TRANSDERMAL FORMULATIONS FOR PHOSPHODIESTERASE-5 INHIBITORS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63/137, 126, filed January 13, 2021, the entire contents of which is expressly incorporated herein by reference.

BACKGROUND

[0002] Phosphodiesterase-5 (PDE5) inhibitors, e.g. , sildenafil, have been shown to effectively treat erectile disfunction. However, when taken orally, a PDE5 inhibitor must pass through the gastrointestinal (GI) tract. This reduces the bioavailability which increases the amount of drug necessary to achieve the desired effect. An ideal erectile disfunction medication can be described as predictable with regards to efficacy and time of onset, well tolerated, easy to administer, and associated with minimal side effects. No such erectile disfunction medication is presently available.

BRIEF DESCRIPTION OF THE DRAWINGS

[0003] FIG. 1 is graph showing PK data showing resulting mean plasma concentration from applied topical sildenafil.

SUMMARY

[0004] The present disclosure solves the problems described above by providing topical, transdermal formulations comprising Phosphodiesterase-5 (PDE5) inhibitors.

[0005] An aspect of the present disclosure is a formulation for transdermal delivery of a phosphodiesterase-5 (PDE5) inhibitor through the skin of a subject. In this aspect, the formulation comprising a therapeutically effective amount of a PDE5 inhibitor and a penetrant portion, in which the penetrant portion comprises: a phospholipid, a fatty acid ester formed from a low molecular weight alcohol, and a long-chain fatty acids, and, optionally, one or more of a viscosity-improving agent, a penetration enhancer, and an emulsifier.

[0006] In embodiments, the phospholipid is selected from phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, inositol phosphatide, and sphingomyelin. In some cases, the phospholipid is phosphatidylcholine.

[0007] In embodiments, the penetrant portion comprises two or more phospholipids.

[0008] In embodiments, the phospholipid is in an amount from about 3% to about 15% w/w of the formulation.

[0009] In embodiments, the low molecular weight alcohol is selected from isopropanol, methanol, ethanol, butanol, glycerol, cetyl alcohol.

[0010] In embodiments, the low molecular weight alcohol is isopropanol. [0011] In 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.

[0012] In embodiments, the penetrant portion comprises two or more fatty acid esters.

[0013] In embodiments, the fatty acid ester is in an amount from about 5% to about 20% w/w of the formulation.

[0014] In embodiments, the long-chain fatty acid is selected from a linoleic, oleic, stearic acid, linolenic, palmitic, arachidonic, palmitoleic, myristic, eicosenoic, benehic, euricic, and lignoceric add In some cases, the long-chain fatty acid is linoleic acid. In various cases, the long-chain fatty acid is oleic acid. In other 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.

[0015] In embodiments, the long-chain fatty acid is in an amount from about 0.1% to about 10% w/w of the formulation.

[0016] In embodiments, the penetrant portion comprises two or more long-chain fatty acids.

[0017] In embodiments, the penetrant portion comprises a viscosity -improving agent.

[0018] In embodiments, the viscosity -improving agent is a pol oxamer. In some cases, the poloxamer is selected from poloxamer 407, poloxamer 188, poloxamer 184, and poloxamer 124.

[0019] In embodiments, the viscosity-improving agent is a surfactant. In some cases, the surfactant is selected from sodium lauryl sulfate (sodium dodecyl sulfate); poly oxy ethylated castor oil derivatives such as HCO-60 surfactant; nonoxynol; octoxynol; phenylsulfonate; poloxamers such as Pluronic® F68, Pluronic® F127, and Pluronic® L62; poly oleates; Rewopal® HVIO, sodium laurate, sodium oleate; sorbitan dilaurate; sorbitan dioleate; sorbitan monolaurate such as Span® 20; sorbitan monooleates; sorbitan trilaurate; sorbitan trioleate; sorbitan monopalmitate such as Span® 40; sorbitan stearate such as Span® 85; polyethylene glycol nonylphenyl ether such as Synperonic®NP; p-(l,l,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 poly oxy ethylenesorbitan trioleate such as Tween® 85. In various cases, the surfactant is sodium lauryl sulfate.

[0020] In embodiments, the penetrant portion comprises two or more viscosity -improving agents. [0021] In embodiments, the viscosity -improving agent is in an amount from about 5% to about 20% w/w of the formulation.

[0022] In embodiments, the penetrant portion comprises a penetration enhancer.

[0023] In embodiments, the penetration enhancer is an alcohol or a terpene. In some cases, the penetration enhancer as an alcohol is selected from benzyl alcohol, ethanol, propylene glycol, and polyethylene glycol. In various cases, the penetration enhancer is benzyl alcohol. In some cases, the penetration enhancer as a terpene is selected from limonene, menthol, borneol, and camphor. In varoius cases, the penetration enhancer further acts as a preservative.

[0024] In embodiments, the penetrant portion comprises two or more penetration enhancers.

[0025] In embodiments, the penetration enhancer is in an amount from about 0.5% to about 5% w/w of the formulation.

[0026] In embodiments, the penetrant portion comprises at least one penetration enhancer and at least one viscosity-improving agent.

[0027] In embodiments, the penetrant portion comprises an emulsifier.

[0028] In embodiments, the emulsifier is selected from polyglyceryl-4-laurate, polyglyceryl-4- oleate, span 60, cetyl alcohol, and polyglyceryl-3-oleate.

[0029] In embodiments, the penetrant portion comprises two or more penetration enhancers.

[0030] In embodiments, the emulsifier is in an amount from about 0.5 to about 10% w/w of the formulation.

[0031] In embodiments, the penetrant portion comprises at least one emulsifier and at least one viscosity-improving agent.

[0032] In embodiments, the penetrant portion comprises at least one emulsifier and at least one penetration enhancer.

[0033] In embodiments, the penetrant portion comprises at least one emulsifier, at least one viscosity - improving agent, and at least one penetration enhancer.

[0034] Another aspect of the present disclosure is a formulation for transdermal delivery of a phosphodiesterase-5 (PDE5) inhibitor through the skin of a subject. In this aspect, the formulation comprising a therapeutically effective amount of a PDE5 inhibitor and a penetrant portion, in which the penetrant portion comprises: a phospholipid, a fatty acid ester formed from a low molecular weight alcohol, and a long-chain fatty acids. In this aspect, phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, inositol phosphatide, or sphingomyelin is the phospholipid; isopropyl palmitate, isopropyl myristate, isopropyl linoleate, isopropyl oleate, ethyl laurate, or ethyl myristate is the fatty acid ester; and a linoleic, oleic, stearic acid, linolenic, palmitic, arachidonic, palmitoleic, myristic, eicosenoic, benehic, euricic, or lignoceric acid is the long-chain fatty acid or the long-chain fatty acid is obtained from safflower oil or almond oil.

[0035] A further aspect of the present disclosure is a formulation for transdermal delivery of a phosphodiesterase-5 (PDE5) inhibitor through the skin of a subject. In this aspect, the formulation comprising a therapeutically effective amount of a PDE5 inhibitor and a penetrant portion, in which the penetrant portion comprises: a phospholipid, a fatty acid ester formed from a low molecular weight alcohol, and a long-chain fatty acids, and one or more of a viscosity-improving agent, a penetration enhancer, and an emulsifier. In this aspect, phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, inositol phosphatide, or sphingomyelin is the phospholipid; isopropyl palmitate, isopropyl myristate, isopropyl linoleate, isopropyl oleate, ethyl laurate, or ethyl myristate is the fatty acid ester; and a linoleic, oleic, stearic add, linolenic, palmitic, arachidonic, palmitoleic, myristic, eicosenoic, benehic, euricic, or lignoceric acid is the long-chain fatty acid or the long-chain fatty acid is obtained from safflower oil or almond oil; polyglyceryl-4-laurate, polyglyceryl-4-oleate, span 60, cetyl alcohol, or polyglyceryl -3 -oleate is the penetration enhancer; a pol oxamer (e.g., pol oxamer 407, pol oxamer 188, poloxamer 184, and poloxamer 124) or sodium lauryl sulfate is the viscosity -improving agent; benzyl alcohol, ethanol, propylene glycol, polyethylene glycol, limonene, menthol, borneol, or camphor is the penetration enhancer.

[0036] In embodiments, the penetrant portion is in an amount from about 70% to about 98 % w/w of the formulation.

[0037] In embodiments, the penetrant portion comprises water.

[0038] In embodiments, the penetrant portion comprises water in an amount from about 50% to about 80% w/w of the formulation.

[0039] In embodiments, the formulation comprises a phospholipid, an emollient/moisturizer, a fatty acid, an alcohol, an oil, a surfactant, water, and aPDE5 inhibitor.

[0040] An additional aspect of the present disclosure is a formulation for transdermal delivery of a phosphodiesterase-5 (PDE5) inhibitor through the skin of a subject. In this aspect, the formulation comprising a phospholipid in an amount from about 5% to about 15% w/w of the formulation; an emollient/moisturizer in an amount from about 10% to about 20% w/w of the formulation; a fatty add in an amount from about 0.5% to about 2% w/w of the formulation; an alcohol in an amount from about 0.5% to about 2% w/w of the formulation; an oil in an amount from about 1% to about 5% w/w of the formulation; a surfactant in an amount from about 0.5% to about 2% w/w of the formulation; w ater in an amount from about 30% to about 80% w/w of the formulation; and atherapeutically effective amount of a phosphodiesterase-5 (PDE5) inhibitor in an amount from about 0.05% to about 5% w/w of the formulation. In some cases, the PDE5 inhibitor is in an amount from about 0.05% to about 0.1% w/w of the formulation. In other cases, the PDE5 inhibitor is in an amount from about 0.1% to about 1% w/w of the formulation. In various cases, the PDE5 inhibitor is in an amount from about 1% to about 5% w/w of the formulation.

[0041] In an aspect, the present disclosure provides a transdermal delivery formulation for transdermal delivery of a phosphodi esterase- 5 (PDE5) inhibitor through the skin of a subject. In this aspect, the transdermal delivery formulation comprises: a) a PDE5 inhibitor at 0.05 to 5% w/w; b) propylene glycol at 2 to 10% w/w; c) phosphatidylcholine at 2 to 10% w/w; d) benzyl alcohol at 0.5 to 5% w/w; e) isopropyl palmitate at 2 to 15 % w/w; f) stearic acid at 0.1 to 2% w/w; g) oleic acid at 0.2 to 5%; h) a surfactant at 1 to 15%; and i) water in an amount less than about 50 % w/w.

[0042] In another aspect, the present disclosure provides a transdermal delivery formulation for transdermal delivery of a phosphodi esterase- 5 (PDE5) inhibitor through the skin of a subject. In this aspect, the transdermal delivery formulation comprises: a) a PDE5 inhibitor at 0.05 to 5% w/w; b) phosphatidylcholine at 2 to 15% w/w; c) isopropyl palmitate at 2 to 25 % w/w; d) benzyl alcohol at 0.5 to 5% w/w; e) stearic acid at 0. 1 to 3% w/w; f) oleic acid at 0.2 to 5%; g) a surfactant at 1 to 15%; and h) water in an amount of about 60 % w/w. In some cases, the PDE5 inhibitor is in an amount from about 0.05% to about 0.1% w/w of the formulation. In other cases, the PDE5 inhibitor is in an amount from about 0. 1% to about 1% w/w of the formulation. In various cases, the PDE5 inhibitor is in an amount from about 1% to about 5% w/w of the formulation.

[0043] In embodiments, the formulation has apH from about 7 to about 10.5.

[0044] In embodiments, the formulation has a pH from about 9 to about 11.

[0045] In embodiments, the PDE5 inhibitor is at least one of sildenafil, vardenafil, avanafil, tadalafil, lodenafil, mirodenafil, udenafil, gisadenafil, and dipyridamole.

[0046] In embodiments, the PDE5 inhibitor comprises sildenafil.

[0047] In embodiments, the formulation further comprises an at least second PDE5 inhibitor. In some cases, the at least second PDE5 inhibitor is selected from sildenafil, vardenafil, avanafil, tadalafil, lodenafil, mirodenafil, udenafil, gisadenafil, and dipyridamole.

[0048] In embodiments, transdermal delivery provides systemic administration of the PDE5 inhibitor.

[0049] In yet another aspect, the present disclosure provides a transdermal delivery formulation for transdermal delivery of a phosphodiesterase-5 (PDE5) inhibitor through the skin of a subject. In this aspect, the PDE5 inhibitor comprises sildenafil and the transdermal delivery formulation comprises: a) sildenafil at 0.5 to 5% w/w; b) propylene glycol at 2 to 10% w/w; c) phosphatidylcholine at 2 to 10% w/w; d) benzyl alcohol at 0.5 to 5% w/w; e) isopropyl palmitate at 2 to 15 % w/w; f) stearic acid at 0.1 to 2% w/w; g) oleic acid at 0.2 to 5%; h) a surfactant at 1 to 15%; and i) water in an amount less than about 50 % w/w.

[0050] In a further aspect, the present disclosure provides a transdermal delivery formulation for transdermal delivery of a phosphodi esterase- 5 (PDE5) inhibitor through the skin of a subject. In this aspect, the PDE5 inhibitor comprises sildenafil and the transdermal delivery formulation comprises: a) sildenafil at 0.5 to 5% w/w; b) phosphatidylcholine at 2 to 15% w/w; c) isopropyl palmitate at 2 to 25 % w/w; d) benzyl alcohol at 0.5 to 5% w/w; e) stearic acid at 0. 1 to 3% w/w; I) oleic acid at 0.2 to 5%; g) a surfactant at 1 to 15%; and h) water in an amount of about 60 % w/w.

[0051] In an additional aspect, the present disclosure provides a method for transdermally delivering at least one phosphodi esterase- 5 (PDE5) inhibitor. In this aspect, the method comprises a step of applying to the skin of a subject an effective amount of any herein disclosed formulation.

[0052] In embodiments, the subject has a neurologic disease. In some cases, the neurologic disease is characterized by age-related cognitive decline. In some cases, the neurologic disease is Alzheimer's disease. [0053] In embodiments, the subject has pulmonary hypertension, heart diseases such as congestive heart failure and diastolic dysfunction, or Raynaud’s disease.

[0054] In embodiments, the subject has reduced peripheral blood circulation due to diabetes.

[0055] In embodiments, the dosage of the PDE5 inhibitor is less than the dosage of a formulation when used for treating erectile disfunction.

[0056] In embodiments, the formulation is applied to the to the skin of the subj ect for 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.

[0057] In embodiments, the formulation is applied to the to the skin of the subject once daily, twice daily, thrice daily, once every few days, or once weekly.

[0058] In embodiments, the subj ect has erectile disfunction.

[0059] In embodiments, the subject has a female sexual arousal disorder.

[0060] An aspect of the present disclosure is a method for treating erectile disfunction or a female sexual arousal disorder in a subject in need thereof. In this aspect, the method comprises applying a formulation for transdermal delivery to the skin of a subject, in which the formulation comprises a therapeutically effective amount of a phosphodiesterase-5 (PDE5) inhibitor and a penetrant portion, in which the penetrant portion comprises: a phospholipid, a fatty acid ester formed from a low molecular weight alcohol, and a long-chain fatty acids, and, optionally, one or more of a viscosity -improving agent, a penetration enhancer, and an emulsifier.

[0061] Another aspect of the present disclosure is a method for treating erectile disfunction or a female sexual arousal disorder in a subject in need thereof. In this aspect, the method comprises applying a formulation for transdermal delivery to the skin of a subject, in which the formulation comprises a therapeutically effective amount of a phosphodiesterase-5 (PDE5) inhibitor and apenetrant portion, in which the penetrant portion comprises: a phospholipid, a fatty acid ester formed from a low molecular weight alcohol, and a long-chain fatty acids. In this aspect, phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, inositol phosphatide, or sphingomyelin is the phospholipid; isopropyl palmitate, isopropyl myristate, isopropyl linoleate, isopropyl oleate, ethyl laurate, or ethyl myristate is the fatty acid ester; and a linoleic, oleic, stearic acid, linolenic, palmitic, arachidonic, palmitoleic, myristic, eicosenoic, benehic, euricic, or lignoceric acid is the long-chain fatty acid or the long-chain fatty acid is obtained from safflower oil or almond oil.

