration through the skin avoids the drug being degraded in the gastrointestinal tract or liver. Transdermal delivery is therefore of particular interest for molecules with limited systemic bioavailability and short half-lives. Drugs that are absorbed slowly are more effective. Transdermal patches or creams allow the drug to be released in small amounts over an extended period of time.

[0058] Transdermal delivery is effective for the delivery of hydrophobic chemicals, such as steroid hormones. For example, transdermal patches are a common means of administering steroid medications for contraception, hormone replacement therapy, and the prevention of motion sickness. Common medications that can be delivered by transdermal patches include painkillers, nicotine, hormones, and medications for angina and motion sickness.

[0059] Drugs that are not hydrophobic chemicals are generally not suitable for topical administration. To be effective, the active drug or agent in a topical composition must penetrate the structurally complex and relatively thick skin. Molecules traveling through the skin must first penetrate the stratum corneum and its surface materials. Next, the molecule must penetrate through the epidermis, papillary dermis, and capillary walls into the vascular or lymphatic system. To be absorbed, the molecule must overcome the different penetration resistances of each layer.

[0060] Strategies have been devised to improve transdermal drug delivery. These strategies can be classified as physical, chemical, mechanical, or biochemical. Combinations of these strategies can enhance efficacy or extend the duration of transdermal delivery. Physical methods include abrasion and tape stripping, which physically disrupt the skin. Another physical method is prolonged occlusion, which alters the barrier properties of the stratum corneum. After 24–28 hours of occlusion, keratinocytes swell with hydration, expanding the intercellular spaces and expanding the fissure network. This expansion ultimately leads to connections between systems that would otherwise remain discontinuous. This creates pores in the stratum corneum, allowing polar and nonpolar substances to penetrate more easily.

[0061] Lecithin organogel (LO) is a common component of transdermal penetration agents. LO possesses properties of both oil-based and water-based formulations, making it useful for delivering various drugs through the skin. LO is typically a gel containing an organic medium in the liquid phase. They can have a jelly-like structure consisting of a three-dimensional network of entangled inverted cylindrical micelles, which immobilizes the continuous phase and transforms it from a liquid to a viscous gel.

[0062] Another approach involves the use of chemical penetration enhancers (CPEs). Chemical penetration enhancers (CPEs) are molecules that interact with components of the stratum corneum (SC), the outermost layer of skin, to increase its permeability. However, despite efforts to improve CPEs, CPEs have little effect on increasing the skin penetration rate of drugs. CPEs can also cause skin damage, inflammation, and sensitization. Furthermore, they are generally ineffective for drugs with high molecular weights, such as peptides, proteins, and nucleic acids.

[0063] Various methods can be used to enhance transdermal drug delivery, but these methods have limitations. Most efforts to enhance transdermal penetration have focused on the stratum corneum, the outermost layer of skin. These typically rely on strong solvents (e.g., alcohol, DMSO) or patch-based systems. This approach limits the molecular size, lipophilicity, and potency of drugs that can be used. Essentially, current approaches are primarily limited to small, lipophilic, and highly potent drugs.

[0064] Exemplary Aspects of the Disclosure The present disclosure provides improved formulations and methods for transdermal penetration that work with a variety of drugs and active agents. These formulations and methods overcome the barriers presented by the stratum corneum as well as deeper layers of the skin. Furthermore, they do so without the use of harsh solvents and are effective for the delivery of high molecular weight drugs such as peptides, proteins, and nucleic acids.

[0065] One aspect of the present disclosure is a formulation for transdermal delivery of a drug through the skin of a subject. The formulation comprises a therapeutically effective amount of the drug and a penetrating moiety. The penetrating moiety comprises a phospholipid, a fatty acid ester formed from a low molecular weight alcohol, and a long-chain fatty acid, and optionally one or more of a viscosity-improving agent, a penetration enhancer, and an emulsifier.

[0066] Another aspect of the present disclosure is a formulation for transdermal delivery of a drug through the skin of a subject. The formulation comprises a therapeutically effective amount of the drug and a penetrating moiety comprising a phospholipid, a fatty acid ester formed from a low molecular weight alcohol, and a long-chain fatty acid. In this aspect, the phospholipid is phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, inositol phosphatide, or sphingomyelin; the fatty acid ester is isopropyl palmitate, isopropyl myristate, isopropyl linoleate, isopropyl oleate, ethyl laurate, or ethyl myristate; and the long-chain fatty acid is linoleic acid, oleic acid, stearic acid, linolenic acid, palmitic acid, arachidonic acid, palmitoleic acid, myristic acid, eicosenoic acid, benehic acid, euric acid, or lignoceric acid, or the long-chain fatty acid is derived from safflower oil or almond oil.

[0067] A further aspect of the present disclosure is a formulation for transdermal delivery of a drug through the skin of a subject. The formulation comprises a therapeutically effective amount of the drug and a penetrating moiety, the penetrating moiety comprising one or more of a phospholipid, a fatty acid ester formed from a low molecular weight alcohol, a long-chain fatty acid, and a viscosity-improving agent, a penetration enhancer, and an emulsifier. In this aspect, the phospholipid is phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, inositol phosphatide, or sphingomyelin; the fatty acid ester is isopropyl palmitate, isopropyl myristate, isopropyl linoleate, isopropyl oleate, ethyl laurate, or ethyl myristate; and the penetrating moiety is linoleic acid, oleic acid, stearic acid, linolenic acid, palmitic acid, arachidonic acid, palmitoleic acid, myristic acid, eicosenoic acid, benehic acid, euric acid, or the like. , or lignoceric acid is the long-chain fatty acid, or the long-chain fatty acid is derived from safflower oil or almond oil; polyglyceryl-4-laurate, polyglyceryl-4-oleate, Span 60, cetyl alcohol, or polyglyceryl-3-oleate is the penetration enhancer; poloxamer (e.g., poloxamer 407, poloxamer 188, poloxamer 184, and poloxamer 124) or sodium lauryl sulfate is the viscosity improver; and benzyl alcohol, ethanol, propylene glycol, polyethylene glycol, limonene, menthol, borneol, or camphor is the penetration enhancer.

[0068] An additional aspect of the present disclosure is a formulation for transdermal delivery of a drug through the skin of a subject. The formulation includes a phospholipid in an amount of about 5% to about 15% by weight of the formulation, an emollient / moisturizer in an amount of about 10% to about 20% by weight of the formulation, a fatty acid in an amount of about 0.5% to about 2% by weight of the formulation, an alcohol in an amount of about 0.5% to about 2% by weight of the formulation, an oil in an amount of about 1% to about 5% by weight of the formulation, a surfactant in an amount of about 0.5% to about 2% by weight of the formulation, water in an amount of about 30% to about 80% by weight of the formulation, and a therapeutically effective amount of a drug in an amount of about 0.001% to about 30% by weight of the formulation. In some cases, the drug is in an amount of about 0.001% to about 0.01% by weight of the formulation. In other cases, the drug is in an amount of about 0.011% to about 0.1% by weight of the formulation. In various cases, the drug is present in an amount of about 0.11% to about 1.0% by weight of the formulation. In further cases, the drug is present in an amount of about 1% to about 10% by weight of the formulation. In additional cases, the drug is present in an amount of about 11% to about 20% by weight of the formulation. In alternative cases, the drug is present in an amount of about 21% to about 30% by weight of the formulation.

[0069] In one aspect, the present disclosure provides a formulation for transdermal delivery of a drug through the skin of a subject.The formulation comprises phosphatidylcholine in an amount of about 7.64% by weight of the formulation, isopropyl palmitate in an amount of about 13.30% by weight of the formulation, stearic acid in an amount of about 0.62% by weight of the formulation, benzyl alcohol in an amount of about 1.39% by weight of the formulation, safflower oil in an amount of about 2.93% by weight of the formulation, oleic acid in an amount of about 0.97% by weight of the formulation, polyglyceryl-4-laurate in an amount of about 1.06% by weight of the formulation, deionized water in an amount of about 60.84% ​​by weight of the formulation, poloxamer 407 in an amount of about 9.25% by weight of the formulation, and a therapeutically effective amount of a drug in an amount of about 2% by weight of the formulation.In some cases, the amount of the drug is not about 2% by weight of the formulation, but the amount of the drug is less than about 2%, and the amount of water is increased proportionately. In other cases, rather than the amount of drug being about 2% by weight of the formulation, the amount of drug is greater than about 2% and the amount of water is reduced proportionately. In various cases, the amount of drug is less than about 30%.

[0070] In another aspect, the present disclosure provides a formulation for transdermal delivery of a drug through the skin of a subject. The formulation comprises phosphatidylcholine in an amount of about 7.66% by weight of the formulation, isopropyl palmitate in an amount of about 13.34% by weight of the formulation, benzyl alcohol in an amount of about 1.39% by weight of the formulation, stearic acid in an amount of about 0.68% by weight of the formulation, carthamus tinctorius (safflower) oil in an amount of about 2.79% by weight of the formulation, polyglyceryl-4-laurate in an amount of about 1.07% by weight of the formulation, oleic acid in an amount of about 1.06% by weight of the formulation, deionized water in an amount of about 61.73% by weight of the formulation, poloxamer 407 in an amount of about 9.28% by weight of the formulation, and a therapeutically effective amount of a drug in an amount of about 1.00% by weight of the formulation. In some cases, the amount of drug is not about 1% by weight of the formulation, the amount of drug is less than about 1%, and the amount of water is increased proportionately. In other cases, rather than the amount of drug being about 1% by weight of the formulation, the amount of drug is greater than about 1% and the amount of water is reduced proportionately. In various cases, the amount of drug is less than about 30%.

[0071] In a further aspect, the disclosure provides a formulation for transdermal delivery of a drug through the skin of a subject, the formulation comprising a therapeutically effective amount of the drug and a penetrating moiety, the penetrating moiety comprising phosphatidylcholine in an amount of about 3% to about 15% by weight of the formulation, isopropyl palmitate in an amount of about 5% to about 20% by weight of the formulation, stearic acid in an amount of about 0.1% to about 10% by weight of the formulation, benzyl alcohol in an amount of about 0.5% to about 5% by weight of the formulation, polyglyceryl-4-laurate in an amount of about 0.5% to about 10% by weight of the formulation, and poloxamer 407 in an amount of about 5% to about 20% by weight of the formulation.

[0072] In yet another aspect, the present disclosure provides a method for transdermally delivering at least one agent, the method comprising applying to the skin of a subject an effective amount of any of the formulations disclosed herein.

[0073] One aspect of the present disclosure is a method for treating or alleviating the symptoms of a disease or disorder. The method includes administering any of the transdermal formulations disclosed herein to a subject in need thereof and administering to the subject in need thereof a composition comprising one or more agents selected from Table 1. In some cases, the transdermal formulation is administered before, simultaneously with, or after administration of the composition. In various cases, the amount of the one or more agents is an effective dose of the agent listed in Table 1. In some cases, the composition is administered by a standard route for the agent. In some cases, the standard route is oral, topical, enteral, parenteral, intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection. In various cases, the composition is a liquid, suspension, gel, geltab, semisolid, tablet, sachet, troche, pill, or capsule.

[0074] Another aspect of the present disclosure is the use of any of the transdermal formulations disclosed herein in a method for treating or alleviating a symptom of a disease or disorder.

[0075] A further aspect of the present disclosure is a method for manufacturing a medicament for treating or alleviating a symptom of a disease or disorder, comprising combining a penetrating moiety listed in any of the formulations disclosed herein with one or more agents listed in Table 1.

[0076] Any aspect or embodiment described herein may be combined with any other aspect or embodiment disclosed herein.

[0077] Transdermal delivery formulation components Embodiments include transdermal lotions or creams for administering a drug to a subject. They are placed on the skin and deliver a specific amount of drug through the skin. The drug can be delivered through the skin to a localized subcutaneous location. For example, a lotion can reduce inflammation due to an autoimmune response. The lotion or cream can be applied directly to the affected area. Alternatively, the drug can enter the circulation for systemic distribution.

[0078] In alternative embodiments, the agent can be administered using a transdermal or medicated adhesive patch. To release the agent, the patch can utilize a porous membrane covering a reservoir of agent. Alternatively, the agent can be embedded in a layer of adhesive that releases the agent when it dissolves or melts.

[0079] An advantage of the transdermal drug delivery route over other types of delivery is that the formulation can provide a controlled release of the agent. Traditional transdermal delivery systems are generally ineffective for use with agents and drugs that are large and / or hydrophilic molecules.

[0080] There are other advantages to administering drugs transdermally. Proteins and peptides, such as those used in anti-aging treatments, can be broken down by stomach acid and enzymes. Transdermal administration is not affected by stomach or digestive tract problems. Furthermore, people can benefit from drugs that are absorbed slowly and regularly. Transdermal formulations allow the drug to be released in small amounts over a long period of time.

[0081] Other advantages relate to dosing. Large doses of agents can often cause dose-dependent toxicity. For example, oral administration of vitamin A can lead to hypervitaminosis A. The main problems associated with vitamin A are its half-life, rapid absorption (due to its lipophilicity), and its toxicity (due to high loading and frequent administration). Some drugs also undergo first-pass metabolism, which prevents delivery of the drug to the desired site of action. Furthermore, many hydrophilic or lipophilic agents exhibit either poor solubility or poor absorption when administered orally. Transdermal formulations allow effective concentrations of agents to be applied to the desired site without painful delivery.

[0082] Additionally, the transdermal formulations of the present disclosure can deliver active agents to the bloodstream of an animal, thereby providing systemic administration of the agent (e.g., the agents disclosed in Table 1). In particular, the transdermal formulations of the present disclosure can provide higher concentrations of molecules (especially those of insoluble molecules) and can provide systemic administration of molecules that are poorly absorbed by the intestinal epithelium. Molecules that are not suitable for enteral delivery, or molecules that are suitable but at low doses, can also be administered systemically via the transdermal formulations of the present disclosure.

[0083] In one embodiment, the drug is delivered by transdermal administration. There are numerous situations in which the formulations of the present invention are useful. For athletes, transdermal delivery formulations can deliver sufficient amounts of lactic acid neutralizers, such as ketone compounds, to fatigued muscles to alleviate the burning sensation athletes experience due to lactic acid buildup. This allows athletes to continue performing at optimal levels for longer periods of time. Furthermore, athletes and others who "train" require a large amount of energy, particularly due to the need for energy production in the areas of muscle tissue being trained, which necessitates the consumption of large amounts of calories. These nutrients can be delivered directly, rather than requiring oral intake, which can be counterproductive and relatively time-consuming.

[0084] The transdermal formulations of the present disclosure can deliver drugs of various sizes, including drugs with molecular weights of less than 500 Da, such as nicotine (162.2 Da), diphenhydramine hydrochloride (291.8 Da), and hydrocortisone (362.5 Da); drugs with molecular weights of 500 Da to 1000 Da, such as sildenafil citrate (666.7 Da), neratinib (557 Da), and doxycycline hyclate (512.9 Da); and drugs with molecular weights of more than 1000 Da, such as cyclosporin A (1202.6 Da), vancomycin hydrochloride (1485.70 Da), and RBD protein (10,000+ Da).

[0085] The drugs are (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine; (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide; 2-fluoro-N-methyl-4-[7-quinolin-6-yl-methyl)-imidazo[1,2-B][1,2,4]triazin-2yl]benzamide; 4-(3-amino-6-( (1S,3S,4S)-3-Fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide;4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile;Abacavir;Abiraterone acetate;Abiratone acetate;Abobotulinumtoxin A;Acalabrutinib;Acarbose;Acetaminophen;Acetazolamide;Acetylsalicylic acid;Acitretin;Acyclovir;Adalimumab Adapalene; Adapalene; Afoxolaner; Agalsidase beta; Albendazole; Alectinib; Alectinib; Alendronate sodium; Alglucosidase alfa; Alitretinoin; Alogliptin; Alpelisib; Aluminum hydroxide; Ambrisentan; Amiodarone; Amitriptyline; Amlodipine; Amlodipine; Amlodipine besylate; Amlodopine besylate; Amorolfine hydrochloride; Amoxicillin; Amphotericin B; Amphotericin B liposomal; Ampicillin; Amprenavir; Antihemophilic factor, Fc fusion protein Protein; Apalutamide; Apatinib; Apixaban; Apremilast; Aprepitant; Aripiprazole; Artemether; Aspirin; Atazanavir; Atenolol; Atomoxetine; Atorvastatin; Avapritinib; Axitinib (Inritin); Azacitidine; Azathioprine; Azelaic acid; Azilsartan medoxomil; Azithromycin; Baclofen; Baricitinib; Basiliximab; Batimastat (BB-94); Becaplermin; Belmosudil; Bendamustine; Benzoyl peroxide; Benzoyl peroxide;Betamethasone dipropionate; Betamethasone valerate; Bexarotene; Bictegravir; Bimatoprost; Binimetinib (Mektobi); Bortezomib; Bortezomib (Velcade); Bosentan; Bosutinib (Bosurif); Botulinum toxin A; Branched-chain amino acids; Brexpiprazole; Brimonidine; Brimonidine tartrate; Brodalumab; Buproprion; Cabazitaxel; Cabozantinib; Cabozantinib (Cometriz); Calcifezi ol;calcipotriene;calcipotriene;calcipotriol;calcitonin;calcitriol;calcium carbonate;canagliflozin;canakinumab;capecitabine;capmatinib;capsaicin;carbamazepine;carbidopa;carfilzomib;carfilzomib (cyprolis);cariprazine;carvedilol;CD-12681;CEE-321;cefazolin;cefepime;cefoperazone;cefotaxime sodium;cerebrospinal fluid; Coxib; Celecoxib; Cemiplimab; Ceritinib; Chlorothiazide; Chlorpromazine; Chlorthalidone; Cinacalcet; Ciprofloxacin; Cisapride; Citalopram; Citric acid; Clarithromycin; Clavulanate; Clindamycin phosphate; Clobazam; Clobetasol propionate; Clofazimine; Clomiphene; Clonidine; Clopidogrel; Clopidogrel bisulfate; Cobicistat; Cobicistat; Colcosine; Co Ristine; Corticotropin; Crisaborole; Crizanlizumab; Crizotinib (Xalkori); Cyclobenzaprine; Cyclosporine; Dabigatran etexilate; Dabrafenib; Dabrafenib; Dabrafenib; Dacomitinib (Vidinpro); Dalbavancin; Dalfopristin; Danazol; Dapagliflozin; Dapsone; Daptomycin; Darunavir; Dasatinib; Decitabine; Defatted peanuts (Arachis hypogaea) powder; deferasirox; delgocitinib; deoxycholic acid; desipramine; desonide; dexlansoprazole; dexmethylphenidate; dextroamphetamine / amphetamine salts; diclofenac; diclofenac sodium; diflucortolone; diflucortolone; difinisal; digoxin; diloxanide; dimethyl fumarate; diphenhydramine hydrochloride; diphtheria vaccine; docetaxel;Dolutegravir; Dolutegravir; Donepezil; Doxercalciferol; Doxycycline; Doxycycline ER; Doxycycline hyclate (B); Doxycycline monohydrate (A); Dronabinol; Dronedarone; Drospirenone; Dukoral / ShanChol cholera vaccine; Duloxetine; Dupilumab; Durvalumab; Dutasteride; Duvelisib; Ecallantide; Edoxaban; Efavirenz; Efavirenz; Elafibranol; Elagolix sodium; Elbasvir; Eletriptan; Eltrombopag; Elvitegravir; Empagliflozin; Emtricitabine; Emtricitabine; Emtricitabine; Emtricitabine; Emtricitabine; Emtricitabine; Emtricitabine; Emtricitabine; Encorafenib (Braftovi); Enfuviritide; Enoxaparin sodium; Entecavir; Entrectinib; Enzalutamide; Epinephrine; Erdafitinib; Erenumab; Eribulin; Erlotinib; Erlotinib hydrochloride (Tarceva); Ertapenem; Erythromycin; Escitalopram; Esketamine (Ketamine); Esomeprazole; E Sopremazole; Estradiol; Estrogen-conjugated; Etanercept; Ethinyl estradiol; Ethinyl estradiol; Ethinyl estradiol; Etonogestrel; Etonogestrel; Etravirine; Etretinate; Everolimus; Everolimus (Afinitor); Everolimus (Votuvia, Zotres / Certican); Ezetimibe; Ezetimibe; Ezetimibe; Famotidine; Fasinumab; Febuxostat; Fedratinib; Fenofibrate; Ferric carboxymaltose; Fexofenadine hydrochloride; Fil Gotinib; Filgrastim; Fingolimod; Fluocinolone acetonide; Fluocinolone acetonide; Fluoxetine; Flurbiprofen; Folic acid; Forskolin; Fostamatinib; Fulvestrant; Furosemide; Fusidic acid; Fusidic acid; Gabapentin; Ganetespib; Gefitinib (Iressa); Gilteritinib; Glasdedib (Daurismo) or Glasdedib maleate; Glecaprevir; Glibenclamide; Glimepiride; Glipizide; Glucagon; Glucosamine; Glutaric anhydride; Glycopyrrolate; Goserelin; Goserelin LA;Granisetron; Grazoprevir; Griseofulvin; Halobetasol propionate; Haloperidol; Heparin sodium; Heplisub B vaccine; Hyaluronic acid; Hydrochlorothiazide; Hydrochlorothiazide; Hydrochlorothiazide; Hydrocortisone; Hydrocortisone acetate; Hydroquinone; Hydroxychloroquine; Hydroxyprogesterone; Ibrutinib; Ibrutinib (Imbruvica); Ibuprofen; Icatibant acetate; Idelalisib; Imatinib; Imatinib (Gleevec); Imatinib mesylate ;Imiglucerase;Inclisiran;Indinavir;Indomethacin;Infliximab;Ingenol mebuate;Inotersen;Insulin A;Insulin glargine;Interferon beta-1b;Iopanoic acid;Irbesartan;Isoconazole;Isoconazole;Isotretinoin;Itraconazole;Ivacaftor;Ivacaftor;Ivermectin;Ixazomib;Ketoconazole;Ketone bodies;Ketoprofen;Keilvir;Lacosamide;Lamictal;Lamivudine;Lansoprazole;Lapatinib;Lapatinib (Tycarb);Larotrectinib ;ledipasvir;leflunomide;lenalidomide;lenvatinib;LEO-138559;LEO-152020;leuprolide;levetiracetam;levodopa;levodopa / benserazide;levonorgestrel;levothyroxine;linagliptin;linezolid;lisinopril;L-lysine free base;lofexidine;lopinavir;loratadine;lorlatinib (Lorviqua);losartan;lovastatin;lubiprostone;lumacaftor / ivacaftor;lumefantrine;lurasidone;ruspatercept;lymecycline;macitentan;magneto sodium;magnesium lactate;marimastat (BB-2516);marizomib (NPI-0052);mebendazole;mefloquine;melatonin;meloxicam;memantine hydrochloride;meningococcal [serotype b] vaccine;mesalazine;metformin;metformin;metformin;methotrexate;methyl aminolevulinate hydrochloride;methylphenidate;methylprednisolone;metoprolol succinate;metronidazole;midostaurin;minoxidil;mirabegron;mizolastine MR;montelukast;mycophenolate mofetil;N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)-isonicotinamide;N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)-pyridine-3-carboxamide hydrochloride Salts; Nalidixic acid (quinolone antibiotic); Naloxone; Naproxen; Navitoclax (ABT-263); Nebivolol; Nelfinavir; Nemolizumab; Neomycin; Neovastat (AE-941); Neratinib - free base; Neratinib (Nerlynx); Neratinib maleate; Nevirapine; Niclosamide; Nifedipine; Nilotinib; Nilotinib; Nilotinib (Tasigna); Nintedanib; Niratimib; Nitric oxide; Nitrofurantoin; Norethindrone acetate; Nusinersen; NVP-AUY922; Nystatin; Obatoclax (GX15-070);Octreotide acetate;Ofatumumab;Ofloxacin;Olanzapine;Olaparib;Olmesartan medoxomil;Ormacostat;Omalizumab;Oseltamivir;Osimertinib;Osimertinib mesylate;Oxaprozin;Ozanimod;Paclitaxel;Paclitaxel protein-bound;Palbociclib (Ibrance);Paliperidone palmitate;Pantoprazole;Parathyroid hormone;Paricalcitol;Patisiran;Pazopanib;Pazopanib (Votrient);Pazopanib hydrochloride;Peficitinib;Pegfilg rastim; pembrolizumab (Keytruda); pemetrexed; pemigatinib; perifosine; pexidartinib; phenazopyridine; phenytoin; pibrentasvir; piperacillin; pirfenidone; piroxicam; pomalidomide; ponatinib; ponatinib (lclusig); posaconazole; pralsetinib; pravastatin; prednicarbate; prednisone; pregabalin; prinomastat (AG-3340); progesterone; propanolol; protamine sulfate; psilocybin; pyrantel; pyrimethamine; quetiapine;Quinupristin; Raloxifene; Raltegravir; Ranibizumab; Ranitidine; Ranolazine; Levimastat (BMS-275291); Regorafenib; Regorafenib (Stivarga); Relugolix (Orgovix); Remibrutinib; Resiquimod; Retinal; Retinol; Ribociclib; Ribo; Ciclib succinate; rifampin; rilpivirine; rilpivirine; rimegepant; riociguat; risdipram; risperidone; ritonavir; rivaroxaban; rosuvastatin; rosuvastatin calcium; rotigotine; roxadustat; rucaparib camsylate (Rubraca); ruxolitinib; ruxolitinib (Jafaki); sacubitril, valsartan; salicylic acid; sapropterin; saquinavir; sarilumab; saxagliptin, metformin; secukinumab; selexipag; selinexor; selpercatinib; Selpercatinib (LOXO-292); selumetinib; semaglutide; sertraline; sevoflurane; sildenafil; sildenafil citrate; simvastatin; siponimod; siremadrine; sirolimus; sitagliptin; sitagliptin phosphate monohydrate; sodium bicarbonate or sodium carbonate; sodium deoxycholate; sodium nitrate; sofosbuvir; sofosbuvir; solifenacin; somatropin; sonidegib phosphate; sorafenib; sorafenib (Nexavar); spartalizumab; spironolactone; cetylcholine Sufentanil; Sugammadex; Sulbactam; Sulbactam; Sulfadiazine; Sulfamethoxazole; Sulfasalazine; Sumatriptan; Sunitinib; Sunitinib; Sunitinib (Sutent); Sunitinib malate (Sutent); Tacrolimus; TAF; TAF; TAF; TAF; Talazoparib-Talzenna; Talinolol; Tamoxifen; Tamsulosin; Tazarotene; Tazobactam; TDF; TDF; Temsirolimus (CCl-779, Torisel); Teneligliptin; Tenofovir alafenamide; Tenofovir disoproxil fumarate Salts; Tepotinib; Terbinafine; Terfenadine; Teriflunomide; Testosterone; Tezacaftor; THC; Ticagrelor; Tigecycline; Timolol; Timolol maleate; Tipranavir; Tisagenlecleucel; Tisagenlecleucel (Kymriah); Tivozanib; Tofacitinib citrate; Tolvaptan; Tralokinumab; Tramadol; Trametinib; Trametinib; Trametinib; Trametinib (Mekinist); Tranexamic acid; Travoprost; Trazodone; Tretinoin; Tretinoin; Triamcinolone;Triclabendazole; trifarotene; trimethoprim; triptorelin; tris; tucatinib; ubrogepant; umbralisib; upadacitinib; valproic acid; valsartan; vancomycin; vancomycin hydrochloride (A); vancomycin hydrochloride (B); vandetanib; vandetanib (Caprelsa); varenicline; vasopressin; velpatasvir; velpatasvir; vemurafenib; venetoclax; verapamil hydrochloride; vilazodone; vildagliptin; vismodegib; vitamin B6; vitamin D; vonoprazan; voriconazole; vortioxetine; voxilaprevir; warfarin sodium; zanubrutinib; zinc; zoledronic acid; and zolpidem.

[0086] In some cases, the therapeutic agent comprises two or more agents.In these cases, the first agent and at least the second agent may be selected from the group consisting of abacavir, dolutegravir, and lamivudine; adapalene and benzoyl peroxide; amlodipine and valsartan; amlodipine besylate and valsartan; amoxicillin and clavulanate; ampicillin and sulbactam; artemether and lumefantrine; betamethasone valerate and fusidic acid; bictegravir, emtricitabine, and TAF; bimatoprost and timolol maleate; brimonidine and timolol; calcipotriene and betamethasone dipropionate tazone; canagliflozin and metformin; carbidopa and levodopa; cefoperazone and sulbactam; dabrafenib and trametinib; darunavir, cobicistat, emtricitabine, and tenofovir alafenamide; diflucortolone and isoconazole; drospirenone and ethinyl estradiol; efavirenz, emtricitabine, and TDF; elbasvir and grazoprevir; elvitegravir, cobicistat, emtricitabine, and TAF; emtricitabine, rilpivirine, and TAF ;Emtricitabine and TAF;Emtricitabine and tenofovir disoproxil fumarate;Ethinyl estradiol and etonogestrel;Ezetimibe and atorvastatin;Ezetimibe and simvastatin;Fluocinolone acetonide, hydroquinone, and tretinoin;Fusidic acid and hydrocortisone acetate;Glecaprevir and pibrentasvir;Hydrochlorothiazide and valsartan;Irbesartan and hydrochlorothiazide;Ledipasvir and sofosbuvir;Linagliptin and metformin;Losartan and hydrocortisone Selected from the group consisting of chlorothiazide; metformin and sitagliptin; norethindrone acetate and ethinyl estradiol; piperacillin and tazobactam; pregabalin and celecoxib; quinupristin and dalfopristin; rilpivirine and emtricitabine and TDF; sofosbuvir and velpatasvir; sofosbuvir, velpatasvir and voxilaprevir; tezacaftor and ivacaftor; trametinib and dabrafenib; trametinib and dabrafenib; and zinc, magnesium, and vitamin B6.

[0087] Throughout this disclosure, drugs, agents, or other components are described as being provided in a particular range of doses, amounts, concentrations, percentages, units, volumes, etc. For example, a drug may be provided in a dose range of about 1 mg to about 10 mg. As used herein, the range of about 1 mg to about 10 mg includes all doses therebetween and any subranges therebetween. More specifically, doses may be about 1 mg, about 1.01 mg, about 1.02 mg, about 1.03 mg, about 1.04 mg, about 1.05 mg, about 1.06 mg, about 1.07 mg, about 1.08 mg, about 1.09 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 ... 0.4mg, about 2.5mg, about 2.6mg, about 2.7mg, about 2.8mg, about 2.9mg, about 3mg, about 3.1mg, about 3.2mg, about 3.3mg, about 3.4mg, about 3.5mg, about 3.6mg, about 3.7mg, about 3.8mg, about 3.9mg, about 4mg, about 4.1mg, about 4.2mg, about 4.3mg, about 4.4mg, about 4.5mg, about 4.6mg, about 4.7mg, about 4.8mg, about 4.9mg, about 5mg , about 5.1mg, about 5.2mg, about 5.3mg, about 5.4mg, about 5.5mg, about 5.6mg, about 5.7mg, about 5.8mg, about 5.9mg, about 6mg, about 6.1mg, about 6.2mg, about 6.3mg, About 6.4mg, about 6.5mg, about 6.6mg, about 6.7mg, about 6.8mg, about 6.9mg, about 7mg, about 7.1mg, about 7.2mg, about 7.3mg, about 7.4mg, about 7.5mg, about 7.6mg, about The dose may be 7.7 mg, about 7.8 mg, about 7.9 mg, about 8 mg, about 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9 mg, about 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg, about 10 mg, and any dose therebetween.Further, the ranges are about 1 mg to about 2 mg, about 1 mg to about 3 mg, about 1 mg to about 5 mg, about 1 mg to about 7 mg, about 1 mg to about 8 mg, about 2 mg to about 3 mg, about 2 mg to about 4 mg, about 2 mg to about 6 mg, about 2 mg to about 8 mg, about 2 mg to about 9 mg, about 2 mg to about 5 mg, about 2 mg to about 7 mg, about 3 mg to about 4 mg, about 3 mg to about 5 mg, about 3 mg to about 7 mg, about 3 mg to about 9 mg, about 3 mg to about 10 mg, about 3 mg to about 6 mg, about 3 mg to about 8 mg, about 4 mg to about 5 mg, about 4 mg to about 6 mg, about It may be 4 mg to about 8 mg, about 4 mg to about 10 mg, about 4 mg to about 7 mg, about 4 mg to about 9 mg, about 5 mg to about 6 mg, about 5 mg to about 7 mg, about 5 mg to about 9 mg, about 5 mg to about 8 mg, about 5 mg to about 10 mg, about 6 mg to about 7 mg, about 6 mg to about 8 mg, about 6 mg to about 10 mg 10 mg, about 6 mg to about 9 mg, about 7 mg to about 8 mg, about 7 mg to about 9 mg, about 7 mg to about 10 mg, about 8 mg to about 9 mg, about 8 mg to about 10 mg, or about 9 mg to about 10 mg, and any subrange therebetween.