[0062] A further aspect of the present disclosure is a method for treating erectile disfunction or a female sexual arousal disorder in a subject in need thereof. In this aspect, the method comprises applying a formulation for transdermal delivery to the skin of a subject, in which the formulation comprises a therapeutically effective amount of a phosphodiesterase-5 (PDE5) inhibitor and apenetrant portion, in which the penetrant portion comprises: a phospholipid, a fatty acid ester formed from a low molecular weight alcohol, and a long-chain fatty acids, and one or more of a viscosity -improving agait, a penetration enhancer, and an emulsifier. . In this aspect, phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, inositol phosphatide, or sphingomyelin is the phospholipid; isopropyl palmitate, isopropyl myristate, isopropyl linoleate, isopropyl oleate, ethyl laurate, or ethyl myristate is the fatty acid ester; and a linoleic, oleic, stearic acid, linolenic, palmitic, arachidonic, palmitoleic, myristic, eicosenoic, benehic, euricic, or lignoceric acid is the long-chain fatty acid or the long-chain fatty acid is obtained from safflower oil or almond oil; polyglyceryl-4-laurate, polyglyceryl-4-oleate, span 60, cetyl alcohol, or poly glyceryl -3- oleate is the penetration enhancer; a pol oxamer (e.g., pol oxamer 407, pol oxamer 188, pol oxamer 184, and poloxamer 124) or sodium lauryl sulfate is the viscosity-improving agent; benzyl alcohol, ethanol, propylene glycol, polyethylene glycol, limonene, menthol, borneol, or camphor is the penetration enhancer.

[0063] In embodiments, the PDE5 inhibitor is at least one of sildenafil, vardenafil, avanafil, tadalafil, lodenafil, mirodenafil, udenafil, gisadenafil, and dipyridamole.

[0064] In embodiments, the PDE5 inhibitor comprises sildenafil.

[0065] In embodiments, the formulation further comprises an at least second PDE5 inhibitor. In some cases, the at least second PDE5 inhibitor is selected from sildenafil, vardenafil, avanafil, tadalafil, lodenafil, mirodenafil, udenafil, gisadenafil, and dipyridamole.

[0066] An additional aspect of the present disclosure is a method of treating erectile disfunction or a female sexual arousal disorder comprising applying a phosphodiesterase-5 (PDE5) inhibitor to a skin surface of a subject. In this aspect, the PDE5 inhibitor is applied to the skin surface with atransdermal delivery formulation comprising: a) a PDE5 inhibitor at 0.05 to 5% w/w; b) phosphatidylcholine at 2 to 15% w/w; c) isopropyl palmitate at 2 to 25 % w/w; d) benzyl alcohol at 0.5 to 5% w/w; e) stearic acid at 0. 1 to 3% w/w; f) oleic acid at 0.2 to 5%; g) a surfactant at 1 to 15%; and h) water in an amount of about 60 % w/w. In some cases, the PDE5 inhibitor is at least one of sildenafil, vardenafil, avanafil, tadalafil, lodenafil, mirodenafil, udenafil, gisadenafil, and dipyridamole.

[0067] In an aspect, the present disclosure provides a use of any herein disclosed transdermal formulation in a method for treating a disease or disorder or reducing a symptom thereof.

[0068] In an additional aspect, the present disclosure provides a method for manufacturing a medicament for treating a disease or disorder or reducing a symptom thereof comprising combining a penetrant portion as recited in any herein disclosed transdermal formulation with one or more phosphodiesterase-5 (PDE5) inhibitors. In some cases, the PDE5 inhibitor is at least one of sildenafil, vardenafil, avanafil, tadalafil, lodenafil, mirodenafil, udenafil, gisadenafil, and dipyridamole.

[0069] Any aspect or embodiment described herein can be combined with any other aspect or embodiment as disclosed herein. DETAILED DESCRIPTION

Introduction

[0070] Erectile dysfunction (ED), also called impotence, can be defined as the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance. ED is the most common sexual problem in men and is estimated to affect approximately 40% of men by age 40, with the prevalence increasing to approximately 70% by age 70. The global market for ED is estimated at $4.28 billion and is expected to reach $5.18 billion by 2022.

[0071] ED can have physical or psychological causes. In 80% of cases, a physical cause can be identified. Common medical causes include heart disease, atherosclerosis, high cholesterol, high blood pressure, diabetes, obesity, metabolic syndrome, Parkinson’s disease, multiple sclerosis, Peyronie’s disease, neurogenic disorders such as diabetic neuropathy, kidney failure, hyperprolactinemia, sleep disorders, and age. ED can also be caused by certain prescription medications (SSRIs, beta blockers, alpha-2 adrenergic receptor agonists, thiazides, hormone modulators, and 5 alpha- reductase inhibitors), tobacco use, alcoholism or other substance abuse, treatments for prostate cancer or enlarged prostate, and some surgeries. Though less common, psychological causes of ED include stress, depression, anxiety, or other mental health conditions. Additionally, there are often psychological consequences to ED such as diminished self-image and the condition can contribute to stress, anxiety, and depression.

[0072] The increased incidence of ED can be attributed to the prevalence of chronic diseases that are associated with a sedentary lifestyle. One factor leading to ED is diabetes mellitus, a well-known cause of neuropathy. ED is also related to generally poor physical health, poor dietary habits, obesity, and most specifically cardiovascular disease, such as coronary artery disease and peripheral vascular disease. ED has a particularly high correlation with arterial disease. One study demonstrated that 49% of patients with coronary artery disease also experienced symptoms of ED. Accordingly, screening for cardiovascular risk factors, such as smoking, dyslipidemia, hypertension, and alcoholism, can be helpful.

[0073] The treatments for ED can begin with lifestyle changes. Addressing the underlying causes, lifestyle modifications, and addressing psychosocial problems can be helpful. Exercise, particularly of the aerobic type, can be effective for preventing ED during midlife. Counseling can be used if the underlying cause is psychological, including how to lower stress or anxiety related to sex. Patients with ED often resort to oral medication when lifestyle changes are ineffective.

[0074] The most common oral medication used for ED is the drug sildenafil. Sildenafil was initially developed for potential use in hypertension and angina pectoris. However, the first clinical trials suggested the drug had little effect on angina, but it could induce marked penile erections. Thereafter, it was marketed as a medication for erectile dysfunction using the brand name Viagra.

[0075] Other common PDE5 inhibitors include vardenafil, avanafil, tadalafil, lodenafil, mirodenafil, udenafil, gisadenafil, and dipyridamole. [0076] Nitrous oxide (NO) relaxes the cavemosal smooth muscle, compressing the veins in the paiis and occluding local venous return, resulting in an erection. NO utilizes the guanosine triphosphate and cyclic guanosine monophosphate (cGMP) pathway by stimulating cGMP to decrease intracellular calcium, which leads to the cavemosal smooth muscle relaxation that is needed for erection.

[0077] Sildenafil improves blood flow due to its role as a phosphodiesterase-5 (PDE5) inhibitor. It acts by blocking phosphodiesterase 5 (PDE5), an enzyme that promotes breakdown of cGMP, which regulates blood flow in the penis. PDE5 inhibitors prevent the hydrolysis of cGMP, allowing for increased blood flow and a prolonged erection. There are numerous PDE5 inhibitors currently available in the United States: sildenafil, vardenafil, avanafil, tadalafil, lodenafil, mirodenafil, udenafil, gisadenafil, and dipyridamole. Sildenafil held 65% of the ED market share in 2018. Due to sildenafil’s improvement to blood flow, it can also be used for other pulmonary conditions like pulmonary arterial hypertension.

[0078] Sildenafil is taken orally and typically starts to work within 30 - 60 minutes. Though it is often effective for treating ED, oral delivery has significant drawbacks. Oral delivery has a long onset of action and a low bioavailability because it passes through the gastrointestinal tract. Intravenous delivery is not practical due to the indication and aversion of needle-phobic patients. Additionally, sildenafil can have side effects when circulated systemically including decreased blood pressure^ headache, flushing, nasal congestion, nausea, and in some cases hearing and vision loss.

[0079] Although oral PDE5 inhibitors can be effective, they are associated with treatment failure in up to half of patients, resulting in discontinuation due to either noneffectiveness or psychosocial reasons. Further, oral PDE5 inhibitors are associated with systemic side effects and are contraindicated with the use of nitrates, a cardiovascular agent commonly used in this older population.

[0080] The effectiveness of sildenafil along with the drawbacks of current delivery methods have raised interest in delivering the drug transdermally. Effective topical delivery would allow circumvention of the GI tract, increased bioavailability and allow for lower doses which would reduce the risk of side effects. However, the molecule’s various characteristics, including its size, make it a difficult for topical drug delivery. Previous attempts at transdermal administration have shown unfavorable bioavailability and slow time of onset.

[0081] Sildenafil is a difficult molecule to delivery transdermally due to some of its applicable characteristics falling outside of the Lipinski Rule of 5 for Transdermal Drug Delivery (TDD). The Lipinski Rule of 5 for TDD predicts the viability of transdermal delivery of drugs based on molecular weight, number of H-bond donors, number of H-bond acceptors, and logP value. Sildenafil has an H- bond donor count and logP within the range for Rule of 5 for TDD. However, it has a molecular weight of 474.6 g/mol which is larger than the Lipinski upper threshold of 335 g/mol. It also has eight H-bond acceptors which exceed the Lipinski threshold of five. With half of the characteristics falling outside of the limits set by the Rule of 5 for TDD, traditional topical delivery systems are generally ineffective for transporting sildenafil through the skin. [0082] Embodiments of the present disclosure include formulations and methods for transdermal administration of sildenafil. Transdermal administration presents several benefits. When taken orally, sildenafil must pass through the gastrointestinal (GI) tract. This reduces the bioavailability which increases the amount of drug necessary to achieve the desired effect. Hence, circumventing the GI tract allows for administration of small amounts with high efficacy. Transdermal administration of topical sildenafil is also preferable to intravenous administration. Intravenous injections are generally disfavored for obvious reasons including safety and convenience. Additionally, by applying sildenafil topically -directly to affected areas, there is less reliance on the drug to be transported systemically. This reduces the amount of drug needed for a desired effect.

Illustrative aspects of the present disclosure

[0083] The term transdermal administration refers to applying a substance onto the skin so that it is 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 one’s skin. The solution or patch includes a medicament that is released into the skin. As the layers of skin absorb the solution, the medicament is absorbed via the blood vessels into the bloodstream. From there, the substance can be circulated through the body.

[0084] There are obvious advantages to transdermal administration of medicaments. The consumer does not have to schedule and remember to consume doses of pills. Further, transdermal administration is not affected by stomach or digestive issues. Administration across the skin enables drugs to avoid degradation in the gastrointestinal tract or liver. Transdermal delivery is therefore of particular interest for molecules with limited systemic bioavailabilities and short half-lives. Drugs that are absorbed slowly can be more effective. With a transdermal patch or cream, a medicament can be released in small quantities over a long period of time

[0085] An aspect of the present disclosure is a formulation for transdermal delivery of a phosphodiesterase-5 (PDE5) inhibitor through the skin of a subject. In this aspect, the formulation comprising a therapeutically effective amount of a PDE5 inhibitor and a penetrant portion, in which the penetrant portion comprises: a phospholipid, a fatty acid ester formed from a low molecular weight alcohol, and a long-chain fatty acids, and, optionally, one or more of a viscosity -improving agent, a penetration enhancer, and an emulsifier.

[0086] Another aspect of the present disclosure is a formulation for transdermal delivery of a phosphodiesterase-5 (PDE5) inhibitor through the skin of a subject. In this aspect, the formulation comprising a therapeutically effective amount of a PDE5 inhibitor and a penetrant portion, in which the penetrant portion comprises: a phospholipid, a fatty acid ester formed from a low molecular weight alcohol, and a long-chain fatty acids. In this aspect, phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, inositol phosphatide, or sphingomyelin is the phospholipid; isopropyl palmitate, isopropyl myristate, isopropyl linoleate, isopropyl oleate, ethyl laurate, or ethyl myristate is the fatty acid ester; and a linoleic, oleic, stearic acid, linolenic, palmitic, arachidonic, palmitoleic, myristic, eicosenoic, benehic, euricic, or lignoceric acid is the long-chain fatty acid or the long-chain fatty acid is obtained from safflower oil or almond oil.

[0087] A further aspect of the present disclosure is a formulation for transdermal delivery of a phosphodiesterase-5 (PDE5) inhibitor through the skin of a subject. In this aspect, the formulation comprising a therapeutically effective amount of a PDE5 inhibitor and a penetrant portion, in which the penetrant portion comprises: a phospholipid, a fatty acid ester formed from a low molecular weight alcohol, and a long-chain fatty acids, and one or more of a viscosity-improving agent, a penetration enhancer, and an emulsifier. In this aspect, phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, inositol phosphatide, or sphingomyelin is the phospholipid; isopropyl palmitate, isopropyl myristate, isopropyl linoleate; isopropyl oleate, ethyl laurate, or ethyl myristate is the fatty acid ester; and a linoleic, oleic, stearic add, linolenic, palmitic, arachidonic, palmitoleic, myristic, eicosenoic, benehic, euricic, or lignoceric acid is the long-chain fatty acid or the long-chain fatty acid is obtained from safflower oil or almond oil; polyglyceryl-4-laurate, polyglyceryl-4-oleate, span 60, cetyl alcohol, or polyglyceryl -3 -oleate is the penetration enhancer; a pol oxamer (e.g., pol oxamer 407, pol oxamer 188, pol oxamer 184, and poloxamer 124) or sodium lauryl sulfate is the viscosity -improving agent; benzyl alcohol, ethanol, propylene glycol, polyethylene glycol, limonene, menthol, borneol, or camphor is the penetration enhancer.

[0088] An additional aspect of the present disclosure is a formulation for transdermal delivery of a phosphodiesterase-5 (PDE5) inhibitor through the skin of a subject. In this aspect, the formulation comprising a phospholipid in an amount from about 5% to about 15% w/w of the formulation; an emollient/moisturizer in an amount from about 10% to about 20% w/w of the formulation; a fatty add in an amount from about 0.5% to about 2% w/w of the formulation; an alcohol in an amount from about 0.5% to about 2% w/w of the formulation; an oil in an amount from about 1% to about 5% w/w of the formulation; a surfactant in an amount from about 0.5% to about 2% w/w of the formulation; w ater in an amount from about 30% to about 80% w/w of the formulation; and atherapeutically effective amount of a phosphodiesterase-5 (PDE5) inhibitor in an amount from about 0.05% to about 5% w/w of the formulation. In some cases, the PDE5 inhibitor is in an amount from about 0.05% to about 0.1% w/w of the formulation. In other cases, the PDE5 inhibitor is in an amount from about 0. 1% to about 1% w/w of the formulation. In various cases, the PDE5 inhibitor is in an amount from about 1% to about 5% w/w of the formulation.

[0089] In an aspect, the present disclosure provides a transdermal delivery formulation for transdermal delivery of a phosphodiesterase-5 (PDE5) inhibitor through the skin of a subject. In this aspect, the transdermal delivery formulation comprises: a) a PDE5 inhibitor at 0.05 to 5% w/w; b) propylene glycol at 2 to 10% w/w; c) phosphatidylcholine at 2 to 10% w/w; d) benzyl alcohol at 0.5 to 5% w/w; e) isopropyl palmitate at 2 to 15 % w/w; f) stearic acid at 0.1 to 2% w/w; g) oleic acid at 0.2 to 5%; h) a surfactant at 1 to 15%; and i) water in an amount less than about 50 %w/w.

[0090] In another aspect, the present disclosure provides a transdermal delivery formulation for transdermal delivery of a phosphodi esterase- 5 (PDE5) inhibitor through the skin of a subject. In this aspect, the transdermal delivery formulation comprises: a) a PDE5 inhibitor at 0.05 to 5% w/w; b) phosphatidylcholine at 2 to 15% w/w; c) isopropyl palmitate at 2 to 25 % w/w; d) benzyl alcohol at 0.5 to 5% w/w; e) stearic acid at 0. 1 to 3% w/w; 1) oleic acid at 0.2 to 5%; g) a surfactant at 1 to 15%; and h) water in an amount of about 60 %w/w In some cases, the PDE5 inhibitor is in an amount from about 0.05% to about 0.1% w/w of the formulation. In other cases, the PDE5 inhibitor is in an amount from about 0. 1% to about 1% w/w of the formulation. In various cases, the PDE5 inhibitor is in an amount from about 1% to about 5% w/w of the formulation.