[0088] The amount of drug in the transdermal delivery formulations disclosed herein may range from about 0.001% to about 30% (w / w) or (w / v) percentage of the formulation or solution, for example, about 0.0005%, 0.0006%, 0.0007%, 0.0008%, 0.0009%, 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, The agent may comprise 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30%, or any amount (w / w) or (w / v) therebetween. The agents and their various dose ranges listed in Table 1 herein can be used at the above doses or at any dose from about 0.001% to about 30%. By way of example, the various doses listed above may be used with fulvestrant, eltrombopag, selpercatinib (LOXO-292), ertapenem, erlotinib, sugammadex, nebivolol, azilsartan medoxomil, nifedipine, triptorelin, elagolix sodium, olmesartan medoxomil, oseltamivir, selinexor, levetiracetam, leuprolide, goserelin, lenvatinib, ethinyl estradiol (etonogestrel), paclitaxel protein-bound, bendamustine, acyclovir, adalimumab, alpelisib, ampicillin (sulphosphamide), fluticasone, fluoxetine, fluoxetine-10 ... bactam), azithromycin, branched-chain amino acids, calcium carbonate, capsaicin, cemiplimab, citric acid, clonidine, crisaborole, docetaxel, ecallantide, erenumab, etanercept, fasinumab, filgrastim, forskolin, fulvestrant, glutaric acid anhydride, glycopyrrolate, goserelin LA, heparin sodium, infliximab, ketoprofen, linezolid, L-lysine free base, magnesium lactate, metronidazole, olaparib, ormacostat, omalizumab, parathyroid hormone, piperacillin (tazobactam),Quinupristin (dalfopristin), salicylic acid, sarilumab, secukinumab, sodium nitrate, sulfasalazine, tigecycline, tisagenlecleucel, tranexamic acid, triamcinolone, vitamin D, zinc, magnesium, vitamin B6, aspirin, becaplermin, buproprion, cefazolin, clarithromycin, cyclobenzaprine, furosemide, gabapentin, halobetasol propionate, inotersen, levodopa (carbidopa), melatonin, meloxicam, neomycin, neratinib, patisiran, prednisone, rifapril Bociclib, sonidegib phosphate, sufentanil citrate, tramadol, trametinib plus dabrafenib, zoledronic acid or niritimibe, glecaprevir, pibrentasvir, sofosbuvir, velpatasvir, emtricitabine, tenofovir disoproxil fumarate, lenalidomide, abacavir, dolutegravir, lamivudine, paliperidone palmitate, sitagliptin phosphate monohydrate, empagliflozin, dolutegravir, linagliptin, metformin, elvitegravir, cobicistat, emtricitabine, TAF, metformin, Sitagliptin, esomeprazole, acarbose, afoxolaner, agalsidase beta, alglucosidase alfa, alogliptin, antihemophilic factor, Fc fusion protein, aprepitant, aripiprazole, atazanavir, atomoxetine, azacitidine, basiliximab, bictegravir, emtricitabine, TAF, bimatoprost, timolol maleate, bosentan, brexpiprazole, brimonidine, timolol, calcipotriol, calcitonin, canagliflozin, metformin, canakinumab, cariprazine, clobazam, Romiphene, clopidogrel bisulfate, crizanlizumab, dapagliflozin, darunavir, cobicistat, emtricitabine, tenofovir alafenamide, dexlansoprazole, dexmethylphenidate, diphtheria vaccine, donepezil, dronedarone, Ducarol / Shancor cholera vaccine, duloxetine, dupilumab, durvalumab, efavirenz, emtricitabine, TAF, elafibranor, elbasvir, grazoprevir, eltrombopag, emtricitabine, rilpivirine, TAF, emtricitabine, TAF,Entecavir, erenumab, esketamine (ketamine), ezetimibe, atorvastatin, ezetimibe, simvastatin, febuxostat, glimepiride, glucosamine, granisetron, heplisub-b vaccine, imiglucerase, inclisiran, insulin glargine, interferon beta-1b, ketone, lamictal, ledipasvir, sofosbuvir, lofexidine, losartan, hydrochlorothiazide, lubiprostone, lurasidone, luspatercept, memantine hydrochloride, mesalazine, methylphenidin Date, mirabegron, montelukast, mycophenolate mofetil, naloxone, nilotinib, nitric oxide, octreotide acetate, ofatumumab, olanzapine, osimertinib mesylate, pantoprazole, pegfilgrastim, psilocybin, quetiapine, raltegravir, ranibizumab, ranolazine, rilpivirine, emtricitabine, TDF, risperidone, rosuvastatin calcium, roxadustat, sapropterin, saxagliptin, metformin, semaglutide, sevoflurane, sofosbuvir fluoxetine, spartalizumab, teneligliptin, tezacaftor, ivacaftor, THC, ticagrelor, tolvaptan, travoprost, vasopressin, vildagliptin, vilazodone, vonoprazan, vortioxetine, zolpidem, atenolol, carvedilol, citalopram, dextroamphetamine / amphetamine salts, enfubilitide, escitalopram, esopremazole, fluoxetine, givosiran, glipizide, glucagon, lisinopril, nifedipine, pravasta acetaminophen, propanolol, ranitidine, sertraline, trazodone, valsartan, calcipotriene, diflucortolone, methylprednisolone, delgocitinib, isoconazole, azelaic acid, calcipotriene (with or without betamethasone dipropionate), diflucortolone (with or without isoconazole), betamethasone valerate (with or without fusidic acid), fusidic acid (with or without hydrocortisone acetate), hydrocortisone acetate (with or without fusidic acid), fusidic acid (with or without betamethasone valerate).Betamethasone dipropionate (with or without calcipotriene), isoconazole (with or without diflucortolone), baclofen, ingenol mebuate, octreotide acetate, epinephrine, fingolimod, trametinib and dabrafenib, trametinib, dabrafenib (with or without trametinib), amlodipine besylate, apixaban, amlodopine besylate (with or without valsartan), ruxolitinib, everolimus (Afinitor / Votubia and Zotres / Certican), silemadrine, valsartan (with or without amlodopine besylate), eletriptan, valsartan, venetoclax, eltrombopag, sildenafil This may be applicable to: methicillin-resistant Staphylococcus aureus, remibrutinib, decitabine, canakinumab, sacubitril (with or without valsartan), vildagliptin, midostaurin, dabrafenib, roxadustat, protamine sulfate, heparin sodium, omalizumab, imatinib mesylate, calcitonin, diclofenac sodium, sumatriptan, progesterone, deferasirox, azacitidine, doxycycline, secukinumab, cyclosporine, pazopanib hydrochloride, celecoxib, brodalumab, ofatumumab, pregabalin, tralokinumab, crizanlizumab, daptomycin, nilotinib, vancomycin, cefepime, metformin, and ribociclib succinate.

[0089] An effective dose of a drug and / or active agent may be in an amount of about 0.0001 mg to about 10 mg, e.g., about 0.0001 mg, 0.0002 mg, 0.0003 mg, 0.0004 mg, 0.0005 mg, 0.0006 mg, 0.0007 mg, 0.0008 mg, 0.0009 mg, 0.001 mg, 0.002 mg, 0.003 mg, 0.004 mg, 0.005 mg, 0.006 mg, 0.007 mg, 0.008 mg, 0.009 mg, 0.01 mg, 0.015 mg, 0.02 mg, 0.025 mg, 0.03 mg, 0.035 mg, 0.04 mg, 0.0 45mg, 0.05mg, 0.055mg, 0.06mg, 0.065mg, 0.07mg, 0.075mg, 0.08mg, 0.085mg, 0.09mg, 0.095mg, 0.1mg, 0.15mg, 0.2mg, 0.25mg, 0.3mg, 0.35mg, 0.4mg , 0.45mg, 0.5mg, 0.55mg, 0.6mg, 0.65mg, 0.7mg, 0.75mg, 0.8mg, 0.85mg, 0.9mg, 0.95mg, 1mg, 1.1mg, 1.2mg, 1.3mg, 1.4mg, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg, 2mg, 2.1mg, 2.2mg, 2.3mg, 2.4mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9mg, 3mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8mg, 3.9mg, 4m g, 4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5mg, 5.1mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8mg, 5.9mg, 6mg, 6.1mg, 6 The dose may be 0.2mg, 6.3mg, 6.4mg, 6.5mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7mg, 7.1mg, 7.2mg, 7.3mg, 7.4mg, 7.5mg, 7.6mg, 7.7mg, 7.8mg, 7.9mg, 8mg, 8.1mg, 8.2mg, 8.3mg, 8.4mg, 8.5mg, 8.6mg, 8.7mg, 8.8mg, 8.9mg, 9mg, 9.1mg, 9.2mg, 9.3mg, 9.4mg, 9.5mg, 9.6mg, 9.7mg, 9.8mg, 9.9mg, or 10mg, or any dose therebetween.The various drugs and their dose ranges listed in Table 1 can be used in the above doses. By way of example, the above various doses can be used with lenalidomide, empagliflozin, linagliptin, metformin, elvitegravir, cobicistat, emtricitabine, TAF, aripiprazole, brexpiprazole, cariprazine, clobazam, dapagliflozin, dexmethylphenidate, donepezil, entecavir, ezetimibe, atorvastatin, simvastatin, glimepiride, granisetron, interferon beta-1b, lofexidine, lubiprostone, Memantine hydrochloride, montelukast, naloxone, octreotide acetate, olanzapine, pegfilgrastim, ranibizumab, risperidone, rosuvastatin calcium, saxagliptin, metformin, semaglutide, somatropin, THC, tolvaptan, vortioxetine, zolpidem, carvedilol, dextroamphetamine / amphetamine salts, escitalopram, esopremazole, fluoxetine, glipizide, glucagon, lisinopril, nifedipine, pravastatin, nebiazepam Borol, nifedipine, triptorelin, leuprolide, goserelin, lenvatinib, ethinyl estradiol, etonogestrel, capsaicin, clonidine, fasinumab, filgrastim, glycopyrrolate, goserelin LA, ormacostat, parathyroid hormone, triamcinolone, vitamin D, zinc, magnesium, vitamin B6, becaplermin, cyclobenzaprine, halobetasol propionate, carbidopa, levodopa, melatonin, meloxicam, prednisone, quencher This may be applicable to sufentanil acetate, trametinib plus dabrafenib, zoledronic acid, calcitonin, everolimus (Afinitor / Votubia and Zotres / Certican), trametinib (alone or in combination with dabrafenib), amlodipine besylate (in combination with valsartan), apixaban, amlodopine besylate, ruxolitinib, silemadrine (alone or in combination with valsartan), eletriptan, valsartan (alone or in combination with amlodopine besylate), and venetoclax.

[0090] An effective dose of a drug and / or active agent may be in an amount of about 10 mg to about 1000 mg, for example, about 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103 mg, 1 g, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75 mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350m g, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, 490mg, 500 The dose may be 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 640 mg, 660 mg, 680 mg, 700 mg, 720 mg, 740 mg, 760 mg, 780 mg, 800 mg, 820 mg, 840 mg, 860 mg, 880 mg, 900 mg, 920 mg, 940 mg, 960 mg, 980 mg, or 1000 mg, or any dose therebetween. The various drugs and their dose ranges listed in Table 1 can be used in the above doses. By way of example, the various doses listed above may be used with glecaprevir, pibrentasvir, sofosbuvir, velpatasvir, emtricitabine, tenofovir disoproxil fumarate, lenalidomide, abacavir, dolutegravir, lamivudine, paliperidone palmitate, sitagliptin phosphate monohydrate, empagliflozin, dolutegravir, linagliptin, metformin, elvitegravir, cobicistat, emtricitabine, TAF, metformin, sitagliptin, esomeprazole, acarbose, afoxolaner, agalsidase beta,Alglucosidase alfa, alogliptin, aprepitant, aripiprazole, atazanavir, atomoxetine, azacitidine, basiliximab, bictegravir, emtricitabine, TAF, bosentan, canagliflozin, metformin, canakinumab, clobazam, clomiphene, clopidogrel bisulfate, crizanlizumab, dapagliflozin, darunavir, cobicistat, emtricitabine, tenofovir alafenamide, dexlansoprazole, dexmethylphenidate, donepezil, dronedarone, duloxetine, dupilumab, Durvalumab, efavirenz, emtricitabine, TDF, elbasvir, grazoprevir, eltrombopag, emtricitabine, rilpivirine, TAF, emtricitabine, TAF, erenumab, esketamine (ketamine), ezetimibe, atorvastatin, ezetimibe, simvastatin, febuxostat, glucosamine, inclisiran, lamictal, ledipasvir, sofosbuvir, losartan, hydrochlorothiazide, lurasidone, luspatercept, memantine hydrochloride, methylphenidate, mirabegron, montelukast st, mycophenolate mofetil, nilotinib, ofatumumab, olanzapine, osimertinib mesylate, pantoprazole, quetiapine, raltegravir, ranolazine, rilpivirine, emtricitabine, TDF, risperidone, rosuvastatin calcium, roxadustat, sapropterin, saxagliptin, metformin, sofosbuvir, velpatasvir, voxilaprevir, spartalizumab, teneligliptin, tezacaftor, ivacaftor, ticagrelor, tolvaptan, vildagliptin, vilazodone, vonopharmaceuticals Razan, vortioxetine, zolpidem, atenolol, carvedilol, citalopram, dextroamphetamine / amphetamine salts, enfubilitide, escitalopram, esopremazole, fluoxetine, givosiran, glipizide, glucagon, lisinopril, nifedipine, pravastatin, propanolol, ranitidine, sertraline, trazodone, valsartan, fulvestrant, eltrombopag, selpercatinib (LOXO-292), ertapenem, erlotinib, sugammadex, nebivolol, azilsartan medoxomil,Nifedipine, triptorelin, elagolix sodium, olmesartan medoxomil, oseltamivir, selinexor, levetiracetam, raplolide, lenvatinib, paclitaxel protein binding, bendamustine, acyclovir, adalimumab, alpelisib, ampicillin, sulbactam, azithromycin, branched-chain amino acids, calcium carbonate, capsaicin, cemiplimab, citric acid, crisaborole, docetaxel, ecallantide, erenumab, etanercept, fasinumab, forskolin, fulvestrant, glutaric anhydride , glycopyrrolate, goserelin LA, heparin sodium, infliximab, ketoprofen, linezolid, L-lysine free base, magnesium lactate, metronidazole, olaparib, ormacostat, omalizumab, piperacillin, tazobactam, quinupristin, dalfopristin, salicylic acid, sarilumab, secukinumab, sodium nitrate, sulfasalazine, tigecycline, tranexamic acid, triamcinolone, zinc, magnesium, vitamin B6, aspirin, bupropion, cefazolin, clarithromycin, cyclobenzaprine , furosemide, gabapentin, inotersen, carbidopa, levodopa, meloxicam, neomycin, neratinib, patisiran, prednisone, ribociclib, sonidegib phosphate, tramadol, trametinib + dabrafenib, niradimibe, dabrafenib (combined with trametinib), amlodipine besylate, apixaban, amlodopine besylate (with or without valsartan), ruxolitinib, everolimus (Afinitor / Votvia, Zotres / Certican), silemadrine, eletriptan, valsartan, venetoclax, Eltro Mbopag, sildenafil, remibrutinib, decitabine, canakinumab, sacubitril (with or without valsartan), vildagliptin, midostaurin, dabrafenib, roxadustat, protamine sulfate, heparin sodium, omalizumab, imatinib mesylate, diclofenac sodium, sumatriptan, progesterone, deferasirox, azacitidine, doxycycline, secukinumab, cyclosporine, pazopanib hydrochloride, celecoxib, brodalumab, ofatumumab, pregabalin, tralokinumab, crizanlizumab,This may be applicable to daptomycin, nilotinib, vancomycin, cefepime, metformin, and ribociclib succinate.

[0091] An effective dose of the drug and / or active agent may be in an amount of about 1 g to about 30 g, e.g., about 1 g, 1.1 g, 1.2 g, 1.3 g, 1.4 g, 1.5 g, 1.6 g, 1.7 g, 1.8 g, 1.9 g, 2 g, 2.1 g, 2.2 g, 2.3 g, 2.4 g, 2.5 g, 2.6 g, 2.7 g, 2.8 g, 2.9 g, 3 g, 3.1 g, 3.2 g, 3.3 g, 3.4 g, 3.5 g, 3.6 g, 3.7 g, 3.8 g, 3.9 g, 4 g, 4.1 g, 4.2 g, 4.3 g, 4.4 g, 4.5 g, 4.6 g, 4.7 g, 4.8 g, 4.9 g, 5 g, 6 g, 7 g, 8 g, 9 g, 10 g, 11 g, 12 g, 13 g, 14 g, 15 g, 16 g, 17 g, 18 g, 19 g, 20 g, 21 g, 22 g, 23 g, 24 g, 25 g, 26 g, 27 g, 28 g, 29 g, 30 g, 31 g, 32 g, 33 g, 34 g, 35 g, 36 g, 37 g, 38 g, 39 g, 40 g, 41 g, 42 g, 43 g, 44 g, 45 g, 46 g, 47 g, 48 g, 49 g, 50 g, 51 g, 52 g, 53 g, 54 g, The dosage ranges may be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 g, or any dose therebetween. The various drugs and their dosage ranges listed in Table 1 can be used in the dosages listed above. By way of example, the various doses above would be applicable to linagliptin, metformin, alglucosidase alfa, canagliflozin, metformin, darunavir, cobicistat, emtricitabine, tenofovir alafenamide, mesalazine, ofatumumab, quetiapine, raltegravir, ranolazine, sapropterin, ertapenem, acyclovir, ampicillin, sulbactam, branched chain amino acids, calcium carbonate, citric acid, metronidazole, tranexamic acid, cefazolin, neomycin, imatinib mesylate, cyclosporine, pazopanib hydrochloride, ofatumumab, vancomycin, cefepime, and metformin.

[0092] An effective dose of a drug and / or active agent can be an amount of about 5 IU / kg to about 100 IU / kg, e.g., about 5 IU / kg, 10 IU / kg, 15 IU / kg, 20 IU / kg, 25 IU / kg, 30 IU / kg, 35 IU / kg, 40 IU / kg, 45 IU / kg, 50 IU / kg, 55 IU / kg, 60 IU / kg, 65 IU / kg, 70 IU / kg, 75 IU / kg, 80 IU / kg, 85 IU / kg, 90 IU / kg, 95 IU / kg, or 100 IU / kg, or any dose therebetween. The various drugs and their dosage ranges listed in Table 1 can be used in the dosages described above. By way of example, the various dosages listed above would be applicable to antihemophilic factor, Fc fusion protein, calcitonin, and heparin sodium.

[0093] An effective dose of the drug and / or agent may be in an amount of about 0.1 mg / ml to about 10 mg / ml, for example, about 0.1 mg / ml, 0.2 mg / ml, 0.3 mg / ml, 0.4 mg / ml, 0.5 mg / ml, 0.6 mg / ml, 0.7 mg / ml, 0.8 mg / ml, 0.9 mg / ml, 1 mg / ml, 1.1 mg / ml, 1.2 mg / ml, 1.3 mg / ml, 1.4 mg / ml, 1.5 mg / ml, 1.6 mg / ml, 1.7 mg / ml, 1.8 mg / ml, 1.9 mg / ml, 2 mg / ml, 2.1 mg / ml, 2.2 mg / ml, 2.3mg / ml, 2.4mg / ml, 2.5mg / ml, 2.6mg / ml, 2.7mg / ml, 2.8mg / ml, 2.9mg / ml, 3mg / ml, 3.1mg / ml, 3.2mg / ml, 3.3mg / ml, 3.4mg / ml, 3.5mg / ml, 3.6 mg / ml, 3.7mg / ml, 3.8mg / ml, 3.9mg / ml, 4mg / ml, 4.1mg / ml, 4.2mg / ml, 4.3mg / ml, 4.4mg / ml, 4.5mg / ml, 4.6mg / ml, 4.7mg / ml, 4.8mg / ml, 4.9mg / m l, 5mg / ml, 5.1mg / ml, 5.2mg / ml, 5.3mg / ml, 5.4mg / ml, 5.5mg / ml, 5.6mg / ml, 5.7mg / ml, 5.8mg / ml, 5.9mg / ml, 6mg / ml, 6.1mg / ml, 6.2mg / ml, 6.3 mg / ml, 6.4mg / ml, 6.5mg / ml, 6.6mg / ml, 6.7mg / ml, 6.8mg / ml, 6.9mg / ml, 7mg / ml, 7.1mg / ml, 7.2mg / ml, 7.3mg / ml, 7.4mg / ml, 7.5mg / ml, 7.6mg / m The dose range may be 1, 7.7 mg / ml, 7.8 mg / ml, 7.9 mg / ml, 8 mg / ml, 8.1 mg / ml, 8.2 mg / ml, 8.3 mg / ml, 8.4 mg / ml, 8.5 mg / ml, 8.6 mg / ml, 8.7 mg / ml, 8.8 mg / ml, 8.9 mg / ml, 9 mg / ml, 9.1 mg / ml, 9.2 mg / ml, 9.3 mg / ml, 9.4 mg / ml, 9.5 mg / ml, 9.6 mg / ml, 9.7 mg / ml, 9.8 mg / ml, 9.9 mg / ml, or 10 mg / ml, or any dose therebetween. The various drugs and their dose ranges listed in Table 1 can be used in the above doses.By way of example, the various dosages above would be applicable to bimatoprost, timolol maleate, brimonidine, and timolol.

[0094] An effective amount of drug and / or active agent in the formulation can be in an amount of about 0.001% to about 10%, for example, about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%, or any dose therebetween. The various drugs and their dose ranges listed in Table 1 can be used in the above doses. By way of example, the above doses would be applicable to calcipotriene, sevoflurane, travoprost, calcipotriene, diflucortolone, methylprednisolone, delgocitinib, isoconazole, azelaic acid, calcipotriene (with or without betamethasone dipropionate), diflucortolone (with or without isoconazole), betamethasone valerate (with or without fusidic acid), fusidic acid (with or without hydrocortisone acetate), hydrocortisone acetate (with or without fusidic acid), fusidic acid (with or without betamethasone valerate), betamethasone dipropionate (with or without calcipotriene), and isoconazole (with or without diflucortolone).

[0095] An effective dose of calcitonin can be an amount from about 50 IU to about 150, e.g., about 50 IU, 55 IU, 60 IU, 65 IU, 70 IU, 75 IU, 80 IU, 85 IU, 90 IU, 95 IU, 100 IU, 105 IU, 110 IU, 115 IU, 120 IU, 125 IU, 130 IU, 135 IU, 140 IU, 145 IU, or 150 IU, or any dose therebetween.

[0096] An effective dose of the drug and / or active agent may range from about 0.1 ml to about 5 ml, for example, about 0.1 ml, 0.2 ml, 0.3 ml, 0.4 ml, 0.5 ml, 0.6 ml, 0.7 ml, 0.8 ml, 0.9 ml, 1 ml, 1.1 ml, 1.2 ml, 1.3 ml, 1.4 ml, 1.5 ml, 1.6 ml, 1.7 ml, 1.8 ml, 1.9 ml, 2 ml, 2.1 ml, 2.2 ml, 2.3 ml, 2.4 ml , 2.5 ml, 2.6 ml, 2.7 ml, 2.8 ml, 2.9 ml, 3 ml, 3.1 ml, 3.2 ml, 3.3 ml, 3.4 ml, 3.5 ml, 3.6 ml, 3.7 ml, 3.8 ml, 3.9 ml, 4 ml, 4.1 ml, 4.2 ml, 4.3 ml, 4.4 ml, 4.5 ml, 4.6 ml, 4.7 ml, 4.8 ml, 4.9 ml, or 5 ml, or any volume therebetween. The various drugs and their dosage ranges listed in Table 1 can be used in the above dosages. By way of example, the above various dosages would be applicable to diphtheria vaccine, Dukarol / ShanChol cholera vaccine, and heplisav-B vaccine.

[0097] An effective dose of a drug and / or active agent may be in an amount of about 50 U to about 6000 U, e.g., about 50 U, 100 U, 150 U, 200 U, 250 U, 300 U, 350 U, 400 U, 450 U, 500 U, 550 U, 600 U, 650 U, 700 U, 750 U, 800 U, 850 U, 900 U, 950 U, 1000 U, 1100 U, 1200 U, 1300 U, 1400 U, 1500 U, 1600 U, 1700 U, 1800 U, 1900 U, 2000 U, 2100 U, 2200 U, 2300 U, 2400 U, 2500 U, 2600 U, 2700 U, 2800 U, 2900 U, 3000 U, 3100 U, 3200 U, 3300 U, 3400 U, 3500 U, 3600 U, 3700 U, 3800 U, 3900 U, 4000 U, 4100 U, 4200 U, 4300 U, 4400 U, 4500 U, 4600 U, 4700 U, 4800 U, 4900 U, 5000 U, 5100 U, 5200 U, 5300 U, 5400 U, 5500 U, 5600 U, 5700 U, 5800 U, 5900 U, 6000 U, 610 The dose may be 0 U, 2700 U, 2800 U, 2900 U, 3000 U, 3100 U, 3200 U, 3300 U, 3400 U, 3500 U, 3600 U, 3700 U, 3800 U, 3900 U, 4000 U, 4100 U, 4200 U, 4300 U, 4400 U, 4500 U, 4600 U, 4700 U, 4800 U, 4900 U, 5000 U, 5100 U, 5200 U, 5300 U, 5400 U, 5500 U, 5600 U, 5700 U, 5800 U, 5900 U, or 6000 U, or any dose therebetween. The various drugs and their dose ranges listed in Table 1 can be used at the doses listed above. By way of example, the various doses above would be applicable to imiglucerase and insulin glargine.

[0098] An effective dose of nitric oxide can be maintained at about 20 ppm for about 14 days.

[0099] An effective dose of vasopressin is an amount of about 0.005 units / minute to about 0.15 units / minute, for example, about 0.005 units / minute, 0.006 units / minute, 0.007 units / minute, 0.008 units / minute, 0.009 units / minute, 0.01 units / minute, 0.015 units / minute, 0.02 units / minute, 0.025 units / minute, 0.03 units / minute, 0.035 units / minute, 0.04 units / minute, 0.045 units / minute, 0.05 units / minute, 0.055 units / minute, 0.06 units / minute, units / minute, 0.065 units / minute, 0.07 units / minute, 0.075 units / minute, 0.08 units / minute, 0.085 units / minute, 0.09 units / minute, 0.095 units / minute, 0.105 units / minute, 0.110 units / minute, 0.115 units / minute, 0.12 units / minute, 0.125 units / minute, 0.13 units / minute, 0.135 units / minute, 0.14 units / minute, 0.145 units / minute, or 0.15 units / minute, or any dose therebetween.

[0100] List of transdermal drugs Table 1 lists drugs that can be transdermally administered according to some embodiments. "% Solution" indicates the relative dose, which is the amount in the transdermal solution. Notably, when a row in the Drug column of Table 1 lists two or more drugs separated by a plus sign, such as "glecaprevir + pibrentasvir" and "abacavir + dolutegravir + lamivudine," these drugs in the series can be used alone or in combination. Thus, glecaprevir can be used alone or in combination with pibrentasvir. Furthermore, when two or more effective doses are separated by a comma (in a row in the "Effective Dose" column), the first effective dose refers to the first-listed drug, the second effective dose refers to the second-listed drug, etc., where the first-listed effective dose may be for the first-listed drug alone or in the listed combination, and / or the second-listed effective dose may be for the second-listed drug alone or in the listed combination. Also, for row values ​​in the "Solution % (Relative Dose)" column, when two or more Solution % values ​​are separated by a comma, the first Solution % refers to the first-listed agent, the second active Solution % refers to the second-listed agent, the first listed Solution % may be for the first-listed agent alone or in the specified combination, and / or the second listed Solution % may be for the second-listed agent alone or in the specified combination. Thus, in a row in Table 1 describing "glecaprevir + pibrentasvir," the effective dose of glecaprevir is 150-450 mg, and its Solution % is 15%-30%, and the effective dose of pibrentasvir is 60-180 mg, and its Solution % is 6%-18%. As noted above, these effective doses and Solution % values ​​may be for each agent alone or for two (or more) agents combined.

[0101]

Table 1-1

[0102]

Table 1-2

[0103]

Table 1-3

[0104]

Table 1-4

[0105]

Table 1-5

[0106]

Table 1-6

[0107]

Table 1-7

[0108]

Table 1-8

[0109]

Table 1-9

[0110]

Table 1-10

[0111]

Table 1-11

[0112]

Table 1-12

[0113]

Table 1-13

[0114]

Table 1-14

[0115]

Table 1-15

[0116]

Table 1-16

[0117]

Table 1-17

[0118]

Table 1-18

[0119]

Table 1-19

[0120]

Table 1-20

[0121]

Table 1-21

[0122]

Table 1-22

[0123]

Table 1-23

[0124]

Table 1-24

[0125]

Table 1-25

[0126]

Table 1-26

[0127]

Table 1-27

[0128]

Table 1-28

[0129]

Table 1-29

[0130] [Table 1-30]

[0131] [Table 1-31]

[0132] [Table 1-32]

[0133] [Table 1-33]

[0134] [Table 1-34]

[0135] [Table 1-35]

[0136] Transdermal delivery of water-insoluble molecules The various transdermal formulations of the present disclosure can successfully deliver (with relatively high bioavailability) a range of active agents that are completely insoluble, at least partially, or largely insoluble. This ability to deliver insoluble active agents contradicts the commonly held belief that active agents generally need to be solubilized for transdermal drug delivery.

[0137] There are many pharmacologically active drugs that are poorly soluble in aqueous media and / or acidic solutions, and these drugs have proven difficult to deliver to a subject transdermally or orally because they are not absorbed in the small intestine or cannot be solubilized in a transdermal formulation and penetrate the skin. It has generally been believed that pharmacologically active drugs must be fully or partially dissolved in an aqueous solution to be absorbed by a subject and achieve a reasonably high bioavailability in the subject. For orally administered drugs, it is believed that the drug must be fully or partially dissolved in an aqueous medium to dissolve in the stomach and be absorbed in the small intestine. For transdermally administered drugs, it is believed that the drug must be fully or mostly dissolved in the formulation to penetrate the skin and achieve high or relatively high bioavailability in the subject.

[0138] Such drugs that are poorly soluble in aqueous media are classified as Class 2 and Class 4 drugs in the Biopharmaceutical Classification System (BCS). The BCS is a scientific framework for predicting in vivo drug performance through in vitro measurements of solubility and permeability. Solubility is the degree to which a drug can dissolve in gastrointestinal (GI) fluids, and permeability is the degree to which a solubilized drug can cross the cell membranes lining the GI tract. According to the BCS, a drug has high solubility if less than 250 mL of aqueous medium (pH 1-7.5) dissolves the highest formulated dose of API. Class 2 and Class 4 drugs do not meet this solubility standard and therefore have low solubility. Class 2 drugs have high permeability, while Class 4 drugs have low permeability.

[0139] Various transdermal formulations of the present disclosure are effective in delivering insoluble Class 2 and Class 4 molecules with high or relatively high bioavailability in a subject. Example 32 illustrates the delivery of essentially insoluble Class 2 or Class 4 molecules with high or relatively high bioavailability in a subject by a transdermal formulation of the present disclosure, as well as several partially soluble molecules with improved bioavailability in a subject. In Example 32, the following molecules were included in a transdermal formulation containing one of hydrocortisone, sildenafil citrate, cyclosporine, eletriptan, neratinib maleate, or neratinib free base. In particular, the following molecules typically do not solubilize in aqueous media at >2% (hydrocortisone), >1% (sildenafil citrate, cyclosporine, or apixaban), >0.1% (neratinib maleate or neratinib free base), or >0.002% (eletriptan).

[0140] In addition to the above insoluble Class 2 and Class 4 molecules shown in Example 32, the pharmacologically active agents listed in the table below also achieve high or moderately high bioavailability when administered with the transdermal formulations of the present disclosure.

[0141] [Table 2-1]

[0142] [Table 2-2]

[0143] [Table 2-3]

[0144] [Table 2-4]

[0145] [Table 2-5]

[0146] In addition to the insoluble Class 2 and Class 4 drugs described above, kinase inhibitors are particularly known to be insoluble drugs that are difficult to deliver to a subject. Similarly, the following kinase inhibitors also achieve high or moderately high bioavailability when administered with the transdermal formulations of the present embodiments. The kinase inhibitors in the table below belong to the same class of drug and / or the same class in the Biopharmaceutical Classification System as one or more of the drugs listed in the table below.

[0147] [Table 3-1]

[0148] [Table 3-2]

[0149] [Table 3-3]

[0150] Without wishing to be bound by theory, the mechanism of action for transdermally delivering an insoluble Class 2 or Class 4 drug with high or moderately high bioavailability may include one or more components in the transdermal formulations of the present embodiments that partially degrade one or more layers of skin tissue (e.g., the core, stratum lucidum, stratum granulosum, stratum spinosum, stratum basale), allowing the drug to penetrate the dermis and enter the target tissue at high local concentrations, providing high or moderately high bioavailability in the target tissue. In other embodiments, the mechanism of action may include one or more components in the transdermal formulations of the present embodiments that partially degrade one or more layers of skin tissue (e.g., the core, stratum lucidum, stratum granulosum, stratum spinosum, stratum basale) to allow the drug to penetrate the dermis and enter the bloodstream, delivering the insoluble Class 2 or Class 4 drug systemically while bypassing the gastrointestinal tract.

[0151] Any of the transdermal formulations disclosed herein can provide systemic administration of an agent (eg, an agent disclosed in Table 1) via transdermal delivery of the agent.