[0091] In yet another aspect, the present disclosure provides a transdermal delivery formulation for transdermal delivery of a phosphodi esterase- 5 (PDE5) inhibitor through the skin of a subject. In this aspect, the PDE5 inhibitor comprises sildenafil and the transdermal delivery formulation comprises: a) sildenafil at 0.5 to 5% w/w; b) propylene glycol at 2 to 10% w/w; c) phosphatidylcholine at 2 to 10% w/w; d) benzyl alcohol at 0.5 to 5% w/w; e) isopropyl palmitate at 2 to 15 % w/w; 1) stearic acid at 0.1 to 2% w/w; g) oleic acid at 0.2 to 5%; h) a surfactant at 1 to 15%; and i) water in an amount less than about 50 % w/w.

[0092] In a further aspect, the present disclosure provides a transdermal delivery formulation for transdermal delivery of a phosphodi esterase- 5 (PDE5) inhibitor through the skin of a subject. In this aspect, the PDE5 inhibitor comprises sildenafil and the transdermal delivery formulation comprises: a) sildenafil at 0.5 to 5% w/w; b) phosphatidylcholine at 2 to 15% w/w; c) isopropyl palmitate at 2 to 25 % w/w; d) benzyl alcohol at 0.5 to 5% w/w; e) stearic acid at 0. 1 to 3% w/w; 1) oleic acid at 0.2 to 5%; g) a surfactant at 1 to 15%; and h) water in an amount of about 60 % w/w.

[0093] In an additional aspect, the present disclosure provides a method for transdermally delivering at least one phosphodi esterase- 5 (PDE5) inhibitor. In this aspect, the method comprises a step of applying to the skin of a subject an effective amount of any herein disclosed formulation.

[0094] An aspect of the present disclosure is a method for treating erectile disfunction or a female sexual arousal disorder in a subject in need thereof. In this aspect, the method comprises applying a formulation for transdermal delivery to the skin of a subject, in which the formulation comprises a therapeutically effective amount of a phosphodiesterase-5 (PDE5) inhibitor and a penetrant portion, in which the penetrant portion comprises: a phospholipid, a fatty acid ester formed from a low molecular weight alcohol, and a long-chain fatty acids, and, optionally, one or more of a viscosity -improving agent, a penetration enhancer, and an emulsifier.

[0095] Another aspect of the present disclosure is a method for treating erectile disfunction or a female sexual arousal disorder in a subject in need thereof. In this aspect, the method comprises applying a formulation for transdermal delivery to the skin of a subject, in which the formulation comprises a therapeutically effective amount of a phosphodiesterase-5 (PDE5) inhibitor and apenetrant portion, in which the penetrant portion comprises: a phospholipid, a fatty acid ester formed from a low molecular weight alcohol, and a long-chain fatty acids. In this aspect, phosphatidylcholine; hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, inositol phosphatide, or sphingomyelin is the phospholipid; isopropyl palmitate, isopropyl myristate, isopropyl linoleate, isopropyl oleate, ethyl laurate, or ethyl myristate is the fatty acid ester; and a linoleic, oleic, stearic acid, linolenic, palmitic, arachidonic, palmitoleic, myristic, eicosenoic, benehic, euricic, or lignoceric acid is the long-chain fatty acid or the long-chain fatty acid is obtained from safflower oil or almond oil.

[0096] A further aspect of the present disclosure is a method for treating erectile disfunction or a female sexual arousal disorder in a subject in need thereof. In this aspect, the method comprises applying a formulation for transdermal delivery to the skin of a subject, in which the formulation comprises a therapeutically effective amount of a phosphodiesterase-5 (PDE5) inhibitor and apenetrant portion, in which the penetrant portion comprises: a phospholipid, a fatty acid ester formed from a low molecular weight alcohol, and a long-chain fatty acids, and one or more of a viscosity -improving agait, a penetration enhancer, and an emulsifier. . In this aspect, phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, inositol phosphatide, or sphingomyelin is the phospholipid; isopropyl palmitate, isopropyl myristate, isopropyl linoleate, isopropyl oleate, ethyl laurate, or ethyl myristate is the fatty acid ester; and a linoleic, oleic, stearic acid, linolenic, palmitic, arachidonic, palmitoleic, myristic, eicosenoic, benehic, euricic, or lignoceric acid is the long-chain fatty acid or the long-chain fatty acid is obtained from safflower oil or almond oil; polyglyceryl-4-laurate, polyglyceryl-4-oleate, span 60, cetyl alcohol, or poly glyceryl -3- oleate is the penetration enhancer; a pol oxamer (e.g., pol oxamer 407, pol oxamer 188, pol oxamer 184, and poloxamer 124) or sodium lauryl sulfate is the viscosity-improving agent; benzyl alcohol, ethanol, propylene glycol, polyethylene glycol, limonene, menthol, borneol, or camphor is the penetration enhancer.

[0097] An additional aspect of the present disclosure is a method of treating erectile disfunction or a female sexual arousal disorder comprising applying a phosphodiesterase-5 (PDE5) inhibitor to a skin surface of a subject. In this aspect, the PDE5 inhibitor is applied to the skin surface with a transdermal delivery formulation comprising: a) a PDE5 inhibitor at 0.05 to 5% w/w; b) phosphatidylcholine at 2 to 15% w/w; c) isopropyl palmitate at 2 to 25 % w/w; d) benzyl alcohol at 0.5 to 5% w/w; e) stearic acid at 0. 1 to 3% w/w; f) oleic acid at 0.2 to 5%; g) a surfactant at 1 to 15%; and h) water in an amount of about 60 %w/w. In some cases, the PDE5 inhibitor is at least one of sildenafil, vardenafil, avanafil, tadalafil, lodenafil, mirodenafil, udenafil, gisadenafil, and dipyridamole.

[0098] In an aspect, the present disclosure provides a use of any herein disclosed transdermal formulation in a method for treating a disease or disorder or reducing a symptom thereof.

[0099] In an additional aspect, the present disclosure provides a method for manufacturing a medicament for treating a disease or disorder or reducing a symptom thereof comprising combining a penetrant portion as recited in any herein disclosed transdermal formulation with one or more phosphodiesterase-5 (PDE5) inhibitors. In some cases, the PDE5 inhibitor is at least one of sildenafil, vardenafil, avanafil, tadalafil, lodenafil, mirodenafil, udenafil, gisadenafil, and dipyridamole.

[00100] In any of the above aspects, the PDE5 inhibitor may be at least one of sildenafil, vardenafil, avanafil, tadalafil, lodenafil, mirodenafil, udenafil, gisadenafil, and dipyridamole.

Transdermal delivery formulation components

[00101] Sildenafil is an amphoteric drug with a pH-dependent solubility. The chemical structure possesses a basic functional group (NH-piperazine), characterized by a pK value of 8.7, in addition to a weak acidic moiety (HN-amide). Herein we describe formulations for transdermal administration of sildenafil. In an embodiment, a transdermal delivery formulation comprises the components of Table 1:

Table 1

[00102] In another embodiment, a transdermal delivery formulation comprises the components of

Table 2:

Table 2

Other phosphodiesterase type 5 inhibitors (PDE5 inhibitors)

[00103] Additional embodiments include formulations for transdermal administration of phosphodiesterase type 5 inhibitors (PDE5 inhibitors). Other PDE5 inhibitors include vardenafil, avanafil, tadalafil, lodenafil, mirodenafil, udenafil, gisadenafil, and dipyridamole. The compounds are also prescription drugs taken orally for ED. In an embodiment, a transdermal delivery formulation comprises the components of Table 3:

Table 3

[00104] In another embodiment, a transdermal delivery formulation comprises the components of

Table 4:

Table 4

Generic phosphodiesterase type 5 inhibitor (PDE5 inhibitor) formulations

[00105] In an embodiment, a transdermal delivery formulation comprises the components of Table

5A:

Table 5A

[00106] In Table 5 A, where an ingredient has weight percent that ranges from 5 to 15% (e.g., for the phospholipid), as an example, that ingredient may be present in the formulation at any percentage (w/w or w/v) from about 5% to about 15%. The weight percentage may be about 5 % to about 15 %. The weight percentage may 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 %, 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 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 11 % to about 12 %, about 11 % to about 13 %, about 11 % to about 14 %, about 11 % to about 15 %, about 12 % to about 13 %, about 12 % to about 14 %, about 12 % to about 15 %, about 13 % to 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 may be at most about 6 %, about 7 %, about 8 %, about 9 %, about 10 %, about 11 %, about 12 %, about 13 %, about 14 %, or about 15 %. Moreover, the weight percentage may be about 5 % to about 6 %. The weight percentage may be 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 about5.4 %, about 5. 1 %to about5.5 %, about 5. 1 % to about5.6 %, 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 about5.7 %, about 5.2 %to about5.8 %, about 5.2 % to about5.9 %, 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 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 %, about5.7 % to about5.9 %, 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 may 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 may be at least about 5 %, about 5.1 %, about 5.2 %, about 5.3 %, about 5.4 %, about 5.5 %, about5.6 %, about 5.7 %, about 5. 8 %, or about 5.9 %. The weight percentage may be at most 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 %. Further, the weight percentage may be about 5 % to about 5. 1 %. The weight percentage may be 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 %, about 5.01 % to about 5.06 %, about 5.01 % to about5.07 %, about5.01 %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 5.03 % 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 about5.06 %, about5.04 %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 5.07 %, 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 may 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 may be at least about 5 %, about 5.01 %, about 5.02 %, about5.03 %, about 5.04 %, about 5.05 %, about 5.06 %, about 5.07 %, about 5.08 %, or about 5.09 %. The weight percentage may be at most 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 %.

[00107] The other ranges (e.g., 10 - 20% for the Emollient/moisturizer; 0.5 - 2% for the Fatty add; 0.5 - 2% for the Alcohol; 1 - 5%for the Oil; 0.5 - 2% for the Surfactant; 50 - 80% for the water; and 0.05% - 5% for the PDE5 inhibitor) recited in the above table include similar ranges and subranges and values within ranges. The present disclosure contemplates all similar ranges and subranges and values within ranges for each ingredient included in a formulation.

[00108] The present disclosure contemplates all similar ranges and subranges and values within ranges for each ingredient included in a formulation.

[00109] In some cases, the PDE5 inhibitor is in an amount from about 0.05% to about 0. 1% w/w of the formulation. In some embodiments, the PDE5 inhibitor is in an amount from about 0. 1% to about 1% w/w of the formulation. In other embodiments, the PDE5 inhibitor is in an amount from about 1% to about 5% w/w of the formulation. The present disclosure contemplates all similar ranges and subranges and values within ranges for the PDE5 inhibitor or inhibitors included in a formulation [00110] In various embodiments, a transdermal delivery formulation comprises the components of Table 5B:

Table 5B viscosity-improving agent

[00111] In Table 5B, where an ingredient has weight percent that ranges from 5 to 20% (e. g., for the Fatty acid ester and viscosity-improving agent), as an example, that ingredient may be present in the formulation at any percentage (w/w or w/v) from about 5% to about 20%. The weight percentage may be about 5 % to about 20 %. The weight percentage may 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 %, 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 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 about 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 may 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 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 may be at most 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 %. Moreover, the weight percentage may be about 5 % to about 6 %. The weight percentage may be 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. 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 %, about5.4 %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 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 may 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 may 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 may be at most 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 %. Further, the weight percentage may be about 5 % to about 5. 1 %. The weight percentage may be 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 %, about 5.01 % to about 5.06 %, 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 about5.04 %, about5.02 %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 5.03 % to about 5.05 %, about 5.03 % to about 5.06 %, about 5.03 % to about5.07 %, about5.03 %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 5.07 %, 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 may be about 5 %, about 5.01 %, about 5.02 %, about5.03 %, about 5.04 %, about 5.05 %, about5.06 %, about 5.07 %, about 5.08 %, about 5.09 %, or about 5.1 %. The weight percentage may 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 may be at most 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 %.

[00112] The other ranges (e.g., 3 - 15% for the phospholipids; 0.1 - 10% for the Long-chain fatty acids; 30 - 90% for the water; 0.05% - 5% for the PDE5 inhibitor; 0.5-5% for the penetration enhancer; and 0.5-10% for the emulsifier) recited in the above table include similar ranges and subranges and values within ranges. The present disclosure contemplates all similar ranges and subranges and values within ranges for each ingredient included in a formulation.

[00113] In some cases, the PDE5 inhibitor is in an amount from about 0.05% to about 0.1% w/w of the formulation. In some embodiments, the PDE5 inhibitor is in an amount from about 0. 1 % to about 1% w/w of the formulation. In other embodiments, the PDE5 inhibitor is in an amount from about 1% to about 5% w/w of the formulation. The present disclosure contemplates all similar ranges and subranges and values within ranges for the PDE5 inhibitor or inhibitors included in a formulation Vardenafil

[00114] In one embodiment, atransdermal delivery formulation includes vardenafil. Vardenafil is a PDE5 inhibitor often used for treating ED that is sold under the trade names Levitra, Staxyn, and Vivanza. The difference between the vardenafil molecule and sildenafil citrate is a nitrogen atom's position and the change of sildenafil's piperazine ring methyl group to an ethyl group. Vardenafil's relatively short effective time is comparable to but somewhat longer than sildenafil's. An advantage that vardenafil has over sildenafil is that it does not inhibit phosphodiesterase-6 to alter color perception, a rare side effect which sometimes occurs with sildenafil.

[00115] Because vardenafil has a similar structure to sildenafil, it is also a difficult molecule to delivery transdermally. Based on the Lepinski Rule of 5 for Transdermal Drug Delivery TDD, traditional topical delivery systems are generally ineffective for transporting vardenafil through the skin.

Tadalafil

[00116] In another embodiment, a transdermal delivery formulation tadalafil. Vardenafil is a PDE5 inhibitor often used for treating ED that is sold under the trade name Cialis. Tadalafil is structurally different from both sildenafil and vardenafil. Tadalafil is an annulated 2,5-diketopiperazine. It is also a 1,2,3,4-tetrahydro-P-carboline. [00117] Tadalafil's pharmacologic distinction is its longer half-life (17.5 hours), compared to sildenafil and vardenafil, which are both 4 - 5 hours. This translates to a longer duration of action, which is partly why is can be referred to as "The Weekend Pill. " Furthermore, the longer half-life is the basis for tadalafil's daily therapeutic use in treating pulmonary arterial hypertension.

[00118] Tadalafil has a similar structure to Sildenafil and is also a difficult molecule to delivery transdermally. Based on the Lepinski Rule of 5 for Transdermal Drug Delivery TDD, traditional topical delivery systems are generally ineffective for transporting tadalafil through the skin.

Avanafil

[00119] In one embodiment, a transdermal delivery formulation comprises the PDE5 inhibitor avanafil. Avanafil is a PDE5 inhibitor often used for treating ED that is sold under the trade name Stendra or Spedra. An advantage of avanafil is that it has very fast onset of action compared with other PDE5 inhibitors. It is absorbed quickly, reaching a maximum serum concentration in about thirty to forty-five minute

[00120] It is a member of pyrimidines, an aromatic amide, an organochlorine compound, a member of prolinols and a monocarboxylic acid amide. As with the other PDE5 inhibitors, traditional topical delivery systems are generally ineffective for transporting avanafil through the skin.

Methods of transdermal delivery

[00121] In an embodiment, for treating a sexual disfunction, the patient applies the cream directly to the genital area prior to sexual activity (e.g. 15 to 30 minutes). In applying a transdermal delivery formulation of the invention, a transdermal delivery formulation itself is simply placed on the skin and spread across the surface and/or massaged to aid in penetration. The amount of transdermal delivery formulation used is typically sufficient to cover a desired surface area. In some embodiments, a protective cover is placed over the formulation once it is applied and left in place for a suitable amount of time, i.e., 5 minutes, 10 minutes, 20 minutes or more; in some embodiments an hour or two. The protective cover can simply be a bandage including a bandage supplied with a cover that is impermeable to moisture. This essentially locks in the contact of a transdermal delivery formulation to the skin and prevents distortion of a transdermal delivery formulation by evaporation in some cases. The composition can be applied to the skin using standard procedures for application such as a brush, a syringe, a gauze pad, a dropper, or any convenient applicator. More complex application method^ including the use of delivery devices, may also be used, but are not required. In an alternative to administering topically to intact skin, the surface of the skin may also be disrupted mechanically by the use of spring systems, laser powered systems, systems propelled by Lorentz force or by gas or shock waves including ultrasound and may employ microdermabrasion such as by the use of sandpaper or its equivalent or using microneedles or electroporation devices. Simple solutions of the agent(s) as well as the above-listed formulations that penetrate intact skin may be applied using occlusive patches, such as those in the form micro-patches. External reservoirs of the formulations for extended administration may also be employed. [00122] In an alternative to administering topically to intact skin, the surface of the skin can also be disrupted mechanically by the use of spring systems, laser powered systems, use of iontophoresis^ systems propelled by Lorentz force or by gas or shock waves including ultrasound and may employ microdermabrasion such as by the use of sandpaper or its equivalent or using microneedles or electroporation devices. Simple solutions of the agent(s) as well as the above-listed transdermal delivery formulations that penetrate intact skin may be applied using occlusive patches, such as those in the form micro-patches. External reservoirs of the formulations for extended administration may also be employed.

[00123] A transdermal delivery formulation can be applied in a single, one-time application, or as needed. The present compositions can be administered, for example, at a frequency of once per day to hourly if needed. The presently described formulations can be topically administered once or more per day for a period of time from 1 week to 4 weeks, of from 1 week to 2 weeks, for 1 week, for 2 weeks, for 3 weeks, for 4 weeks, or for 4 weeks or more. In some instances, it may also be desirable to continue treatment indefinitely. A suitable administration for a transdermal delivery formulation comprising a skin cream, lotion or ointment, for example is once, twice, three, four times daily, or hourly if needed. [00124] It is understood that a specific dose level for any particular patient will vary depending upon a variety of factors, including the activity of the specific active agent; the age, body weight, general health and diet of the patient; the time of administration; the rate of excretion; possible drug combinations; the severity of the particular condition being treated; the area to be treated and the form of administration. One of ordinary skill in the art would appreciate the variability of such factors and would be able to establish specific dose levels using no more than routine experimentation.

[00125] Pharmacokinetic parameters such as bioavailability, absorption rate constant, apparent volume of distribution, unbound fraction, total clearance, fraction excreted unchanged, first-pass metabolism, elimination rate constant, half-life, and mean residence time can be determined by methods well known in the art.

[00126] A transdermal delivery formulation in accordance with the subj ect matter described herein may be a topical dosage form packaged in, for example, a multi-use or single-use package, including for example, a tube, a bottle, a pump, a container or bottle, a vial, a j ar, a packet, or a blister package. Single dosage kits and packages containing a once per day amount of the transdermal delivery formulation may be prepared. Single dose, unit dose, and once-daily disposable containers of the transdermal delivery formulation are also provided.

[00127] Further, the patient can increase the dose with a second application if the response is suboptimal. Although Sildenafil is used in this example, the formulation can be used with other PDE5 inhibitors including vardenafil, avanafil, tadalafil, lodenafil, mirodenafil, udenafil, gisadenafil, and dipyridamole that are conventionally taken by mouth. Formulations for transdermal delivery

[00128] Phosphatides - Soy lecithin contains about 57.5 % w/w phosphatides. The primary phosphatides found in Soy Lecithin are inositol phosphatides (20.5 % w/w of Soy lecithin), phosphatidylcholine (20%), and phosphatidylethanolamine (11 % w/w of Soy lecithin). In some embodiments, phosphatidylcholine is used for the full amount (57.5 % w/w of Soy lecithin) as it is known to aide in skin penetration. Other phosphatides include phosphatidic acid, phosphatidylserine and phosphatidylinositol.

[00129] In various embodiments, a formulation lacks a natural (e.g. , plant or animal derived) lecithin. [00130] In an embodiment, a 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.

[00131] Sterols - Soy lecithin contains about 2.5 % w/w sterols. In some embodiments, benzyl alcohol is used in substitution of the sterol in a transdermal delivery formulation to act as a penetration enhancer. In another embodiment, a sterol is cholesterol, ergosterol, hopanoids, hydroxy steroid, phytosterol and/or other steroids.

[00132] In an embodiment, a 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.

[00133] Carbohydrates - Soy lecithin contains about 5 % w/w free carbohydrates. In some embodiments, glucose is used in substitution of a free carbohydrate to maintain the ratio of sugars in the transdermal delivery formulation disclosed herein. In another embodiment, a carbohydrate is a monosaccharide, a disaccharide, a polyol, a malto-oligosaccharide, an oligosaccharide, a starch, a polysaccharide. In a further embodiment, a carbohydrate is glucose, galactose, fructose, xylose, sucrose, lactose, maltose, trehalose, sorbitol, mannitol, maltodextrins, raffinose, stachyose, fructooligosaccharide, amylose, amylopectin, modified starches, glycogen, cellulose, hemicellulose, pectin and/or hydrocolloid.

[00134] In various embodiments, a transdermal delivery formulation contains no glucose.

[00135] In an embodiment, a transdermal delivery formulation contains a carbohydrate 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 w/w of the transdermal delivery formulation [00136] Moisture - In some embodiments, the transdermal delivery formulation maintains the about 1 % w/w of water contained in soy lecithin.

[00137] In an embodiment, a 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 w/w of the transdermal delivery formulation.

[00138] Fatty acids - Soy lecithin contains about 34 % w/w fatty acids, including 18-19 % w/w linoleic acid, 1-2 % w/w alpha-linoleic acid, 8-9 % w/w oleic acid, about 5 % w/w Palmitic acid, and 1-2 % w/w stearic acids. In some embodiments, the fatty acids are similar to the fatty acids contained in soy lecithin. In an embodiment, alpha-linoleic is removed from the transdermal delivery formulation as it is known to oxidize and can become rancid. In some embodiments, the amount of stearic acid has been increased (i.e. , enhancing with stability of the formulation) or linoleic acid (i.e. , enhances skin penetration). In some embodiments, a seed oil such as purified safflower oil is used in a transdermal delivery formulation due to its similarity to the fatty acids found in soy lecithin, its relative availability and its low cost. In some embodiments, the fatty acid content of a transdermal formulation can be adjusted with a different seed oil through the addition of smaller amounts of the fatty acids disclosed herein.

[00139] In various embodiments, a formulation lacks a natural (e.g. , plant or animal derived) lecithin.

[00140] In an embodiment, a transdermal delivery formulation contains a carbohydrate 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 w/w of the transdermal delivery formulation [00141] In a further embodiment, a fatty acid is a saturated or an unsaturated fatty acid. In another embodiment, an unsaturated fatty acid is myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaidic acid, a-Linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid and/or docosahexaenoic acid. In an embodiment, a 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 and include 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, help oil and/or canola/ rapeseed oil.

[00142] In some embodiments, carotenoids are excluded from the formulations disclosed herein.

[00143] In an aspect, the concentration of phosphatidylcholine in a transdermal delivery formulation is at least 10%, at least 15%, at least 20%, at least 25%, at least28.75%, at least 30%, at least 35%, at least 40% or more. In an aspect, the concentration of phosphatidylcholine in a transdermal delivery formulation is not more than 10%, not more than 15%, not more than 20%, not more than 25%, not more than 28.75%, not more than 30%, not more than 35%, not more than 40% or more. In an aspect, the concentration of phosphatidylcholine in a 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 an aspect, the concentration of phosphatidylcholine in a transdermal delivery formulation is from 10% to 40%, is from 15% to 35%, is from 20% to 30%, is from 25% to 30%, is from 28% to 29%.

[00144] In another aspect, the concentration of glucose in a transdermal delivery formulation is 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 aspect, the concentration of glucose in a 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 aspect, the concentration of glucose in a transdermal delivery formulation is no more than 1%, no more than 2%, no more than 2.5%, no more than 3%, no more than 4%, no more than 5%, no more than 6%, no more than 7%, no more than 8%, no more than 9% or more. In another aspect, the concentration of Glucose in a transdermal delivery formulation is from 1% to 10%, is from 2% to 9%, is from 2.5% to 5%, is from 2% to 3%, is from 3% to 8%, if from 4% to 7%, if from 5% to 6%, is from 2% to 4%, if from 1.5% to 3.55. In an embodiment, a transdermal delivery formulation contains no glucose. In another embodiment, a transdermal delivery formulation does not contain a carbohydrate.

[00145] In a further embodiment, the concentration of benzyl alcohol in a 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 an embodiment, the concentration of Benzyl Alcohol in a 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 a transdermal formulation is at from 0.25% to 5 %; from 0.5% to 4%, from 0.75% to 3%, from 1% to 2.5% or from 0.5% to 2%. In afurther embodiment, the concentration of benzyl alcohol in atransdermal formulation is no more than 0.25%, no more than 0.5%, no more than 0.75%, no more than 1%, no more than 2%, no more than 2.5%, no more than 3%, no more than 4%, no more than 5%.

[00146] In an embodiment, the concentration of deionized water in a 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 an embodiment, the concentration of deionized water in a 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 an embodiment, the concentration of deionized water in atransdermal formulation is from 0.1% to 5%, from 0.2% to 4 %, from 0.3% to 3%, 0.4% - 2%, 0.5% to 1 %, from 0.6% 10.9%, from 0.7% to 0.8%, from 0.4% to 1.5%, from 0.3% to 0.7% or from 0.4% to 0.6%. In an embodiment, the concentration of deionized water in a transdermal formulation is no more than 0.1 %, no more than 0.2%, no more than 0.3%, no more than 0.4%, no more than 0.5%, no more than 0.6%, no more than 0.7%, no more than 0.8%, no more than 0.9%, no more than 1%, no more than 2%, no more than 3%, no more than 4%, no more than 5% or more.

[00147] In an embodiment, the concentration of safflower oil in a 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 an aspect, the concentration of Safflower oil in a 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 an aspect, the concentration of Safflower oil in a transdermal delivery formulation is from 1% to 20%, from 5% to 19%, from 7.5 % to 18%, from 10% to 17%, from 11 % to 16%, from 11.06%, 12% from 11 % to 12%, from 12% to 14%, from 13% to 14%, from 10% to 12%, from 10.5% to 12.5% orfrom l l%to 11.25%. In an aspect, the concentration of Safflower oil in a transdermal delivery formulation is no more than 1%, no more than 5%, no more than 7.5%, no more than 10%, no more than 11%, no more than 11.06%, no more than 12%, no more than 13%, no more than 14%, no more than 15%, no more than 16%, no more than 17 %, no more than 18%, no more than 19%, no more than 20 %, no more than or more.

[00148] In an embodiment, the concentration of oleic acid in a 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 a further embodiment, the concentration of oleic acid in a 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 a further embodiment, the concentration of oleic acid in a transdermal delivery formulation is no more than 1%, no more than 2%, no more than 3%, no more than 3.65%, no more than 4%, no more than 5%, no more than 6%, no more than 7%, no more than 8%, no more than 9%, no more than 10% or more. In another embodiment, the concentration of stearic acid in a transdermal formulation is from 1 % to 10%, from 2% to 9%, from 2% to 3%, from 3% to 4%, from 3% to 8%, from 4% to 7%, from 5% to 6%, from 2 to 2.5% or from 2.5% to 4%.

[00149] In another embodiment, the concentration of stearic acid in a 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 add in a transdermal formulation is no more than 1%, no more than 2%, no more than 2.34%, no more than 3%, no more than 4%, no more than 5%, no more than 6%, no more than 7%, no more than 8%, no more than 9%, no more than 10% or more. In another embodiment, the concentration of stearic acid in a 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 aspect, the concentration of stearic acid in a transdermal formulation is from 1% to 10%, from 2% to 9%, from 2% to 3%, from 2.34% to 2.5%, from 3% to 8%, from 4% to 7%, from 5% to 6% or from 1.5% to 2.5%.

[00150] In an embodiment, the concentration of isopropyl palmitate in a 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 an embodiment, the concentration of isopropyl palmitate in a 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 an embodiment, the concentration of isopropyl palmitate in a transdermal formulation is no more than 10%, no more than 20%, no more than 25%, no more than 30%, no more than 40%, no more than 45%, no more than 50%, no more than 55%, no more than 60%, no more than 65%, no more than 70%, no more than 75% or more. In an embodiment, the concentration of isopropyl palmitate in a transdermal formulation is from 10% to 75%, from 20% to 70%, from 25% to 65%, from 30% to 60%, from 40% to 55%, from 45% to 50%, from 40% to 60%, from 45% to 55% or from 47% to 53%.

[00151] In certain embodiments, a transdermal delivery formulation use buffers which do not have counterions and thus have reduced or eliminated the risk of hypernatremia. Tris-base buffers have other potentially beneficial characteristics including a demonstrated antitumor effect in vivo. Accordingly, certain embodiments of the formulation incorporate a Tris-base in an amount of up to about 60.0 % w/w; up to about 50.0 % w/w; up to about 45.0 % w/w; up to about 40.0 % w/w; up to about 35.0 % w/w; up to about 30.0 % w/w; up to about 25.0 % w/w; up to about 20.0 % w/w; up to about 17.0 % w/w; up to about 15.0 % w/w; up to about 10.0 % w/w; or up to about 5.0 % w/w.

[00152] Certain components or ingredients of transdermal delivery formulation provided herein may be supplemented with components described in greater detail in the inventor’s related applications mentioned above, including United states 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 PCT/US18/28017 by Bruce Sand filed April 17, 2018, entitled ‘Parental non-systemic administration of buffering agents for inhibiting metastasis of solid tumors, hyperpigmentation and gout’, all incorporated by reference in their entirety herein.

Methods for treating neurologic diseases

[00153] Transdermal formulations of the present disclosure are useful in treating or reducing the symptoms of a neurologic disorder. Without wishing to be bound by theory, the PDE5 inhibitors promote blood circulation and some neurological disorders, e.g., Alzheimer’s, are benefited from increased blood circulation. See, e.g., the world wide web (at) everydayhealth.com/alzheimers- disease/viagra-may-significantly-cut-alzheimers-risk-study-f inds. Thus, in some embodiments, the formulations and method of the present disclosure are useful in treating Alzheimer's disease and other disorders characterized by age-related cognitive.