[0152] wound healing Various transdermal formulations of the present disclosure are effective in promoting wound healing. Without being bound by theory, the mechanism of action may be reducing infection, reducing inflammation, and / or helping the body heal.

[0153] For example, without being bound by any particular theory, one possible mechanism by which the transdermal formulations of the present disclosure may aid in wound healing is by adjusting the microenvironment of the wound tissue to a physiologically normal pH, and / or by using a buffering agent to reduce the body's inflammatory response, and / or by delivering one or more agents listed in Table 1 that may have a wound healing effect. Various agents listed in Table 1 may directly promote wound healing. In some cases, the agent is an antibiotic or other anti-infective agent. In some cases, the agent is a steroid, retinoid, or other dermatological enhancer. In some cases, the agent is a buffering agent (e.g., NaHCO3). Non-limiting examples of antibiotics and other anti-infective agents include vancomycin, doxycycline, ampicillin, sulbactam, amoxicillin, azithromycin, clavulanate, piperacillin, tazobactam, amphotericin B, clarithromycin, daptomycin, doxycycline ER, ivermectin, lymecycline, neomycin, and tigecycline. These agents may be used alone or in any combination.

[0154] Inflammation is a natural response to physical trauma experienced by a subject and is an important aspect of the body's healing response. Aspects of inflammation that may be associated with wound healing include, among other symptoms, acidification of the wound tissue microenvironment in and around the wound tissue, overproduction of leukocytes, activation of macrophages, production of cytokines, activation of neutrophils, eosinophils, lymphocytes, plasma cells, bone marrow granulocytes and histiocytes, increased blood flow, swelling, stiffness, fatigue, fever, and pain, which may vary depending on the type and severity of the wound, including whether the wound is infected. Damaged tissue tends to trigger an inflammatory response in the body, and the normal wound healing process progresses from an inflammatory phase after injury to a tissue formation phase and then a tissue remodeling phase.

[0155] In some cases, a subject may partially or completely fail to progress from the inflammatory stage to the tissue formation stage, and the wound healing process may be halted or delayed, or may progress to the tissue formation or tissue remodeling stage without progressing beyond the inflammatory stage. The inflammation in the damaged tissue then becomes chronic and begins to damage the body's healthy tissue, including newly generated and newly remodeled tissue, potentially leading to DNA damage, tissue death, and scar tissue formation. In some embodiments, the wound tissue may partially or completely fail to progress from the inflammatory stage and continue to have an acidic tissue microenvironment within and around the wound tissue. In some embodiments, the acidic tissue microenvironment may be the result of tissue acidification due to ischemia. The generation and maintenance of an acidic tissue microenvironment may trigger an inflammatory process in the wound tissue on an ongoing basis and stimulate the production of inflammatory cytokines by the stroma or endothelium of the wound tissue. In a healthy regenerative and remodeling response, angiogenesis occurs and the injured tissue returns to a physiological pH (e.g., neutral or slightly basic, pH 7.4).

[0156] However, if an acidic tissue microenvironment or tissue acidification due to ischemia cannot be resolved during wound healing, the wound tissue will remain partially inflamed as it progresses through the tissue formation and tissue remodeling stages, and then the inflammatory processes that were initially beneficial in the wound healing process may begin to damage the new tissue. For example, the maintenance of an acidic tissue microenvironment continues to stimulate inflammatory processes such as the production of inflammatory cytokines, excessive production of leukocytes, activation of macrophages, activation of neutrophils, swelling, stiffness, and pain, among other possible inflammatory processes. Various inflammatory processes can damage newly formed tissue or slow the tissue formation and tissue remodeling processes. For example, overproduction of white blood cells, activation of macrophages, and activation of neutrophils may target and phagocytose newly formed cells and newly remodeled tissue, or ongoing swelling and stiffness of the wound may reduce blood flow and the influx of fresh oxygen and nutrients necessary for the injured tissue to heal, or ongoing stiffness and pain may prevent the subject from moving or exercising the tissue during the healing process, which is necessary to stimulate the influx of blood flow, fresh oxygen, and nutrients, and stimulate the formation of healthy tissue, which requires biomechanically normal levels of stress and strain on the tissue to promote proper gene transcription and proper tissue formation.

[0157] In some embodiments, the transdermal formulations of the present disclosure are effective in promoting wound healing by adjusting the acidic tissue microenvironment to a neutral pH, a slightly basic pH, a basic pH, or a physiological pH (e.g., about 7.4) using a buffering agent. In some embodiments, adjusting the acidic tissue microenvironment to a higher pH using a buffering agent can reduce or eliminate one or more inflammatory processes, which can aid in wound healing. Possible mechanisms by which buffering agents aid in wound healing by reducing inflammation may include inactivating macrophages and / or neutrophils, reducing white blood cell production, reducing swelling, stiffness, and pain, and increasing blood flow to the wound tissue.

[0158] In some embodiments, the transdermal formulations of the present disclosure are effective in promoting wound healing by delivering an anti-infective agent to prevent the wound from becoming infected. In some embodiments, the anti-infective agent is an antibiotic, as described above. Possible mechanisms by which anti-infective agents aid in wound healing include preventing uncontrolled bacterial growth in wound tissue, reducing inflammation associated with infection, and diverting the body's resources from fighting infection to cell division, tissue production, and tissue remodeling.

[0159] In some embodiments, the transdermal formulations of the present disclosure for wound healing include both an anti-infective agent, another agent, and / or a buffering agent. In some embodiments, the transdermal formulations of the present disclosure for wound healing include both an antibiotic and a buffering agent. In some embodiments, the transdermal formulations of the present disclosure include one of the agents listed in Table 1 and a buffering agent, e.g., NaHCO3. In some embodiments, the transdermal formulations of the present disclosure for wound healing include both an antibiotic, another agent from Table 1, and a buffering agent. Possible mechanisms for the combination of a buffering agent, an antibiotic, and another agent from Table 1 to aid in wound healing include those described above and a synergistic effect resulting from the combination of an antibiotic and a buffering agent. In some embodiments, the combination of a buffer, an antibiotic, and / or another agent from Table 1 in a transdermal formulation of the present disclosure provides a greater wound healing effect (e.g., a shorter time to wound closure and restoration of healthy functional tissue) than either the antibiotic or buffer individually or compared to healing an untreated wound, in amounts that are 10, 20, 30, 40, 50, 60, or 75% greater.

[0160] In some embodiments, the transdermal formulations of the present disclosure are effective in promoting wound healing by delivering skin repair agents to wound tissue, such as steroids or retinoids to skin tissue, which, in some embodiments, can aid the wound healing process by stimulating collagen production in newly formed skin tissue without causing the overproduction of scar tissue.

[0161] In some embodiments, the wound assisted by the transdermal formulation of the present disclosure is a diabetic foot ulcer. Diabetic foot ulcers are open sores or wounds that occur in approximately 15% of diabetic patients, usually on the soles of the feet. Of those who develop a foot ulcer, 6% will be hospitalized due to infection or ulcer-related complications. In some embodiments, the use of a transdermal formulation described herein containing a buffer, an antibiotic, both a buffer and an antibiotic, or other combination of agents listed in Table 1 may aid in the healing of a diabetic foot ulcer, shorten the time to closure of an open diabetic foot ulcer, or shorten the time to the formation of healthy or physiologically functioning tissue. In some embodiments, the use of a transdermal formulation described herein containing a buffer, an antibiotic, and / or another agent listed in Table 1 treats diabetic foot ulcers. In some embodiments, the use of a transdermal formulation described herein containing a buffer, an antibiotic, and / or another agent listed in Table 1 prevents diabetic foot ulcers. In some embodiments, use of a transdermal formulation described herein that includes a buffer, an antibiotic, and / or another agent listed in Table 1 reduces the likelihood of a diabetic foot ulcer by 25, 50, 75, 85, 90, or 95%. In some embodiments, use of a transdermal formulation described herein that includes a buffer, an antibiotic, and / or another agent listed in Table 1 reduces the likelihood of a diabetic foot ulcer becoming infected by 25, 50, 75, 85, 90, or 95%. In some embodiments, use of a transdermal formulation described herein that includes a buffer, an antibiotic, and / or another agent listed in Table 1 reduces the likelihood of hospitalization due to an infected diabetic foot ulcer by 25, 50, 75, 85, 90, or 95%.

[0162] Cancer and Tumors Cancer is generally defined as a group of diseases involving abnormal cell growth that can invade or spread to other parts of the body. Traditional cancer treatments are aimed at removing cancerous tissue and preventing metastasis. Such treatment options include surgery, chemotherapy, radiation therapy, hormone therapy, targeted therapy, and palliative care. Treatment is usually based on the type, location, and grade of the cancer, as well as the patient's health and preferences.

[0163] A promising area for therapeutic development includes targeted therapy using small molecules. Many embodiments provided herein are directed to various methods of treating cancer and / or tumors. An exemplary embodiment of a method of treating cancer in a patient according to the present invention comprises topically and / or transdermally administering to a patient in need thereof an effective amount of a transdermal delivery formulation comprising one or more small molecules, wherein the administration is effective to inhibit or prevent the growth of a tumor or tumor cells.

[0164] Another embodiment is directed to a method for preventing tumor metastasis, comprising topically and / or transdermally administering to a patient in need thereof an effective amount of a transdermal delivery formulation comprising one or more small molecules, which administration is effective to inhibit or prevent metastasis of tumor or cancer cells.

[0165] Another embodiment is directed to a method for preventing intravasation of tumor cells, comprising topically and / or transdermally administering to a patient in need thereof an effective amount of a transdermal delivery formulation comprising one or more small molecules, which administration is effective to inhibit or prevent intravasation of tumor cells.

[0166] Another embodiment is directed to a method of treating cancer, comprising: i) selecting a therapeutic agent (e.g., a small molecule kinase inhibitor) described herein, formulating the therapeutic agent in a transdermal delivery formulation comprising one or more small molecules, and iii) administering the formulation topically and / or transdermally in an amount effective to inhibit or prevent tumor or tumor cell growth.

[0167] Another embodiment is directed to extending the duration of or maintaining remission of a cancer or tumor, and comprises topically and / or transdermally administering to a patient in need thereof an effective amount of a transdermal delivery formulation comprising one or more small molecules, which administration is effective to extend the duration of or maintain remission of a cancer or tumor.

[0168] In another embodiment, a method of treating cancer in a patient comprises topically and / or transdermally administering to a patient in need thereof an effective amount of a transdermal delivery formulation comprising one or more small molecules, wherein the administration is effective to alter the activity of one or more cell signaling proteins in the patient, the altered protein activity inhibiting the growth of solid tumor or cancer cells.

[0169] In other embodiments, methods for targeting serine / threonine / tyrosine kinases in a patient are provided. These embodiments generally involve topically and / or transdermally administering to a patient in need thereof an effective amount of a transdermal delivery formulation comprising one or more small molecules, which administration is effective to inhibit important cancer targets, such as serine / threonine / tyrosine kinases, in the patient. In other embodiments, methods are provided for inhibiting or preventing tumor metastasis in a patient.

[0170] In other embodiments, methods are provided for inhibiting or preventing tumor cell intravasation in a patient. These embodiments generally involve topically and / or transdermally administering to a patient in need thereof an effective amount of a transdermal delivery formulation comprising one or more small molecules, which administration is effective to inhibit or prevent tumor cell intravasation.

[0171] The formulations provided herein are used in methods of treating a number of cancers, including, but not limited to, breast cancer, prostate cancer, pancreatic cancer, lung cancer, bladder cancer, skin cancer, colorectal cancer, kidney cancer, liver cancer, and thyroid cancer.

[0172] The formulations provided herein are also used in methods of treating cancer or tumors, including adrenocortical carcinoma, basal cell carcinoma, bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, retinoblastoma, gastric (stomach) cancer, gastrointestinal tumors, glioma, head and neck cancer, hepatocellular (liver) cancer, pancreatic islet cell tumor (endocrine pancreatic), renal (renal cell) cancer, laryngeal cancer, non-small cell lung cancer, small cell lung cancer, medulloblastoma, melanoma, pancreatic cancer, prostate cancer, kidney cancer, rectal cancer, and thyroid cancer.

[0173] Another example of a biological therapeutic agent used in the treatment of certain cancers in certain embodiments is an angiogenesis inhibitor. Therefore, the formulations of the present invention can be combined with an angiogenesis inhibitor to enhance anti-tumor effects. Angiogenesis is the growth of new blood vessels. This process enables tumor growth and metastasis. Inhibiting angiogenesis helps prevent metastasis and stop the spread of tumor cells. Angiogenesis inhibitors include, but are not limited to, angiostatin, endostatin, thrombospondin, platelet factor 4, cartilage-derived inhibitor (CDI), retinoids, interleukin-12, tissue inhibitor of metalloproteinases 1, 2, and 3 (TIMP-1, TIMP-2, TIMP-3), and proteins that block the angiogenic signaling cascade, such as anti-VEGF (vascular endothelial growth factor) and IFN-α. To combat various types of cancer, e.g., solid tumor cancers such as lung cancer and breast cancer, angiogenesis inhibitors can be administered or co-administered in combination with tumor-specific constructs, including, for example, antigen-binding constructs capable of mediating ADCC and / or complement binding or chemotherapeutic complex antigen binding of the present invention. Other examples of biological therapeutic agents include inhibitors of E-cadherin and epidermal growth factor receptor (EGFR). Known inhibitors include erlotinib, anti-integrin drugs (cilengitide), cariporide, eniporide, and amiloride.

[0174] In another aspect, the formulations of the invention can be administered in combination or co-administered with disease-modifying antirheumatic drugs (DMAR drugs) for the treatment of rheumatoid arthritis, psoriasis, ulcerative colitis, systemic lupus erythematosus (SLE), Crohn's disease, ankylosing spondylitis, and various inflammatory disease processes. In such treatments, the constructs of the invention, e.g., antigen-binding constructs, are commonly administered in combination with compounds such as azathioprine, cyclosporine, gold, hydroxychloroquine, methotrexate, penicaramine, sulfasalazine, and the like.

[0175] In another embodiment, the formulations provided herein can be used in conjunction with palliative (non-curative) surgery to surgically remove tumors. In this embodiment, one or more formulations of the present invention can be administered before or after surgical removal of the tumor to kill cancer cells not removed during surgery, thereby reducing the likelihood of metastasis and recurrence. Other diseases, symptoms, and disorders described herein can be treated using the formulations and methods provided herein.

[0176] Another example of a biological therapeutic agent used in the treatment of certain cancers in certain embodiments is an angiogenesis inhibitor. Therefore, the formulations of the present invention can be combined with an angiogenesis inhibitor to enhance anti-tumor effects. Angiogenesis is the growth of new blood vessels. This process enables tumor growth and metastasis. Inhibiting angiogenesis helps prevent metastasis and stop the spread of tumor cells. Angiogenesis inhibitors include, but are not limited to, angiostatin, endostatin, thrombospondin, platelet factor 4, cartilage-derived inhibitor (CDI), retinoids, interleukin-12, tissue inhibitor of metalloproteinases 1, 2, and 3 (TIMP-1, TIMP-2, TIMP-3), and proteins that block the angiogenic signaling cascade, such as anti-VEGF (vascular endothelial growth factor) and IFN-α. To combat various types of cancer, e.g., solid tumor cancers such as lung cancer and breast cancer, angiogenesis inhibitors can be administered or co-administered in combination with tumor-specific constructs, including, for example, antigen-binding constructs capable of mediating ADCC and / or complement binding or chemotherapeutic complex antigen binding of the present invention. Other examples of biological therapeutic agents include inhibitors of E-cadherin and epidermal growth factor receptor (EGFR). Known inhibitors include erlotinib, anti-integrin drugs (cilengitide), cariporide, eniporide, and amiloride.

[0177] In another aspect, the formulations of the invention can be administered in combination or co-administered with disease-modifying antirheumatic drugs (DMAR drugs) for the treatment of rheumatoid arthritis, psoriasis, ulcerative colitis, systemic lupus erythematosus (SLE), Crohn's disease, ankylosing spondylitis, and various inflammatory disease processes. In such treatments, the constructs of the invention, e.g., antigen-binding constructs, are typically administered in combination with compounds such as azathioprine, cyclosporine, gold, hydroxychloroquine, methotrexate, penicaramine, sulfasalazine, and the like.

[0178] In another embodiment, the formulations provided herein can be used in conjunction with palliative (non-curative) surgery to surgically remove tumors. In this embodiment, one or more formulations of the present invention can be administered before or after surgical removal of the tumor to kill cancer cells not removed during surgery, thereby reducing the likelihood of metastasis and recurrence. Other diseases, symptoms, and disorders described herein can be treated using the formulations and methods provided herein.

[0179] The formulations provided herein are also used in methods of treating cancer or tumors, including, but not limited to, adrenocortical carcinoma, basal cell carcinoma, bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, retinoblastoma, gastric (stomach) cancer, gastrointestinal tumors, glioma, head and neck cancer, hepatocellular (liver) cancer, pancreatic islet cell tumor (endocrine pancreatic), renal (renal cell) cancer, laryngeal cancer, non-small cell lung cancer, small cell lung cancer, medulloblastoma, melanoma, pancreatic cancer, prostate cancer, kidney cancer, rectal cancer, and thyroid cancer.

[0180] Although preferred embodiments of the methods provided herein are typically directed to a particular cancer, solid tumor, or group thereof, a more complete, but still non-limiting, list of suitable cancers and tumors that may be tested for efficacy according to the embodiments provided herein includes: lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, AIDS-related cancer, Kaposi's sarcoma (soft tissue sarcoma), AIDS-related lymphoma (lymphoma), primary CNS lymphoma (lymphoma), anal cancer, astrocytoma, atypical teratoma / rhabdoid tumor, childhood, central nervous system (brain tumor), basal cell carcinoma, cholangiocarcinoma, bladder cancer. Pediatric bladder cancer, bone cancer (including Ewing's sarcoma, osteosarcoma, and malignant fibrous histiocytoma), brain tumor, breast cancer, pediatric breast cancer, bronchial tumor, Burkitt's lymphoma (non-Hodgkin's lymphoma), carcinoid tumor (gastrointestinal), pediatric carcinoid tumor, cardiac (heart) tumor, central nervous system tumor, atypical teratoma / rhabdoid tumor, childhood (brain tumor), embryonal tumor, childhood (brain tumor), germ cell tumor (pediatric brain tumor) tumors), primary CNS lymphoma, cervical cancer, childhood cervical cancer, bile duct cancer, chordoma (childhood), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative neoplasm, colorectal cancer, childhood colorectal cancer, craniopharyngioma (childhood brain tumor), cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), embryonal tumors, (childhood brain CNS cancer), endometrial cancer (uterine cancer), ependymoma, esophageal cancer, childhood esophageal cancer, esthesioneuroblastoma (head Neck cancer), Ewing's sarcoma (bone cancer), extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, pediatric intraocular melanoma, intraocular melanoma, retinoblastoma, fallopian tube cancer, osteofibrous histiocytoma (malignant and osteosarcoma), gallbladder cancer, gastric (stomach) cancer, pediatric gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (gist) (soft tissue sarcoma), pediatric gastrointestinal stromal tumor, reproductive Cell tumors, pediatric central nervous system germ cell tumors, pediatric extracranial germ cell tumors, extragonadal germ cell tumors, ovarian germ cell tumors, testicular cancer, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, heart tumors, hepatocellular (liver) cancer, histiocytosis (Langerhans cell carcinoma), Hodgkin's lymphoma, hypopharyngeal carcinoma (head and neck cancer), intraocular melanoma, pediatric intraocular melanoma, islet cell tumors (pancreatic neuroendocrine tumors), Kaposi's sarcoma (soft tissue sarcoma), kidney (renal cell) cancer,Langerhans cell histiocytosis, laryngeal cancer (head and neck cancer), leukemia, lip and oral cancer (head and neck cancer), liver cancer, lung cancer (non-small cell and small cell), childhood lung cancer, lymphoma, male breast cancer, malignant fibrous histiocytoma and osteosarcoma of bone, melanoma, childhood melanoma, melanoma (intraocular), childhood intraocular melanoma, Merkel cell carcinoma (skin cancer), mesothelioma, childhood mesothelioma, metastatic cancer, occult primary metastatic squamous cell cervical cancer (head and neck cancer), midline carcinoma with nut gene alterations, oral cancer (head and neck cancer), multiple endocrine neoplasia syndrome - rare childhood cancer, multiple myeloma / Plasma cell neoplasms, mycosis fungoides (lymphoma), myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, myeloid leukemia, chronic (CML), myeloid leukemia (acute AML), myeloproliferative neoplasms, nasal cavity and paranasal sinus cancer (head and neck cancer), nasopharyngeal carcinoma (head and neck cancer), neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer (lip cancer, oral cavity cancer, oropharyngeal cancer), osteosarcoma and malignant fibrous histiocytoma of bone, ovarian cancer, pediatric ovarian cancer, pancreatic cancer, pediatric pancreatic cancer, pancreatic neuroendocrine tumors (pancreatic islet cell tumors), papillomatosis, paraganglioma, pediatric paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pediatric pheochromocytoma, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, pregnancy and breast cancer, primary central nervous system (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, recurrent cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, childhood rhabdomyosarcoma (soft tissue sarcoma), childhood vascular tumor (soft tissue sarcoma), Ewing's sarcoma (bone cancer), Kaposi's sarcoma (soft tissue sarcoma), osteosarcoma (bone cancer), soft tissue sarcoma, uterine sarcoma, Sézary syndrome (lymphoma) ), skin cancer, pediatric skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, cutaneous squamous cell carcinoma, occult primary squamous cell cervical cancer, gastric cancer, pediatric stomach, T-cell lymphoma, testicular cancer, pediatric testicular cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, renal pelvis and ureter (transitional cell carcinoma of the kidney), ureter and renal pelvis (transitional cell carcinoma of the kidney, renal cell carcinoma), urethral cancer, uterine cancer (endometrium), uterine sarcoma, vaginal cancer, pediatric vaginal cancer, vascular tumors (soft tissue sarcoma), vulvar cancer, Wilms' tumor (and other pediatric kidney tumors).

[0181] Bortezomib and carfilzomib target the proteosome; batimastat, neovastat, prinomastat, levimastat, ganetespib, and NVP-AUY922 target MMPs and HSPs; and obatoclax and navitoclax target apoptosis. The molecular targets of the remaining drugs are tyrosine and serine / threonine kinases.

[0182] Although preferred embodiments of the methods provided herein are typically directed to a particular cancer, solid tumor, or group thereof, a more complete, but still non-limiting, list of suitable cancers and tumors that may be tested for efficacy according to the embodiments provided herein includes: lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, AIDS-related cancer, Kaposi's sarcoma (soft tissue sarcoma), AIDS-related lymphoma (lymphoma), primary CNS lymphoma (lymphoma), anal cancer, astrocytoma, atypical teratoma / rhabdoid tumor, childhood, central nervous system (brain tumor), basal cell carcinoma, cholangiocarcinoma, bladder cancer. Pediatric bladder cancer, bone cancer (including Ewing's sarcoma, osteosarcoma, and malignant fibrous histiocytoma), brain tumor, breast cancer, pediatric breast cancer, bronchial tumor, Burkitt's lymphoma (non-Hodgkin's lymphoma), carcinoid tumor (gastrointestinal), pediatric carcinoid tumor, cardiac (heart) tumor, central nervous system tumor, atypical teratoma / rhabdoid tumor, childhood (brain tumor), embryonal tumor, childhood (brain tumor), germ cell tumor (pediatric brain tumor) tumors), primary CNS lymphoma, cervical cancer, childhood cervical cancer, bile duct cancer, chordoma (childhood), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative neoplasm, colorectal cancer, childhood colorectal cancer, craniopharyngioma (childhood brain tumor), cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), embryonal tumors, (childhood brain CNS cancer), endometrial cancer (uterine cancer), ependymoma, esophageal cancer, childhood esophageal cancer, esthesioneuroblastoma (head Neck cancer), Ewing's sarcoma (bone cancer), extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, pediatric intraocular melanoma, intraocular melanoma, retinoblastoma, fallopian tube cancer, osteofibrous histiocytoma (malignant and osteosarcoma), gallbladder cancer, gastric (stomach) cancer, pediatric gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (gist) (soft tissue sarcoma), pediatric gastrointestinal stromal tumor, reproductive Cell tumors, pediatric central nervous system germ cell tumors, pediatric extracranial germ cell tumors, extragonadal germ cell tumors, ovarian germ cell tumors, testicular cancer, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, heart tumors, hepatocellular (liver) cancer, histiocytosis (Langerhans cell carcinoma), Hodgkin's lymphoma, hypopharyngeal carcinoma (head and neck cancer), intraocular melanoma, pediatric intraocular melanoma, islet cell tumors (pancreatic neuroendocrine tumors), Kaposi's sarcoma (soft tissue sarcoma), kidney (renal cell) cancer,Langerhans cell histiocytosis, laryngeal cancer (head and neck cancer), leukemia, lip and oral cancer (head and neck cancer), liver cancer, lung cancer (non-small cell and small cell), childhood lung cancer, lymphoma, male breast cancer, malignant fibrous histiocytoma and osteosarcoma of bone, melanoma, childhood melanoma, melanoma (intraocular), childhood intraocular melanoma, Merkel cell carcinoma (skin cancer), mesothelioma, childhood mesothelioma, metastatic cancer, occult primary metastatic squamous cell cervical cancer (head and neck cancer), midline carcinoma with nut gene alterations, oral cancer (head and neck cancer), multiple endocrine neoplasia syndrome - rare childhood cancer, multiple myeloma / Plasma cell neoplasms, mycosis fungoides (lymphoma), myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, myeloid leukemia, chronic (CML), myeloid leukemia (acute AML), myeloproliferative neoplasms, nasal cavity and paranasal sinus cancer (head and neck cancer), nasopharyngeal carcinoma (head and neck cancer), neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer (lip cancer, oral cavity cancer, oropharyngeal cancer), osteosarcoma and malignant fibrous histiocytoma of bone, ovarian cancer, pediatric ovarian cancer, pancreatic cancer, pediatric pancreatic cancer, pancreatic neuroendocrine tumors (pancreatic islet cell tumors), papillomatosis, paraganglioma, pediatric paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pediatric pheochromocytoma, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, pregnancy and breast cancer, primary central nervous system (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, recurrent cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, childhood rhabdomyosarcoma (soft tissue sarcoma), childhood vascular tumor (soft tissue sarcoma), Ewing's sarcoma (bone cancer), Kaposi's sarcoma (soft tissue sarcoma), osteosarcoma (bone cancer), soft tissue sarcoma, uterine sarcoma, Sézary syndrome (lymphoma) ), skin cancer, pediatric skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, cutaneous squamous cell carcinoma, occult primary squamous cell cervical cancer, gastric cancer, pediatric stomach, T-cell lymphoma, testicular cancer, pediatric testicular cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, renal pelvis and ureter (transitional cell carcinoma of the kidney), ureter and renal pelvis (transitional cell carcinoma of the kidney, renal cell carcinoma), urethral cancer, uterine cancer (endometrium), uterine sarcoma, vaginal cancer, pediatric vaginal cancer, vascular tumors (soft tissue sarcoma), vulvar cancer, Wilms' tumor (and other pediatric kidney tumors).

[0183] Alternatively, the formulations and / or compounds provided herein are co-administered or administered to an animal, subject, or patient in combination with one or more chemotherapeutic compounds, such as alkylating agents, antibodies and related agents with anti-tumor properties, anthracyclines, antimetabolites, anti-tumor antibiotics, aromatase inhibitors, cytoskeletal disrupting agents (e.g., taxanes), epothilones, histone deacetylase inhibitors, kinase inhibitors, nucleoside analogs, topoisomerase inhibitors, retinoids, vinca alkaloids and derivatives. The administration or co-administration of one or more formulations or compositions of the invention and one or more chemotherapeutic agents can be used to treat tumors or cancer in an animal, subject, or patient.

[0184] By way of example, alkylating agents can be administered in combination with, or co-administered with, or as part of, the formulations provided herein. Examples of alkylating agents that can be co-administered include mechlorethamine, chlorambucil, ifosfamide, melphalan, busulfan, carmustine, lomustine, procarbazine, dacardazine, cisplatin, carboplatin, mitomycin C, cyclophosphamide, ifosfamide, thiotepa, and dacarbazine, and analogs thereof. See, for example, U.S. Pat. No. 3,046,301, which describes the synthesis of chlorambucil, U.S. Pat. No. 3,732,340, which describes the synthesis of ifosfamide, U.S. Pat. No. 3,018,302 regarding the synthesis of cyclophosphamide, U.S. Pat. No. 3,032,584, which describes the synthesis of melphalan, and Braunwald et al., "Harrison's Principles of Internal Medicine," 15th Ed., McGraw-Hill, New York, NY, pp. 536-544 (2001), for clinical aspects of cyclophosphamide, chlorambucil, melphalan, ifosfamide, procarbazine, hexamethylmelamine, cisplatin, and carboplatin. Examples of nucleoside analogs include, but are not limited to, fludarabine pentostatin, methotrexate, fluorouracil, fluorodeoxyuridine, CB3717, azacitidine, cytarabine, floxuridine, mercaptopurine, 6-thioguanine, cladribine, and analogs thereof.

[0185] In another embodiment, the formulations provided herein are administered together with chemosensitizing agents, such as those described in U.S. Patent No. 3,923,785, which describes the synthesis of pentostatin; U.S. Patent No. 4,080,325, which describes the synthesis of methotrexate; U.S. Patent No. 2,802,005, which describes the synthesis of fluorouracil; and Braunwald et al., "Harrison's Principles of Internal Medicine," 15th Ed., McGraw-Hill, New York, NY, pp. 536-544 (2001), for the clinical aspects of methotrexate, 5-fluorouracil, cytosine arabinoside, 6-mercaptopurine, 6-thioguanine, and fludarabine phosphate. The preparation and dosing schedules of such chemotherapeutic agents can be used according to the manufacturer's instructions or can be determined empirically by those skilled in the art. Preparation and dosing schedules for such chemotherapeutic agents are also described in Chemotherapy Service Ed., MCPerry, Williams & Wilkins, Baltimore, Md. (1992), incorporated herein by reference.

[0186] In another aspect, the formulations provided herein can be administered in combination or co-administered with diterpenoid compounds, including, but not limited to, paclitaxel, docetaxel, cabazitaxel, and the like.

[0187] In another embodiment, the formulations provided herein can be administered or co-administered in combination with a compound that inhibits topoisomerase II or a compound that interacts with intracellular nucleic acids. Such compounds include, for example, doxorubicin, epirubicin, etoposide, teniposide, mitoxantrone, and their analogs. In one example, this combination is used in combination with high-dose chemotherapy and autologous stem cell support (HDC-ASCT) to reduce tumor cell contamination of peripheral blood progenitor cells (PBSCs). See U.S. Patent No. 6,586,428 to Geroni et al.

[0188] In another embodiment, the formulations provided herein can be administered in combination or simultaneously with immunotherapeutic agents. Immunotherapy has become a promising approach for treating cancer. Kruger C., et al., Immune-based therapies in cancer, Histol. Histopathol. 2007, v22, 687-696. The types of immunotherapies used to treat cancer can be classified as active, passive, or hybrid (active and passive). Active immunotherapy directs the immune system to attack tumor cells by targeting TAAs. Passive immunotherapy enhances existing anti-tumor responses and includes the use of cytokines, checkpoint inhibitors, monoclonal antibodies, lymphocytes, and cytokines. Suitable immunotherapeutic agents or immunotherapies can be biologic agents or biologically active agents, such as antibodies or modified antibodies, or cell-based therapies, such as chimeric antigen receptor therapy (CAR-T). It is recognized that the categorization and classification of agents, such as biologic agents, immunotherapeutics, cell-based therapies, and biotherapeutics, may overlap. Examples of approved antibody immunotherapeutics include alemtuzumab, atezolizumab, avelumab, ipilimumab, durvalumab, nivolumab, ofatumumab, rituximab, and trastuzumab. These and others are suitable for use in certain embodiments provided herein.

[0189] In another aspect, the formulations can be administered in combination or simultaneously with biotherapeutics and other therapeutic agents. For example, virurisin (Lorus Therapeutics) is believed to stimulate the release of tumor necrosis factor TNF-α by tumor cells in vitro and stimulate macrophage cell activation. It can be used in combination with one or more formulations of the present invention to increase apoptosis in cancer cells and treat various types of cancer, including pancreatic cancer, malignant melanoma, Kaposi's sarcoma (KS), lung cancer, breast cancer, uterine cancer, ovarian cancer, and cervical cancer. Another example is CpG 7909 (Coley Pharmaceutical Group), which is believed to activate NK cells and monocytes and enhance ADCC. Cytokines, such as interferons and interleukins (e.g., EPO, thrombopoietin), are biotherapeutics useful in certain embodiments in combination with one or more formulations of the present invention. Other types of suitable biotherapeutics include protein-based agents, such as RNA and enzymes. These and other therapeutic agents can also be used in combination with the formulations provided herein.

[0190] Table 2A lists several small molecule inhibitors for cancer treatment, along with their specific targets and cancer types. According to some embodiments, the agents are administered transdermally. Table 1 lists other anti-cancer molecules and, in some cases, effective doses and percentages of transdermal formulations.

[0191] [Table 4-1]

[0192] [Table 4-2]

[0193] [Table 4-3]

[0194] [Table 4-4]

[0195] Table 2B below lists possible indications for some of the drugs listed in Table 1.