[00154] In embodiments, the present compositions are used to treat, control or prevent one or more neurologic diseases, including ADHD, AIDS — Neurological Complications, Absence of the Septum Pellucidum, Acquired Epileptiform Aphasia, Acute Disseminated Encephalomyelitis, Adrenoleukodystrophy, Agenesis of the Corpus Callosum, Agnosia, Aicardi Syndrome, Alexander Disease, Alpers' Disease, Alternating Hemiplegia, Alzheimer's Disease, Amyotrophic Lateral Sclerosis^ Anencephaly, Aneurysm, Angelman Syndrome, Angiomatosis, Anoxia, Aphasia, Apraxia, Arachnoid Cysts, Arachnoiditis, Arnold-Chiari Malformation, Arteriovenous Malformation, Aspartame, Asperger Syndrome, Ataxia Telangiectasia, Ataxia, Attention Deficit-Hyperactivity Disorder, Autism, Autonomic Dysfunction, Back Pain, Barth Syndrome, Batten Disease, Behcet's Disease, Bell's Palsy, Benign Essential Blepharospasm, Benign Focal Amyotrophy, Benign Intracranial Hypertension, Bernhardt-Roth Syndrome, Binswanger's Disease, Blepharospasm, Bloch-Sulzberger Syndrome, Brachial Plexus Birth Injuries, Brachial Plexus Injuries, Bradbury -Eggleston Syndrome, Brain Aneurysm, Brain Injury, Brain and Spinal Tumors, Brown-Sequard Syndrome, Bulbospinal Muscular Atrophy, Canavan Disease, Carpal Tunnel Syndrome, Causalgia, Cavernomas, Cavernous Angioma, Cavernous Malformation, Central Cervical Cord Syndrome, Central Cord Syndrome, Central Pain Syndrome, Cephalic Disorders, Cerebellar Degeneration, Cerebellar Hypoplasia, Cerebral Aneurysm, Cerebral Arteriosclerosis, Cerebral Atrophy, Cerebral Beriberi, Cerebral Gigantism, Cerebral Hypoxia, Cerebral Palsy, Cerebro-Oculo-Facio-Skeletal Syndrome, Charcot-Marie-Tooth Disorder, Chiari Malformation, Chorea, Choreoacanthocytosis, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Chronic Orthostatic Intolerance, Chronic Pain, Cockayne Syndrome Type II, Coffin Lowry Syndrome, Coma, including Persistent Vegetative State, Complex Regional Pain Syndrome, Congenital Facial Diplegia, Congenital Myasthenia, Congenital Myopathy, Congenital Vascular Cavernous Malformations, Corticobasal Degeneration, Cranial Arteritis, Craniosynostosis, Creutzfeldt -Jakob Disease, Cumulative Trauma Disorders, Cushing's Syndrome, Cytomegalic Inclusion Body Disease (CIBD), Cytomegalovirus Infection, Dancing Eyes-Dancing Feet Syndrome, Dandy-Walker Syndrome. Dawson Disease, De Morsi er's Syndrome, Dejerine-Klumpke Palsy, Dementia — Multi-Infarct, Dementia — Subcortical, Dementia With Lewy Bodies, Dermatomyositis, Developmental Dyspraxia, Devic's Syndrome, Diabetic Neuropathy, Diffuse Sclerosis, Dravet's Syndrome, Dysautonomia, Dysgraphia, Dyslexia, Dysphagia, Dyspraxia, Dystonias, Early Infantile Epileptic Encephalopathy, Empty Sella Syndrome, Encephalitis Lethargica, Encephalitis and Meningitis, Encephaloceles. Encephalopathy, Encephalotrigeminal Angiomatosis, Epilepsy, Erb's Palsy, Erb-Duchenne and Dejerine-Klumpke Palsies, Fabry's Disease, Fahr's Syndrome, Fainting, Familial Dysautonomia, Familial Hemangioma, Familial Idiopathic Basal Ganglia Calcification, Familial Spastic Paralysis, Febrile Seizures (e.g., GEFS and GEFS plus), Fisher Syndrome, Floppy Infant Syndrome, Friedreich's Ataxia, Gaucher's Disease, Gerstmann's Syndrome, Gerstmann-Straussler-Scheinker Disease, Giant Cell Arteritis, Giant Cell Inclusion Disease, Globoid Cell Leukodystrophy, Glossopharyngeal Neuralgia, Guillain-Barre Syndrome, HTLV-1 Associated Myelopathy, Hallervorden-Spatz Disease, Head Injury, Headache, Hemi crania Continua, Hemifacial Spasm, Hemiplegia Alterans, Hereditary Neuropathies, Hereditary Spastic Paraplegia, Heredopathia Atactica Polyneuritiformis, Herpes Zoster Oticus, Herpes Zoster, Hirayama Syndrome, Holoprosencephaly, Huntington's Disease, Hydranencephaly, Hydrocephalus — Normal Pressure, Hydrocephalus, Hydromyel ia, Hypercortisolism, Hypersomnia, Hypertonia, Hypotonia, Hypoxia, Immune-Mediated Encephalomyelitis, Inclusion Body Myositis, Incontinentia Pigmenti, Infantile Hypotonia, Infantile Phytanic Acid Storage Disease, Infantile Refsum Disease, Infantile Spasms, Inflammatory Myopathy, Intestinal Lipodystrophy, Intracranial Cysts, Intracranial Hypertension, Isaac's Syndrome, Joubert Syndrome, Keams-Sayre Syndrome, Kennedy's Disease, Kinsbourne syndrome, Kleine-Levin syndrome, Klippel F eil Syndrome, Klippel -Trenaunay Syndrome (KTS), Kluver-Bucy Syndrome, Korsakoffs Amnesic Syndrome, Krabbe Disease, Kugelberg-Welander Disease, Kuru, Lambert-Eaton Myasthenic Syndrome, Landau-Kleffher Syndrome, Lateral Femoral Cutaneous Nerve Entrapment, Lateral Medullary Syndrome, Learning Disabilities, Leigh's Disease, Lennox- Gastaut Syndrome, Lesch-Nyhan Syndrome, Leukodystrophy, Levine-Critchley Syndrome, Lewy Body Dementia, Lissencephaly, Locked-In Syndrome, Lou Gehrig's Disease, Lupus — Neurological Sequelae, Lyme Disease — Neurological Complications, Machado- Joseph Disease, Macrencephaly, Megalencephaly, Melkersson-Rosenthal Syndrome, Meningitis, Menkes Disease, Meralgia Paresthetica, Metachromatic Leukodystrophy, Microcephaly, Migraine, Miller Fisher Syndrome, Mini-Strokes, Mitochondrial Myopathies, Mobius Syndrome, Monomelic Amyotrophy, Motor Neuron Diseases, Moyamoya Disease, Mucolipidoses, Mucopolysaccharidoses, Multi-Infarct Dementia, Multifocal Motor Neuropathy, Multiple Sclerosis, Multiple System Atrophy with Orthostatic Hypotension, Multiple System Atrophy, Muscular Dystrophy, Myasthenia — Congenital, Myasthenia Gravis, Myelinoclastic Diffuse Sclerosis, Myoclonic Encephalopathy of Infants, Myoclonus, Myopathy — Congenital, Myopathy — Thyrotoxic, Myopathy, Myotonia Congenita, Myotonia, Narcolepsy, Neuroacanthocytosis, Neurodegeneration with Brain Iron Accumulation, Neurofibromatosis, Neuroleptic Malignant Syndrome, Neurological Complications of AIDS, Neurological Manifestations of Pompe Disease, Neuromyelitis Optica, Neuromyotonia, Neuronal Ceroid Lipofuscinosis, Neuronal Migration Disorders, Neuropathy — Hereditary, Neurosarcoidosis, Neurotoxicity, Nevus Cavemosus, Niemann-Pick Disease, O'Sullivan-McLeod Syndrome, Occipital Neuralgia, Occult Spinal Dysraphism Sequence, Ohtahara Syndrome. Olivopontocerebellar Atrophy, Opsoclonus Myoclonus, Orthostatic Hypotension, Overuse Syndrome. Pain — Chronic, Paraneoplastic Syndromes, Paresthesia, Parkinson's Disease, Pamyotonia Congenita, Paroxysmal Choreoathetosis, Paroxysmal Hemicrania, Parry -Romberg, Pelizaeus-Merzbacher Disease, PenaShokeir II Syndrome, Perineural Cysts, Periodic Paralyses, Peripheral Neuropathy, Periventricular Leukomalacia, Persistent Vegetative State, Pervasive Developmental Disorders, Phytanic Acid Storage Disease, Pick's Disease, Piriformis Syndrome, Pituitary Tumors, Polymyositis, Pompe Disease, Porencephaly, Post-Polio Syndrome, Postherpetic Neuralgia, Postinfectious Encephalomyelitis, Postural Hypotension, Postural Orthostatic Tachycardia Syndrome, Postural Tachycardia Syndrome, Primary Lateral Sclerosis, Prion Diseases, Progressive Hemifacial Atrophy, Progressive Locomotor Ataxia, Progressive Multifocal Leukoencephalopathy, Progressive Sclerosing Poliodystrophy, Progressive Supranuclear Palsy, Pseudotumor Cerebri, Pyridoxine Dependent and Pyridoxine Responsive Siezure Disorders, Ramsay Hunt Syndrome Type I, Ramsay Hunt Syndrome Type n, Rasmussen's Encephalitis and other autoimmune epilepsies, Reflex Sympathetic Dystrophy Syndrome, Refsum Disease — Infantile, Refsum Disease, Repetitive Motion Disorders, Repetitive Stress Injuries, Restless Legs Syndrome, Retro virus- Associated Myelopathy, Rett Syndrome, Reye's Syndrome, Riley- Day Syndrome, SUNCT Headache, Sacral Nerve Root Cysts, Saint Vitus Dance, Salivary Gland Disease, Sandhoff Disease, Schilder's Disease, Schizencephaly, Seizure Disorders, Septo-Optic Dysplasia, Severe Myoclonic Epilepsy of Infancy (SMEI), Shaken Baby Syndrome, Shingles, Shy- Drager Syndrome, Sjogren's Syndrome, Sleep Apnea, Sleeping Sickness, Soto's Syndrome, Spasticity, Spina Bifida, Spinal Cord Infarction, Spinal Cord Injury, Spinal Cord Tumors, Spinal Muscular Atrophy, Spinocerebellar Atrophy, Steele-Richardson-Olszewski Syndrome, Stiff-Person Syndrome; Striatonigral Degeneration, Stroke, Sturge-Weber Syndrome, Subacute Sclerosing Panencephalitis. Subcortical Arteriosclerotic Encephalopathy, Swallowing Disorders, Sydenham Chorea, Syncope, Syphilitic Spinal Sclerosis, Syringohydromyelia, Syringomyelia, Systemic Lupus Erythematosus, Tabes Dorsalis, Tardive Dyskinesia, Tarlov Cysts, Tay-Sachs Disease, Temporal Arteritis, Tethered Spinal Cord Syndrome, Thomsen Disease, Thoracic Outlet Syndrome, Thyrotoxic Myopathy, Tic Douloureux, Todd's Paralysis, Tourette Syndrome, Transient Ischemic Attack, Transmissible Spongiform Encephalopathies, Transverse Myelitis, Traumatic Brain Injury, Tremor, Trigeminal Neuralgia, Tropical Spastic Paraparesis, Tuberous Sclerosis, Vascular Erectile Tumor, Vasculitis including Temporal Arteritis, Von Economo's Disease, Von Hippel-Lindau disease (VHL), Von Recklinghausen's Disease, Wallenberg's Syndrome, Werdnig-Hoffman Disease, Wernicke-Korsakoff Syndrome, West Syndrome, Whipple's Disease, Williams Syndrome, Wilson's Disease, X-Linked Spinal and Bulbar Muscular Atrophy, and Zellweger Syndrome.

[00155] When treating a neurological disorder, a formulation of the present disclosure may be topically administered nearby blood vessels that feed the affected tissue or organ. As an example, when treating Alzheimer’s, the formulation may be applied to the skin overlaying the carotid arteries; therelty promoting delivery of the PED5 inhibitor to the cortex.

[00156] In these, other non-ED uses, the dosage of the PDE5 inhibitor may be less than the dosage of a formulation when used for treating ED.

[00157] Dosing can be single dosage or cumulative (serial dosing), and can be readily determined tty one skilled in the art. A transdermal delivery formulation of the present invention may be admini stered once, twice, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty or more times to a subject. For instance, treatment of a disease may comprise a one-time administration of an effective dose of a transdermal delivery formulation as disclosed herein. Alternatively, treatment of a disease may comprise multiple administrations of an effective dose of a transdermal delivery formulation as carried out over a range of time periods, such as, e.g. , once daily, twice daily, thrice daily, once every few days, or once weekly. The timing of administration can vary from individual to individual, depending upon such factors as the severity of an individual's symptoms. For example, an effective dose of a transdermal delivery formulation as disclosed herein can be administered to an individual once daily for an indefinite period of time, or until the individual no longer requires therapy. A person of ordinary skill in the art will recognize that the condition of the individual can be monitored throughout the course of treatment and that the effective amount of a transdermal delivery formulation disclosed herein that is administered can be adjusted accordingly. In one embodiment, atransdermal delivery formulation as disclosed herein is capable of decreasing the time to resolve the symptoms of a disease, including in an individual suffering from a disease by, e.g., 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% as compared to a patient not receiving the same treatment.

[00158] In an embodiment, the period of administration of atransdermal delivery formulation is for 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 a further embodiment, a period of during which administration is stopped is for 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. Other non-ED uses

[00159] Because PDE5 inhibitors have the ability to widen arteries enough to lower blood pressure; the formulations of the present disclosure can be used to treat pulmonary hypertension and heart diseases such as congestive heart failure and diastolic dysfunction, as well as Raynaud’s disease.

[00160] Also, the formulations of the present disclosure can be used to improve lung function at high altitudes (e.g., mountain sickness) by reducing pulmonary artery pressure.

[00161] Further, in some embodiments, the formulations may be used to help peripheral blood circulation in diabetic patients.

[00162] There is some evidence showing that PED5 inhibitors may be effective for the treatment of female sexual arousal disorder. Without wishing to be bound by theory, improved blood flow to the female reproductive parts may promote arousal and increase sensitivity and stimulation. Thus, in some embodiments, formulations of the present disclosure may be administered to female subject in need thereof.

[00163] When treating a non-ED disorder, a formulation of the present disclosure may be topically administered nearby blood vessels that feed the affected tissue or organ. As an example, when treating reduced peripheral circulation, e.g., in a diabetic patient, the formulation may be applied to the skin overlaying the arteries feeding the hands or feet; thereby promoting delivery of the PED5 inhibitor where needed.

[00164] In these, other non-ED uses, the dosage of the PDE5 inhibitor may be less than the dosage of a formulation when used for treating ED.

[00165] Dosing can be single dosage or cumulative (serial dosing), and can be readily determined by one skilled in the art. A transdermal delivery formulation of the present invention may be admini stered once, twice, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty or more times to a subject. For instance, treatment of a disease may comprise a one-time administration of an effective dose of a transdermal delivery formulation as disclosed herein. Alternatively, treatment of a disease may comprise multiple administrations of an effective dose of a transdermal delivery formulation as carried out over a range of time periods, such as, e.g. , once daily, twice daily, thrice daily, once every few days, or once weekly. The timing of administration can vary from individual to individual, depending upon such factors as the severity of an individual's symptoms. For example, an effective dose of a transdermal delivery formulation as disclosed herein can be administered to an individual once daily for an indefinite period of time, or until the individual no longer requires therapy. A person of ordinary skill in the art will recognize that the condition of the individual can be monitored throughout the course of treatment and that the effective amount of a transdermal delivery formulation disclosed herein that is administered can be adjusted accordingly. In one embodiment, atransdermal delivery formulation as disclosed herein is capable of decreasing the time to resolve the symptoms of a disease, including in an individual suffering from a disease by, e.g., 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% as compared to a patient not receiving the same treatment.

[00166] In an embodiment, the period of administration of atransdermal delivery formulation is for 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 a further embodiment, a period of during which administration is stopped is for 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. Iron

[00167] A transdermal delivery formulation containing iron may be formulated at acidic pH to minimize the spontaneous oxidation Fe(II) into Fe(III). Suitable nonlimiting exemplary iron chelators include deferoxamine, ethylenediaminetetraacetic acid (EDTA), l,2-diethyl-3-hydroxypyridin-4-one (CP94), Desferol, Deferiprone and Deferasirox, succimer, trientine, Desferrithiocin, Clioquinol, O- trensox, Tachpyr, Dexrazoxane, Triapine, Pyridoxal isonicotinoyl hydrazone, Di-2-pyridylketone thiosemicarbazone series, Flavan-3-ol, Curcumin, Apocynin, Kolaviron, Floranol, Baicalein, Baicalin, ligustrazine, Quercetin, Epigallocatechin gallate, Theaflavin, Phytic acid, and Genistein.

[00168] Suitable nonlimiting exemplary antioxidants include glutathione, vitamin C, vitamin E, superoxide dismutase, catalase, pNaKtide, Butylated hydroxytoluene, Butylated hydroxyanisole, tert- Butylhydroquinone, HP beta CD, resveratrol, retinol, coenzyme qlO, niacinamide, polyphenol^ flavenoids, beta- carotene, lutein, and lycopene.

[00169] A transdermal delivery formulation can include mixtures wherein the components interact synergistically and induce skin permeation enhancements better than that induced by the individual components. Synergies between chemicals can be exploited to design potent permeation enhancers that overcome the efficacy limitations of single enhancers. Several embodiments disclosed herein utilize three to five distinct permeation enhancers.

[00170] In some embodiments, a transdermal delivery formulation comprises phosphatidylcholine in amount less than 12 % w/w or 18 % w/w of the formulation. In some embodiments, the transdermal delivery formulation comprises a phospholipid in amount less than 12 % w/w or 18 % w/w of the formulation. In some embodiments, the transdermal delivery formulation comprises a mixture of tri decane and undecane in amount less than 2 % w/w, 5 % w/w, or 8 % w/w of the formulation. In some embodiments, the formulation comprises Cetiol Ultimate® in an amount less than about 2 % w/w, 5 % w/w, or 10 % w/w, or an equivalent mixture of tridecane and undecane. In some embodiments, the transdermal delivery formulation comprises cetyl alcohol in amount less than 2 % w/w, 5 % w/w, or 8 % w/w of the formulation. In some embodiments, the transdermal delivery formulation comprises benzyl alcohol in an amount less than about 2 % w/w, 5 % w/w, or 8 % w/w. In some embodiment^ the transdermal delivery formulation comprises stearic acid in an amount less than 2 % w/w, 5 % w/w, or 8 % w/w of the formulation.