[0196] [Table 5]

[0197] Another aspect of the present disclosure is a method for treating or alleviating a symptom of a disease or disorder, comprising administering to a subject in need thereof any of the transdermal formulations disclosed herein and administering to the subject in need thereof a composition comprising one or more agents selected from Table 1.

[0198] In embodiments of this method, the transdermal formulation is administered before, simultaneously with, or after administration of the composition.

[0199] In some embodiments of this method, the amount of one or more agents is an effective dose of an agent listed in Table 1.

[0200] In various embodiments of this method, the composition is administered by a standard route of administration, for example, oral, topical, enteral, parenteral, intravenous injection or infusion, intraperitoneal, intramuscular, or subcutaneous injection. The composition can be a liquid, suspension, gel, geltab, semisolid, tablet, sachet, lozenge, pill, or capsule.

[0201] In an embodiment of this method, the formulation comprises: (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine; (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide; 2-fluoro-N-methyl-4-[7-quinolin-6-yl-methyl)-imidazo[1,2-B][1,2,4]triazin-2yl]benzamide; 4 -(3-Amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide;4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile;Abacavir;Abiraterone acetate;Abiratone acetate;Abobotulinumtoxin A;Acalabrutinib;Acarbose;Acetaminophen;Acetazolamide;Acetylsalicylic acid;Acitretin;Acitretin Clovir; Adalimumab; Adapalene; Adapalene; Afoxolaner; Agalsidase beta; Albendazole; Alectinib; Alectinib; Alendronate sodium; Alglucosidase alfa; Alitretinoin; Alogliptin; Alpelisib; Aluminum hydroxide; Ambrisentan; Amiodarone; Amitriptyline; Amlodipine; Amlodipine; Amlodipine besylate; Amlodopine besylate; Amorolfine hydrochloride; Amoxicillin; Amphotericin B; Amphotericin B liposomal; Ampicillin; Amprenavir; Antithrombotic Anti-inflammatory factors, Fc fusion proteins; apalutamide; apatinib; apixaban; apremilast; aprepitant; aripiprazole; artemether; aspirin; atazanavir; atenolol; atomoxetine; atorvastatin; avapritinib; axitinib (Inritin); azacitidine; azathioprine; azelaic acid; azilsartan medoxomil; azithromycin; baclofen; baricitinib; basiliximab; batimastat (BB-94); becaplermin; belmosudil; bendamustine; benzoyl peroxide;Benzoyl peroxide; betamethasone dipropionate; betamethasone valerate; bexarotene; bictegravir; bimatoprost; binimetinib (Mektobi); bortezomib; bortezomib (Velcade); bosentan; bosutinib (Bosurif); botulinum toxin A; branched-chain amino acids; brexpiprazole; brimonidine; brimonidine tartrate; brodalumab; buproprion; cabazitaxel; cabozantinib; cabozantinib (Cometriz); Calcifediol; Calcipotriene; Calcipotriene; Calcipotriol; Calcitonin; Calcitriol; Calcium carbonate; Canagliflozin; Canakinumab; Capecitabine; Capmatinib; Capsaicin; Carbamazepine; Carbidopa; Carfilzomib; Carfilzomib (Cyprolis); Cariprazine; Carvedilol; CD-12681; CEE-321; Cefazolin; Cefepime; Cefoperazone; Cefotaxime sodium Celecoxib; Celecoxib; Cemiplimab; Ceritinib; Chlorothiazide; Chlorpromazine; Chlorthalidone; Cinacalcet; Ciprofloxacin; Cisapride; Citalopram; Citric acid; Clarithromycin; Clavulanate; Clindamycin phosphate; Clobazam; Clobetasol propionate; Clofazimine; Clomiphene; Clonidine; Clopidogrel; Clopidogrel bisulfate; Cobicistat; Cobicistat; Colcosine ; colistin; corticotropin; crisaborole; crizanlizumab; crizotinib (xalkori); cyclobenzaprine; cyclosporine; dabigatran etexilate; dabrafenib; dabrafenib; dabrafenib; dacomitinib (visimpro); dalbavancin; dalfopristin; danazol; dapagliflozin; dapsone; daptomycin; darunavir; dasatinib; decitabine; defatted peanuts (Arachis hypogaea) powder; deferasirox; delgocitinib; deoxycholic acid; desipramine; desonide; dexlansoprazole; dexmethylphenidate; dextroamphetamine / amphetamine salts; diclofenac; diclofenac sodium; diflucortolone; diflucortolone; difinisal; digoxin; diloxanide; dimethyl fumarate; diphenhydramine hydrochloride; diphtheria vaccine;Docetaxel; Dolutegravir; Dolutegravir; Donepezil; Doxercalciferol; Doxycycline; Doxycycline ER; Doxycycline hyclate (B); Doxycycline monohydrate (A); Dronabinol; Dronedarone; Drospirenone; Dukoral / ShanChol cholera vaccine; Duloxetine; Dupilumab; Durvalumab; Dutasteride; Duvelisib; Ecallantide; Edoxaban; Efavirenz; Efavirenz; Elafibranol; Elagolix sodium; Elbasvir; Eletriptan; El Thrombopag; Elvitegravir; Empagliflozin; Emtricitabine; Entricitabine; Entricitabine; Entricitabine; Encorafenib (Braftovi); Enfuviritide; Enoxaparin sodium; Entecavir; Entrectinib; Enzalutamide; Epinephrine; Erdafitinib; Erenumab; Eribulin; Erlotinib; Erlotinib hydrochloride (Tarceva); Ertapenem; Erythromycin; Escitalopram; Esketamine (Ketamine); Esome Prazol; Esopremazole; Estradiol; Estrogen-conjugated; Etanercept; Ethinyl estradiol; Ethinyl estradiol; Ethinyl estradiol; Etonogestrel; Etonogestrel; Etravirine; Etretinate; Everolimus; Everolimus (Afinitor); Everolimus (Votuvia, Zotres / Certican); Ezetimibe; Ezetimibe; Ezetimibe; Famotidine; Fasinumab; Febuxostat; Fedratinib; Fenofibrate; Ferric carboxymaltose; Fexofenadine Hydrochloride; Filgotinib; Filgrastim; Fingolimod; Fluocinolone acetonide; Fluocinolone acetonide; Fluoxetine; Flurbiprofen; Folic acid; Forskolin; Fostamatinib; Fulvestrant; Furosemide; Fusidic acid; Fusidic acid; Gabapentin; Ganetespib; Gefitinib (Iressa); Gilteritinib; Glasdedib (Daurismo) or Glasdedib maleate; Glecaprevir; Glibenclamide; Glimepiride; Glipizide; Glucagon; Glucosamine; Glutaric anhydride; Glycopyrrolate; Goserelin;Goserelin LA; Granisetron; Grazoprevir; Griseofulvin; Halobetasol propionate; Haloperidol; Heparin sodium; Heplisub B vaccine; Hyaluronic acid; Hydrochlorothiazide; Hydrochlorothiazide; Hydrochlorothiazide; Hydrocortisone; Hydrocortisone acetate; Hydroquinone; Hydroxychloroquine; Hydroxyprogesterone; Ibrutinib; Ibrutinib (Imbruvica); Ibuprofen; Icatibant acetate; Idelalisib; Imatinib; Imatinib (Gleevec); Imatinib mesylate; Imiglucerase; Inclisiran; Indinavir; Indomethacin; Infliximab; Ingenol mebuate; Inotersen; Insulin A; Insulin glargine; Interferon beta-1b; Iopanoic acid; Irbesartan; Isoconazole; Isoconazole; Isotretinoin; Itraconazole; Ivacaftor; Ivermectin; Ixazomib; Ketoconazole; Ketone bodies; Ketoprofen; Keilvir; Lacosamide; Lamictal; Lamivudine; Lansoprazole; Lapatinib; Lapatinib (Tycar) ib); larotrectinib; ledipasvir; leflunomide; lenalidomide; lenvatinib; LEO-138559; LEO-152020; leuprolide; levetiracetam; levodopa; levodopa / benserazide; levonorgestrel; levothyroxine; linagliptin; linezolid; lisinopril; L-lysine free base; lofexidine; lopinavir; loratadine; lorlatinib (Lorviqua); losartan; lovastatin; lubiprostone; lumacaftor / ivacaftor; lumefantrine; lurasidone; ruspatercept; rimecycline methicone; macitentan; magnesium; magnesium lactate; marimastat (BB-2516); marizomib (NPI-0052); mebendazole; mefloquine; melatonin; meloxicam; memantine hydrochloride; meningococcal [serotype b] vaccine; mesalazine; metformin; metformin; methotrexate; methyl aminolevulinate hydrochloride; methylphenidate; methylprednisolone; metoprolol succinate; metronidazole; midostaurin; minoxidil; mirabegron; mizolastine MR; montelukast;Mycophenolate mofetil;N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)-isonicotinamide;N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)-pyrimidin-4-yl Zin-3-carboxamide hydrochloride; Nalidixic acid (quinolone antibiotic); Naloxone; Naproxen; Navitoclax (ABT-263); Nebivolol; Nelfinavir; Nemolizumab; Neomycin; Neovastat (AE-941); Neratinib free base; Neratinib (Nerlynx); Neratinib maleate; Nevirapine; Niclosamide; Nifedipine; Nilotinib; Nilotinib; Nilotinib (Tasigna); Nintedanib; Niratimib; Nitric oxide; Nitrofurantoin; Norethindrone acetate; Nusinersen; NVP-AUY922; Na Istatin; Obatoclax (GX15-070); Octreotide acetate; Ofatumumab; Ofloxacin; Olanzapine; Olaparib; Olmesartan medoxomil; Ormacostat; Omalizumab; Oseltamivir; Osimertinib; Osimertinib mesylate; Oxaprozin; Ozanimod; Paclitaxel; Paclitaxel protein-bound; Palbociclib (Ibrance); Paliperidone palmitate; Pantoprazole; Parathyroid hormone; Paricalcitol; Patisiran; Pazopanib; Pazopanib (Votrient); Pazopanib hydrochloride; Peficitinib; pegfilgrastim; pembrolizumab (Keytruda); pemetrexed; pemigatinib; perifosine; pexidartinib; phenazopyridine; phenytoin; pibrentasvir; piperacillin; pirfenidone; piroxicam; pomalidomide; ponatinib; ponatinib (lclusig); posaconazole; pralsetinib; pravastatin; prednicarbate; prednisone; pregabalin; prinomastat (AG-3340); progesterone; propanolol; protamine sulfate; psilocybin; pyrantel;Pyrimethamine; quetiapine; quinupristin; raloxifene; raltegravir; ranibizumab; ranitidine; ranolazine; levimastat (BMS-275291); regorafenib; regorafenib (Stivarga); relugolix (Orgovix); remibrutinib; resiquimod; retinal; retino; Ribociclib; Ribociclib succinate; Rifampin; Rilpivirine; Rilpivirine; Rimegepant; Riociguat; Risdipram; Risperidone; Ritonavir; Rivaroxaban; Rosuvastatin; Rosuvastatin calcium; Rotigotine; Roxadustat; Rucaparib camsylate (Rubraca); Ruxolitinib; Ruxolitinib (Jafaki); Sacubitril, valsartan; Salicylic acid; Sapropterin; Saquinavir; Sarilumab; Saxagliptin, metformin; Secukinumab; Selexipag; Serine Xar; Selpercatinib; Selpercatinib (LOXO-292); Selumetinib; Semaglutide; Sertraline; Sevoflurane; Sildenafil; Sildenafil citrate; Simvastatin; Siponimod; Siremadrine; Sirolimus; Sitagliptin; Sitagliptin phosphate monohydrate; Sodium bicarbonate or sodium carbonate; Sodium deoxycholate; Sodium nitrate; Sofosbuvir; Sofosbuvir; Solifenacin; Somatropin; Sonidegib phosphate; Sorafenib; Sorafenib (Nexavar); Spartalizumab Spironolactone; Sufentanil citrate; Sugammadex; Sulbactam; Sulbactam; Sulfadiazine; Sulfamethoxazole; Sulfasalazine; Sumatriptan; Sunitinib; Sunitinib; Sunitinib (Sutent); Sunitinib malate (Sutent); Tacrolimus; TAF; TAF; TAF; TAF; Talazoparib - Talzenna; Talinolol; Tamoxifen; Tamsulosin; Tazarotene; Tazobactam; TDF; TDF; Temsirolimus (CCl-779, Torisel); Teneligliptin; Tenofovir alafenamide; Te Nofovir disoproxil fumarate; tepotinib; terbinafine; terfenadine; teriflunomide; testosterone; tezacaftor; THC; ticagrelor; tigecycline; timolol; timolol maleate; tipranavir; tisagenlecleucel; tisagenlecleucel (Kymriah); tivozanib; tofacitinib citrate; tolvaptan; tralokinumab; tramadol; trametinib; trametinib; trametinib; trametinib (Mekinist); tranexamic acid; travoprost; trazodone; tretinoin;Tretinoin; Triamcinolone; Triclabendazole; Trifalotene; Trimethoprim; Triptorelin; Tris; Tucatinib; Ubrogepant; Umbralisib; Upadacitinib; Valproic acid; Valsartan; Valsartan; Valsartan; Valsartan; Vancomycin; Vancomycin hydrochloride (A); Vancomycin hydrochloride (B); Vandetanib; Vandetanib (Caprelsa); Varenicline; Vasopressin; Velpatasvir; Velpatasvir; Vemurafenib; Venetoclax; Verapamil hydrochloride; Vilazodone; Vildagliptin; Vismo The composition includes a drug selected from degib; vitamin B6; vitamin D; vonoprazan; voriconazole; vortioxetine; voxilaprevir; warfarin sodium; zanubrutinib; zinc; zoledronic acid; and zolpidem, wherein the drug in the composition is (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine; (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)- 5-(Trifluoromethyl)picolinamide;2-Fluoro-N-methyl-4-[7-quinolin-6-yl-methyl]-imidazo[1,2-B][1,2,4]triazin-2yl]benzamide;4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide;4-(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile ;Abacavir;Abiraterone acetate;Abiraterone acetate;Abobotulinum toxin A;Acalabrutinib;Acarbose;Acetaminophen;Acetazolamide;Acetylsalicylic acid;Acitretin;Acyclovir;Adalimumab;Adapalene;Adapalene;Afoxolaner;Agalsidase beta;Albendazole;Alectinib;Alectinib;Alendronate sodium;Alglucosidase alfa;Alitretinoin;Alogliptin;Alpelisib;Aluminum hydroxide;Ambrisentan;Amiodarone;Amitriptyline;Amlodipine;Amlodipine; Amlodipine besylate; Amlodopine besylate; Amorolfine hydrochloride; Amoxicillin; Amphotericin B; Amphotericin B liposomal; Ampicillin; Amprenavir; Antihemophilic factor, Fc fusion protein; Apalutamide; Apatinib; Apixaban; Apremilast; Aprepitant; Aripiprazole; Artemether; Aspirin; Atazanavir; Atenolol; Atomoxetine; Atorvastatin; Avapritinib; Axitinib (Inritin); Azacitidine; Azathioprine; Azelaic acid; Azilsal Tamoxifen; Azithromycin; Baclofen; Baricitinib; Basiliximab; Batimastat (BB-94); Becaplermin; Belmosudil; Bendamustine; Benzoyl peroxide; Benzoyl peroxide; Betamethasone dipropionate; Betamethasone valerate; Bexarotene; Bictegravir; Bimatoprost; Binimetinib (Mektobi); Bortezomib; Bortezomib (Velcade); Bosentan; Bosutinib (Boslif); Botulinum toxin A; Branched-chain amino acids; Brexpiprazole; Brimonidine; Brimonidine tartrate; Brodalumab; Bupivacaine Loprion; Cabazitaxel; Cabozantinib; Cabozantinib (Cometriz); Calcifediol; Calcipotriene; Calcipotriene; Calcipotriene; Calcipotriol; Calcitonin; Calcitriol; Calcium carbonate; Canagliflozin; Canakinumab; Capecitabine; Capmatinib; Capsaicin; Carbamazepine; Carbidopa; Carfilzomib; Carfilzomib (Cyprolis); Cariprazine; Carvedilol; CD-12681; CEE-321; Cefazolin; Cefepime; Cefoperazone; Cefotaxime sodium; Celecoxib ;Celecoxib;Cemiplimab;Ceritinib;Chlorothiazide;Chlorpromazine;Chlorthalidone;Cinacalcet;Ciprofloxacin;Cisapride;Citalopram;Citric acid;Clarithromycin;Clavulanate;Clindamycin phosphate;Clobazam;Clobetasol propionate;Clofazimine;Clomiphene;Clonidine;Clopidogrel;Clopidogrel bisulfate;Cobicistat;Cobicistat;Colcosin;Colistin;Coricotropin;Crisaborole;Crizanlizumab;Crizotinib (Xalkori);Cyclobenzaprine;Cyclosporine; Dabigatran etexilate; Dabrafenib; Dacomitinib (Vizinpro); Dalbavancin; Dalfopristin; Danazol; Dapagliflozin; Dapsone; Daptomycin; Darunavir; Dasatinib; Decitabine; Deferasirox; Delgocitinib; Deoxycholic acid; Desipramine; Desonide; Dexlansoprazole; Dexmethylphenidate; Dextroamphetamine / amphetamine salts; Diclofenac; Diclofenac sodium; Diflucortolone; Diflucortolone; Difinisal; Digoxin; Diloxanide; Dimethyl fumarate; Diphenhydramine hydrochloride; Diphtheria vaccine; Docetaxel; Dolutegravir; Dolutegravir; Donepezil Zil; doxercalciferol; doxycycline; doxycycline ER; doxycycline hyclate (B); doxycycline monohydrate (A); dronabinol; dronedarone; drospirenone; Dukoral / ShanChol cholera vaccine; duloxetine; dupilumab; durvalumab; dutasteride; duvelisib; ecallantide; edoxaban; efavirenz; efavirenz; elafibranor; elagolix sodium; elbasvir ;Eletriptan;Eltrombopag;Elvitegravir;Empagliflozin;Emtricitabine;Emtricitabine;Emtricitabine;Emtricitabine;Emtricitabine;Emtricitabine;Emtricitabine;Emtricitabine;Encorafenib (Braftovi);Enfuviritide;Enoxaparin sodium;Entecavir;Entrectinib;Enzalutamide;Epinephrine;Erdafitinib;Erenumab;Eribulin;Erlotinib;Erlotinib hydrochloride (Tarceva); ertapenem; erythromycin; escitalopram; esketamine (ketamine); esomeprazole; esopremazole; estradiol; estrogen-conjugated; etanercept; ethinyl estradiol; ethinyl estradiol; ethinyl estradiol; etonogestrel; etonogestrel; etravirine; etretinate; everolimus; everolimus (Afinitor); everolimus (Votubia, Zotres / Certican);Ezetimibe; Ezetimibe; Ezetimibe; Famotidine; Fasinumab; Febuxostat; Fedratinib; Fenofibrate; Ferric carboxymaltose; Fexofenadine hydrochloride; Filgotinib; Filgrastim; Fingolimod; Fluocinolone acetonide; Fluocinolone acetonide; Fluoxetine; Flurbiprofen; Folic acid; Forskolin; Fostamatinib; Fulvestrant; Furosemide; Fusidic acid; Fusidic acid; Gabapentin; Ganetespib; Gefitinib (Iressa); Gilteritinib; Glasdegib (Dow Lismo) or glasdezib maleate; glecaprevir; glibenclamide; glimepiride; glipizide; glucagon; glucosamine; glutaric anhydride; glycopyrrolate; goserelin; goserelin LA; granisetron; grazoprevir; griseofulvin; halobetasol propionate; haloperidol; heparin sodium; heplisub B vaccine; hyaluronic acid; hydrochlorothiazide; hydrochlorothiazide; hydrocortisone; hydrocortisone acetate; hydroquinone; hydroxychlorothiazide Roquine; Hydroxyprogesterone; Ibrutinib; Ibrutinib (Imbruvica); Ibuprofen; Icatibant acetate; Idelalisib; Imatinib; Imatinib (Gleevec); Imatinib mesylate; Imiglucerase; Inclisiran; Indinavir; Indomethacin; Infliximab; Ingenol mebuate; Inotersen; Insulin A; Insulin glargine; Interferon beta-1b; Iopanoic acid; Irbesartan; Isoconazole; Isoconazole; Isotretinoin; Itraconazole; Ivacaftor; Ivacaftor; Ibe Lumectin; Ixazomib; Ketoconazole; Ketone bodies; Ketoprofen; Keilvir; Lacosamide; Lamictal; Lamivudine; Lansoprazole; Lapatinib; Lapatinib (Tycarb); Larotrectinib; Ledipasvir; Leflunomide; Lenalidomide; Lenvatinib; LEO-138559; LEO-152020; Leuprolide; Levetiracetam; Levodopa; Levodopa / Benserazide; Levonorgestrel; Levothyroxine; Linagliptin; Linezolid; Lisinopril; L-lysine free base; Lofexidine; Lopinavir; Loratadine;Lorlatinib (Lorviqua); losartan; lovastatin; lubiprostone; lumacaftor / ivacaftor; lumefantrine; lurasidone; ruspatercept; lymecycline; macitentan; magnesium; magnesium lactate; marimastat (BB-2516); marizomib (NPI-0; 052); Mebendazole; Mefloquine; Melatonin; Meloxicam; Memantine hydrochloride; Meningococcal [serotype b] vaccine; Mesalazine; Metformin; Metformin; Metformin; Methformin; Methotrexate; Methyl aminolevulinate hydrochloride; Methylphenidate; Methylprednisolone; Metoprolol succinate; Metronidazole; Midostaurin; Minoxidil; Mirabegron; Mizolastine MR; Montelukast; Mycophenolate mofetil; N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4- N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)-pyridine-3-carboxamide hydrochloride;Nalidixic acid (quinolone antibiotic);Naloxone;Naproxen;Navitoclax ( ABT-263; Nebivolol; Nelfinavir; Nemolizumab; Neomycin; Neovastat (AE-941); Neratinib-free base; Neratinib (Nerlynx); Neratinib maleate; Nevirapine; Niclosamide; Nifedipine; Nilotinib; Nilotinib; Nilotinib (Tasigna); Nintedanib; Niratimib; Nitric oxide; Nitrofurantoin; Norethindrone acetate; Nusinersen; NVP-AUY922; Nystatin; Obatoclax (GX15-070); Octreotide acetate; Ofatumumab; Ofloxacin; Olanzapi Olaparib; Olmesartan medoxomil; Ormacostat; Omalizumab; Oseltamivir; Osimertinib; Osimertinib mesylate; Oxaprozin; Ozanimod; Paclitaxel; Paclitaxel protein-bound; Palbociclib (Ibrance); Paliperidone palmitate; Pantoprazole; Parathyroid hormone; Paricalcitol; Patisiran; Pazopanib; Pazopanib (Votrient); Pazopanib hydrochloride; Peficitinib; Pegfilgrastim; Pembrolizumab (Keytruda); Pemetrexed; Pemigatinib; Perifosine;Pexidartinib; Phenazopyridine; Phenytoin; Pibrentasvir; Piperacillin; Pirfenidone; Piroxicam; Pomalidomide; Ponatinib; Ponatinib (lclusig); Posaconazole; Pralsetinib; Pravastatin; Prednicarbate; Prednisone; Pregabalin; Prinomastat (AG-3340); Progesterone; Propanolol; Protamine sulfate; Psilocybin; Pyrantel; Pyrimethamine; Quetiapine; Quinupristin; Raloxifene; Raltegravir; Ranibizumab; Ranitidine; Ranolazine ; Levimastat (BMS-275291); Regorafenib; Regorafenib (Stivarga); Relugolix (Orgovix); Remibrutinib; Resiquimod; Retinal; Retinol; Ribociclib; Ribociclib succinate; Rifampin; Rilpivirine; Rilpivirine; Rilpivirine; Rimegepant; Riociguat; Risdipram; Risperidone; Ritonavir; Rivaroxaban; Rosuvastatin; Rosuvastatin calcium; Rotigotine; Roxadustat; Rucaparib camsylate (Rubraca); Ruxolitinib; Ruxolitinib Nib (Jafaki); Sacubitril, Valsartan; Salicylic acid; Sapropterin; Saquinavir; Sarilumab; Saxagliptin, Metformin; Secukinumab; Selexipag; Selinexor; Selpercatinib; Selpercatinib (LOXO-292); Selumetinib; Semaglutide; Sertraline; Sevoflurane; Sildenafil; Sildenafil citrate; Simvastatin; Siponimod; Siremadrine; Sirolimus; Sitagliptin; Sitagliptin phosphate monohydrate; Sodium bicarbonate or sodium carbonate; Sodium deoxycholate; Nitric acid Sodium; Sofosbuvir; Sofosbuvir; Sofosbuvir; Solifenacin; Somatropin; Sonidegib phosphate; Sorafenib; Sorafenib (Nexavar); Spartalizumab; Spironolactone; Sufentanil citrate; Sugammadex; Sulbactam; Sulbactam; Sulfadiazine; Sulfamethoxazole; Sulfasalazine; Sumatriptan; Sunitinib; Sunitinib; Sunitinib (Sutent); Sunitinib malate (Sutent); Tacrolimus; TAF; TAF; TAF; TAF; Talazoparib-Talzenna); Talinolol;Tamoxifen; Tamsulosin; Tazarotene; Tazobactam; TDF; TDF; Temsirolimus (CCl-779, Torisel); Teneligliptin; Tenofovir alafenamide; Tenofovir disoproxil fumarate; Tepotinib; Terbinafine; Terfenadine; Teriflunomide; Testosterone; Tezacaftor; THC; Ticagrelor; Tigecycline; Timolol; Timolol maleate; Tipranavir; Tisagenlecleucel; Tisagenlecleucel (Kymriah); Tivozanib; Tofacitinib citrate; Tolvaptan; Tralokinumab; Tramadol; Trametinib; Trametinib; Trametinib; Trametinib; Trametinib (Mekinist); Tranexamic acid; Travoprost; Trazodone; Tretinoin; Tretinoin; Selected from triansinolone; triclabendazole; trifalotene; trimethoprim; triptorelin; Tris; tucatinib; ubrogepant; umbralisib; upadacitinib; valproic acid; valsartan; valsartan; valsartan; valsartan; vancomycin; vancomycin hydrochloride (A); vancomycin hydrochloride (B); vandetanib; vandetanib (Caprelsa); varenicline; vasopressin; velpatasvir; velpatasvir; vemurafenib; venetoclax; verapamil hydrochloride; vilazodone; vildagliptin; vismodegib; vitamin B6; vitamin D; vonoprazan; voriconazole; vortioxetine; voxilaprevir; warfarin sodium; zanubrutinib; zinc; zoledronic acid; and zolpidem. Any agent in Table 1 can be used in a transdermal formulation as a combination therapy with a composition comprising any agent in Table 1. In some cases, the agent in the formulation is the same as the agent in the composition. In other cases, the agent in the formulation is different from the agent in the composition. In still other cases, the agent in the formulation is also the agent in the composition, and the composition further comprises another agent in Table 1. In further cases, the agent in the composition is also the agent in the formulation, and the formulation further comprises another agent in Table 1.

[0202] The transdermal formulations of the present disclosure (and comprising an agent in Table 1) can be administered in combination therapy with pembrolizumab (Keytruda). Generally, pembrolizumab is administered by intravenous infusion. Thus, in embodiments, a transdermal formulation comprising an agent in Table 1 is co-administered with an intravenous infusion composition comprising pembrolizumab.

[0203] Iron-containing transdermal delivery formulations can be formulated at an acidic pH to minimize spontaneous oxidation of Fe(II) to Fe(III). Suitable, non-limiting exemplary iron chelators include deferoxamine, ethylenediaminetetraacetic acid (EDTA), 1,2-diethyl-3-hydroxypyridin-4-one (CP94), desferal, deferiprone, and deferasirox, succimer, trientine, desferrithiocin, clioquinol, O-trensox, takupir, dexrazoxane, triapine, pyridoxal isonicotinoyl hydrazone, di-2-pyridyl ketone thiosemicarbazone series, flavan-3-ol, curcumin, apocynin, kolaviron, floranol, baicalein, baicalin, ligustrazine, quercetin, epigallocatechin gallate, theaflavin, phytic acid, and genistein. Suitable non-limiting exemplary antioxidants include glutathione, vitamin C, vitamin E, superoxide dismutase, catalase, pNaKtide, butylated hydroxytoluene, butylated hydroxyanisole, tert-butylhydroquinone, HP beta CD, resveratrol, retinol, coenzyme q10, niacinamide, polyphenols, flavonoids, beta carotene, lutein, and lycopene.

[0204] In any of the anesthetic compositions in transdermal delivery formulations, it may be desirable to administer epinephrine in conjunction with the transdermal anesthetic. Alternatively, treating the epinephrine with a chelating agent, such as the iron chelator Desferal®, can stabilize the epinephrine sufficiently for inclusion in the transdermal delivery formulation.

[0205] Suitable doses of iron or iron-containing transdermal delivery formulations to be topically administered to a subject (e.g., a human patient) as a transdermal delivery formulation are at least about 500 mg, at least about 750 mg, at least about 1000 mg, at least about 1.5 g, at least about 2.0 g, at least about 2.5 g, at least about 3.0 g, at least about 3.5 g, at least about 4.0 g, at least about 4.5 g, at least about 5.0 g, at least about 6.0 g, at least about 7.0 g, at least about 8.0 g, at least about 9.0 g, at least about 10.0 g, at least about 11 g, at least about 12 g, at least about 13 g, at least about 14 g, at least about 15 g, at least about 20 g, at least about 25 g, at least about 30 g, at least about 35 g, at least about 40 g, at least about 45 g, at least about 50 g, or more. This dose is typically administered daily, twice daily, or three times daily, but can also be administered four times daily, five times daily, or more than six times daily.

[0206] Alternatively, a suitable daily dose of iron or an iron-containing transdermal delivery formulation administered topically to a subject as a transdermal delivery formulation is at least about 10 mg / kg, at least about 25 mg / kg, at least about 30 mg / kg, at least about 35 mg / kg, at least about 40 mg / kg, at least about 45 mg / kg, at least about 50 mg / kg, at least about 55 mg / kg, at least about 60 mg / kg, at least about 65 mg / kg, at least about 70 mg / kg, at least about 75 mg / kg, at least about 80 mg / kg, at least about 90 mg / kg, at least about 100 mg / kg, at least about 125 mg / kg, at least about 150 mg / kg, at least about 200 mg / kg, at least about 250 mg / kg, at least about 300 mg / kg, at least about 350 mg / kg, at least about 40 ... g / kg, at least about 160 mg / kg, at least about 170 mg / kg, at least about 175 mg / kg, at least about 180 mg / kg, at least about 190 mg / kg, at least about 200 mg / kg, at least about 225 mg / kg, at least about 250 mg / kg, at least about 275 mg / kg, at least about 300 mg / kg, at least about 325 mg / kg, at least about 350 mg / kg, at least about 375 mg / kg, at least about 400 mg / kg, at least about 425 mg / kg, at least about 450 mg / kg, at least about 475 mg / kg, up to at least about 500 mg / kg or more.

[0207] In another embodiment, a suitable daily dose of iron or an iron-containing transdermal delivery formulation administered topically to a subject as a transdermal delivery formulation is from about 10 mg / kg to about 1.0 g / kg, and more typically, the daily dose is from about 10 mg / kg to about 500 mg / kg, from about 25 mg / kg to about 500 mg / kg, from about 50 mg / kg to about 300 mg / kg, from about 75 mg / kg to about 300 mg / kg, from about 75 mg / kg to about 250 mg / kg, from about 100 mg / kg to about 300 mg / kg, from about 75 mg / kg to about 200 mg / kg, from about 100 mg / kg to about 200 mg / kg, or alternative ranges.

[0208] The transdermal delivery formulations comprise a mixture, and the components interact synergistically to induce a better skin penetration enhancement than that induced by each individual component. The synergistic interaction between chemicals can be utilized to design a powerful penetration enhancer that overcomes the limited effectiveness of a single enhancer. Some embodiments disclosed herein utilize one or more different penetration enhancers.

[0209] For example, emergency medical treatment for individuals needing blood-balancing agents containing easily metabolized nutrients such as electrolytes and glucose, which are typically administered intravenously, can instead be administered non-invasively by massaging the formulation through the skin, allowing for systemic delivery and altering levels in the bloodstream.

[0210] In some embodiments, athletic performance ingredients include beta-alanine, L-carnitine, adenosine triphosphate, glucose, creatine monohydrate, beta-hydroxybeta-methylbutyrate (HMB), branched-chain amino acids (leucine, isoleucine, valine), glutathione, sodium phosphate, and caffeine. Medical nutritional ingredients include amino acids, glucose, lipids, and Na. + , K. + , Ca 2+ , Mg 2+ , acetate, Cl - , P, multivitamins, and trace elements, while ingredients for weight loss include conjugated linoleic acid, ephedra, caffeine, and salicin.

[0211] Embodiments include transdermal lotions or creams for administering a drug to a subject. They are placed on the skin and deliver a specific amount of drug through the skin. The drug can be delivered through the skin to a localized subcutaneous location. For example, a lotion can reduce inflammation due to an autoimmune response. The lotion or cream can be applied directly to the affected area. Alternatively, the drug can enter the circulation for systemic distribution.

[0212] In alternative embodiments, the agent can be administered using a transdermal or medicated adhesive patch. To release the agent, the patch can utilize a porous membrane covering a reservoir of agent. Alternatively, the agent can be embedded in a layer of adhesive that releases the agent when it dissolves or melts.

[0213] An advantage of the transdermal drug delivery route over other types of delivery is that the formulation can provide a controlled release of the agent. Traditional transdermal delivery systems are generally ineffective for use with agents and drugs that are large and / or hydrophilic molecules.

[0214] There are other advantages to administering drugs transdermally. Proteins and peptides, such as those used in anti-aging treatments, can be broken down by stomach acid and enzymes. Transdermal administration is not affected by stomach or digestive tract problems. Furthermore, people can benefit from drugs that are absorbed slowly and regularly. Transdermal formulations allow the drug to be released in small amounts over a long period of time.

[0215] Other advantages relate to dosing. Large doses of agents can often cause dose-dependent toxicity. For example, oral administration of vitamin A can lead to hypervitaminosis A. The main problems associated with vitamin A are its half-life, rapid absorption (due to its lipophilicity), and its toxicity (due to high loading and frequent administration). Some drugs also undergo first-pass metabolism, which prevents delivery of the drug to the desired site of action. Furthermore, many hydrophilic or lipophilic agents exhibit either poor solubility or poor absorption when administered orally. Transdermal formulations allow effective concentrations of agents to be applied to the desired site without painful delivery.

[0216] In one embodiment, the drug is delivered by transdermal administration. There are numerous situations in which the formulations of the present invention are useful. For athletes, transdermal delivery formulations can deliver sufficient amounts of lactic acid neutralizers, such as ketone compounds, to fatigued muscles to alleviate the burning sensation athletes experience due to lactic acid buildup. This allows athletes to continue performing at optimal levels for longer periods of time. Furthermore, athletes and others who "train" require a large amount of energy, particularly due to the need for energy production in the areas of muscle tissue being trained, which necessitates the consumption of large amounts of calories. These nutrients can be delivered directly, rather than requiring oral intake, which can be counterproductive and relatively time-consuming.

[0217] The relationship between abnormal protein phosphorylation and disease pathology or prognosis is well known. Protein kinases are a large and diverse family of enzymes that catalyze protein phosphorylation and play important roles in cell signaling.

[0218] Therefore, protein kinases represent an important group of drug targets. The widespread presence of overactive protein kinases in cancer cells suggests that molecules that inhibit these enzymes may act as antitumor agents. A variety of protein kinase inhibitors are clinically used to treat diseases such as cancer and chronic inflammatory diseases such as diabetes and stroke.

[0219] Protein kinases exert positive or negative regulatory effects depending on the target protein. Protein kinases are involved in specific signaling pathways that regulate cellular functions, including metabolism, cell cycle progression, cell adhesion, vascular function, apoptosis, and angiogenesis. Dysfunction of cell signaling is associated with many diseases, including cancer and diabetes. Regulation of signaling by cytokines and the relationship between signaling molecules and proto-oncogenes and tumor suppressor genes have also been documented. A relationship between diabetes and related conditions and deregulated levels of protein kinases has also been documented. See, for example, Sridhar et al., Pharmaceutical Research, 17(1):1345-1353 (2000). Viral infections and associated conditions are also implicated in the regulation of protein kinases. See, for example, Park et al., Cell, 101(7):777-787 (2000).

[0220] Protein kinases can be broadly classified into groups based on the identity of the amino acids they target (serine / threonine, tyrosine, lysine, and histidine). For example, tyrosine kinases include receptor tyrosine kinases (RTKs), such as growth factor receptors, and non-receptor tyrosine kinases, such as the Src kinase family. There are also dual-specificity protein kinases, such as cyclin-dependent kinases (CDKs) and mitogen-activated protein kinases (MAPKs), that target both tyrosine and serine / threonine. A given cell contains many protein kinases, some of which phosphorylate other protein kinases. Some protein kinases phosphorylate a wide variety of proteins, while others phosphorylate only one protein. As expected, there are many classes of protein kinases. Upon receiving a signal, some proteins can undergo autophosphorylation.

[0221] Protein tyrosine kinases (PTKs) constitute a large family of kinases that regulate cell signaling related to proliferation, differentiation, adhesion, motility, and death. Tyrosine kinase members include Yes, BMX, Syk, EphA1, FGFR3, RKY, MUSK, JAK1, and FGFR. Tyrosine kinases are divided into two classes: receptor tyrosine kinases and non-receptor tyrosine kinases. The tyrosine kinase family is large, consisting of at least 90 characterized kinases, including at least 58 receptor kinases and at least 32 non-receptor kinases, for a total of at least 30 subfamilies. Tyrosine kinases are involved in diabetes and cancer and are associated with various congenital syndromes.

[0222] Nonreceptor tyrosine kinases are a group of intracellular enzymes that lack extracellular or transmembrane sequences. Currently, over 32 nonreceptor tyrosine kinase families have been identified, including the Src, Btk, Csk, ZAP70, and Kak families. The Src family of nonreceptor tyrosine kinases is the largest and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk protein tyrosine kinases. The Src family of kinases is associated with oncogenesis, cell proliferation, and tumor progression. Many protein tyrosine kinases have been shown to participate in cell signaling pathways involved in various pathological conditions, including cancer, hyperproliferative disorders, and immune disorders.

[0223] Other proteins that play important roles in cell signaling include matrix metalloproteinases (MMPs), heat shock proteins (HSPs), and proteosome proteins. Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases or matrixins, are calcium-dependent, zinc-containing endopeptidase metalloproteinases. Other family members include adamalysins, serralysins, and astacins. MMPs belong to a larger family of proteases known as the metzincin superfamily. Collectively, these enzymes can degrade extracellular matrix proteins and process numerous bioactive molecules. They are known to be involved in the cleavage of cell surface receptors, the release of apoptotic ligands (e.g., FAS ligand), and the inactivation of chemokines and cytokines. MMPs are also thought to play a major role in cellular behaviors such as cell proliferation, migration (adhesion / dispersion), differentiation, angiogenesis, apoptosis, and host defense.

[0224] Heat shock proteins (HSPs) are a family of proteins produced by cells in response to exposure to stressful conditions. They were first described in the context of heat shock but are now known to be expressed during cold, UV exposure, and other stresses, such as wound healing and tissue remodeling. Many members of this group perform chaperone functions by stabilizing new proteins to ensure their correct folding or by assisting in the refolding of proteins damaged by cellular stress. The proteasome is a protein complex that degrades unnecessary or damaged proteins through proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that aid in such reactions are called proteases. The proteasome is part of the primary mechanism by which cells regulate the concentrations of specific proteins and degrade misfolded proteins.

[0225] Embodiments include transdermally administering an agent to modulate one or more of (a) serine / threonine / tyrosine kinases, (b) matrix metalloproteinases (MMPs), (c) heat shock proteins (HSPs), or (d) proteosomes. The agent can be a small molecule cancer drug administered using the formulations described herein.

[0226] Transdermal delivery formulation components Embodiments include transdermal lotions or creams for administering medication to a subject, which are placed on the skin and deliver a specific amount of medication through the skin, where the medication can be delivered through the skin to a localized subcutaneous location.

[0227] In alternative embodiments, the agent can be administered using a transdermal or medicated adhesive patch. To release the agent, the patch can utilize a porous membrane covering a reservoir of agent. Alternatively, the agent can be embedded in a layer of adhesive that releases the agent when it dissolves or melts.

[0228] An advantage of the transdermal drug delivery route over other types of delivery is that the formulation can provide a controlled release of the agent. Traditional transdermal delivery systems are generally ineffective for use with agents and drugs that are large and / or hydrophilic molecules.

[0229] There are other advantages to administering drugs transdermally. Small molecules can be inactivated or degraded by the stomach or liver. Transdermal administration is not affected by stomach or digestive tract problems. Additionally, people can benefit from drugs that are absorbed slowly and regularly. Transdermal formulations allow the drug to be released in small amounts over an extended period of time.

[0230] Other advantages relate to dosing. Large doses of agents can often cause dose-dependent toxicity. For example, oral administration of vitamin A can lead to hypervitaminosis A. The main problems associated with vitamin A are its half-life, rapid absorption (due to its lipophilicity), and its toxicity (due to high loading and frequent administration). Some drugs also undergo first-pass metabolism, which prevents delivery of the drug to the desired site of action. Furthermore, many hydrophilic or lipophilic agents exhibit either poor solubility or poor absorption when administered orally. Transdermal formulations allow effective concentrations of agents to be applied to the desired site without painful delivery.

[0231] In one embodiment, the present disclosure demonstrates transdermal delivery of agents such as drugs without the many negative effects on color, flavor, graininess, and stability that come with using lecithin organogel. Moreover, this method demonstrates improved transdermal penetration.

[0232] In one embodiment, the transdermal delivery formulation contains a phosphatide in a concentration of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70% or more w / w of the transdermal delivery formulation.

[0233] Phosphatides - Soybean lecithin contains approximately 57.5% by weight of phosphatides. The main phosphatides found in soybean lecithin are inositol phosphatide (20.5% by weight of soybean lecithin), phosphatidylcholine (20%), and phosphatidylethanolamine (11% by weight of soybean lecithin). In some embodiments, phosphatidylcholine is used in total (57.5% by weight of soybean lecithin) because it is known to aid skin penetration. Other phosphatides include phosphatidic acid, phosphatidylserine, and phosphatidylinositol.

[0234] In various embodiments, the formulation lacks natural (e.g., plant or animal-derived) lecithin.

[0235] In one embodiment, the transdermal delivery formulation contains a sterol or benzyl alcohol in a concentration of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or more w / w of the transdermal delivery formulation.

[0236] Sterols—Soy lecithin contains approximately 2.5% sterols by weight. In some embodiments, benzyl alcohol is used in place of sterols in transdermal delivery formulations to act as a permeation enhancer. In other embodiments, the sterol is cholesterol, ergosterol, hopanoids, hydroxysteroids, phytosterols, and / or other steroids.

[0237] In one embodiment, the transdermal delivery formulation contains carbohydrates in a concentration of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70% or more by weight of the transdermal delivery formulation.

[0238] Carbohydrates—Soy lecithin contains approximately 5% by weight of free carbohydrates. In some embodiments, glucose is used in place of free carbohydrates to maintain the sugar ratio in the transdermal delivery formulations disclosed herein. In another embodiment, the carbohydrate is a monosaccharide, disaccharide, polyol, maltooligosaccharide, oligosaccharide, starch, or polysaccharide. In a further embodiment, the carbohydrate is glucose, galactose, fructose, xylose, sucrose, lactose, maltose, trehalose, sorbitol, mannitol, maltodextrin, raffinose, stachyose, fructooligosaccharide, amylose, amylopectin, modified starch, glycogen, cellulose, hemicellulose, pectin, and / or hydrocolloid.

[0239] In various embodiments, the transdermal delivery formulation does not include glucose.

[0240] Moisture - In some embodiments, the transdermal delivery formulation holds about 1% water by weight in soy lecithin.

[0241] In one embodiment, the transdermal delivery formulation contains water in a concentration of at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70% or more by weight of the transdermal delivery formulation.

[0242] Fatty Acids—Soybean lecithin contains approximately 34% fatty acids by weight, including 18-19% linoleic acid, 1-2% α-linoleic acid, 8-9% oleic acid, approximately 5% palmitic acid, and 1-2% stearic acid. In some embodiments, the fatty acids are similar to those contained in soybean lecithin. In one embodiment, α-linolenic acid is omitted from the transdermal delivery formulation because it is known to oxidize and potentially become rancid. In some embodiments, the amount of stearic acid is increased (i.e., to improve formulation stability) or the amount of linoleic acid is increased (i.e., to improve skin penetration). In some embodiments, seed oils such as refined safflower oil are used in transdermal delivery formulations due to their similarity to the fatty acids found in soybean lecithin, their relative availability, and their low cost. In some embodiments, the fatty acid content of the transdermal formulation can be adjusted with different seed oils through the addition of smaller amounts of the fatty acids disclosed herein.

[0243] In various embodiments, the formulation lacks natural (e.g., plant or animal-derived) lecithin.

[0244] In a further embodiment, the fatty acid is saturated or unsaturated. In another embodiment, the unsaturated fatty acid is myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaidic acid, α-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, and / or docosahexaenoic acid. In one embodiment, the saturated fatty acid is caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, and / or cerotic acid. In another embodiment, the fatty acid is a dietary fat, including duct fat, lard, tallow, butter, coconut oil, cocoa butter, palm kernel oil, palm oil, cottonseed oil, wheat germ oil, soybean oil, olive oil, corn oil, sunflower oil, safflower oil, hemp oil, and / or canola / rapeseed oil.

[0245] In some embodiments, carotenoids are excluded from the disclosed formulations.

[0246] In one embodiment, the transdermal delivery formulation comprises the components of Table 3A:

[0247] [Table 6]

[0248] In Table 3A, as an example, if an ingredient has a weight percentage in the range of 5-15%, that ingredient can be present in the formulation at any percentage (w / w or w / v) between about 5% and about 15%. The weight percentage can be about 5% to about 15%. The weight percentage can be about 5% to about 6%, about 5% to about 7%, about 5% to about 8%, about 5% to about 9%, about 5% to about 10%, about 5% to about 11%, about 5% to about 12%, about 5% to about 13%, about 5% to about 14%, about 5% to about 15%, about 6% to about 7%, about 6% to about 8%, about 6% to about 9%, and about 6% to about 10%. , about 6% to about 11%, about 6% to about 12%, about 6% to about 13%, about 6% to about 14%, about 6% to about 15%, about 7% to about 8%, about 7% to about 9%, about 7% to about 10%, about 7% to about 11%, about 7% to about 12%, about 7% to about 13%, about 7% to about 14%, about 7% to about 15%, about 8% to about 9%, about 8% to about 1 0%, about 8% to about 11%, about 8% to about 12%, about 8% to about 13%, about 8% to about 14%, about 8% to about 15%, about 9% to about 10%, about 9% to about 11%, about 9% to about 12%, about 9% to about 13%, about 9% to about 14%, about 9% to about 15%, about 10% to about 11%, about 10% to about 12%, about 10% to about 13 The weight percentage may be about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 13% to about 15%, or about 14% to about 15%. The weight percentage may be about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15%. The weight percentage may be at least about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, or about 14%. The weight percentage can be up to about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15%. Additionally, the weight percentage can be from about 5% to about 6%.The weight percentages are about 5% to about 5.1%, about 5% to about 5.2%, about 5% to about 5.3%, about 5% to about 5.4%, about 5% to about 5.5%, about 5% to about 5.6%, about 5% to about 5.7%, about 5% to about 5.8%, about 5% to about 5.9%, about 5% to about 6%, about 5.1% to about 5.2%, about 5.1% to about 5.3%, about 5.1% to about 5.4%, about 5.1% to about 5.5%, about 5% to about 5.6% .1% to about 5.6%, about 5.1% to about 5.7%, about 5.1% to about 5.8%, about 5.1% to about 5.9%, about 5.1% to about 6%, about 5.2% to about 5.3%, about 5.2% to about 5.4%, about 5.2% to about 5.5%, about 5.2% to about 5.6%, about 5.2% to about 5.7%, about 5.2% to about 5.8%, about 5.2% to about 5.9%, about 5.2% to about 6%, about 5.3% to about 5.4 %, about 5.3% to about 5.5%, about 5.3% to about 5.6%, about 5.3% to about 5.7%, about 5.3% to about 5.8%, about 5.3% to about 5.9%, about 5.3% to about 6%, about 5.4% to about 5.5%, about 5.4% to about 5.6%, about 5.4% to about 5.7%, about 5.4% to about 5.8%, about 5.4% to about 5.9%, about 5.4% to about 6%, about 5.5% to about 5.6%, about 5.5% to The weight percentage may be about 5.7%, about 5.5% to about 5.8%, about 5.5% to about 5.9%, about 5.5% to about 6%, about 5.6% to about 5.7%, about 5.6% to about 5.8%, about 5.6% to about 5.9%, about 5.6% to about 6%, about 5.7% to about 5.8%, about 5.7% to about 5.9%, about 5.7% to about 6%, about 5.8% to about 5.9%, about 5.8% to about 6%, or about 5.9% to about 6%. The weight percentage can be at least about 5%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, about 5.5%, about 5.6%, about 5.7%, about 5.8%, or about 5.9%. The weight percentage can be up to about 5.1%, about 5.2%, about 5.3%, about 5.4%, about 5.5%, about 5.6%, about 5.7%, about 5.8%, about 5.9%, or about 6%. Additionally, the weight percentage can be between about 5% and about 5.1%.The weight percentages are about 5% to about 5.01%, about 5% to about 5.02%, about 5% to about 5.03%, about 5% to about 5.04%, about 5% to about 5.05%, about 5% to about 5.06%, about 5% to about 5.07%, about 5% to about 5.08%, about 5% to about 5.09%, about 5% to about 5.1%, about 5.01% to about 5.02%, about 5.01% to about 5.03%, about 5.01% to about 5.04%, about 5.01% to about 5.05%, and about 5.01% to about 5.0 6%, about 5.01% to about 5.07%, about 5.01% to about 5.08%, about 5.01% to about 5.09%, about 5.01% to about 5.1%, about 5.02% to about 5.03%, about 5.02% to about 5.04%, about 5.02% to about 5.05%, about 5.02% to about 5.06%, about 5.02% to about 5.07%, about 5.02% to about 5.08%, about 5.02% to about 5.09%, about 5.02% to about 5.1%, about 5.03% to about 5.04%, about 5.0 3% to about 5.05%, about 5.03% to about 5.06%, about 5.03% to about 5.07%, about 5.03% to about 5.08%, about 5.03% to about 5.09%, about 5.03% to about 5.1%, about 5.04% to about 5.05%, about 5.04% to about 5.06%, about 5.04% to about 5.07%, about 5.04% to about 5.08%, about 5.04% to about 5.09%, about 5.04% to about 5.1%, about 5.05% to about 5.06%, about 5.05% to about 5.0 7%, about 5.05% to about 5.08%, about 5.05% to about 5.09%, about 5.05% to about 5.1%, about 5.06% to about 5.07%, about 5.06% to about 5.08%, about 5.06% to about 5.09%, about 5.06% to about 5.1%, about 5.07% to about 5.08%, about 5.07% to about 5.09%, about 5.07% to about 5.1%, about 5.08% to about 5.09%, about 5.08% to about 5.1%, or about 5.09% to about 5.1%. The weight percentage can be about 5%, about 5.01%, about 5.02%, about 5.03%, about 5.04%, about 5.05%, about 5.06%, about 5.07%, about 5.08%, about 5.09%, or about 5.1%. The weight percentage can be at least about 5%, about 5.01%, about 5.02%, about 5.03%, about 5.04%, about 5.05%, about 5.06%, about 5.07%, about 5.08%, or about 5.09%.The weight percentage can be up to about 5.01%, about 5.02%, about 5.03%, about 5.04%, about 5.05%, about 5.06%, about 5.07%, about 5.08%, about 5.09%, or about 5.1%.

[0249] Other ranges listed in Table 3A include similar ranges, subranges, and values ​​within the ranges.

[0250] In some cases, the agent is present in an amount of about 0.001% to about 0.01% by weight of the formulation, about 0.011% to about 0.1% by weight of the formulation, about 0.11% to about 1.0% by weight of the formulation, about 1% to about 10% by weight of the formulation, about 11% to about 20% by weight of the formulation, or about 21% to about 30% by weight of the formulation.

[0251] In various embodiments, the transdermal delivery formulation comprises the components of Table 3B:

[0252] [Table 7]

[0253] In Table 3B, as an example, if an ingredient has a weight percentage in the range of 5-20% (for fatty acid esters and viscosity enhancers), that ingredient can be present in the formulation at any percentage (w / w or w / v) between about 5% and about 20%. The weight percentage can be between about 5% and about 20%.The weight percentages are about 5% to about 6%, about 5% to about 7%, about 5% to about 8%, about 5% to about 9%, about 5% to about 10%, about 5% to about 11%, about 5% to about 12%, about 5% to about 13%, about 5% to about 14%, about 5% to about 15%, about 6% to about 7%, about 6% to about 8%, about 6% to about 9%, about 6% to about 10%, about 6% to about 11%, about 6% to about 12%, about 6% to about 13%, about 6% to about 14%, about 6% to about 15%, about 7% to about 8%, about 7% to about 9%, about 7% to about 10%, about 7% to about 11%, about 7% to about 12%, about 7% to about 13%, and about 7% to about 1 4%, about 7% to about 15%, about 8% to about 9%, about 8% to about 10%, about 8% to about 11%, about 8% to about 12%, about 8% to about 13%, about 8% to about 14%, about 8% to about 15%, about 9% to about 10%, about 9% to about 11%, about 9% to about 12%, about 9% to about 13%, about 9% to about 14%, about 9% to about 15%, about 10% to about 11%, about 10% to about 12%, about 10% to about 13%, about 10% to about 14%, about 10% to about 15%, about 10% to about 16%, about 10% to about 17%, about 10% to about 18%, about 10% to about 19%, about 10% to about 20%, about 11% to About 12%, about 11% to about 13%, about 11% to about 14%, about 11% to about 15%, about 11% to about 16%, about 11% to 17%, about 11% to about 18%, about 11% to about 19%, about 11% to about 20%, about 12% to about 13%, about 12% to about 14%, about 12% to about 15%, about 12% to about 16%, about 12% to about 17%, about 12% to about 18%, about 12% to about 19%, about 12% to about 20%, about 13% to about 14%, about 13% to about 15%, about 13% to about 16%, about 13% to about 17%, about 13% to about 18%, about 13% to about 19%, about 13% to about 20% , about 14% to about 15%, about 14% to about 16%, about 14% to about 17%, about 14% to about 18%, about 14% to about 19%, about 14% to about 20%, about 15% to about 16%, about 15% to about 17%, about 15% to about 18%, about 15% to about 19%, about 15% to about 20%, about 16% to about 17%, about 16% to about 18%, about 16% to about 19%, about 16% to about 20%, about 17% to about 18%, about 17% to about 19%, about 17% to about 20%, about 18% to about 19%, about 18% to about 20%, or about 19% to about 20%, and any range therebetween.The weight percentage can be about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%. The weight percentage can be at least about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, or about 14%. The weight percentage can be up to about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%. Furthermore, the weight percentage can be between about 5% and about 6%. The weight percentages are about 5% to about 5.1%, about 5% to about 5.2%, about 5% to about 5.3%, about 5% to about 5.4%, about 5% to about 5.5%, about 5% to about 5.6%, about 5% to about 5.7%, about 5% to about 5.8%, about 5% to about 5.9%, about 5% to about 6%, about 5.1% to about 5.2%, about 5.1% to about 5.3%, about 5.1% to about 5.4%, about 5.1% to about 5.5%, about 5% to about 5.6% .1% to about 5.6%, about 5.1% to about 5.7%, about 5.1% to about 5.8%, about 5.1% to about 5.9%, about 5.1% to about 6%, about 5.2% to about 5.3%, about 5.2% to about 5.4%, about 5.2% to about 5.5%, about 5.2% to about 5.6%, about 5.2% to about 5.7%, about 5.2% to about 5.8%, about 5.2% to about 5.9%, about 5.2% to about 6%, about 5.3% to about 5.4 %, about 5.3% to about 5.5%, about 5.3% to about 5.6%, about 5.3% to about 5.7%, about 5.3% to about 5.8%, about 5.3% to about 5.9%, about 5.3% to about 6%, about 5.4% to about 5.5%, about 5.4% to about 5.6%, about 5.4% to about 5.7%, about 5.4% to about 5.8%, about 5.4% to about 5.9%, about 5.4% to about 6%, about 5.5% to about 5.6%, about 5.5% to It can be about 5.7%, about 5.5% to about 5.8%, about 5.5% to about 5.9%, about 5.5% to about 6%, about 5.6% to about 5.7%, about 5.6% to about 5.8%, about 5.6% to about 5.9%, about 5.6% to about 6%, about 5.7% to about 5.8%, about 5.7% to about 5.9%, about 5.7% to about 6%, about 5.8% to about 5.9%, about 5.8% to about 6%, or about 5.9% to about 6%.The weight percentage can be about 5%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, about 5.5%, about 5.6%, about 5.7%, about 5.8%, about 5.9%, or about 6%. The weight percentage can be at least about 5%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, about 5.5%, about 5.6%, about 5.7%, about 5.8%, or about 5.9%. The weight percentage can be up to about 5.1%, about 5.2%, about 5.3%, about 5.4%, about 5.5%, about 5.6%, about 5.7%, about 5.8%, about 5.9%, or about 6%. Furthermore, the weight percentage can be between about 5% and about 5.1%.The weight percentages are about 5% to about 5.01%, about 5% to about 5.02%, about 5% to about 5.03%, about 5% to about 5.04%, about 5% to about 5.05%, about 5% to about 5.06%, about 5% to about 5.07%, about 5% to about 5.08%, about 5% to about 5.09%, about 5% to about 5.1%, about 5.01% to about 5.02%, about 5.01% to about 5.03%, about 5.01% to about 5.04%, about 5.01% to about 5.05%, and about 5.01% to about 5.0 6%, about 5.01% to about 5.07%, about 5.01% to about 5.08%, about 5.01% to about 5.09%, about 5.01% to about 5.1%, about 5.02% to about 5.03%, about 5.02% to about 5.04%, about 5.02% to about 5.05%, about 5.02% to about 5.06%, about 5.02% to about 5.07%, about 5.02% to about 5.08%, about 5.02% to about 5.09%, about 5.02% to about 5.1%, about 5.03% to about 5.04%, about 5.0 3% to about 5.05%, about 5.03% to about 5.06%, about 5.03% to about 5.07%, about 5.03% to about 5.08%, about 5.03% to about 5.09%, about 5.03% to about 5.1%, about 5.04% to about 5.05%, about 5.04% to about 5.06%, about 5.04% to about 5.07%, about 5.04% to about 5.08%, about 5.04% to about 5.09%, about 5.04% to about 5.1%, about 5.05% to about 5.06%, about 5.05% to about 5.0 7%, about 5.05% to about 5.08%, about 5.05% to about 5.09%, about 5.05% to about 5.1%, about 5.06% to about 5.07%, about 5.06% to about 5.08%, about 5.06% to about 5.09%, about 5.06% to about 5.1%, about 5.07% to about 5.08%, about 5.07% to about 5.09%, about 5.07% to about 5.1%, about 5.08% to about 5.09%, about 5.08% to about 5.1%, or about 5.09% to about 5.1%. The weight percentage can be about 5%, about 5.01%, about 5.02%, about 5.03%, about 5.04%, about 5.05%, about 5.06%, about 5.07%, about 5.08%, about 5.09%, or about 5.1%. The weight percentage can be at least about 5%, about 5.01%, about 5.02%, about 5.03%, about 5.04%, about 5.05%, about 5.06%, about 5.07%, about 5.08%, or about 5.09%.The weight percentage can be up to about 5.01%, about 5.02%, about 5.03%, about 5.04%, about 5.05%, about 5.06%, about 5.07%, about 5.08%, about 5.09%, or about 5.1%.

[0254] Other ranges set forth in Table 3B set forth in the table above (e.g., 3-15% for phospholipids, 0.1-10% for long chain fatty acids, 30-90% for water, 0.05%-5% for PDE5 inhibitors, 0.5-5% for penetration enhancers, 0.5-10% for emulsifiers) include similar ranges and subranges and values ​​therein. The present disclosure contemplates all similar ranges and subranges and values ​​therein for each component included in the formulation.

[0255] In some cases, the agent is present in an amount of about 0.001% to about 0.01% by weight of the formulation, about 0.011% to about 0.1% by weight of the formulation, about 0.11% to about 1.0% by weight of the formulation, about 1% to about 10% by weight of the formulation, about 11% to about 20% by weight of the formulation, or about 21% to about 30% by weight of the formulation. The present disclosure contemplates all similar ranges and subranges, and values ​​within the ranges, for the PDE5 inhibitor(s) present in the formulation.

[0256] In another embodiment, the transdermal delivery formulation comprises the components of Table 4:

[0257] [Table 8]

[0258] In another embodiment, the transdermal delivery formulation comprises the components of Table 4:

[0259] [Table 9]

[0260] In some cases, for a Drug "A" or Drug "B" formulation, rather than the amount of drug being about 1% or about 2% by weight of the formulation, the amount of drug is less than about 1% and the amount of water is increased proportionately. In other cases, rather than the amount of drug being about 1% or about 2% by weight of the formulation, the amount of drug is greater than about 2% and the amount of water is decreased proportionately.

[0261] In some embodiments, carotenoids are excluded from the disclosed formulations. In one embodiment, the transdermal delivery formulation comprises the components of Table 6:

[0262] [Table 10]

[0263] In some embodiments, carotenoids are excluded from the disclosed formulations. In one embodiment, the transdermal delivery formulation comprises the components of Table 7:

[0264] [Table 11]

[0265] In one embodiment, the concentration of phosphatidylcholine in the transdermal delivery formulation is at least 10%, at least 15%, at least 20%, at least 25%, at least 28.75%, at least 30%, at least 35%, at least 40%, or more. In one embodiment, the concentration of phosphatidylcholine in the transdermal delivery formulation is 10% or less, 15% or less, 20% or less, 25% or less, 28.75% or less, 30% or less, 35% or less, 40% or less, or more. In one embodiment, the concentration of phosphatidylcholine in the transdermal delivery formulation is about 10%, about 15%, about 20%, about 25%, at least 28.75%, about 30%, about 35%, about 40%, or more. In one embodiment, the concentration of phosphatidylcholine in the transdermal delivery formulation is 10% to 40%, 15% to 35%, 20% to 30%, 25% to 30%, or 28% to 29%.

[0266] In further embodiments, the concentration of benzyl alcohol in the transdermal formulation is at least 0.25%, at least 0.5%, at least 0.75%, at least 1%, at least 2%, at least 2.5%, at least 3%, at least 4%, at least 5%, or more. In one embodiment, the concentration of benzyl alcohol in the transdermal formulation is about 0.25%, about 0.5%, about 0.75%, about 1%, about 2%, about 2.5%, about 3%, about 4%, about 5%, or more. In another embodiment, the concentration of benzyl alcohol in the transdermal formulation is 0.25% to 5%, 0.5% to 4%, 0.75% to 3%, 1% to 2.5%, or 0.5% to 2%. In further embodiments, the concentration of benzyl alcohol in the transdermal formulation is 0.25% or less, 0.5% or less, 0.75% or less, 1% or less, 2% or less, 2.5% or less, 3% or less, 4% or less, or 5% or less.

[0267] In one embodiment, the concentration of deionized water in the transdermal formulation is at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, at least 0.9%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, or more. In one embodiment, the concentration of deionized water in the transdermal formulation is about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, or more. In one embodiment, the concentration of deionized water in the transdermal formulation is 0.1% to 5%, 0.2% to 4%, 0.3% to 3%, 0.4% to 2%, 0.5% to 1%, 0.6% to 0.9%, 0.7% to 0.8%, 0.4% to 1.5%, 0.3% to 0.7%, or 0.4% to 0.6%. In one embodiment, the concentration of deionized water in the transdermal formulation is 0.1% or less, 0.2% or less, 0.3% or less, 0.4% or less, 0.5% or less, 0.6% or less, 0.7% or less, 0.8% or less, 0.9% or less, 1% or less, 2% or less, 3% or less, 4% or less, 5% or less, or more.

[0268] In one embodiment, the concentration of safflower oil in the transdermal delivery formulation is at least 1%, at least 5%, at least 7.5%, at least 10%, at least 11%, at least 11.06%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, or more. In one embodiment, the concentration of safflower oil in the transdermal delivery formulation is about 1%, about 5%, about 7.5%, about 10%, about 11%, about 11.06%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, or more. In one embodiment, the concentration of safflower oil in the transdermal delivery formulation is 1% to 20%, 5% to 19%, 7.5% to 18%, 10% to 17%, 11% to 16%, 11.06%, 12%, 11% to 12%, 12% to 14%, 13% to 14%, 10% to 12%, 10.5% to 12.5%, or 11% to 11.25%. In one embodiment, the concentration of safflower oil in the transdermal delivery formulation is 1% or less, 5% or less, 7.5% or less, 10% or less, 11% or less, 11.06% or less, 12% or less, 13% or less, 14% or less, 15% or less, 16% or less, 17% or less, 18% or less, 19% or less, or 20% or less.

[0269] In further embodiments, the concentration of oleic acid in the transdermal delivery formulation is at least 1%, at least 2%, at least 3%, at least 3.65%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, or more. In further embodiments, the concentration of oleic acid in the transdermal delivery formulation is about 1%, about 2%, about 3%, about 3.65%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, or more. In further embodiments, the concentration of oleic acid in the transdermal delivery formulation is 1% or less, 2% or less, 3% or less, 3.65% or less, 4% or less, 5% or less, 6% or less, 7% or less, 8% or less, 9% or less, 10% or less, or more. In another embodiment, the concentration of oleic acid in the transdermal formulation is 1% to 10%, 2% to 9%, 2% to 3%, 3% to 4%, 3% to 8%, 4% to 7%, 5% to 6%, 2 to 2.5%, or 2.5% to 4%.