[00171] A suitable dose of iron or an iron containing transdermal delivery formulation administered topically as a transdermal delivery formulation for a subject (e.g. a human patient) is 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 a day, or three times a day, but it may also be administered four times a day, five times a day, or more than five times a day.

[00172] Alternatively, a suitable daily dose of iron or an iron containing transdermal delivery formulation administered topically as a transdermal delivery formulation for a subj ect 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 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 45 Omg/kg, at least about 475 mg/kg, up to at least about 500 mg/kg or more.

[00173] In another aspect, a suitable daily dose of iron or an iron containing transdermal delivery formulation administered topically as atransdermal delivery formulation for a subj ect is about 10 mg/kg to about 1.0 g/kg, and more typically the daily dose is about 10 mg/kg to about 500 mg/kg, about 25 mg/kg to about 500 mg/kg, about 50mg/kg to about 300 mg/kg, about 75 mg/kg to about 300 mg/kg, about 75mg/kg to about 250 mg/kg, about 100 mg/kg to about 300 mg/kg, about 75 mg/kg to about 200 mg/kg, about 100 mg/kg to about 200 mg/kg, or alternative ranges.

[00174] In one aspect, disclosed herein is a transdermal delivery formulation for transdermal delivery ketone components through the skin of a subject, comprising: a ketone component in an amount between about 10-60 % w/w; a transdermal delivery formulation in an amount less than about 60 % w/w, and water in an amount less than about 50 % w/w.

[00175] In some embodiments, the one or more ketone components are formulated with Aveeno® moisturizers, cream, oils, lotions; Jergens® moisturizers, cream, oils, lotions; Honest Company® moisturizers, cream, oils, lotions; Dermologica® moisturizers, cream, oils, lotions; or St. Ives™ moisturizers, cream, oils, lotions. In some embodiments, the commercial lotions, moisturizers, etc. are formulated with the ketone component in an amount between about 10-60 % w/w or at least 10% w/w, at least 20% w/w, at least 30% w/w, at least 40 % w/w, at least 50% w/w, at least 60% w/w, at least 75% w/w or more.

[00176] For topical administration, and in particular transdermal administration, a transdermal delivery formulation will comprise penetrants including either or both chemical penetrants (CPEs) and peptide-based cellular penetrating agents (CPPs) that encourage transmission across the dermis and/or across membranes including cell membranes, as would be the case in particular for administration by suppository or intranasal administration, but for transdermal administration as well. In some embodiments, suitable penetrants include those that are described in the above-referenced US2009/0053290, W02014/209910, and WO2017/127834. In addition to transdermal deliveiy formulations with penetrants, transdermal delivery can be affected by mechanically disrupting the surface of the skin to encourage penetration, or simply by supplying the formulation applied to the skin under an occlusive patch.

[00177] Alternatively, the transdermal delivery formulation comprises a completion component as well as one or more electrolytes sufficient to impart viscosity and viscoelasticity, one or more surfactants and an alcohol. The completion component can be a polar liquid, a non-polar liquid or an amphiphilic substance. The penetrant may further comprise a keratinolytic agent effective to reduce thiol linkages, disrupt hydrogen bonding and/or effect keratin lysis and/or a cell penetrating peptide (sometimes referred to as a skin-penetrating peptide) and/or a permeation enhancer. [00178] Suitable gelling components also include isopropyl palmitate, ethyl laurate, ethyl myristate and isopropyl myristate. In some embodiments, a transdermal delivery formulation comprises a gelling agent in an amount less than 5 % w/w of a transdermal delivery formulation. Certain hydrocarbon^ such as cyclopentane, cyclooctane, /ra s ¹ - decalin, /rans-pinane. n-pentane, w-hexane. n-hexadecane may also be used. In some embodiments, the transdermal delivery formulation comprises a mixture of xanthan gum, sclerotium gum, pullulan, or a combination thereof in an amount less than 2 % w/w, 5 % w/w, or 10 % w/w of the formulation. In some embodiments, a transdermal delivery formulation comprises Siligel™ in an amount between about 1-5 % w/w or 5-15 % w/w, or an equivalent mixture of xanthan gum, sclerotium gum, and pullulan. In some embodiments, a transdermal delivery formulation comprises a mixture of caprylic triglycerides and capric triglycerides in amount less than 2 % w/w, 8 % w/w, or 10 % w/w of the formulation. In some embodiments, a transdermal delivery formulation comprises Myritol® 312 in an amount between about 0.5-10 % w/w, or an equivalent mixture of caprylic triglycerides and capric triglycerides.

[00179] In some embodiments, a transdermal delivery formulation is in an amount between about 10-90 % w/w or 10-50 % w/w of the formulation or at least 10% w/w, at least 20% w/w, at least 30% w/w, at least 40 % w/w, at least 50% w/w, at least 60% w/w, at least 70% w/w, at least 80% w/w, at least 90% w/w or at least 95% w/w. In some embodiments, a transdermal delivery formulation comprises phosphatidyl choline in amount less than 7 % w/w, less than 8% w/w, less than 9% w/w, less than 10% w/w, less than 11% w/w, less than 12 % w/w, less than 13% w/w, less than 14% w/w, less than 15% w/w, less than 16% w/w, less than 17% w/w or less than 18 % w/w of the formulation In some embodiments, a transdermal delivery formulation comprises a phospholipid in amount less than 20 % w/w, less than 30 % w/w, less than 40 % w/w, less than or 50 % w/w of the formulation. In some embodiments, a transdermal delivery formulation comprises a mixture of tridecane and undecane in amount less than 2 % w/w, 3 % w/w, 4 % w/w, 5 % w/w, 6 % w/w, 7 % w/w, or 8 % w/w of the formulation. In some embodiments, the formulation comprises Cetiol Ultimate® in an amount less than about 2 % w/w, 3 % w/w, 4 % w/w, 5 % w/w, 6 % w/w, 7 % w/w, 8 % w/w, 9 % w/w, or 10 % w/w, or an equivalent mixture of tridecane and undecane. In some embodiments, a transdermal delivery formulation comprises cetyl alcohol in amount less than 2 % w/w, 3 % w/w, 4 % w/w, 5 % w/w, 6 % w/w, 7 % w/w, 8 % w/w, 9 % w/w, or 10 % w/w of the formulation. In some embodiments, the formulation comprises benzyl alcohol in an amount less than about 2 % w/w, 3 % w/w, 4 % w/w, 5 % w/w, 6 % w/w, 7 % w/w, 8 % w/w, 9 % w/w, or 10 % w/w. In some embodiments, a transdermal delivery formulation comprises stearic acid in an amount less than 2 % w/w, 3 % w/w, 4 % w/w, 5 % w/w, 6 % w/w, 7 % w/w, 8 % w/w, 9 % w/w, or 10 % w/w of the formulation. In some embodiment^ the transdermal delivery formulation comprises phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, one or more phosphatides, one or more Inositol phosphatides, or combinations thereof, in amount less than 30 % w/w or in amount less than 12 % w/w of the formulation. [00180] An additional component in a transdermal delivery formulation of the disclosure is an alcohol. Benzyl alcohol and ethanol are illustrated in the Examples. In particular, derivatives of benzyl alcohol which contain substituents on the benzene ring, such as halo, alkyl and the like. The weight percentage of benzyl or other related alcohol in the final composition is 0.5-20% w/w, and again, intervening percentages such as 1 % w/w, 2% w/w, 53 % w/w, 4 % w/w, 5 % w/w, 6 % w/w, 7 % w/w, 8 % w/w, 9 % w/w, or 10 % w/w, and other intermediate weight percentages are included. Due to the aromatic group present in a transdermal delivery formulation such as benzyl alcohol, the molecule has a polar end (the alcohol end) and anon-polar end (the benzene end). This enables the agent to dissolve a wider variety of transdermal delivery formulation components.

[00181] In some embodiments, as noted above, the performance of a transdermal delivery formulation is further improved by including a nonionic detergent and polar gelling agent or including a powdered surfactant. In both aqueous and anhydrous forms of the composition, detergents, typically nonionic detergents are added. In general, the nonionic detergent should be present in an amount between about 1% w/w to 30% w/w of a transdermal delivery formulation. Typically, in the compositions wherein a transdermal delivery formulation is topped off with a polar or aqueous solution containing detergent, the amount of detergent is relatively low - e.g, 2-25 % w/w, or 5-15 % w/w or 7- 12 % w/w of a transdermal delivery formulation. However, in compositions that are essentially anhydrous and are topped-off by powdered detergent, relatively higher percentages are usually used - e.g, 20-60 % w/w.

[00182] In some embodiments, a transdermal delivery formulation further comprises a detergent portion in an amount between about 1 to 70 % w/w or 1 -60 % w/w of a transdermal delivery formulation. In some embodiments, the nonionic detergent provides suitable handling properties whereby the formulations are gel-like or creams at room temperature. To exert this effect, the detergent, typically a poloxamer, is present in an amount between about 2-12 % w/w of a transdermal delivery formulation, preferably between about 5-25 % w/w in polar formulations. In the anhydrous forms of the compositions, the detergent is added in powdered or micronized form to bring the composition to 100% and higher amounts are used. In compositions with polar constituents, rather than bile salts, the nonionic detergent is added as a solution to bring the composition to 100%. If smaller amounts of detergent solutions are needed due to high levels of the remaining components, more concentrated solutions of the nonionic detergent are employed. Thus, for example, the percent detergent in the solution may be 10% to 40% or 20% or 30% and intermediate values depending on the percentages of the other components.

[00183] Suitable nonionic detergents include poloxamers such as the non-ionic surfactant Pluronic® and 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 polyethyleneoxide. Other nonionic surfactants include long chain alcohols and copolymers of hydrophilic and hydrophobic monomers where blocks of hydrophilic and hydrophobic portions are used.

[00184] In some embodiments, atransdermal delivery formulation also contains surfactant, typically, nonionic surfactant at 2-25% w/w of a transdermal delivery formulation along with a polar solvent wherein the polar solvent is present in an amount at least in molar excess of the nonionic surfactant In these embodiments, typically, the composition comprises the above-referenced amounts of a transdermal delivery formulation and benzyl alcohol along with a ketone component with a sufficient amount of a polar solution, typically an aqueous solution or polyethylene glycol solution that itself contains 10%-40% of surfactant, typically nonionic surfactant to bring the composition to 100%.

[00185] Other examples of surfactants include poly oxy ethylated castor oil derivatives such as HCO- 60 surfactant sold by the HallStar Company; nonoxynol; octoxynol; phenyl sulfonate; poloxamers such as those sold by BASF as Pluronic® F68, Pluronic® F127, and Pluronic® L62; poly oleates; 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 monooleates; sorbitan trilaurate; sorbitan trioleate; sorbitan monopalmitate such as Span® 40 sold by Sigma-Aldrich; sorbitan stearate such as Span® 85 sold by Sigma-Aldrich; polyethylene glycol nonylphenyl ether such as Synperonic® NP sold by Sigma-Aldrich; p-(l,l,3,3-tetramethylbutyl)- phenyl ether sold as Triton™ X-100 sold by Sigma- Aldrich; and polysorbates such as poly oxy ethylaie (20) sorbitan monolaurate sold as Tween® 20, 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 poly oxy ethylenesorbitan trioleate sold as Tween® 85 by Sigma- Aldrich. The weight percentage range of nonionic surfactant is in the range of 3% w/w- 15% w/w, and again includes intermediate percentages such as 5 % w/w, 7 % w/w, 10 % w/w, 12 % w/w, and the like. In some embodiments, the detergent portion comprises a nonionic surfactant in an amount between about 1-30 % w/w of the formulation; and a polar solvent in an amount less than 5 % w/w of the formulation. In some embodiments, the nonionic surfactant is a pol oxamer and the polar solvent is water, an alcohol, or a combination thereof In some embodiments, the detergent portion comprises poloxamer, propylene glycol, glycerin, ethanol, 50 %w/v sodium hydroxide solution, or a combination thereof. In some embodiments, the detergent portion comprises glycerin in an amount less than 3 % w/w of the formulation.

[00186] In the presence of a polar gelling agent, such as water, glycerol, ethylene glycol or formamide, amicellular structure is also often achieved. Typically, the polar agent is in molar excess of the nonionic detergent. The inclusion of the nonionic detergent/polar gelling agent combination results in a more viscous and cream-like or gel-like formulation which is suitable for application directly to the skin. This is typical of the aqueous forms of the composition.

[00187] In some embodiments other additives are included such as a gelling agent, a dispersing agent and a preservative. An example of a suitable gelling agent is hydroxypropylcellulose, which is generally available in grades from viscosities of from about 5 cps to about 25,000 cps such as about 1500 cps. All viscosity measurements are assumed to be made at room temperature unless otherwise stated. The concentration of hydroxypropylcellulose may range from about 1% w/w to about 2% w/w of the composition. Other gelling agents are known in the art and can be used in place of, or in addition to hydroxypropylcellulose. An example of a suitable dispersing agent is glycerin. Glycerin is typically included at a concentration from about 5 % w/w to about 25 % w/w of the composition. A preservative may be included at a concentration effective to inhibit microbial growth, ultraviolet light and/ or oxy gen- induced breakdown of composition components, and the like. When a preservative is included, it mac range in concentration from about 0.01 % w/w to about 1.5 % w/w of the composition.

[00188] Additional components that may also be included in a transdermal delivery formulation are fatty acids, terpenes, lipids, and cationic, and anionic detergents. In some embodiments, a transdermal delivery formulation further comprises tranexamic acid in an amount less than 2 % w/w, 5 % w/w, or 10 % w/w of the formulation. In some embodiments, a transdermal delivery formulation further comprises a polar solvent in an amount less than 2 % w/w, 5 % w/w, 10 % w/w, or 20 % w/w of the transdermal delivery formulation. In some embodiments, a 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, a transdermal delivery formulation further comprises almond oil in an amount less than about 5 % w/w. In some embodiments, a formulation further comprises a mixture of thermoplastic polyurethane and polycarbonate in an amount less than about 5 % w/w. In some embodiments, a transdermal delivery formulation further comprises phosphatidylethanolamine in an amount less than about 5 % w/w. In some embodiments, a transdermal delivery formulation further comprises an inositol phosphatide in an amount less than about 5 % w/w.

[00189] Other solvents and related compounds that may be used in some embodiments include acetamide and derivatives, acetone, n-alkanes (chain length between 7 and 16), alkanols, diols, short chain fatty acids, cyclohexyl- 1, 1 -dimethylethanol, dimethyl acetamide, dimethyl formamide, ethanol, ethanol/d-limonene combination, 2-eihyl- 1,3 -hexanediol, ethoxydiglycol (Transcutol® by Gattefosse. Lyon, France), glycerol, glycols, lauryl chloride, limonene N-methylformamide, 2-phenylethanol, 3- phenyl- 1 -propanol, 3-phenyl-2-propen-l-ol, polyethylene glycol, polyoxyethylene sorbitan monoesters, polypropylene glycol 425, primary alcohols (tri decanol), 1,2-propane diol, butanediol, G-G, triols or their mixtures and apolar lipid compound selected fromCie or Cis monounsaturated alcohol, Ci6 orC'ix branched saturated alcohol and their mixtures, propylene glycol, sorbitan monolaurate sold as Span® 20 by Sigma- Aldrich, squalene, triacetin, trichloroethanol, trifluoroethanol, trimethylene glycol and xylene.