[0270] In another embodiment, the concentration of stearic acid in the transdermal formulation is at least 1%, at least 2%, at least 2.34%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, or more. In another embodiment, the concentration of stearic acid in the transdermal formulation is 1% or less, 2% or less, 2.34% or less, 3% or less, 4% or less, 5% or less, 6% or less, 7% or less, 8% or less, 9% or less, 10% or less, or more. In another embodiment, the concentration of stearic acid in the transdermal formulation is about 1%, about 2%, about 2.34%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, or more. In another embodiment, the concentration of stearic acid in the transdermal formulation is 1% to 10%, 2% to 9%, 2% to 3%, 2.34% to 2.5%, 3% to 8%, 4% to 7%, 5% to 6%, or 1.5 to 2.5%.

[0271] In one embodiment, the concentration of isopropyl palmitate in the transdermal formulation is at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, or more. In one embodiment, the concentration of isopropyl palmitate in the transdermal formulation is about 10%, about 20%, about 25%, about 30%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or more. In one embodiment, the concentration of isopropyl palmitate in the transdermal formulation is 10% or less, 20% or less, 25% or less, 30% or less, 40% or less, 45% or less, 50% or less, 55% or less, 60% or less, 65% or less, 70% or less, 75% or less, or more. In one embodiment, the concentration of isopropyl palmitate in the transdermal formulation is 10% to 75%, 20% to 70%, 25% to 65%, 30% to 60%, 40% to 55%, 45% to 50%, 40% to 60%, 45% to 55%, or 47% to 53%.

[0272] In one embodiment, the concentration of poloxamer 407 in the transdermal delivery formulation is at least 10%, at least 15%, at least 20%, at least 25%, at least 28.75%, at least 30%, at least 35%, at least 40%, or more. In one embodiment, the concentration of poloxamer 407 in the transdermal delivery formulation is 10% or less, 15% or less, 20% or less, 25% or less, 28.75% or less, 30% or less, 35% or less, 40% or less, or more. In one embodiment, the concentration of poloxamer 407 in the transdermal delivery formulation is about 10%, about 15%, about 20%, about 25%, at least 28.75%, about 30%, about 35%, about 40%, or more. In one embodiment, the concentration of poloxamer 407 in the transdermal delivery formulation is 10% to 40%, 15% to 35%, 20% to 30%, 25% to 30%, or 28% to 29%.

[0273] In another embodiment, the formulation contains glucose. The concentration of glucose in the transdermal delivery formulation is, for example, at least 1%, at least 2%, at least 2.5%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or more. In another embodiment, the concentration of glucose in the transdermal delivery formulation is about 1%, about 2%, about 2.5%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or more. In another embodiment, the concentration of glucose in the transdermal delivery formulation is 1% or less, 2% or less, 2.5% or less, 3% or less, 4% or less, 5% or less, 6% or less, 7% or less, 8% or less, 9% or less, or more. In other aspects, the concentration of glucose in the transdermal delivery formulation is 1% to 10%, 2% to 9%, 2.5% to 5%, 2% to 3%, 3% to 8%, 4% to 7%, 5% to 6%, 2% to 4%, or 1.5% to 3.5%. In various embodiments, the transdermal delivery formulation does not contain glucose.

[0274] Specific components or ingredients of the transdermal delivery formulations provided herein may be supplemented by components described in more detail in the inventor's related applications, including U.S. Application No. 16 / 132,358, filed September 14, 2018, entitled "Methods and Formulations For Transdermal Administration Of Buffering Agents," PCT / US18 / 51250, filed September 14, 2018, entitled "Methods of Administration and Treatment," and PCT / US18 / 28017, filed April 17, 2018, by Bruce Sand, entitled "Parental non-systemic administration of buffering agents for inhibiting metastasis of solid tumors, hyperpigmentation and gout," each of which is incorporated by reference in its entirety.

[0275] Transdermal delivery formulations can include mixtures in which the components interact synergistically to induce a better skin penetration enhancement than that induced by the individual components. Synergy between chemicals can be exploited to design powerful penetration enhancers that overcome the limited effectiveness of a single enhancer. Some embodiments disclosed herein utilize 3-5 different penetration enhancers.

[0276] In some embodiments, the transdermal delivery formulation contains phosphatidylcholine in an amount less than 12% or 18% by weight of the formulation. In some embodiments, the transdermal delivery formulation contains phospholipids in an amount less than 12% or 18% by weight of the formulation. In some embodiments, the transdermal delivery formulation contains a mixture of tridecane and undecane in an amount less than 2%, 5%, or 8% by weight of the formulation. In some embodiments, the formulation contains Cetiol Ultimate® or an equal weight mixture of tridecane and undecane in an amount less than about 2%, 5%, or 10% by weight. In some embodiments, the transdermal delivery formulation contains cetyl alcohol in an amount less than 2%, 5%, or 8% by weight of the formulation. In some embodiments, the transdermal delivery formulation contains benzyl alcohol in an amount less than about 2%, 5%, or 8% by weight. In some embodiments, the transdermal delivery formulation contains stearic acid in an amount less than 2%, 5%, or 8% by weight of the formulation.

[0277] For topical administration, and particularly for transdermal administration, transdermal delivery formulations include penetrants, including chemical penetrants (CPEs) and / or peptide-based cell penetrants (CPPs), which facilitate penetration through the dermis and / or membranes, including cell membranes, as in the case of transdermal administration. In some embodiments, suitable penetrants include those described in the above-referenced US2009 / 0053290, WO2014 / 209910, and WO2017 / 127834. In addition to transdermal delivery formulations that include penetrants, transdermal delivery can be achieved by mechanically disrupting the skin surface to facilitate penetration, or simply by providing the formulation applied to the skin under an occlusive patch.

[0278] Alternatively, the transdermal delivery formulation includes a completion component, plus one or more electrolytes, one or more surfactants, and an alcohol sufficient to impart viscosity and viscoelasticity. The completion component can be a polar liquid, a non-polar liquid, or an amphiphile. The penetrating agent can further include a keratin degrading agent, and / or a cell-penetrating peptide (sometimes referred to as a skin-penetrating peptide), and / or a penetration enhancer effective to reduce thiol bonds, break hydrogen bonds, and / or effect keratinocyte lysis.

[0279] Suitable gelling components also include isopropyl palmitate, ethyl laurate, ethyl myristate, and isopropyl myristate. In some embodiments, the transdermal delivery formulation contains a gelling agent in an amount less than 5% by weight of the transdermal delivery formulation. Certain hydrocarbons, such as cyclopentane, cyclooctane, trans-decalin, trans-pinane, n-pentane, n-hexane, and n-hexadecane, can also be used. In some embodiments, the transdermal delivery formulation contains xanthan gum, sclerotium gum, pullulan, or a mixture of combinations thereof in an amount less than 2%, 5%, or 10% by weight of the formulation. In some embodiments, the transdermal delivery formulation contains Siligel™ or an equal mixture of xanthan gum, sclerotium gum, and pullulan in an amount of about 1 to about 5% by weight or about 5 to about 15% by weight. In some embodiments, the transdermal delivery formulation comprises a mixture of caprylic triglyceride and capric triglyceride in an amount less than 2%, 8%, or 10% by weight of the formulation. In some embodiments, the transdermal delivery formulation comprises Myritol® 312 in an amount of about 0.5 to about 10% by weight, or an equal mixture of caprylic triglyceride and capric triglyceride.

[0280] In some embodiments, the transdermal delivery formulation comprises about 10 to about 90% by weight, or about 10 to about 50% by weight, or at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% by weight of the formulation. In some embodiments, the transdermal delivery formulation comprises phosphatidylcholine in an amount less than 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, or 18% by weight of the formulation. In some embodiments, the transdermal delivery formulation comprises phospholipid in an amount less than 20%, 30%, 40%, or 50% by weight of the formulation. In some embodiments, the transdermal delivery formulation comprises a mixture of tridecane and undecane in an amount less than 2%, 3%, 4%, 5%, 6%, 7%, or 8% by weight of the formulation. In some embodiments, the formulation comprises Cetiol Ultimate® or an equivalent mixture of tridecane and undecane in an amount less than about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% by weight of the formulation. In some embodiments, the transdermal delivery formulation comprises cetyl alcohol in an amount less than 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% by weight of the formulation. In some embodiments, the formulation comprises benzyl alcohol in an amount less than about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% by weight of the formulation. In some embodiments, the transdermal delivery formulation comprises stearic acid in an amount less than 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% by weight of the formulation. In some embodiments, the transdermal delivery formulation comprises phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, one or more phosphatides, one or more inositol phosphatides, or a combination thereof in an amount less than 30% by weight, or less than 12% by weight of the formulation.

[0281] Additional components in the transdermal delivery formulation of the present disclosure are alcohols. Benzyl alcohol and ethanol are described in the Examples. Specifically, derivatives of benzyl alcohol containing substituents on the benzene ring, such as halo, alkyl, etc., are used. The weight percentage of benzyl or other related alcohols in the final composition is 0.5 to 20% by weight, including intermediate percentages such as 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% by weight, as well as other intermediate weight percentages. The aromatic group present in the transdermal delivery formulation, such as benzyl alcohol, provides the molecule with a polar end (alcohol end) and a nonpolar end (benzene end). This allows the agent to dissolve a wider variety of transdermal delivery formulation components.

[0282] In some embodiments, the performance of transdermal delivery formulations is further improved by including a nonionic detergent and a polar gelling agent, or by including a powder surfactant, as described above. In both aqueous and anhydrous forms of the composition, a detergent, typically a nonionic detergent, is added. Generally, the nonionic detergent should be present in an amount of about 1% to about 30% by weight of the transdermal delivery formulation. Typically, in compositions where the transdermal delivery formulation is supplemented with a polar or aqueous solution containing detergent, the amount of detergent is relatively small, e.g., 2-25%, 5-15%, or 7-12% by weight of the transdermal delivery formulation. However, in compositions that are substantially anhydrous and supplemented with powder detergent, relatively high percentages, e.g., 20-60% by weight, are commonly used.

[0283] In some embodiments, the transdermal delivery formulation further comprises a surfactant in an amount of about 1 to about 70% by weight or about 1 to about 60% by weight of the transdermal delivery formulation. In some embodiments, the non-ionic detergent provides suitable handling properties, and the formulation is gel-like or creamy at room temperature. To achieve this effect, the detergent, typically a poloxamer, is present in an amount of about 2 to about 12% by weight of the transdermal delivery formulation, preferably about 5 to about 25% by weight in polar formulations. In anhydrous forms of the composition, the detergent is added in powder or micronized form to make up the composition and higher amounts are used. In compositions containing polar components, the non-ionic detergent is added as a solution rather than a bile salt to make up the composition. If a smaller amount of detergent solution is required due to the amount of remaining components, a more concentrated solution of non-ionic detergent is used. Thus, for example, the percentage of detergent in the solution can be 10% to 40%, or 20%, or 30%, and intermediate values, depending on the percentage of other components.

[0284] Suitable nonionic detergents include poloxamers, such as the nonionic surfactant Pluronic®, as well as any other surfactant characterized by a combination of hydrophilic and hydrophobic moieties. Poloxamers are triblock copolymers of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyethylene oxide. Other nonionic surfactants include long-chain alcohols and copolymers of hydrophilic and hydrophobic monomers, in which blocks of hydrophilic and hydrophobic moieties are used.

[0285] In some embodiments, the transdermal delivery formulation also contains a surfactant, typically a non-ionic surfactant, at 2-25% by weight of the transdermal delivery formulation, along with the polar solvent, with the polar solvent present in at least a molar excess relative to the non-ionic surfactant. In these embodiments, the composition typically includes a sufficient amount of a polar solution, typically an aqueous solution or a polyethylene glycol solution, which itself contains 10-40% surfactant, typically a non-ionic surfactant, along with the above-mentioned amounts of the transdermal delivery formulation and benzyl alcohol to bring the composition to 100%.

[0286] Other examples of surfactants include polyoxyethylated castor oil derivatives, such as HCO-60 surfactant sold by HallStar Company; nonoxynol; octoxynol; phenylsulfonates; poloxamers such as those sold by BASF, such as Pluronic® F68, Pluronic® F127, and Pluronic® L62; polyoleates; Rewopal® HVIO, sodium laurate, sodium lauryl sulfate (sodium dodecyl sulfate); sodium oleate; sorbitan dilaurate; sorbitan dioleate; sorbitan monolaurate, such as Span® 20 sold by Sigma-Aldrich; sorbitan monooleate; sorbitan trilaurate; sorbitan trioleate; sorbitan monopalmitate, such as Span® 40 sold by Sigma-Aldrich; sorbitan stearate, such as Span® 85 sold by Sigma-Aldrich; Sigma-Aldrich. p-(1,1,3,3-tetramethylbutyl)-phenyl ether, sold as Triton™ X-100 by Sigma-Aldrich; and polysorbates such as polyoxyethylene (20) sorbitan monolaurate, sold as Tween® 20 by Sigma-Aldrich, polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), sold as Tween® 40, polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), sold as Tween® 60, polysorbate 80 (polyoxyethylene (20) sorbitan monooleate), sold as Tween® 80, and polyoxyethylene sorbitan trioleate, sold as Tween® 85.The weight percentage range for the nonionic surfactant ranges from 3% to 15% by weight, again including intermediate percentages such as 5%, 7%, 10%, 12%, etc. In some embodiments, the surfactant portion comprises a nonionic surfactant in an amount of about 1% to about 30% by weight of the formulation and a polar solvent in an amount less than 5% by weight of the formulation. In some embodiments, the nonionic surfactant is a poloxamer and the polar solvent is water, alcohol, or a combination thereof. In some embodiments, the surfactant portion comprises a poloxamer, propylene glycol, glycerin, ethanol, 50% by weight sodium hydroxide solution, or a combination thereof. In some embodiments, the surfactant portion comprises glycerin in an amount less than 3% by weight of the formulation.

[0287] In the presence of polar gelling agent, such as water, glycerol, ethylene glycol or formamide, micelle structure is also often realized.Usually, polar agent is in molar excess with respect to nonionic detergent.By including the combination of nonionic detergent / polar gelling agent, more viscous and creamy or gel-like formulations are obtained, which are suitable for direct application to skin.This is characteristic of the aqueous form of composition.

[0288] In some embodiments, other additives such as gelling agents, dispersing agents, and preservatives are included. An example of a suitable gelling agent is hydroxypropyl cellulose, which is generally available in grades with viscosities ranging from about 5 cps to about 25,000 cps, e.g., about 1500 cps. All viscosity measurements are assumed to be performed at room temperature unless otherwise noted. The concentration of hydroxypropyl cellulose may range from about 1% to about 2% by weight of the composition. Other gelling agents are known in the art and can be used in place of or in addition to hydroxypropyl cellulose. An example of a suitable dispersing agent is glycerin. Glycerin is typically included at a concentration of about 5% to about 25% by weight of the composition. Preservatives can be included at a concentration effective to inhibit microbial growth, ultraviolet light- and / or oxygen-induced destruction of composition components, and the like. If a preservative is included, its concentration may vary from about 0.01% to about 1.5% by weight of the composition.

[0289] Additional components that can also be included in transdermal delivery formulations include fatty acids, terpenes, lipids, and cationic and anionic detergents. In some embodiments, the transdermal delivery formulation further comprises tranexamic acid in an amount less than 2%, 5%, or 10% by weight of the formulation. In some embodiments, the transdermal delivery formulation further comprises a polar solvent in an amount less than 2%, 5%, 10%, or 20% by weight of the transdermal delivery formulation. In some embodiments, the transdermal delivery formulation further comprises a humectant, an emulsifier, an emollient, or a combination thereof. In some cases, the humectant is propylene glycol. In some cases, the emulsifier is polyglyceryl-4-laurate, cetyl alcohol, or Durosoft PK-SG. In some cases, the emollient is derived from almond oil. In some embodiments, the transdermal delivery formulation further comprises almond oil in an amount less than about 5% by weight. In some embodiments, the formulation further comprises a mixture of thermoplastic polyurethane and polycarbonate in an amount less than about 5% by weight. In some embodiments, the transdermal delivery formulation further comprises phosphatidylethanolamine in an amount less than about 5% by weight. In some embodiments, the transdermal delivery formulation further comprises inositol phosphatide in an amount less than about 5% by weight.

[0290] Other solvents and related compounds that can be used in some embodiments include acetamide and derivatives, acetone, n-alkanes (chain length 7-16), alkanols, diols, short chain fatty acids, cyclohexyl-1,1-dimethylethanol, dimethylacetamide, dimethylformamide, ethanol, ethanol / d-limonene combinations, 2-ethyl-1,3-hexanediol, ethoxydiglycol (Transcutol® from Gattefosse, Lyon, France), glycerol, glycol, lauryl chloride, limonene N-methylformamide, 2-phenylethanol, 3-phenyl-1-propanol, 3-phenyl-2-propen-1-ol, polyethylene glycol, polyoxyethylene sorbitan monoesters, polypropylene glycol 425, primary alcohols (tridecanol), 1,2-propanediol, butanediol, C16 or C 18 Monounsaturated alcohol, C 16 or C 18 Included are C3-C6 triols or mixtures thereof and polar lipid compounds selected from branched chain saturated alcohols, and mixtures thereof, propylene glycol, sorbitan monolaurate sold by Sigma-Aldrich as Span® 20, squalene, triacetin, trichloroethanol, trifluoroethanol, trimethylene glycol, and xylene.

[0291] Fatty alcohols, fatty acids, and fatty acid esters are biphasic fluidizers that can be used in some embodiments. Examples of suitable fatty alcohols include fatty alcohol, decanol, lauryl alcohol (dodecanol), unoleyl alcohol, nerolidol, 1-nonanol, n-octanol, and oleyl alcohol. Examples of suitable fatty acid esters include butyl acetate, cetyl lactate, decyl N,N-dimethylamino acetate, decyl N,N-dimethylamino isopropionate, diethylene glycol oleate, diethyl sebacate, diethyl succinate, diisopropyl sebacate, dodecyl N,N-dimethylamino acetate, dodecyl (N,N-dimethylamino)-butyrate, dodecyl N,N-dimethylamino isopropionate, dodecyl 2-(dimethylamino)propionate, E0-5-oleyl ether, ethyl acetate, ethyl acetoacetate, ethyl propionate, glycerol monoether, glycerol monolaurate, glycerol monooleate, glycerol monolinoleate, isopropyl isostearate, isopropyl linoleate, isopropyl myristate, Isopropyl myristate / fatty acid monoglyceride combination, isopropyl palmitate, methyl acetate, methyl caprate, methyl laurate, methyl propionate, methyl valerate, 1-monocaproylglycerol, medium chain monoglyceride, benzyl nicotinate, octyl acetate, octyl N,N-dimethylaminoacetate, oleyl oleate, n-pentyl N-acetylprolinate, propylene glycol monolaurate, sorbitan dilaurate, sorbitan dioleate, sorbitan monolaurate, sorbitan monooleate, sorbitan trilaurate, sorbitan trioleate, sucrose coconut fatty ester mixture, sucrose monolaurate, sucrose monooleate, tetradecyl N,N-dimethylaminoacetate.Examples of suitable fatty acids include alkanoic acid, caprylic acid, diacid, ethyloctadecanoic acid, hexanoic acid, lactic acid, lauric acid, linoelaidic acid, linoleic acid, linolenic acid, neodecanoic acid, oleic acid, palmitic acid, pelargonic acid, propionic acid, and vaccenic acid. Examples of suitable fatty alcohol ethers include monoglyceryl ether, E0-2 oleyl ether, E0-5 oleyl ether, E0-10 oleyl ether, ether derivatives of polyglycerols and alcohols, and (1-O-dodecyl-3-O-methyl-2-O-(2',3'-dihydroxypropylglycerol).

[0292] Examples of completing agents that can be used in some embodiments include β- and γ-cyclodextrin complexes, hydroxypropyl methylcellulose (e.g., Carbopol® 934), liposomes, naphthalenediamide diimides, and naphthalenediester diimides.

[0293] One or more antioxidants such as vitamin C, vitamin E, proanthocyanidins, and α-lipoic acid may be included, typically at concentrations of 0.1% to 2.5% by weight.

[0294] In some applications, it is desirable to adjust the pH of the transdermal delivery formulation to aid penetration or to adjust the disposition of the target compound in the subject. In some cases, the pH is adjusted to a level of pH 9-11 or 10-11, which can be done by providing an appropriate buffer or simply adjusting the pH with a base.

[0295] Transdermal delivery formulations may contain other components that act as excipients or serve purposes other than muscle performance and recovery. For example, preservatives, such as antioxidants (e.g., ascorbic acid or alpha-lipoic acid), and antibacterial agents may be included. Components other than the therapeutically active ingredient and the components primarily responsible for transdermal penetration may include those that serve aesthetic purposes, such as menthol or other aromatic compounds, and components that affect the physical state of the composition, such as emulsifiers, e.g., Durosoft®. Typically, these components are present in very small percentages in the composition. These latter adjuncts are understood to be neither therapeutic ingredients nor components primarily responsible for skin penetration. Components primarily affecting skin penetration have been described in detail above. However, some of these substances may also have the ability to affect skin penetration. See, for example, Kunta, J. Ret al., J. Pharm. Sci. (1997) 86:1369-1373, which describes the permeability of menthol.

[0296] The application method is determined by the nature of treatment, but may not be as critical as the nature of the formulation itself.When applying to skin area, it may be useful to prepare the skin by cleansing or exfoliating in some cases.In some cases, it is useful to adjust the pH of the skin area before applying the transdermal delivery formulation itself.The application of transdermal delivery formulation can be by simply massaging it onto the skin, or by using a device such as a syringe or pump.Patches can also be used.In some cases, it is useful to cover the application area to prevent the evaporation or loss of the transdermal delivery formulation.

[0297] When the application area is essentially skin, it is useful to seal the application area after applying the transdermal delivery formulation, so that permeation can occur and skin barrier can be restored.The convenient way to do this is to apply a composition that contains linoleic acid, and effectively close the entrance path provided by the permeation agent of the present invention.This application can also be carried out by directly dabbing on the skin area, or can be more precisely applied in a measured amount.

[0298] In addition to the compositions and preparations of the present invention themselves, the method can also use post-treatment with linoleic acid.Because transdermal treatment generally opens the skin barrier, in fact, this is the purpose, but it is useful to seal the application area after treatment is completed.Therefore, after treatment with transdermal delivery preparation, in order to seal the application area, the skin area can be treated with a composition that contains linoleic acid.The application of linoleic acid is applied to any transdermal procedure that causes the skin to lose its ability to function as a protective layer.In fact, the function of most transdermal treatments is to allow active ingredients to pass through the epidermis at least to the dermis, so when systemic administration is achieved through the dermis itself, it has this effect.

[0299] Additional therapeutic agents can be included in the composition. For example, hydrocortisone or hydrocortisone acetate can be included in an amount ranging from 0.25% to about 0.5% by weight. Menthol, phenols, and terpenoids, such as camphor, can be incorporated for cooling pain relief. For example, menthol can be included in an amount ranging from about 0.1% to about 1.0% by weight.

[0300] Compositions containing an anesthetic are useful for temporarily relieving pain and itching associated with minor burns, cuts, scrapes, skin irritations, inflammation and rashes caused by soaps, detergents or cosmetics, or, as mentioned above, pain associated with the removal of fat deposits.

[0301] Certain embodiments of the transdermal delivery formulations provided herein may be supplemented with formulation components described in more detail in the inventor's related applications, including U.S. Application No. 16 / 132,358, filed September 14, 2018, entitled "Methods and Formulations For Transdermal Administration Of Buffering Agents," International Patent Application No. PCT / US18 / 51250, filed September 14, 2018, entitled "Methods of Administration and Treatment," and International Patent Application No. PCT / US18 / 28017, filed April 17, 2018, entitled "Parental non-systemic administration of buffering agents for inhibiting metastasis of solid tumors, hyperpigmentation and gout," by Bruce Sand, all of which are incorporated herein by reference in their entireties.

[0302] In some particular embodiments, it is desirable to adjust the pH of the transdermal delivery formulation, and the pH is adjusted to a level of pH 9-11, or 10-11, which can be done by providing an appropriate buffer or simply adjusting the pH with a base. In other embodiments, it is desirable to adjust the pH of the transdermal delivery formulation to a level of pH 4-6, and this can be done by providing an appropriate buffer or simply adjusting the pH with an acid.

[0303] For some applications, the formulation for transdermal delivery may contain, for example, Aveeno® in an amount of, for example, about 10 to about 95% by weight, about 20 to about 85% by weight, about 20 to about 75% by weight, or about 20 to about 50% by weight.

[0304] In another aspect, certain embodiments relate to sustained release drug delivery platforms that release a therapeutic compound(s) disclosed and formulated as formulations described herein over a period of, but not limited to, about 3 days after administration, about 7 days after administration, about 10 days after administration, about 15 days after administration, about 20 days after administration, about 25 days after administration, about 30 days after administration, about 45 days after administration, about 60 days after administration, about 75 days after administration, or about 90 days after administration. In other embodiments of this embodiment, the sustained release drug delivery platform releases a therapeutic compound(s) disclosed herein at a substantially first order release rate over a period of, but not limited to, at least 3 days after administration, at least 7 days after administration, at least 10 days after administration, at least 15 days after administration, at least 20 days after administration, at least 25 days after administration, at least 30 days after administration, at least 45 days after administration, at least 60 days after administration, at least 75 days after administration, or at least 90 days after administration.

[0305] The formulations described herein can also contain two or more therapeutic compounds, preferably with complementary activities that do not adversely affect other proteins, which is desirable for the specific indication being treated.The transdermal delivery formulations used for in vivo administration can be sterilized.This can be achieved, for example, but not limited to, by filtration through a sterile filtration membrane before or after preparing the transdermal delivery formulation, or by other methods known in the art, including but not limited to pasteurization.

[0306] Packaging and devices for administration can be determined by various considerations, including, but not limited to, the volume of material to be administered, storage conditions, administration by a skilled healthcare practitioner versus patient self-compliance, dosage regimen, geopolitical environment (e.g., exposure to extreme temperature conditions in developing countries), and other practical considerations.

[0307] In certain embodiments, the kit can include one or more creams or lotions, including, but not limited to, one or more formulations described herein. In various embodiments, the kit can include formulation components for transdermal, topical, or subcutaneous administration formulated for administration as an emulsion-coated patch. In all of these and other embodiments, the kit can contain one or more lotions, creams, patches, etc. according to any of the foregoing, each patch containing a single unit dose for administration to a subject.

[0308] An imaging component can optionally be included, and the packaging can also include written or web-accessible instructions for using the transdermal delivery formulation. The container can include, for example, a vial, a bottle, a patch, a syringe, a pre-filled syringe, a tube, or any of a variety of formats known in the art for multi-dispenser packaging.

[0309] In one embodiment, the concentration of poloxamer 407 in the transdermal delivery formulation is at least 10%, at least 15%, at least 20%, at least 25%, at least 28.75%, at least 30%, at least 35%, at least 40%, or more. In one embodiment, the concentration of poloxamer 407 in the transdermal delivery formulation is 10% or less, 15% or less, 20% or less, 25% or less, 28.75% or less, 30% or less, 35% or less, 40% or less, or more. In one embodiment, the concentration of poloxamer 407 in the transdermal delivery formulation is about 10%, about 15%, about 20%, about 25%, at least 28.75%, about 30%, about 35%, about 40%, or more. In one embodiment, the concentration of poloxamer 407 in the transdermal delivery formulation is 10% to 40%, 15% to 35%, 20% to 30%, 25% to 30%, or 28% to 29%.

[0310] Transdermal delivery formulations can include mixtures in which the components interact synergistically to induce a better skin penetration enhancement than that induced by the individual components. Synergy between chemicals can be exploited to design powerful penetration enhancers that overcome the limited effectiveness of a single enhancer. Some embodiments disclosed herein utilize 3-5 different penetration enhancers.

[0311] Administration and Dosage Provided herein are methods for treating, preventing, or alleviating a disease, disorder, condition, or symptom thereof or a condition related thereto using the transdermal delivery formulations described herein for transdermal delivery. The methods provided herein can include or consist of topical delivery to the skin of one or more of the transdermal delivery formulations described herein in a patient in need thereof. Preferred, but not limited, embodiments relate to methods for treating, preventing, inhibiting, or alleviating a disease, disorder, condition, or symptom described herein.

[0312] Formulations for transdermal delivery can include one or more drugs (eg, of Table 1) and a penetrating moiety.

[0313] The transdermal delivery formulation provided herein can be administered topically in any form.For the administration to treat skin conditions, a sufficient amount of topical composition can be applied to the desired area and surrounding skin, for example, in an amount sufficient to cover the desired skin surface.The transdermal delivery formulation can be applied to any skin surface, including, for example, the skin of face, and the skin of hands, neck, chest and / or scalp.

[0314] In applying the transdermal delivery formulation of the present invention, the transdermal delivery formulation itself is simply placed on the skin, spread on the surface, and / or massaged to aid penetration. The amount of transdermal delivery formulation used is usually sufficient to cover the desired surface area. In some embodiments, once the formulation is applied, a protective cover is placed over it and left in place for a suitable period of time, i.e., 5 minutes, 10 minutes, 20 minutes, or more; in some embodiments, 1 or 2 hours. The protective cover can simply be a bandage, including a bandage with a moisture-impermeable cover. This essentially secures the transdermal delivery formulation in contact with the skin and, in some cases, prevents deformation of the transdermal delivery formulation due to evaporation. The composition can be applied to the skin using standard application methods, such as a brush, syringe, gauze pad, dropper, or any convenient applicator. More complex application methods, including the use of a delivery device, can also be used, but are not required. In an alternative method of topical administration to intact skin, the surface of the skin can be mechanically disrupted by using a spring system, a laser-driven system, a Lorentz force-driven system, or by shock waves containing gas or ultrasound, and microdermabrasion can be used, such as by using sandpaper or its equivalent, or by using a microneedle or electroporation device.A simple solution of the above-mentioned formulation that penetrates intact skin with the agent(s) can be applied using an occlusive patch, such as in the form of a micropatch.An external reservoir of the formulation can also be used for long-term administration.

[0315] In an alternative method of topical administration to intact skin, the surface of the skin can be mechanically disrupted by using a spring system, a laser-driven system, iontophoresis, a Lorentz force-driven system, or shock waves including gas or ultrasound, and microdermabrasion can be used, such as by using sandpaper or its equivalent, or by using a microneedle or electroporation device.A simple solution of the above-mentioned transdermal delivery formulation that penetrates intact skin with the agent(s) can be applied using an occlusive patch, such as one in the form of a micropatch.An external reservoir of the formulation can also be used for long-term administration.

[0316] Thus, in certain embodiments, alternative methods of administering one or more therapeutic compounds or agents (e.g., drugs) through intact skin are provided. By way of non-limiting example, these alternative methods may be selected from the following list: actuation mechanisms, spring systems, laser-driven, energy-driven, Lorentz force, gas / air-driven, shock wave (including ultrasound)-based; load types, liquid, powder, projectile-based; drug delivery mechanisms, nanopatch, sandpaper (microdermabrasion), iontophoretic enabled, microneedle-based; delivery sites, intradermal, intramuscular, and subcutaneous injection-based. Other suitable delivery mechanisms include, but are not limited to, microneedle drug delivery such as the 3M system, Glide SDI (pushing the drug as opposed to "shooting" it), the MIT low-pressure injector, micropatches (single-use particle insertion devices), microelectromechanical systems (MEMS), skin electroporation devices (DEP), Transderm ion-to-skin systems (DEP), TTS transdermal therapeutic systems, membrane-controlled systems (drug reservoirs completely encapsulated in shallow compartments), adhesive diffusion-controlled systems (drug reservoirs within compartments made of a drug-impermeable metal-plastic backing), matrix-dispersed systems (drug reservoirs formed by homogeneously dispersing drug solids in a hydrophilic or lipophilic polymer matrix former onto a dosage disc), and microreservoir systems (combinations of reservoirs and matrix-dispersed drug delivery systems).

[0317] The application method is determined by the nature of treatment, but may not be as critical as the nature of transdermal delivery formulation itself.When applying to skin area, it may be useful to prepare the skin by cleansing or exfoliating in some cases.In some cases, it is useful to adjust the pH of the skin area before applying the formulation itself.The application of transdermal delivery formulation can be by simply massaging it onto the skin, or by using a device such as a syringe or pump.Patches can also be used.In some cases, it is useful to cover the application area to prevent the evaporation or loss of transdermal delivery formulation.

[0318] When the application area is essentially skin, it is useful to seal the application area after applying the transdermal delivery formulation, so that permeation can occur and skin barrier can be restored.The convenient way to do this is to apply a composition that contains linoleic acid, and effectively close the entrance path provided by the permeation agent of the present invention.This application can also be carried out by directly dabbing on the skin area, or can be more precisely applied in a measured amount.

[0319] The transdermal delivery formulations can be applied in a single application, once a week, once every two weeks, once a month, or one to twelve times a day for a period sufficient to alleviate a condition, disease, disorder, or symptom, for example, one week, one to twelve weeks or more, one to six weeks, two to twelve weeks, two to eight weeks, two to six weeks, two to four weeks, four to twelve weeks, four to eight weeks, or four to six weeks. The compositions can be administered as frequently as needed, for example, once a day to once an hour. The formulations described herein can be administered topically one or more times a day for one to four weeks, one to two weeks, one week, two weeks, three weeks, or four weeks or more. In some cases, it may be desirable to continue treatment indefinitely, for example, to inhibit recurrent inflammation. Suitable administration of transdermal delivery formulations, including skin creams, lotions, or ointments, is, for example, once, twice, three times, four times a day, or hourly as needed.