[00190] Fatty alcohols, fatty acids, fatty esters, are bilayer fluidizers that may be used in some embodiments. Examples of suitable fatty alcohols include aliphatic alcohols, decanol, lauryl alcohol (dodecanol), unolenyl alcohol, nerolidol, 1 -nonanol, w-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, diethyleneglycol oleate, diethyl sebacate, diethyl succinate, diisopropyl sebacate, dodecyl N,N-dimethyamino acetate, dodecyl (N,N-dimethylamino)-butyrate, dodecyl N,N- dimethylamino isopropionate, dodecyl 2-(dimethyamino) propionate, E0-5-oleyl ether, ethyl acetate, ethylaceto acetate, ethyl propionate, glycerol monoethers, 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 -monocaproyl glycerol, monoglycerides (medium chain length), nicotinic esters (benzyl), octyl acetate, octyl N,N-dimeihylamino acetate, oleyl oleate, n- pentyl N-acetylprolinate, propylene glycol monolaurate, sorbitan dilaurate, sorbitan dioleate, sorbitan monolaurate, sorbitan monolaurate, sorbitan trilaurate, sorbitan trioleate, sucrose coconut fatty ester mixtures, sucrose monolaurate, sucrose monooleate, tetradecyl N.N-dimethylamino acetate. Examples of suitable fatty acid- include alkanoic acids, caprid acid, diacid, eihyloctadecanoic acid, hexanoic add, 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 a- monoglyceryl ether, E0-2-oleyl ether, E0-5-oleyl ether, E0-10-oleyl ether, ether derivatives of polyglycerols and alcohols, and (l-O-dodecyl-3-O-methyl-2-O-(2',3 '-dihydroxypropyl glycerol).

[00191] Examples of completing agents that may be used in some embodiments include [3- and y- cyclodextrin complexes, hydroxypropyl methylcellulose (e.g., Carbopol® 934), liposomes, naphthalene diamide diimide, and naphthalene di ester diimide.

[00192] One or more anti-oxidants may be included, such as vitamin C, vitamin E, proanthocyanidin and a-lipoic acid typically in concentrations of 0. 1 %-2.5% w/w.

[00193] In some applications, it is desirable to adjust the pH of a transdermal delivery formulation to assist in permeation or to adjust the nature of the ketone component and/or of the target compounds in the subject. In some instances, the pH is adjusted to a level of pH 9-11 or 10-11 which can be done by providing appropriate buffers or simply adjusting the pH with base.

[00194] A transdermal delivery formulation may include other components that act as excipients or serve purposes other than PDE5 inhibitors. For example, preservatives like antioxidants e.g., ascorbic acid or a-lipoic acid and antibacterial agents may be included. Other components apart from therapeutically active ingredients and components that are the primary effectors of dermal penetration may include those provided for aesthetic purposes such as menthol or other aromatics, and componaits that affect the physical state of the composition such as emulsifiers, for example, Durosoft® (which is a mixture of thermoplastic polyurethane and polycarbonate). Typically, these ingredients are present in very small percentages of the compositions. It is understood that these latter ancillary agents are neither therapeutically ingredients nor are they components that are primarily responsible for penetration of the skin. The components that primarily effect skin penetration have been detailed as described above. However, some of these substances have some capability for effecting skin penetration. See, for example, Kunta, J.R. et al, J. Pharm. Sci. (1997) 86: 1369-1373, describing penetration properties of menthol.

[00195] The application method is determined by the nature of the treatment but may be less critical than the nature of the formulation itself. If the application is to a skin area, it may be helpful in some instances to prepare the skin by cleansing or exfoliation. In some instances, it is helpful to adjust the pH of the skin area prior to application of atransdermal delivery formulation itself. The application of atransdermal delivery formulation may be by simple massaging onto the skin or by use of devices such as syringes or pumps. Patches could also be used. In some cases, it is helpful to cover the area of application to prevent evaporation or loss of atransdermal delivery formulation.

[00196] In addition to the compositions and formulations of the invention per se, the methods may employ a subsequent treatment with linoleic acid. As transdermal treatments generally open up the skin barrier, which is, indeed, their purpose, it is useful to seal the area of application after the treatment is finished. Thus, treatment with atransdermal delivery formulation may be followed by treating the skin area with a composition comprising linoleic acid to seal off the area of application. The application of linoleic acid is applicable to any transdermal procedure that results in impairing the ability of the skin to act as a protective layer. Indeed, most transdermal treatments have this effect as their function is to allow the ketone component to pass through the epidermis to the dermis at least, and, if systemic administration is achieved, through the dermis itself.

[00197] Additional therapeutic agents may be included in the compositions. For example^ hydrocortisone or hydrocortisone acetate may be included in an amount ranging from 0.25% w/w to about 0.5% w/w. Menthol, phenol, and terpenoids, e.g., camphor, can be incorporated for cooling pain relief For example, menthol may be included in an amount ranging from about 0.1 % w/w to about 1.0% w/w.

[00198] The formulation described in this specification may also comprise more than one therapeutic compound as desired for the particular indication being treated, preferably those with complementary activities that do not adversely affect the other proteins. A transdermal delivery formulation to be used for in vivo administration can be sterile. This can be accomplished, for instance, without limitation, by filtration through sterile filtration membranes, prior to, or following, preparation of a transdermal delivery formulation or other methods known in the art, including without limitation, pasteurization.

[00199] Packaging and instruments for administration may be determined by a variety of considerations, such as, without limitation, the volume of material to be administered, the conditions for storage, whether skilled healthcare practitioners will administer or patient self-compliance, the dosage regime, the geopolitical environment (e.g. , exposure to extreme conditions of temperature for developing nations), and other practical considerations. [00200] In certain embodiments, kits can comprise, without limitation, one or more cream or lotion comprising one or more formulations described herein. In various embodiments, the kit can comprise formulation components for transdermal, topical, or subcutaneous administration, formulated to be administered as an emulsion coated patch. In all of these embodiments and others, the kits can contain one or more lotion, cream, patch, or the like in accordance with any of the foregoing, wherein each patch contains a single unit dose for administration to a subject.

[00201] Imaging components can optionally be included, and the packaging also can include writer or web-accessible instructions for using a transdermal delivery formulation. A container can include^ for example, a vial, bottle, patch, syringe, pre-filled syringe, tube or any of a variety of formats well known in the art for multi -dispenser packaging.

[00202] Aspects of the present specification disclose that the symptoms associated with a disease or disorder (e.g. ED) described herein are reduced following application of a transdermal delivery formulation 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% 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%. Aspects of the present specification disclose the symptoms associated with disease or disorder are reduced following application of a transdermal delivery formulation 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 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%.

[00203] In another aspect, in certain embodiments a transdermal delivery formulation is administered topically or transdermally such that the dose results in a subject intake of at least about 0. 1 nmol/hr/Kg, at least about 0.5 nmol/hr/Kg, at least about 0.7 nmol/hr/Kg, at least about 1.0 nmol/hr/Kg, at least about 1.1 nmol/hr/Kg, at least about 1.2 nmol/hr/Kg, at least about 1.3 nmol/hr/Kg, at least about 1.4 nmol/hr/Kg, at least about 1.5 nmol/hr/Kg, at least about 1.6 nmol/hr/Kg, at least about 1.7 nmol/hr/Kg, at least about 1. 8 nmol/hr/Kg, at least about 1.9 nmol/hr/Kg, at least about 2.0 nmol/hr/Kg, at least about 2.5 nmol/hr/Kg, at least about 3.0 nmol/hr/Kg, at least about 3.5nmol/hr/Kg, at least about 4.0 nmol/hr/Kg, at least about 5 nmol/hr/Kg, at least about 10 nmol/hr/Kg, at least about 25 nmol/hr/Kg, at least about 50 nmol/hr/Kg, at least about 100 nmol/hr/Kg, at least about 500 nmol/hr/Kg, or at least about 1 pmol/hr/Kg. [00204] In another aspect, in certain embodiments atransdermal delivery formulation is administered topically or transdermally such that the dose results in a peak plasma concentration of a PDE5 inhibitor ranges from about 1 pg/ml to 50 pg/ml, about 5 pg/ml to about 45 pg/ml, about 5 pg/ml to about 40 pg/ml, about 5 pg/ml to about 35 pg/ml, about 5 pg/ml to about 30 pg/ml, about 5 pg/ml to about 25 pg/ml, about 1 pg/ml to about 45 pg/ml, about 1 pg/ml to about 40 pg/ml, about 1 pg/ml to about 35 pg/ml, about 1 pg/ml to about 30 pg/ml, about 1 pg/ml to about 25 pg/ml, about 1 pg/ml to about 20 pg/ml, about 1 pg/ml to about 15 pg/ml, about 1 pg/ml to about 10 pg/ml, about 1 pg/ml to about 9 pg/ml, about 1 pg/ml to about 8 pg/ml, about 1 pg/ml to about 7 pg/ml, about 1 pg/ml to about 6 pg/ml, and about 1 pg/ml to about 5 pg/ml.

[00205] In another aspect, in certain embodiments atransdermal delivery formulation is administered topically or transdermally so that plasma concentration of a PDE5 inhibitor ranges from about 1 ng/ml to 500 pg/ml, about 10 ng/ml to 500 pg/ml, about 100 ng/ml to 500 pg/ml, about 1 pg/ml to 500 pg/ml, about 10 pg/ml to 500 pg/ml, about 25 pg/ml to 500 pg/ml, about 25 pg/ml to about 450 pg/ml, about 25 pg/ml to about 400 pg/ml, about 25 pg/ml to about 350 pg/ml, about 25 pg/ml to about 300 pg/ml, about 25 pg/ml to about 250 pg/ml, about 50 pg/ml to about 500 pg/ml, about 55 pg/ml to about 500 pg/ml, about 60 pg/ml to about 500 pg/ml, about 65 pg/ml to about 500 pg/ml, about 70 pg/ml to about 500 pg/ml, about 75 pg/ml to about 500 pg/ml, about 80 pg/ml to about 500 pg/ml, about 85 pg/ml to about 500 pg/ml, about 90 pg/ml to about 500 pg/ml, about 95 pg/ml to about 500 pg/ml, about 100 pg/ml to about 500 pg/ml, about 110 pg/ml to about 500 pg/ml, about 120 pg/ml to about 500 pg/ml, about 130 pg/ml to about 500 pg/ml, about 140 pg/ml to about 500 pg/ml about 150 pg/ml to about 500 pg/ml, about 160 pg/ml to about 500 pg/ml, about 170 pg/ml to about 500 pg/ml, about 180 pg/ml to about 500 pg/ml, about 200 pg/ml to about 500 pg/ml, about 200 pg/ml to about 490 pg/ml, about 200 pg/ml to about 480 pg/ml, about 200 pg/ml to about 470 pg/ml, about 200 pg/ml to about 460 pg/ml, about 200 pg/ml to about 450 pg/ml, about 200 pg/ml to about 440 pg/ml, about 200 pg/ml to about 430 pg/ml, or about 200 pg/ml to about 400 pg/ml.

[00206] In further embodiments, a transdermal delivery formulation is administered topically or transdermally so that plasma concentration of a PDE5 inhibitor is at least 10 ng/ml, at least 25 ng/ml, at least 50 ng/ml, at least 100 ng/ml, at least 250 ng/ml, at least 0.5 pg/ml, at least 0.75 pg/ml, at least 1 pg/ml, at least 2 pg/ml, at least 3 pg/ml, at least 4 pg/ml, at least 5 pg/ml, at least 6 pg/ml, at least 7 pg/ml, at least 8 pg/ml, at least 9 pg/ml, at least 10 pg/ml, at least 15 pg/ml, at least 20 pg/ml, at least 25 pg/ml, at least 30 pg/ml, at least 35 pg/ml, at least 40 pg/ml, at least 45 pg/ml, at least 50 pg/ml, at least 55 pg/ml, at least 60 pg/ml, at least 65 pg/ml, at least 70 pg/ml, at least 75 pg/ml, at least 80 pg/ml, at least 85 pg/ml, at least 90 pg/ml, at least 95 pg/ml, at least 100 pg/ml or more than 100 pg/ml. [00207] In another aspect, a transdermal delivery formulation (e.g. containing a PDE5 inhibitor) is administered topically or transdermally so that peak plasma concentration is reached in lOmin, 15min, 20min, 30min, 45min, 60min, 75min, 90min, 2hr, 3hr, 4hr, 5hr, 6 hr, 7hr, 8hr, lOhr, 12hr or 24hr after administration. [00208] Aspects of the present specification disclose that the symptoms associated with a disease or disorder (e.g. ED) described herein are reduced following administration of a transdermal delivery formulation of the present invention 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% 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%. Aspects of the present specification disclose the symptoms associated with 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 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%.

[00209] A transdermal delivery formulation as described herein can be used in the manufacture of medicaments (e.g. PDE5 inhibitors) and for the treatment of humans and other animals by administration in accordance with conventional procedures.

[00210] Dosing can be single dosage or cumulative (serial dosing), and can be readily determined tty one skilled in the art. A transdermal delivery formulation of the present invention may be administered once, twice, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty or more times to a subject. For instance, treatment of a disease may comprise a one-time administration of an effective dose of a transdermal delivery formulation as disclosed herein. Alternatively, treatment of a disase may comprise multiple administrations of an effective dose of a transdermal delivery formulation as carried out over a range of time periods, such as, e.g., once daily, twice daily, trice daily, once every few days, or once weekly. The timing of administration can vary from individual to individual, depending upon such factors as the severity of an individual's symptoms. For example, an effective dose of a transdermal delivery formulation as disclosed herein can be administered to an individual once daily for an indefinite period of time, or until the individual no longer requires therapy. A person of ordinary skill in the art will recognize that the condition of the individual can be monitored throughout the course of treatment and that the effective amount of a transdermal delivery formulation disclosed herein that is administered can be adjusted accordingly. In one embodiment, atransdermal delivery formulation as disclosed herein is capable of decreasing the time to resolve the symptoms of a disease, including in an individual suffering from a disease by, e.g. , 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% as compared to a patient not receiving the same treatment.

[00211] In one embodiment, an anti-ED transdermal delivery formulation disclosed herein is capable of increasing the duration of an erection by, e.g. , 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% as compared to a patient not receiving the same treatment. In other aspects of this embodiment, an anti-ED transdermal delivery formulation is capable of increasing the intensity of an erection by, e.g. , 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 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% as compared to a patient not receiving the same treatment.

[00212] In a further embodiment, an anti-ED transdermal delivery formulation and its derivatives have half-lives 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 or 1 day.

[00213] Wide variations in the necessary effective amount are to be expected in view of the differing efficiencies of the various routes of administration. For instance, oral administration of an anti-ED transdermal delivery formulation disclosed herein generally would be expected to require higher dosage levels than administration by inhalation. Similarly, systemic administration of an anti-ED transdermal delivery formulation disclosed herein would be expected to require higher dosage levels than a local administration. Variations in these dosage levels can be adjusted using standard empirical routines of optimization, which are well-known to a person of ordinary skill in the art. The precise therapeutically effective dosage levels and patterns are preferably determined by the attending physician in consideration of the above-identified factors. One skilled in the art will recognize that the condition of the individual can be monitored throughout the course of therapy and that the effective amount of an ED therapeutic disclosed herein that is administered can be adjusted accordingly.

[00214] In an embodiment, a first anti-ED transdermal delivery formulation is administered to an individual and at a later time, a second anti-ED transdermal delivery formulation is administered to the same individual. In an embodiment, a first anti-ED transdermal delivery formulation is administered to an individual at the same time as a second anti-ED transdermal delivery formulation is administered to the individual. [00215] In one aspect, disclosed herein is a formulation for transdermal delivery of an active agent through the skin a subject, wherein the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 % w/w, comprising i. one or more phosphatides and ii. one or more fatty acids; and b) water in an amount less than about 50 % w/w.

[00216] In some embodiments, the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 % w/w, comprising i. one or more phosphatides and ii. one or more fatty acids; and b) water in an amount less than about 50 % w/w, further comprises benzyl alcohol in an amount between about 0.5-5 % w/w.

[00217] In some embodiments, the transdermal delivery formulation comprises benzyl alcohol in an amount less than 5 % w/w of the formulation.

[00218] In some embodiments, the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 % w/w, comprising i. one or more phosphatides and ii. one or more fatty acids; and b) water in an amount less than about 50 % w/w, further comprises Isopropyl Palmitate in an amount between about 5-5 % w/w.

[00219] In some embodiments, the water is deionized water and/ or purified water.

[00220] In some embodiments, the water is in an amount between about 15-40 % w/w of the formulation.

[00221] In some embodiments, the one or more phosphatides in an amount between about 0.5-55 % w/w of the transdermal delivery formulation.