[0320] As noted above, if desired, other therapeutic agents can be used in conjunction with those provided in the compositions described above. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host being treated, the nature of the disease, disorder or condition, and the nature of the active ingredient.

[0321] It is understood that the specific dose level for any particular patient will vary depending on a variety of factors, including the activity of the particular active agent, the patient's age, weight, general health, sex, and diet, the time of administration, the rate of excretion, possible drug combinations, the severity of the specific condition being treated, the area being treated, and the mode of administration. One skilled in the art will understand the variability of such factors and will be able to establish specific dose levels using only routine experimentation.

[0322] Pharmacokinetic parameters such as bioavailability, absorption rate constant, apparent volume of distribution, unbound fraction, total clearance, unchanged excreted fraction, first-pass metabolism, elimination rate constant, half-life, and mean residence time can be determined by methods well known in the art.

[0323] Transdermal delivery formulations according to the subject matter described herein may be, for example, topical dosage forms packaged in multi-use or single-use packages (including, for example, tubes, bottles, pumps, containers or bottles, vials, jars, packets, or blister packages).

[0324] Single dose kits and packages can be prepared containing a once-daily amount of the transdermal delivery formulation. Single dose, unit dose, and once-daily disposable containers of the transdermal delivery formulation are also provided.

[0325] The transdermal delivery formulation remains stable on storage for periods including up to about 5 years, from about 3 months to about 5 years, from about 3 months to about 4 years, from about 3 months to about 3 years, and alternatively, from about 6 months to about 3 years.

[0326] The transdermal delivery formulations described herein remain stable for at least three years at temperatures of 40° C. or less. In one embodiment, the transdermal delivery formulations described herein remain stable for at least two years at temperatures of 40° C. or less. In one embodiment, the transdermal delivery formulations described herein remain stable for at least three years at temperatures of 40° C. or less and humidity of up to 75% RH, for at least two years at temperatures of 40° C. or less and humidity of up to 75% RH, or for at least three years at temperatures of 30° C. or less and humidity of up to 75% RH. In further embodiments, the transdermal delivery formulations described herein according to the subject matter described herein remain stable for extended periods of time when packaged in multi-use containers such as bottle dispensers, and exhibit comparable or better stability when packaged in single-use packages.

[0327] In another aspect, the transdermal delivery formulation of certain embodiments includes a daily dose of a specific buffer compound (e.g., sodium bicarbonate, sodium carbonate, magnesium carbonate, potassium carbonate, potassium bicarbonate, TRIS, lysine, IEPA, etc.). The daily dose for topical or transdermal administration of the transdermal delivery formulation depends on the compound and the animal and can be readily determined by one skilled in the art. Suitable amounts are about 1 mg / kg to about 5 g / kg, more typically about 10 mg / kg to about 5 g / kg, about 25 mg / kg to about 2000 mg / kg, about 50 mg / kg to about 2000 mg / kg, about 25 mg / kg to about 1000 mg / kg, about 50 mg / kg to about 1000 mg / kg, or about 100 mg / kg to about 700 mg / kg. / kg, about 100mg / kg to about 500mg / kg, about 150mg / kg to about 500mg / kg, about 150mg / kg to about 400mg / kg, about 200mg / kg to about 500mg / kg, about 200mg / kg to about 450mg / kg, about 200mg / kg to about 400mg / kg, about 250mg / kg to about 450mg / kg, about 250mg / kg to about 400mg / kg, about 250mg / kg to about 350mg / kg, and about 275mg / kg to about 325mg / kg.

[0328] If desired, other therapeutic agents can be used in conjunction with those provided in the compositions described above. The amount of active ingredient which can be combined with the carrier materials to produce a single dosage form will vary depending upon the host being treated, the nature of the disease, disorder or condition, and the nature of the active ingredient.

[0329] It is understood that the specific dose level for any particular patient will vary depending on a variety of factors, including the activity of the particular active agent, the patient's age, weight, general health, sex, and diet, the time of administration, the rate of excretion, possible drug combinations, the severity of the specific condition being treated, the area being treated, and the mode of administration. One skilled in the art will understand the variability of such factors and will be able to establish specific dose levels using only routine experimentation.

[0330] Pharmacokinetic parameters such as bioavailability, absorption rate constant, apparent volume of distribution, unbound fraction, total clearance, unchanged excreted fraction, first-pass metabolism, elimination rate constant, half-life, and mean residence time can be determined by methods well known in the art.

[0331] Transdermal delivery formulations according to the subject matter described herein may be, for example, topical dosage forms packaged in multi-use or single-use packages (including, for example, tubes, bottles, pumps, containers or bottles, vials, jars, packets, or blister packages).

[0332] Single dose kits and packages can be prepared containing a once-daily amount of the transdermal delivery formulation. Single dose, unit dose, and once-daily disposable containers of the transdermal delivery formulation are also provided.

[0333] Alternatively, a suitable dose for topical or transdermal administration of each of one or more particular buffering compounds (e.g., sodium bicarbonate, sodium carbonate, magnesium carbonate, potassium carbonate, potassium bicarbonate, TRIS, lysine, IEPA, etc.) to a subject is at least about 100 mg, at least about 500 mg, at least about 1 g, at least about 5 g, at least about 10 g, at least about 15 g, at least about 16 g, at least about 17 g, at least about 18 g, at least about 19 g, at least about 20 g, at least about 21 g, at least about 22 g, at least about 23 g, at least about 24 g, at least about 25 g, at least about 26 g, at least about 27 g, at least about 28 g, at least about 29 g, at least about 30 g, at least about 35 g, at least about 40 g, at least about 45 g, at least about 50 g, at least about 60 g, at least about 75 g, at least about 100 g, at least about 200 g, at least about 500 g, or at least about 1.0 kg. The dose can be administered daily, twice a day, three times a day, four times a day, five times a day, or more than six times a day.

[0334] Embodiments herein disclose that the symptoms associated with a disease or disorder described herein are reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% following application of a transdermal delivery formulation, and the severity associated with a disease or disorder described herein is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. Symptoms associated with a disease or disorder are reduced by about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 100%, or about 60% to about 100%. Embodiments of the present specification disclose a reduction of about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

[0335] Embodiments herein disclose that the symptoms associated with a disease or disorder described herein are reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% following administration of a transdermal delivery formulation of the invention, and the severity associated with a disease or disorder described herein is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. Symptoms associated with a disease or disorder are about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about Embodiments of the present specification disclose a reduction of 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

[0336] The transdermal delivery formulations described herein can be used in the manufacture of pharmaceuticals and for the treatment of humans and other animals by administration in accordance with conventional procedures.

[0337] The dose can be a single dose or cumulative (continuous dose), and can be readily determined by one skilled in the art. The transdermal delivery formulation of the present invention can be administered to a subject 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more times. For example, treating a disease can involve administering an effective dose of the transdermal delivery formulation disclosed herein once. Alternatively, treating a disease can involve administering an effective dose of the transdermal delivery formulation multiple times over a range of time periods, such as once daily, twice daily, three times daily, once every few days, or once weekly. The timing of administration can vary between individuals depending on factors such as the severity of the individual's symptoms. For example, an effective dose of the transdermal delivery formulation disclosed herein can be administered to an individual once daily indefinitely, or until the individual no longer requires treatment. Those skilled in the art will recognize that an individual's condition can be monitored throughout the course of treatment, and the effective amount of the transdermal delivery formulations disclosed herein administered can be adjusted accordingly. In one embodiment, the transdermal delivery formulations disclosed herein can reduce the time to resolution of disease symptoms, including that of an individual suffering from a disease, by, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%, compared to a patient not receiving the same treatment.

[0338] In further embodiments, the transdermal delivery formulations and derivatives thereof have a half-life of 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, or more.

[0339] In one embodiment, the administration period of the transdermal delivery formulation is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In further embodiments, the period of time that administration is discontinued is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0340] In aspects of this embodiment, a therapeutically effective amount of a transdermal delivery formulation disclosed herein reduces or alleviates symptoms of a condition such as muscle spasms or muscle pain (e.g., muscle pain or spasms) in an individual by, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. In other aspects of this embodiment, a therapeutically effective amount of a transdermal delivery formulation disclosed herein reduces or alleviates symptoms of a disease in an individual by, for example, up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%, or up to 100%. In yet another aspect of this embodiment, a therapeutically effective amount of a transdermal delivery formulation disclosed herein reduces or alleviates symptoms of a disease in an individual by, for example, about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

[0341] The transdermal delivery formulations disclosed herein may contain a therapeutically effective amount of the transdermal delivery formulation. As used herein, the term "effective amount" is synonymous with "therapeutically effective amount," "effective dose," or "therapeutically effective dose," and when used in connection with reducing or alleviating disease symptoms in an individual, refers to the minimum dose of a therapeutic agent disclosed herein required to achieve the desired therapeutic effect, including a dose sufficient to reduce or alleviate disease symptoms in an individual. The effectiveness of the transdermal delivery formulations disclosed herein in reducing or alleviating disease symptoms in an individual can be determined by observing improvement in the individual based on one or more clinical symptoms and / or physiological indicators related to muscle performance, pain relief, and / or overall health. The maintenance or reduction of disease symptoms can also be subjective to the patient. The effectiveness of the transdermal delivery formulations disclosed herein in an individual can be determined by observing improvement in the individual based on one or more clinical symptoms and / or signs / symptoms, muscle performance, and physiological indicators related to general health. The effectiveness of the transdermal delivery formulations disclosed herein can also extend the lifespan of the individual compared to the same individual when the transdermal delivery formulation is not administered. The effectiveness of the transdermal delivery formulations disclosed herein may also improve an individual's quality of life compared to the same individual when the transdermal delivery formulation is not administered.

[0342] The appropriate effective amount of the transdermal delivery formulation disclosed herein to be administered to an individual can be determined by those skilled in the art by considering factors including, but not limited to, improved muscle performance, pain relief, and / or overall health status, such as the individual's improvement based on one or more clinical symptoms and / or physiological indicators related to the patient's specific characteristics, medical history, and risk factors, or a combination thereof, including, for example, age, weight, and general health. In addition, when repeated administration of a transdermal delivery formulation is used, the effective amount of the transdermal delivery formulation will further depend on factors including, but not limited to, the frequency of administration, the half-life of the transdermal delivery formulation, or any combination thereof. Those skilled in the art will know that, prior to administration to humans or animals, the effective amount of the transdermal delivery formulation disclosed herein can be estimated from in vitro assays and in vivo administration studies using animal models.

[0343] In view of the different efficiencies of various administration routes, the required effective amount is expected to vary widely. For example, oral administration of the transdermal delivery formulations disclosed herein is expected to generally require higher dosage levels than administration by inhalation. Similarly, systemic administration of the transdermal delivery formulations disclosed herein is expected to require higher dosage levels than local administration. These dosage level variations can be adjusted using standard empirical optimization routines, which are well known to those skilled in the art. The exact therapeutically effective dosage level and pattern are preferably determined by the attending physician, taking into account the above-mentioned factors. Those skilled in the art will understand that an individual's condition can be monitored throughout the course of treatment and the effective amount of the therapeutic agent disclosed herein administered can be adjusted accordingly.

[0344] Aspects of the present specification disclose, in part, the reduction or alleviation of symptoms of a condition, such as muscle spasms or pain, in an individual. As used herein, the term "treating" refers to the reduction or alleviation of muscle pain or spasms, as well as the improvement of muscle performance and recovery. For example, the term "treating" can mean reducing or alleviating symptoms in an individual by, for example, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. Actual symptoms associated with conditions, such as muscle spasms and pain, are well known and can be measured by those skilled in the art using commonly known testing procedures. Those skilled in the art will know appropriate symptoms or indicators associated with health and muscle performance and will know how to determine whether an individual is a candidate for the treatments disclosed herein.

[0345] In one embodiment, a first transdermal delivery formulation is administered to an individual, and at a later date, a second transdermal delivery formulation is administered to the same individual. In one embodiment, the first transdermal delivery formulation is administered to the individual at the same time that the second transdermal delivery formulation is administered to the individual.

[0346] The transdermal delivery formulations disclosed herein are administered to an individual, which is typically a human, but can also be an animal, including but not limited to, dogs, cats, birds, cattle, horses, sheep, goats, reptiles, and other animals, whether domesticated or not.

[0347] In one aspect, disclosed herein is a formulation for transdermal delivery of an active agent through the skin, nail, or hair follicle of a subject, the formulation comprising: a) a transdermal delivery formulation comprising: i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids, in an amount of less than about 60% by weight; and b) water in an amount of less than about 50% by weight.

[0348] In some embodiments, the formulation comprises a) a transdermal delivery formulation comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids in an amount of less than about 60% by weight, and b) water in an amount of less than about 50% by weight, and further comprises benzyl alcohol in an amount of about 0.5-5% by weight.

[0349] In some embodiments, the transdermal delivery formulation comprises benzyl alcohol in an amount less than 5% by weight of the formulation.

[0350] In some embodiments, the formulation comprises a) a transdermal delivery formulation comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids in an amount of less than about 60% by weight, and b) water in an amount of less than about 50% by weight, and further comprising isopropyl palmitate in an amount of about 5 to about 20% by weight.

[0351] In some embodiments, the water is deionized and / or purified water.

[0352] In some embodiments, water is present in an amount of about 15 to about 40% by weight of the formulation.

[0353] In some embodiments, the one or more phosphatides are present in an amount of about 0.5 to about 55% by weight of the transdermal delivery formulation.

[0354] In some embodiments, the transdermal delivery formulation comprises phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, or a combination thereof in an amount of less than 30% by weight of the formulation.

[0355] In some embodiments, one or more phosphatides comprise the phosphatidylcholine of the transdermal delivery formulation.

[0356] In some embodiments, the one or more fatty acids are present in an amount of about 1 to about 35% by weight of the transdermal delivery formulation.

[0357] In some embodiments, the one or more fatty acids are present in an amount of about 5 to about 35% by weight of the transdermal delivery formulation.

[0358] In some embodiments, the one or more fatty acids comprise linoleic acid, oleic acid, stearic acid, sunflower oil, or a combination thereof.

[0359] In some embodiments, the one or more fatty acids include linoleic acid.

[0360] In some embodiments, the one or more fatty acids include oleic acid.

[0361] In some embodiments, the one or more fatty acids include stearic acid.

[0362] In some embodiments, the one or more phosphatides are derived from a seed oil in an amount of about 0.5 to about 55% by weight of the transdermal delivery formulation.

[0363] In some embodiments, the one or more phosphatides are derived from a seed oil in an amount of about 5 to about 35% by weight of the transdermal delivery formulation.

[0364] In some embodiments, the one or more phosphatides are derived from safflower oil in an amount of about 0.5 to about 55% by weight of the transdermal delivery formulation.

[0365] In some embodiments, the one or more phosphatides are derived from safflower oil in an amount of about 5 to about 35% by weight of the transdermal delivery formulation.

[0366] In some embodiments, the one or more phosphatides are derived from almond oil in an amount of about 0.5 to about 55% by weight of the transdermal delivery formulation.

[0367] In some embodiments, the one or more phosphatides are derived from almond oil in an amount of about 5 to about 35% by weight of the transdermal delivery formulation.

[0368] In some embodiments, the one or more phosphatides comprise one or more fatty acids derived from soy lecithin.

[0369] In some embodiments, the glucose is present in an amount of about 0.05 to about 10% by weight of the transdermal delivery formulation.

[0370] In some embodiments, the glucose is anhydrous dextrose and is present in an amount of about 0.05 to about 10% by weight of the transdermal delivery formulation.

[0371] In some embodiments, the formulation comprises: a) a transdermal delivery formulation comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids in an amount of less than about 60% by weight; and b) water in an amount of less than about 50% by weight, and further comprising a non-ionic surfactant in an amount of about 2-25% by weight of the transdermal delivery formulation.

[0372] In some embodiments, the formulation comprises a) a transdermal delivery formulation in an amount of less than about 60% by weight, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids, and b) water in an amount of less than about 50% by weight, and further comprises a polar solvent in at least a molar excess of a nonionic surfactant.

[0373] In some embodiments, the non-ionic surfactant is a poloxamer and the polar solvent is water.

[0374] In some embodiments, the formulation comprises a) a transdermal delivery formulation comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids in an amount of less than about 60% by weight, and b) water in an amount of less than about 50% by weight, and further comprises a polar solvent in an amount of less than 5% by weight of the formulation.

[0375] In some embodiments, the transdermal delivery formulation further comprises a surfactant moiety in an amount of about 1 to about 30% by weight of the transdermal delivery formulation.

[0376] In some embodiments, the surfactant portion comprises a nonionic surfactant in an amount of about 2-25% by weight of the transdermal delivery formulation, and a polar solvent in an amount of less than 5% by weight of the transdermal delivery formulation.

[0377] In some embodiments, the transdermal delivery formulation is present in an amount of about 10 to about 60% by weight of the transdermal delivery formulation.

[0378] In some embodiments, the transdermal delivery formulation comprises alcohol in an amount less than 10% by weight of the transdermal delivery formulation.

[0379] In some embodiments, the transdermal delivery formulation further comprises an alcohol, a surfactant, and a polar solvent.

[0380] In some embodiments, the transdermal delivery formulation comprises cetyl alcohol in an amount less than 5% by weight of the formulation.

[0381] In some embodiments, the transdermal delivery formulation comprises ethanol in an amount less than 5% by weight of the formulation.

[0382] In some embodiments, the transdermal delivery formulation comprises glycerin in an amount less than 5% by weight of the formulation.

[0383] In some embodiments, the transdermal delivery formulation comprises propylene glycol in an amount less than 8% by weight of the formulation.

[0384] In some embodiments, the formulation comprises a gelling agent in an amount less than 20% by weight of the formulation.

[0385] In some embodiments, the formulation comprises menthol in an amount of about 0.05% to about 5% by weight of the formulation.

[0386] In some embodiments, the formulation comprises: a) a transdermal delivery formulation in an amount of less than about 60% by weight, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount of less than about 50% by weight.

[0387] In some embodiments, the formulation comprises a) a transdermal delivery formulation in an amount of less than about 60% by weight, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids, and b) water in an amount of less than about 50% by weight, and further comprises a humectant, an emulsifier, an emollient, or a combination thereof.

[0388] In some embodiments, the formulation has a pH of 9-11.

[0389] In some embodiments, the formulation has a pH of 7 to 10.5.

[0390] In some embodiments, the formulation comprises a) a transdermal delivery formulation in an amount of less than about 60% by weight, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids, and b) water in an amount of less than about 50% by weight, and further comprises an active agent.

[0391] In some embodiments, the formulation comprises: a) a transdermal delivery formulation in an amount of less than about 60% by weight, comprising: i. one or more phosphatides; ii. glucose; iii. one or more fatty acids; and b) water in an amount of less than about 50% by weight, and an active agent ingredient in an amount of less than about 60% by weight.

[0392] In some embodiments, the formulation comprises: a) a transdermal delivery formulation in an amount of less than about 60% by weight, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount of less than about 50% by weight, and an active agent component in an amount of less than about 60% by weight, wherein the active agent is a drug.

[0393] In another aspect, disclosed herein is a method for transdermal delivery of an active ingredient, comprising applying an effective amount of a formulation to the skin, nail, or hair follicle of a subject, wherein the formulation comprises: a) a transdermal delivery formulation in an amount of less than about 60% by weight, comprising: i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount of less than about 50% by weight, and further comprising an active agent.

[0394] Combination therapy In some aspects, the present disclosure provides methods for treating or alleviating a symptom of a disease or disorder, the method comprising administering to a subject in need thereof a transdermal formulation disclosed herein and administering to a subject in need thereof a composition comprising one or more agents selected from Table 1.

[0395] In embodiments, the transdermal formulation is administered before, simultaneously with, or after administration of the composition.

[0396] In some embodiments, the amount of one or more agents is an effective dose of an agent listed in Table 1.

[0397] In various embodiments, the composition is administered by a standard route for one or more drugs, for example, oral, topical, enteral, parenteral, intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection.

[0398] In embodiments, the composition is a liquid, suspension, gel, geltab, semisolid, tablet, sachet, lozenge, pill, or capsule.

[0399] Preparations containing buffers An approach to creating electrolyte-balanced formulations is to avoid electrolyte imbalance by incorporating different buffering agents in different amounts or ratios. Non-limiting examples of buffering agents that can be used together in different amounts or ratios include potassium bicarbonate, sodium bicarbonate, calcium carbonate, magnesium carbonate, and potassium carbonate. Specific buffering agent mixtures containing two, three, four, five, or more buffering agents are used depending on the formulation. Furthermore, the relative amounts or ratios of each buffering agent can vary, for example, the relative amounts are 1:1.10 w / w; 1:1.15 w / w; 1:1.20 w / w; 1:1.25 w / w; 1:1.30 w / w; 1:1.35 w / w; 1:1.40 w / w; 1:1.45 w / w; 1:1.50 w / w; 1:1.55 w / w; 1:1.60 w / w; 1:1.65 w / w; 1:1.70 w / w; 1:1.80 w / w; 1:1.90 w / w; ... 1:1.75 w / w; 1:1.80 w / w; 1:1.85 w / w; 1:1.90 w / w; 1:1.95 w / w; 1:2 w / w; 1:2.5 w / w; 1:3 w / w; 1:3.5 w / w; 1:4 w / w, 1:4.5 w / w, 1:5 w / w, 1:5.5 w / w, 1:6 w / w, 1:6.5 w / w, 1:7 w / w, 1:8 w / w, 1:9 w / w, or 1:10 w / w. When two buffers are present, these ratios of buffers can be applied, or three or more types and ratios can be applied between any two buffers.

[0400] For example, a suitable formulation can include about 10-56% by weight of a buffering agent and an osmotic agent. In one aspect, disclosed herein is a transdermal delivery formulation for transdermal delivery of one or more buffering agents through the skin of a subject, the transdermal delivery formulation including a buffering agent comprising a carbonate salt in an amount of about 10-56% by weight, a transdermal delivery formulation in an amount of about 5-55% by weight, and a surfactant in an amount of at least 1% by weight, wherein the formulation includes water in an amount of 0-77% by weight.

[0401] In one embodiment, the carbonate salt, including sodium bicarbonate, in the transdermal delivery formulation is present in an amount by weight of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more.

[0402] In another aspect, disclosed herein is a method for transdermal delivery of a percentage of carbonate, comprising at least: a buffer comprising carbonate in an amount of about 10-45% by weight; a transdermal delivery formulation in an amount of about 5-55% by weight; and a surfactant in an amount of about 1-15% by weight, wherein the formulation comprises water in an amount of about 15-65% by weight, and the amount of carbonate in the formulation is present in an amount of about 15-32% by weight of the formulation.

[0403] In another embodiment, the carbonate-containing buffering agent, including sodium bicarbonate, in the transdermal delivery formulation is present in an amount by weight of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more.

[0404] In another embodiment, the carbonate-containing buffering agent, including sodium bicarbonate, in the transdermal delivery formulation is present in an amount by weight of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more.

[0405] In one aspect, disclosed herein is a formulation for transdermal delivery of one or more buffering agents through the skin of a subject, the formulation comprising a buffering agent comprising a carbonate salt in an amount of about 10-45% by weight, a transdermal delivery formulation in an amount of about 5-55% by weight, and a surfactant moiety in an amount of about 1-15% by weight, wherein the formulation comprises water in an amount of about 15-65% by weight, and the formulation comprises less than about 12% by weight of the transdermal delivery formulation.

[0406] In yet another embodiment, disclosed herein is a formulation for transdermal delivery of a therapeutic agent through the skin of a subject, the formulation comprising at least one active agent in an amount effective to treat a medical condition in the subject, the formulation comprising a buffer comprising a carbonate salt in an amount of about 10 to about 45% by weight, a transdermal delivery formulation in an amount of about 5 to about 55% by weight, and a surfactant moiety in an amount of about 1 to about 15% by weight, the formulation comprising water in an amount of about 15 to about 65% by weight, the carbonate salt of the formulation being present in an amount of about 15 to about 32% by weight of the formulation, and the alkalinity of the formulation enhances penetration of the therapeutic agent through the skin of the subject.

[0407] In one aspect, disclosed herein is a formulation for transdermal delivery of one or more buffering agents through the skin of a subject, the formulation comprising: a buffering agent comprising a carbonate salt in an amount of about 10-45% by weight; a transdermal delivery formulation in an amount of about 5-55% by weight; and a surfactant moiety in an amount of about 1-15% by weight; the formulation comprising water in an amount of about 15-65% by weight; and the formulation comprising less than about 12% by weight of the transdermal delivery formulation.

[0408] In another embodiment, disclosed herein is a method for transdermal delivery of a carbonate salt formulation, wherein the formulation comprises a buffering agent comprising a carbonate salt in an amount of about 10 to about 45% by weight, a transdermal delivery formulation in an amount of about 5 to about 55% by weight, and a surfactant moiety in an amount of about 1 to about 15% by weight, wherein the formulation comprises water in an amount of about 15 to about 65% by weight, wherein the formulation comprises less than about 12% by weight of the transdermal delivery formulation through the skin of a subject, wherein the carbonate salt of the formulation is present in an amount of about 15 to about 32% by weight of the formulation, wherein the formulation comprises less than about 12% by weight of the transdermal delivery formulation, and wherein the alkalinity of the formulation enhances penetration of the therapeutic agent.

[0409] In yet another embodiment, disclosed herein is a formulation for transdermal delivery of a therapeutic agent through the skin of a subject, the formulation comprising at least one active agent in an amount effective to treat a medical condition in the subject, the formulation comprising a buffer comprising a carbonate salt in an amount of about 10 to about 45% by weight, a transdermal delivery formulation in an amount of about 5 to about 55% by weight, and a surfactant moiety in an amount of about 1 to about 15% by weight, the formulation comprising water in an amount of about 15 to about 65% by weight, the carbonate salt of the formulation being present in an amount of about 15 to about 32% by weight of the therapeutic formulation, and the formulation comprising less than about 12% by weight of the transdermal delivery formulation.

[0410] In some embodiments, a suitable transdermal delivery formulation comprises Siligel™ in an amount less than about 5% by weight, water in an amount between about 10 and about 65% by weight, isopropyl palmitate in an amount between about 0.5 and about 10% by weight, stearic acid in an amount between about 0.25 and about 10% by weight, cetyl alcohol in an amount between about 0.25 and about 10% by weight, glycerin in an amount between about 0.25 and about 5% by weight, the transdermal delivery formulation in an amount less than about 5% by weight, ethanol in an amount less than about 5% by weight, benzyl alcohol in an amount less than about 5% by weight, sodium hydroxide 50% by weight in an amount between about 0.1 and about 5% by weight, and sodium bicarbonate in an amount between about 1 and about 32% by weight.

[0411] In some embodiments, suitable transdermal delivery formulations comprise Aveeno® in an amount of about 20 to about 85% by weight, and sodium bicarbonate (3DF) in an amount of about 15 to about 45% by weight.

[0412] In some embodiments, the transdermal delivery formulation comprises Aveeno® in an amount of about 20 to about 85% by weight, and sodium bicarbonate in an amount of about 15 to about 45% by weight.

[0413] In some embodiments, a suitable transdermal delivery formulation comprises Siligel™ in an amount less than about 5% by weight, water in an amount between about 10 and about 55% by weight, isopropyl palmitate in an amount between about 0.5 and about 10% by weight, stearic acid in an amount between about 0.25 and about 5% by weight, cetyl alcohol in an amount between about 0.25 and about 10% by weight, almond oil in an amount between about 0.5 and about 10% by weight, propylene glycol in an amount between about 0.25 and about 10% by weight, ethanol in an amount less than about 5% by weight, benzyl alcohol in an amount less than about 5% by weight, 50% by weight volume of sodium hydroxide in an amount between about 0.1 and about 5% by weight, and sodium bicarbonate in an amount between about 1 and about 32% by weight.

[0414] The surprising benefits achieved by the formulations and methods of the present invention are due, in part, to an improved transdermal delivery formulation that enhances the delivery of carbonate salts through the skin. The transdermal delivery formulations may include a non-ionic surfactant. Applicants have discovered that by using carbonate salts having particle sizes disclosed herein delivered by a penetrant disclosed herein, and in some embodiments, by providing a combination of a non-ionic surfactant and a polar gelling agent, the penetration capacity of the carbonate salts in the resulting formulations and the effective level of delivery of the carbonate salts are improved.

[0415] In transdermal delivery formulations, the osmotic agent is based on an alcohol, such as benzyl alcohol, to provide a final formulation concentration of 0.5-20% by weight, in combination with the existing transdermal delivery agent to provide a 25-70% by weight formulation. These osmotic agents are also useful when the agent is a buffering agent, such as sodium bicarbonate, although the amount required for the transdermal delivery formulation may be less, e.g., less than 12% by weight, when sodium bicarbonate is present in high concentrations as disclosed herein.

[0416] In some embodiments, the buffering component is any weakly basic compound or combination that results in a pH of 7-8. In some embodiments, the formulation has a pH of 7-10. In addition to carbonate and / or bicarbonate, such buffers include lysine buffers, chloroacetic acid buffers, Tris buffers (i.e., buffers using tris(hydroxymethyl)aminoethane), phosphate buffers, and buffers using unnatural amino acids with pKa values ​​similar to that of lysine. In some embodiments, the carbonate and / or bicarbonate is present in an amount of about 7 to about 32% by weight of the formulation. For example, naturally occurring enantiomers of such amino acids, or analogs of lysine with longer or shorter carbon chains or branched forms thereof. Histidine buffers may also be used. Typically, the concentration of the buffering agent in the composition ranges from 10 to 50% by weight. A more typical range for sodium bicarbonate or sodium carbonate, or both, is 10 to 35% by weight. In some embodiments, the carbonate is present in an amount of about 15 to about 32% by weight of the formulation.

[0417] Alternatively, the penetrant component includes a completion component, plus one or more electrolytes, one or more surfactants, and an alcohol sufficient to impart viscosity and viscoelasticity. The completion component can be a polar liquid, a non-polar liquid, or an amphiphile.

[0418] The percentage of carbonate in a transdermal delivery formulation will depend on the amount required to be delivered to provide a beneficial effect in the treatment of the disorder. Generally, carbonate can be present in the formulation in amounts from as low as 1% by weight up to about 50% by weight. Typical concentrations include 15-32% by weight. The required percentage of carbonate depends on the frequency of administration and the time allotted for administration of each application, so the level of carbonate can vary over a wide range. In some embodiments, the carbonate is sodium carbonate and / or sodium bicarbonate milled to a particle size of less than 200 μm. In some embodiments, the carbonate is sodium carbonate and / or sodium bicarbonate milled to a particle size of less than 70 μm. In some embodiments, the carbonate is sodium carbonate and / or sodium bicarbonate milled to a particle size of less than 70 μm, and the sodium bicarbonate is solubilized in the formulation in an amount of less than 20% by weight of the transdermal delivery formulation. In some embodiments, the carbonate salt is sodium carbonate and / or sodium bicarbonate milled to a particle size of less than 70 μm, with a particle size of less than about 10 μm providing improved penetration into the skin of a subject. In some embodiments, the sodium carbonate and / or bicarbonate is jet milled to a particle size of less than about 70 μm. In some embodiments, the sodium bicarbonate is sodium bicarbonate USP Grade 3DF with a particle size distribution of less than 70 μm.

[0419] The transdermal delivery formulations of the present disclosure can be prepared in a variety of ways. Typically, the components of the transdermal delivery formulation are simply mixed in the required amounts. However, in some cases, for example, after dissolving the carbonate salt, it may also be desirable to add a separate preparation containing components that aid in the delivery of the carbonate salt in the form of a carrier. The concentration of these components in the carrier is then somewhat higher than the concentration required in the final transdermal delivery formulation. Thus, sodium bicarbonate can be first dissolved in water and then added to a carrier containing alcohol, the transdermal delivery formulation, and, optionally, a combination of a nonionic surfactant and a polar gelling agent or an ionic detergent. Alternatively, some subset of these components can be mixed first, followed by "topping up" with the remaining components simultaneously or sequentially. The exact manner in which the transdermal delivery formulation is prepared depends on the carbonate salt selected and the desired percentage of the remaining components relative to the carbonate salt. In some embodiments, water is present in an amount of about 10 to about 85%, about 15 to about 50%, or about 15 to about 45% by weight of the formulation.

[0420] Transdermal delivery formulations are multi-component mixtures in which the specific concentration of the penetration enhancer is informed, in part, by the molecular weight of the sodium bicarbonate or sodium bicarbonate and therapeutic agent being delivered. Transdermal delivery formulations allow the sodium bicarbonate and / or therapeutic agent to become bioavailable to the target site within minutes of topical administration. Transdermal delivery formulations allow for the use of minimal concentrations of therapeutic agent, at least 1 / 1000th of the concentrations required by alternative processes, while simultaneously achieving bioactivity and positive clinical outcomes. In some embodiments, the transdermal delivery formulation contains alcohol in an amount less than 5% by weight of the formulation.

[0421] Additional Embodiments Embodiment 1. A formulation for transdermal delivery of a drug through the skin of a subject, comprising a therapeutically effective amount of the drug and a penetrating moiety, wherein the penetrating moiety comprises a) phosphatidylcholine (3-15% by weight), b) isopropyl palmitate (5-20% by weight), c) stearic acid (0.1-5% by weight), d) benzyl alcohol (0.5-5% by weight), e) polyglyceryl-4 laurate (0.5-10% by weight), and f) poloxamer 407 (5-20% by weight).

[0422] Embodiment 2. The agent is (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine; (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide; 2-fluoro-N-methyl-4-[7-quinolin-6-yl-methyl)-imidazo[1,2-B][1,2,4]triazin-2yl]benzamide; 4-(3-azaspiro[4.5]decan-4-amine; (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide; Amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide;4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile;Abacavir;Abiraterone acetate;Abiraterone acetate;Abobotulinumtoxin A;Acalabrutinib;Acarbose;Acetaminophen;Acetazolamide;Acetylsalicylic acid;Acitretin;Acyclovir;Abacavir Darimumab; Adapalene; Adapalene; Afoxolaner; Agalsidase beta; Albendazole; Alectinib; Alectinib; Alendronate sodium; Alglucosidase alfa; Alitretinoin; Alogliptin; Alpelisib; Aluminum hydroxide; Ambrisentan; Amiodarone; Amitriptyline; Amlodipine; Amlodipine; Amlodipine besylate; Amlodopine besylate; Amorolfine hydrochloride; Amoxicillin; Amphotericin B; Amphotericin B liposomal; Ampicillin; Amprenavir; Antihemophilic factor, Fc fusion Synthetic proteins; Apalutamide; Apatinib; Apixaban; Apremilast; Aprepitant; Aripiprazole; Artemether; Aspirin; Atazanavir; Atenolol; Atomoxetine; Atorvastatin; Avapritinib; Axitinib (Inritin); Azacitidine; Azathioprine; Azelaic acid; Azilsartan medoxomil; Azithromycin; Baclofen; Baricitinib; Basiliximab; Batimastat (BB-94); Becaplermin; Belmosudil; Bendamustine; Benzoyl peroxide; Benzoyl peroxide;Betamethasone dipropionate; Betamethasone valerate; Bexarotene; Bictegravir; Bimatoprost; Binimetinib (Mektobi); Bortezomib; Bortezomib (Velcade); Bosentan; Bosutinib (Bosurif); Botulinum toxin A; Branched-chain amino acids; Brexpiprazole; Brimonidine; Brimonidine tartrate; Brodalumab; Buproprion; Cabazitaxel; Cabozantinib; Cabozantinib (Cometriz); Calcifezi ol;calcipotriene;calcipotriene;calcipotriol;calcitonin;calcitriol;calcium carbonate;canagliflozin;canakinumab;capecitabine;capmatinib;capsaicin;carbamazepine;carbidopa;carfilzomib;carfilzomib (cyprolis);cariprazine;carvedilol;CD-12681;CEE-321;cefazolin;cefepime;cefoperazone;cefotaxime sodium;cerebrospinal fluid; Coxib; Celecoxib; Cemiplimab; Ceritinib; Chlorothiazide; Chlorpromazine; Chlorthalidone; Cinacalcet; Ciprofloxacin; Cisapride; Citalopram; Citric acid; Clarithromycin; Clavulanate; Clindamycin phosphate; Clobazam; Clobetasol propionate; Clofazimine; Clomiphene; Clonidine; Clopidogrel; Clopidogrel bisulfate; Cobicistat; Cobicistat; Colcosine; Co Ristine; Corticotropin; Crisaborole; Crizanlizumab; Crizotinib (Xalkori...

Claims

1. A formulation for transdermal delivery of a drug through the skin of a subject, the formulation comprising a therapeutically effective amount of the drug and a penetrating moiety; the penetrating portion comprises a phospholipid, a fatty acid ester formed from a low molecular weight alcohol, and a long chain fatty acid, and optionally one or more of a viscosity improving agent, a penetration enhancer, and an emulsifier; wherein said formulation lacks natural lecithin.

2. 2. The formulation of claim 1, wherein the phospholipid is selected from phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, inositol phosphatides, and sphingomyelin.

3. The formulation of claim 2 , wherein the phospholipid is a phosphatidylcholine.

4. The formulation of any one of claims 1 to 3, wherein the penetrating portion comprises two or more phospholipids.

5. 5. The formulation of any one of claims 1 to 4, wherein the phospholipid is in an amount of about 3% to about 15% by weight of the formulation.

6. The formulation according to any one of claims 1 to 5, wherein the low molecular weight alcohol is selected from isopropanol, methanol, ethanol, butanol, glycerol, cetyl alcohol.

7. The formulation according to any one of claims 1 to 6, wherein the low molecular weight alcohol is isopropanol.

8. 8. The formulation of any one of claims 1 to 7, wherein the fatty acid ester is selected from isopropyl palmitate, isopropyl myristate, isopropyl linoleate, isopropyl oleate, ethyl laurate, and ethyl myristate.

9. 9. The formulation of claim 8, wherein the fatty acid ester is isopropyl palmitate.

10. The formulation of any one of claims 1 to 9, wherein the penetrating moiety comprises two or more fatty acid esters.

11. 11. The formulation of any one of claims 1 to 10, wherein the fatty acid ester is in an amount of about 5% to about 20% by weight of the formulation.

12. 12. The formulation of any one of claims 1 to 11, wherein the long chain fatty acids are selected from linoleic acid, oleic acid, stearic acid, linolenic acid, palmitic acid, arachidonic acid, palmitoleic acid, myristic acid, eicosenoic acid, benehic acid, euricic acid, and lignoceric acid.

13. 13. The formulation of claim 12, wherein the long chain fatty acid is linoleic acid.

14. 13. The formulation of claim 12, wherein the long chain fatty acid is oleic acid.

15. 13. The formulation of claim 12, wherein the long chain fatty acid is stearic acid.

16. The formulation of any one of claims 12 to 15, wherein the long chain fatty acids are obtained from safflower oil or almond oil.

17. 17. The formulation of any one of claims 1 to 16, wherein the long chain fatty acid is in an amount of about 0.1% to about 10% by weight of the formulation.

18. The formulation of any one of claims 1 to 17, wherein the penetrating moiety comprises two or more long chain fatty acids.

19. The formulation of any one of claims 1 to 18, wherein the penetrating portion comprises a viscosity improving agent.

20. The formulation of any one of claims 1 to 19, wherein the viscosity improving agent is a poloxamer.

21. 21. The formulation of claim 20, wherein the poloxamer is selected from poloxamer 407, poloxamer 188, poloxamer 184, and poloxamer 124.

22. A formulation according to any one of claims 1 to 21, wherein the viscosity improving agent is a surfactant.

23. The surfactants include sodium lauryl sulfate (sodium dodecyl sulfate), polyoxyethylated castor oil derivatives such as HCO-60 surfactants, nonoxynol, octoxynol, phenylsulfonates, poloxamers such as Pluronic® F68, Pluronic® F127, and Pluronic® L62, polyoleates, Rewopal® HVIO, sodium laurate, sodium oleate, sorbitan dilaurate, sorbitan dioleate, sorbitan monolaurate such as Span® 20, sorbitan monooleate, sorbitan trilaurate, sorbitan trioleate, sorbitan monopalmitate such as Span® 40, sorbitan stearate such as Span® 85, Synpero® glycerol, sorbitan stearate ...

23. The formulation of claim 22, wherein the polysorbate is selected from polyethylene glycol nonylphenyl ethers such as Tween® NP, p-(1,1,3,3-tetramethylbutyl)-phenyl ethers such as Triton™ X-100, and polysorbates such as polyoxyethylene (20), sorbitan monolaurate such as Tween® 20, polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate) such as Tween® 40, polysorbate 60 (polyoxyethylene (20) sorbitan monostearate) such as Tween® 60, polysorbate 80 (polyoxyethylene (20) sorbitan monooleate) such as Tween® 80, and polyoxyethylene sorbitan trioleate such as Tween® 85.

24. 24. The formulation of claim 23, wherein the surfactant is sodium lauryl sulfate.

25. The formulation of any one of claims 1 to 24, wherein the penetrating portion comprises two or more viscosity improving agents.

26. 26. The formulation of any one of claims 1 to 25, wherein the viscosity improving agent is in an amount of about 5% to about 20% by weight of the formulation.

27. The formulation of any one of claims 1 to 26, wherein the permeation moiety comprises a permeation enhancer.

28. A formulation according to any one of claims 1 to 27, wherein the penetration enhancer is an alcohol or a terpene.

29. 29. The formulation of claim 28, wherein the penetration enhancer as an alcohol is selected from benzyl alcohol, ethanol, propylene glycol, and polyethylene glycol.

30. 30. The formulation of claim 29, wherein the penetration enhancer is benzyl alcohol.

31. 31. A formulation according to any one of claims 28 to 30, wherein the penetration enhancer as a terpene is selected from limonene, menthol, borneol and camphor.

32. A formulation according to any one of claims 27 to 31, wherein the penetration enhancer further acts as a preservative.

33. The formulation of any one of claims 1 to 32, wherein the permeation portion comprises two or more permeation enhancers.

34. 34. The formulation of any one of claims 1 to 33, wherein the penetration enhancer is in an amount of about 0.5% to about 5% by weight of the formulation.

35. A formulation according to any one of claims 1 to 34, wherein the penetration portion comprises at least one penetration enhancer and at least one viscosity improving agent.

36. The formulation of any one of claims 1 to 35, wherein the penetrating portion comprises an emulsifier.

37. A formulation according to any one of claims 1 to 36, wherein the emulsifier is selected from polyglyceryl-4-laurate, polyglyceryl-4-oleate, Span 60, cetyl alcohol, and polyglyceryl-3-oleate.

38. 38. The formulation of any one of claims 1 to 37, wherein the permeation portion comprises two or more permeation enhancers.

39. 39. The formulation of any one of claims 1 to 38, wherein the emulsifier is in an amount from about 0.5% to about 10% by weight of the formulation.

40. 40. The formulation of any one of claims 1 to 39, wherein the penetrating portion comprises at least one emulsifier and at least one viscosity improving agent.

41. A formulation according to any one of claims 1 to 40, wherein the penetration portion comprises at least one emulsifier and at least one penetration enhancer.

42. 42. The formulation of any one of claims 1 to 41, wherein the penetration portion comprises at least one emulsifier, at least one viscosity improving agent, and at least one penetration enhancer.

43. 1. A formulation for transdermal delivery of a drug through the skin of a subject, comprising: The formulation comprises a therapeutically effective amount of a drug and a penetrating moiety; the penetrating moiety comprises a phospholipid, a fatty acid ester formed from a low molecular weight alcohol, and a long chain fatty acid; the phospholipid is phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, inositol phosphatide, or sphingomyelin; the fatty acid ester is isopropyl palmitate, isopropyl myristate, isopropyl linoleate, isopropyl oleate, ethyl laurate, or ethyl myristate; the long chain fatty acid is linoleic acid, oleic acid, stearic acid, linolenic acid, palmitic acid, arachidonic acid, palmitoleic acid, myristic acid, eicosenoic acid, benehic acid, euricic acid, or lignoceric acid, or the long chain fatty acid is obtained from safflower oil or almond oil; wherein said formulation lacks natural lecithin.

44. 1. A formulation for transdermal delivery of a drug through the skin of a subject, comprising: The formulation comprises a therapeutically effective amount of a drug and a penetrating moiety; the penetrating portion comprises one or more of a phospholipid, a fatty acid ester formed from a low molecular weight alcohol, and a long chain fatty acid, as well as a viscosity improver, a penetration enhancer, and an emulsifier; The phospholipid is phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, inositol phosphatide, or sphingomyelin; the fatty acid ester is isopropyl palmitate, isopropyl myristate, isopropyl linoleate, isopropyl oleate, ethyl laurate, or ethyl myristate; the fatty acid ester is linoleic acid, oleic acid, stearic acid, linolenic acid, palmitic acid, arachidonic acid, palmitoleic acid, myristic acid, eicosenoic acid, benehic acid, euricic acid, or lignosyl alcohol; noceric acid is the long chain fatty acid or the long chain fatty acid is derived from safflower oil or almond oil, polyglyceryl-4-laurate, polyglyceryl-4-oleate, Span 60, cetyl alcohol, or polyglyceryl-3-oleate is the penetration enhancer, poloxamer (e.g., poloxamer 407, poloxamer 188, poloxamer 184, and poloxamer 124) or sodium lauryl sulfate is the viscosity improver, and benzyl alcohol, ethanol, propylene glycol, polyethylene glycol, limonene, menthol, borneol, or camphor is the penetration enhancer; wherein said formulation lacks natural lecithin.

45. 45. The formulation of any one of claims 1 to 44, wherein the permeating portion is in an amount of about 70% to about 98% by weight of the formulation.

46. The formulation of any one of claims 1 to 45, wherein the permeable portion comprises water.

47. 47. The formulation of any one of claims 1 to 46, wherein the permeation portion comprises water in an amount of about 50% to about 80% by weight of the formulation.

48. 48. The formulation of any one of claims 1 to 47, wherein the formulation comprises a phospholipid, an emollient / moisturizer, a fatty acid, an alcohol, an oil, a surfactant, water, and a drug.

49. 1. A formulation for transdermal delivery of a drug through the skin of a subject, the formulation comprising a phospholipid in an amount of about 5% to about 15% by weight of the formulation, an emollient / moisturizer in an amount of about 10% to about 20% by weight of the formulation, a fatty acid in an amount of about 0.5% to about 2% by weight of the formulation, an alcohol in an amount of about 0.5% to about 2% by weight of the formulation, an oil in an amount of about 1% to about 5% by weight of the formulation, a surfactant in an amount of about 0.5% to about 2% by weight of the formulation, water in an amount of about 30% to about 80% by weight of the formulation, and a therapeutically effective amount of a drug in an amount of about 0.001% to about 30% by weight of the formulation; wherein said formulation lacks natural lecithin.

50. 50. The formulation of claim 49, wherein the agent is in an amount of about 0.001% to about 0.01% by weight of the formulation.

51. 50. The formulation of claim 49, wherein the agent is in an amount of about 0.011% to about 0.1% by weight of the formulation.

52. 50. The formulation of claim 49, wherein the agent is in an amount of about 0.11% to about 1.0% by weight of the formulation.

53. 50. The formulation of claim 49, wherein the agent is in an amount of about 1% to about 10% by weight of the formulation.

54. 50. The formulation of claim 49, wherein the agent is in an amount of about 11% to about 20% by weight of the formulation.

55. 50. The formulation of claim 49, wherein the agent is in an amount of about 21% to about 30% by weight of the formulation.

56. 1. A formulation for transdermal delivery of a drug through the skin of a subject, the formulation comprising: phosphatidylcholine in an amount of about 7.64% by weight of the formulation; isopropyl palmitate in an amount of about 13.30% by weight of the formulation; stearic acid in an amount of about 0.62% by weight of the formulation; benzyl alcohol in an amount of about 1.39% by weight of the formulation; safflower oil in an amount of about 2.93% by weight of the formulation; oleic acid in an amount of about 0.97% by weight of the formulation; polyglyceryl-4-laurate in an amount of about 1.06% by weight of the formulation; deionized water in an amount of about 60.84% ​​by weight of the formulation; poloxamer 407 in an amount of about 9.25% by weight of the formulation; and a therapeutically effective amount of a drug in an amount of about 2% by weight of the formulation; wherein said formulation lacks natural lecithin.

57. 1. A formulation for transdermal delivery of a drug through the skin of a subject, the formulation comprising: phosphatidylcholine in an amount of about 7.66% by weight of the formulation; isopropyl palmitate in an amount of about 13.34% by weight of the formulation; benzyl alcohol in an amount of about 1.39% by weight of the formulation; stearic acid in an amount of about 0.68% by weight of the formulation; carthamus tinctorius (safflower) oil in an amount of about 2.79% by weight of the formulation; polyglyceryl-4-laurate in an amount of about 1.07% by weight of the formulation; oleic acid in an amount of about 1.06% by weight of the formulation; deionized water in an amount of about 61.73% by weight of the formulation; poloxamer 407 in an amount of about 9.28% by weight of the formulation; and a therapeutically effective amount of a drug in an amount of about 1.00% by weight of the formulation; wherein said formulation lacks natural lecithin.

58. 58. The formulation of claim 56 or claim 57, wherein, rather than the amount of the drug being about 1% or about 2% by weight of the formulation, the amount of the drug is less than about 1% and the amount of water is increased proportionately.

59. 58. The formulation of claim 56 or claim 57, wherein the amount of drug is greater than about 2% and the amount of water is reduced proportionately, rather than the amount of drug being about 1% or about 2% by weight of the formulation.

60. 60. The formulation of claim 59, wherein the amount of the agent is less than about 30%.

61. 1. A formulation for transdermal delivery of a drug through the skin of a subject, the formulation comprising a therapeutically effective amount of a drug and a permeation portion comprising phosphatidylcholine in an amount from about 3% to about 15% by weight of the formulation, isopropyl palmitate in an amount from about 5% to about 20% by weight of the formulation, stearic acid in an amount from about 0.1% to about 10% by weight of the formulation, benzyl alcohol in an amount from about 0.5% to about 5% by weight of the formulation, polyglyceryl-4-laurate in an amount from about 0.5% to about 10% by weight of the formulation, and poloxamer 407 in an amount from about 5% to about 20% by weight of the formulation; wherein said formulation lacks natural lecithin.

62. 62. The formulation of any one of claims 1 to 61, wherein the formulation has a pH of about 7 to about 10.

5.

63. 63. The formulation of any one of claims 1 to 62, wherein the formulation has a pH of about 9 to about 11.

64. 64. The formulation of any one of claims 1 to 63, wherein the agent has a molecular weight of less than about 500 Da, or between about 500 Da and about 1000 Da, or greater than about 1000 Da, such as greater than about 10,000 Da.

65. The agent is (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide, 2-fluoro-N-methyl-4-[7-quinolin-6-yl-methyl)-imidazo[1,2-B][1,2,4]triazin-2yl]benzamide, 4-(3-amino-6- ((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide, 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile, abacavir, abiraterone acetate, abiraterone acetate, abobotulinumtoxin A, acalabrutinib, acarbose, acetaminophen, acetazolamide, acetylsalicylic acid, acitretin, acyclovir, adalim Mab, adapalene, afoxolaner, agalsidase beta, albendazole, alectinib, alectinib, alendronate sodium, alglucosidase alfa, alitretinoin, alogliptin, alpelisib, aluminum hydroxide, ambrisentan, amiodarone, amitriptyline, amlodipine, amlodipine besylate, amlodopine besylate, amorolfine hydrochloride, amoxicillin, amphotericin B, amphotericin B liposomal, ampicillin, amprenavir, antihemophilic factor, Fc fusion Protein, apalutamide, apatinib, apixaban, apremilast, aprepitant, aripiprazole, artemether, aspirin, atazanavir, atenolol, atomoxetine, atorvastatin, avapritinib, axitinib (Inrita), azacitidine, azathioprine, azelaic acid, azilsartan medoxomil, azithromycin, baclofen, baricitinib, basiliximab, batimastat (BB-94), becaplermin, belmosudil, bendamustine, benzoyl peroxide, benzoyl peroxide,Betamethasone dipropionate, betamethasone valerate, bexarotene, bictegravir, bimatoprost, binimetinib (Mektobi), bortezomib, bortezomib (Velcade), bosentan, bosutinib (Bosuthrif), botulinum toxin A, branched-chain amino acids, brexpiprazole, brimonidine, brimonidine tartrate, brodalumab, buproprion, cabazitaxel, cabozantinib, cabozantinib (Cometriz), calcifezi calcipotriene, calcipotriene, calcipotriol, calcitonin, calcitriol, calcium carbonate, canagliflozin, canakinumab, capecitabine, capmatinib, capsaicin, carbamazepine, carbidopa, carfilzomib, carfilzomib (cyprolis), cariprazine, carvedilol, CD-12681, CEE-321, cefazolin, cefepime, cefoperazone, cefotaxime sodium, selenium Coxib, celecoxib, cemiplimab, ceritinib, chlorothiazide, chlorpromazine, chlorthalidone, cinacalcet, ciprofloxacin, cisapride, citalopram, citric acid, clarithromycin, clavulanate, clindamycin phosphate, clobazam, clobetasol propionate, clofazimine, clomiphene, clonidine, clopidogrel, clopidogrel bisulfate, cobicistat, cobicistat, corticosteroids, cocaine, cefotaxime ... Lystin, corticotropin, crisaborole, crizanlizumab, crizotinib (xalkori), cyclobenzaprine, cyclosporine, dabigatran etexilate, dabrafenib, dacomitinib (visimpro), dalbavancin, dalfopristin, danazol, dapagliflozin, dapsone, daptomycin, darunavir, dasatinib, decitabine, defatted peanuts (Arachis hypogaea) powder, deferasirox, delgocitinib, deoxycholic acid, desipramine, desonide, dexlansoprazole, dexmethylphenidate, dextroamphetamine / amphetamine salts, diclofenac, diclofenac sodium, diflucortolone, diflucortolone, difinisal, digoxin, diloxanide, dimethyl fumarate, diphenhydramine hydrochloride, diphtheria vaccine, docetaxel,Dolutegravir, Dolutegravir, Donepezil, Doxercalciferol, Doxycycline, Doxycycline ER, Doxycycline Hyclate (B), Doxycycline Monohydrate (A), Dronabinol, Dronedarone, Drospirenone, Dukoral / ShanChol Cholera Vaccine, Duloxetine, Dupilumab, Durvalumab, Dutasteride, Duvelisib, Ecallantide, Edoxaban, Efavirenz, Elafibranol, Elagolix Sodium, Elbasvir, Eletriptan, Eltrombopag, Elvitegravir, empagliflozin, emtricitabine, encorafenib (braftobi), enfuviritide, enoxaparin sodium, entecavir, entrectinib, enzalutamide, epinephrine, erdafitinib, erenumab, eribulin, erlotinib, erlotinib hydrochloride (Tarceva), ertapenem, erythromycin, escitalopram, esketamine (ketamine), esomeprazole, Sopremazole, estradiol, estrogen-conjugated, etanercept, ethinyl estradiol, ethinyl estradiol, etonogestrel, etravirine, etretinate, everolimus, everolimus (Afinitor), everolimus (Votubia, Zotres / Certican), ezetimibe, ezetimibe, famotidine, fasinumab, febuxostat, fedratinib, fenofibrate, ferric carboxymaltose, fexofenadine hydrochloride, fil Gotinib, filgrastim, fingolimod, fluocinolone acetonide, fluoxetine, flurbiprofen, folic acid, forskolin, fostamatinib, fulvestrant, furosemide, fusidic acid, fusidic acid, gabapentin, ganetespib, gefitinib (Iressa), gilteritinib, glasdigib (Daurismo) or glasdigib maleate, glecaprevir, glibenclamide, glimepiride, glipizide, glucagon, glucosamine, glutaric acid anhydride, glycopyrrolate, goserelin, goserelin LA,Granisetron, grazoprevir, griseofulvin, halobetasol propionate, haloperidol, heparin sodium, heplisub B vaccine, hyaluronic acid, hydrochlorothiazide, hydrochlorothiazide, hydrocortisone, hydrocortisone acetate, hydroquinone, hydroxychloroquine, hydroxyprogesterone, ibrutinib, ibrutinib (Imbruvica), ibuprofen Fen, icatibant acetate, idelalisib, imatinib, imatinib (Gleevec), imatinib mesylate, imiglucerase, inclisiran, indinavir, indomethacin, infliximab, ingenol mebuate, inotersen, insulin A, insulin glargine, interferon beta-1b, iopanic acid, irbesartan, isoconazole, isotretinoin, itraconazole, ivacaftor, ivacaftor, Vermectin, ixazomib, ketoconazole, ketone bodies, ketoprofen, Keirvia, lacosamide, lamictal, lamivudine, lansoprazole, lapatinib, lapatinib (tycarb), larotrectinib, ledipasvir, leflunomide, lenalidomide, lenvatinib, LEO-138559, LEO-152020, leuprolide, levetiracetam, levodopa, levodopa / benserazide, levonorgestrel, levothyroxine, linalool Gliptin, linezolid, lisinopril, L-lysine free base, lofexidine, lopinavir, loratadine, lorlatinib (Lorviqua), losartan, lovastatin, lubiprostone, lumacaftor / ivacaftor, lumefantrine, lurasidone, luspatercept, lymecycline, macitentan, magnesium, magnesium lactate, marimastat (BB-2516), marizomib (NPI-0052), mebendazole, meflo, quinolone, melatonin, meloxicam, memantine hydrochloride, meningococcal [serotype b] vaccine, mesalazine, metformin, methotrexate, methyl aminolevulinate hydrochloride, methylphenidate, methylprednisolone, metoprolol succinate, metronidazole, midostaurin, minoxidil, mirabegron, mizolastine MR, montelukast, mycophenolate mofetil, N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trimethylsilyl)-1,2-propanediol, 1,2-dihydro ... fluoromethyl)-isonicotinamide, N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)-pyridine-3-carboxamide hydrochloride, nalidixic acid (quinolone antibiotic), naloxone, naproxen, navitoclax (ABT-263), nebiboro nal, nelfinavir, nemolizumab, neomycin, neovastat (AE-941), neratinib - free base, neratinib (Nerlynx), neratinib maleate, nevirapine, niclosamide, nifedipine, nilotinib, nilotinib, nilotinib (Tasigna), nintedanib, nirotimibe, nitric oxide, nitrofurantoin, norethindrone acetate, nusinersen, NVP-AUY922, nystatin, obatoclax (GX15-070), octreotide acetate, ofatumumab, ofloxacin, olanzapine, olaparib, olme Sartan medoxomil, ormacostat, omalizumab, oseltamivir, osimertinib, osimertinib mesylate, oxaprozin, ozanimod, paclitaxel, paclitaxel protein-bound, palbociclib (Ibrance), paliperidone palmitate, pantoprazole, parathyroid hormone, paricalcitol, patisiran, pazopanib, pazopanib (Votrient), pazopanib hydrochloride, peficitinib, pegfilgrastim, pembrolizumab (Keytruda), pemetrexed, pemigatinib, perifosine, pexidartinib,Phenazopyridine, phenytoin, pibrentasvir, piperacillin, pirfenidone, piroxicam, pomalidomide, ponatinib, ponatinib (lclusig), posaconazole, pralsetinib, pravastatin, prednicarb, prednisone, pregabalin, pregabalin, prinomastat (AG-3340), progesterone, propanolol, protamine sulfate, psilocybin, pyrantel, pyrimethamine, quetiapine, quinupristin, raloxifene, raltegravir, ranibizumab, ranitidine, ranolazine, revimastat ( BMS-275291), regorafenib, regorafenib (Stivarga), relugolix (Orgovix), remibrutinib, resiquimod, retinal, retinol, ribociclib, ribociclib succinate, rifampin, rilpivirine, rilpivirine, rimegepant, riociguat, risdipram, risperidone, ritonavir, rivaroxaban, rosuvastatin, rosuvastatin calcium, rotigotine, roxadustat, rucaparib camsylate (Rubraca), ruxolitinib, ruxolitinib (Jafaki ), Sacubitril, Valsartan, Salicylic Acid, Sapropterin, Saquinavir, Sarilumab, Saxagliptin, Metformin, Secukinumab, Selexipag, Selinexor, Selpercatinib, Selpercatinib (LOXO-292), Selumetinib, Semaglutide, Sertraline, Sevoflurane, Sildenafil, Sildenafil Citrate, Simvastatin, Siponimod, Siremadrine, Sirolimus, Sitagliptin, Sitagliptin Phosphate Monohydrate, Sodium Bicarbonate or Sodium Carbonate, Sodium Deoxycholate, Sodium Nitrate, Sophos Subvir, sofosbuvir, sofosbuvir, solifenacin, somatropin, sonidegib phosphate, sorafenib, sorafenib (Nexavar), spartalizumab, spironolactone, sufentanil citrate, sugammadex, sulbactam, sulbactam, sulfadiazine, sulfamethoxazole, sulfasalazine, sumatriptan, sunitinib, sunitinib, sunitinib (Sutent), sunitinib malate (Sutent), tacrolimus, TAF, TAF, TAF, TAF, TAF, talazoparib-talzenna), talinolol, tamoxifen,Tamsulosin, tazarotene, tazobactam, TDF, TDF, temsirolimus (CCl-779, Torisel), teneligliptin, tenofovir alafenamide, tenofovir disoproxil fumarate, tepotinib, terbinafine, terfenadine, teriflunomide, testosterone, tezacaftor, THC, ticagrelor, tigecycline, timolol, timolol maleate, Tipranavir, tisagenlecleucel, tisagenlecleucel (Kymriah), tivozanib, tofacitinib citrate, tolvaptan, tralokinumab, tramadol, trametinib, trametinib, trametinib, trametinib (Mekinist), tranexamic acid, travoprost, trazodone, tretinoin, tretinoin, triamcinolone, triclava 65. The formulation of claims 1-64, wherein the vasodilator is at least one of the following: dazol, trifalotene, trimethoprim, triptorelin, tris, tucatinib, ubrogepant, umbralisib, upadacitinib, valproic acid, valsartan, valsartan, valsartan, vancomycin, vancomycin hydrochloride (A), vancomycin hydrochloride (B), vandetanib, vandetanib (Caprelsa), varenicline, vasopressin, velpatasvir, velpatasvir, vemurafenib, venetoclax, verapamil hydrochloride, vilazodone, vildagliptin, vismodegib, vitamin B6, vitamin D, vonoprazan, voriconazole, vortioxetine, voxilaprevir, warfarin sodium, zanubrutinib, zinc, zoledronic acid, and zolpidem.

66. 66. The formulation of claim 65, further comprising at least a second pharmaceutical agent.

67. The first drug and the at least second drug are selected from the group consisting of abacavir, dolutegravir, and lamivudine, adapalene and benzoyl peroxide, amlodipine and valsartan, amlodopine besylate and valsartan, amoxicillin and clavulanate, ampicillin and sulbactam, artemether and lumefantrine, betamethasone valerate and fusidic acid, bictegravir and emtricitabine, and TAF, bimatoprost and timolol maleate, brimonidine and timolol, calcipotriene and betamethasone dipropionate, canag Liflozin and metformin, Carbidopa and Levodopa, Cefoperazone and Sulbactam, Dabrafenib and Trametinib, Darunavir and Cobicistat and Emtricitabine and Tenofovir Alafenamide, Diflucortolone and Isoconazole, Drospirenone and Ethinylestradiol, Efavirenz and Emtricitabine and TDF, Elbasvir and Grazoprevir, Elvitegravir and Cobicistat and Emtricitabine and TAF, Emtricitabine and Rilpivirine and TAF, Emtricitabine and TAF, emtricitabine and tenofovir disoproxil fumarate, ethinyl estradiol and etonogestrel, ezetimibe and atorvastatin, ezetimibe and simvastatin, fluocinolone acetonide and hydroquinone and tretinoin, fusidic acid and hydrocortisone acetate, glecaprevir and pibrentasvir, hydrochlorothiazide and valsartan, irbesartan and hydrochlorothiazide, ledipasvir and sofosbuvir, linagliptin and metformin, losartan and hydrochlorothiazide, metformin, 67. The formulation of claim 66, wherein the medicament is selected from the group consisting of luminol and sitagliptin, norethindrone acetate and ethinyl estradiol, piperacillin and tazobactam, pregabalin and celecoxib, quinupristin and dalfopristin, rilpivirine and emtricitabine and TDF, sofosbuvir and velpatasvir, sofosbuvir and velpatasvir and voxilaprevir, tezacaftor and ivacaftor, trametinib and dabrafenib, trametinib and dabrafenib, and zinc, and magnesium, and vitamin B6.

68. 68. The formulation of any one of claims 1 to 67, wherein transdermal delivery provides systemic administration of the agent.

69. 68. A formulation according to any one of claims 1 to 67 for use in a method for transdermally delivering at least one agent, said method comprising the step of applying an effective amount to the skin of a subject.

70. 68. Use of the transdermal formulation of any one of claims 1 to 67 in the manufacture of a medicament for treating a disease or disorder or alleviating a symptom thereof, said treatment comprising administering to a subject in need thereof the transdermal formulation and administering to the subject in need thereof a composition comprising one or more agents selected from Table 1.

71. 71. The use of claim 70, wherein the transdermal formulation is administered before, simultaneously with, or after administration of the composition.

72. 72. The use of claim 70 or claim 71, wherein the amount of the one or more agents is an effective dose of the agent as set forth in Table 1.

73. The use according to any one of claims 70 to 72, wherein the composition is administered by a standard route for the drug.

74. 74. The use according to claim 73, wherein said standard route is oral, topical, enteral, parenteral, intravenous injection or infusion, intraperitoneal injection, intramuscular injection, or subcutaneous injection.

75. 75. The use according to claim 73 or claim 74, wherein the composition is a liquid, suspension, gel, geltab, semisolid, tablet, sachet, lozenge, pill, or capsule.

76. 69. A transdermal formulation according to any one of claims 1 to 68 for use in a method for treating or alleviating a symptom of a disease or disorder.

77. 67. A method for the manufacture of a medicament for treating or alleviating a symptom of a disease or disorder comprising combining a penetrating moiety according to any one of claims 1 to 63 with one or more agents according to claim 65.

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