[00222] In some embodiments, the transdermal delivery formulation comprises phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, or a combination thereof in amount less than 30 % w/w of the formulation.

[00223] In some embodiments, the one or more phosphatides comprises phosphatidylcholine of the transdermal delivery formulation.

[00224] In some embodiments, the one or more fatty acids in an amount between about 1 -35 % w/w of the transdermal delivery formulation.

[00225] In some embodiments, the one or more fatty acids in an amount between about 5-35 % w/w of the transdermal delivery formulation.

[00226] In some embodiments, the one or more fatty acids comprises Linoleic Acid, Oleic Acid, Stearic Acid, safflower oil, or a combination thereof.

[00227] In some embodiments, the one or more fatty acids comprises Linoleic Acid.

[00228] In some embodiments, the one or more fatty acids comprises Oleic Acid.

[00229] In some embodiments, the one or more fatty acids comprises Stearic Acid.

[00230] In some embodiments, the one or more phosphatides are derived from a seed oil in an amount between about 0.5-55 % w/w of the transdermal delivery formulation.

[00231] In some embodiments, the one or more phosphatides are derived from aseed oil in an amount between about 5-35 % w/w of the transdermal delivery formulation. [00232] In some embodiments, the one or more phosphatides are derived from a safflower oil in an amount between about 0.5-55 % w/w of the transdermal delivery formulation.

[00233] In some embodiments, the one or more phosphatides are derived from a safflower oil in an amount between about 5-35 % w/w of the transdermal delivery formulation.

[00234] In some embodiments, the one or more phosphatides are derived from an almond oil in an amount between about 0.5-55 % w/w of the transdermal delivery formulation.

[00235] In some embodiments, the one or more phosphatides are derived from an almond oil in an amount between about 5-35 % w/w of the transdermal delivery formulation.

[00236] In some embodiments, the one or more phosphatides comprises one or more fatty acids derived from soy lecithin.

[00237] In some embodiments, the glucose in an amount between about 0.05-10 % w/w of the transdermal delivery formulation. In another embodiment, the transdermal delivery formulation contains no glucose.

[00238] In some embodiments, the glucose is anhydrous dextrose in an amount between about 0.05-10 % w/w of the transdermal delivery formulation.

[00239] In some embodiments, the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 % w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 % w/w, further comprises a nonionic surfactant in an amount between about 2-25 % w/w of the transdermal delivery formulation.

[00240] In some embodiments, the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 % w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 % w/w, further comprises a polar solvent at least in an amount in molar excess of the nonionic surfactant.

[00241] In some embodiments, the nonionic surfactant is a pol oxamer and the polar solvent is Wats’. [00242] In some embodiments, the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 % w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 % w/w, further comprises a polar solvent in an amount less than 5 % w/w of the formulation.

[00243] In some embodiments, the transdermal delivery formulation further comprises a detergent portion in an amount between about 1-30 % w/w of the transdermal delivery formulation.

[00244] In some embodiments, the detergent portion comprises a nonionic surfactant in an amount between about 2-25 % w/w of the transdermal delivery formulation; and apolar solvent in an amount less than 5 % w/w of the transdermal delivery formulation.

[00245] In some embodiments, the transdermal delivery formulation is in an amount between about 10-60 % w/w of the transdermal delivery formulation.

[00246] In some embodiments, the transdermal delivery formulation comprises an alcohol in an amount less than 10 % w/w of the transdermal delivery formulation. [00247] In some embodiments, the transdermal delivery formulation further comprises an alcohol, a surfactant, and a polar solvent.

[00248] In some embodiments, the transdermal delivery formulation comprises cetyl alcohol in amount less than 5 % w/w of the formulation.

[00249] In some embodiments, the transdermal delivery formulation comprises ethanol in an amount less than 5 % w/w of the formulation.

[00250] In some embodiments, the transdermal delivery formulation comprises glycerine in an amount less than 5 % w/w of the formulation.

[00251] In some embodiments, the transdermal delivery formulation comprises propylene glycol in an amount less than 8 % w/w of the formulation.

[00252] In some embodiments, the formulation comprises a gelling agent in an amount less than 20 % w/w of the formulation.

[00253] In some embodiments, the formulation comprises menthol in an amount between about 0.05 -

5 % w/w of the formulation.

[00254] In some embodiments, the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 % w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 % w/w, further comprises tranexamic acid in an amount less than 5 % w/w of the formulation.

[00255] In some embodiments, the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 % w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 % w/w, further comprises ahumectant, an emulsifier, an emollient, or a combination thereof.

[00256] In some embodiments, the formulation has a pH of 9- 11.

[00257] In some embodiments, the formulation has a pH of 7-10.5.

[00258] In some embodiments, the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 % w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 % w/w, further comprises an active agent.

[00259] In some embodiments, the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 % w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 % w/w, further comprises an active agent component in an amount less than about 60 % w/w.

[00260] In some embodiments, the formulation comprises a) a transdermal delivery formulation in an amount less than about 60 % w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 % w/w, further comprises an active agent component in an amount less than about 60 % w/w, wherein the active agent is a PDE5 inhibitor. [00261] In some embodiments, the buffering agent is sodium carbonate and/or sodium bicarbonate. [00262] In another aspect disclosed herein is a method to effect transdermal delivery of an active ingredient comprising applying to the skin of a subject an effective amount of the formulation comprising a) a transdermal delivery formulation in an amount less than about 60 % w/w, comprising i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; and b) water in an amount less than about 50 % w/w, further comprises an active agent.

ADDITIONAL EMBODIMENTS

[00263] Embodiment 1. A transdermal delivery formulation for transdermal delivery of sildenafil through the skin of a subject, wherein the transdermal delivery formulation comprises: a) sildenafil at 0.5 to 5% w/w; b) propylene glycol at 2 to 10% w/w; c) phosphatidylcholine at 2 to 10% w/w; d) benzyl alcohol at 0.5 to 5% w/w; e) isopropyl palmitate at 2 to 15 % w/w; f) stearic acid at 0. 1 to 2% w/w; g) oleic acid at 0.2 to 5%; h) a surfactant at 1 to 15%; and i) water in an amount less than about 50 % w/w. [00264] Embodiment 2. The transdermal delivery formulation of Embodiment 1 further comprising sodium carbonate at 2 to 15% w/w.

[00265] Embodiment 3. The transdermal delivery formulation of Embodiment 1 further comprising sodium bicarbonate at 5 to 15% w/w.

[00266] Embodiment 4. The transdermal delivery formulation of Embodiment 1, wherein the surfactant is Poloxamer 407.

[00267] Embodiment 5. The transdermal delivery formulation of Embodiment 1 further comprising polyglyceryl-4 Laurate at 0.2 to 5% w/w.

[00268] Embodiment 6. The transdermal delivery formulation of Embodiment 1 further comprising cetyl alcohol at 0.5 to 5% w/w.

[00269] Embodiment 7. The transdermal delivery formulation of Embodiment 1 further comprising Carthamus Tinctorius oil at 0.5 to 5% w/w.

[00270] Embodiment 8. The transdermal delivery formulation of Embodiment 1, wherein the formulation has a pH of 4.5 - 7.5.

[00271] Embodiment 9. The transdermal delivery formulation of Embodiment 1, wherein the formulation has a pH of 7.5 - 10.5.

[00272] Embodiment 10. The transdermal delivery formulation of Embodiment 1, wherein the formulation further comprises a humectant, an emulsifier, an emollient, or a combination thereof.

[00273] Embodiment 11. A transdermal delivery formulation for transdermal delivery of sildenafil through the skin of a subject, wherein the transdermal delivery formulation comprises: a) sildenafil at 0.5 to 5% w/w; b) phosphatidylcholine at 2 to 15% w/w; c) isopropyl palmitate at 2 to 25 % w/w; d) benzyl alcohol at 0.5 to 5% w/w; e) stearic acid at 0. 1 to 3% w/w; f) oleic acid at 0.2 to 5%; g) a surfactant at 1 to 15%; and h) water in an amount of about 60 % w/w.

[00274] Embodiment 12. The transdermal delivery formulation of Embodiment 11 further comprising Polyglyceryl-4 Laurate at 0.2 to 5% w/w. [00275] Embodiment 13. The transdermal delivery formulation of Embodiment 11 further comprising Carthamus Tinctorius oil at 0.5 to 5% w/w.

[00276] Embodiment 14. The transdermal delivery formulation of Embodiment 11, wherein the surfactant is Poloxamer 407.

[00277] Embodiment 15. The transdermal delivery formulation of Embodiment 11, wherein the formulation has a pH of 4.5 - 7.5.

[00278] Embodiment 16. The transdermal delivery formulation of Embodiment 11, wherein the formulation has a pH of 7.5 - 10.5.

[00279] Embodiment 17. The transdermal delivery formulation of Embodiment 11, wherein the formulation further comprises a humectant, an emulsifier, an emollient, or a combination thereof.

[00280] Embodiment 18. A method of treating erectile disfunction comprising applying the transdermal delivery formulation of Embodiment 1 to a skin surface of a subject.

[00281] Embodiment 19. A method of treating erectile disfunction comprising applying the transdermal delivery formulation of Embodiment 11 to a skin surface of a subject.

[00282] Embodiment 20. A method to effect transdermal delivery of sildenafil comprising applying to a skin surface of a subject an effective amount of a transdermal delivery formulation, wherein the formulation comprises: a) one or more phosphatides; b) one or more fatty acids; c) water in an amount less than about 50 % w/w, and d) Sildenafil.

[00283] Embodiment 21. A method to effect transdermal delivery of vardenafil comprising applying to a skin surface of a subject an effective amount of a transdermal delivery formulation, wherein the formulation comprises: a) one or more phosphatides; b) one or more fatty acids; c) water in an amount less than about 50 % w/w, and d) vardenafil.

[00284] Embodiment 22. A method to effect transdermal delivery of tadalafil comprising applying to a skin surface of a subject an effective amount of a transdermal delivery formulation, wherein the formulation comprises: a) one or more phosphatides; b) one or more fatty acids; c) water in an amount less than about 50 % w/w, and d) tadalafil.

[00285] Embodiment 23. A transdermal delivery formulation for transdermal delivery of a PDE5 inhibitor through the skin of a subject, wherein the transdermal delivery formulation comprises: a) a PDE5 inhibitor at 0.05 to 5% w/w; b) propylene glycol at 2 to 10% w/w; c) phosphatidylcholine at 2 to 10% w/w; d) benzyl alcohol at 0.5 to 5% w/w; e) isopropyl palmitate at 2 to 15 % w/w; 1) stearic acid at 0.1 to 2% w/w; g) oleic acid at 0.2 to 5%; h) a surfactant at 1 to 15%; and i) water in an amount less than about 50 % w/w.

[00286] Embodiment 24. The transdermal delivery formulation of Embodiment 23, wherein the PDE5 inhibitor is sildenafil, vardenafil or tadalafil.

[00287] Embodiment 25. The transdermal delivery formulation of Embodiment 23 further comprising sodium carbonate at 2 to 15% w/w. [00288] Embodiment 26. The transdermal delivery formulation of Embodiment 23 further comprising sodium bicarbonate at 5 to 15% w/w.

[00289] Embodiment 27. The transdermal delivery formulation of Embodiment 23, wherein the surfactant is Poloxamer 407.

[00290] Embodiment 28. The transdermal delivery formulation of Embodiment 23 further comprising polyglyceryl-4 Laurate at 0.2 to 5% w/w.

[00291] Embodiment 29. The transdermal delivery formulation of Embodiment 23 further comprising cetyl alcohol at 0.5 to 5% w/w.

[00292] Embodiment 30. The transdermal delivery formulation of Embodiment 23 further comprising Carthamus Tinctorius oil at 0.5 to 5% w/w.

[00293] Embodiment 31. The transdermal delivery formulation of Embodiment 23, wherein the formulation has a pH of 4.5 -10.5.

[00294] Embodiment 32. A transdermal delivery formulation for transdermal delivery of a PDE5 inhibitor through the skin of a subject, wherein the transdermal delivery formulation comprises: a) a PDE5 inhibitor at 0.05 to 5% w/w; b) phosphatidylcholine at 2 to 15% w/w; c) isopropyl palmitate at 2 to 25 % w/w; d) benzyl alcohol at 0.5 to 5% w/w; e) stearic acid at 0. 1 to 3% w/w; f) oleic acid at 0.2 to 5%; g) a surfactant at 1 to 15%; and h) water in an amount of about 60 % w/w.

[00295] Embodiment 33. The transdermal delivery formulation of Embodiment 32, wherein the PDE5 inhibitor is sildenafil, vardenafil, avanafil or tadalafil.

[00296] Embodiment 34. The transdermal delivery formulation of Embodiment 32 further comprising Polyglyceryl-4 Laurate at 0.2 to 5% w/w.

[00297] Embodiment 35. The transdermal delivery formulation of Embodiment 32 further comprising Carthamus Tinctorius oil at 0.5 to 5% w/w.

[00298] Embodiment 36. The transdermal delivery formulation of Embodiment 32, wherein the surfactant is Poloxamer 407.

[00299] Embodiment 37. The transdermal delivery formulation of Embodiment 32, wherein the formulation has a pH of 4.5 -10.5.

[00300] Embodiment 38. A method of treating erectile disfunction comprising applying a PDE5 inhibitor to a skin surface of a subject, wherein the PDE5 inhibitor is applied to the skin surface with a transdermal delivery formulation comprising: a) a PDE5 inhibitor at 0.05 to 5% w/w; b) phosphatidylcholine at 2 to 15% w/w; c) isopropyl palmitate at 2 to 25 % w/w; d) benzyl alcohol at 0.5 to 5% w/w; e) stearic acid at 0.1 to 3% w/w; 1) oleic acid at 0.2 to 5%; g) a surfactant at 1 to 15%; and h) water in an amount of about 60 % w/w.

[00301] Embodiment 39. The method of treating erectile disfunction of Embodiment 38, wherein the PDE5 inhibitor is sildenafil, vardenafil, avanafil or tadalafil.

[00302] Embodiment 40. A transdermal delivery formulation for transdermal delivery of a PDE5 inhibitor through the skin of a subject, wherein the transdermal delivery formulation comprises: a) a transdermal delivery formulation in an amount less than about 60 % w/w, comprising: i. one or more phosphatides, ii. glucose, and iii. one or more fatty acids; iv. a PDE5 inhibitor; and b) water in an amount less than about 50 % w/w.

[00303] Embodiment 41. The transdermal delivery formulation of Embodiment 40, further comprising benzyl alcohol at about 0.5 - 5 % w/w.

[00304] Embodiment 42. The transdermal delivery formulation of Embodiment 40 wherein the transdermal delivery formulation further comprises benzyl alcohol at less than 5 % w/w of the formulation.

[00305] Embodiment 43. The transdermal delivery formulation of Embodiment 40, further comprising isopropyl palmitate at about 5 - 5 % w/w.

[00306] Embodiment 44. The transdermal delivery formulation of Embodiment 40, wherein the water is deionized water and/or purified water.

[00307] Embodiment 45. The transdermal delivery formulation of Embodiment 40, wherein the water is about 15 - 40 % w/w of the formulation.

[00308] Embodiment 46. The transdermal delivery formulation of Embodiment 40, wherein the one or more phosphatides are between about 0.5 - 55 % w/w of the transdermal delivery formulation.

[00309] Embodiment 47. The transdermal delivery formulation of Embodiment 40, wherein the transdermal delivery formulation further comprises phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, or a combination thereof of less than 30 % w/w of the formulation.

[00310] Embodiment 48. The transdermal delivery formulation of Embodiment 40, wherein the one or more phosphatides comprises phosphatidylcholine.

[00311] Embodiment 49. The transdermal delivery formulation of Embodiment 40, wherein the one or more fatty acids are about 1 - 35 % w/w of the transdermal delivery formulation.

[00312] Embodiment 50. The transdermal delivery formulation of Embodiment 40, wherein the one or more fatty acids are about 5 - 35 % w/w of the transdermal delivery formulation.

[00313] Embodiment 51. The transdermal delivery formulation of Embodiment 40, wherein the one or more fatty acids comprise linoleic acid, oleic acid, stearic acid, safflower oil or a combination thereof. [00314] Embodiment 52. The transdermal delivery formulation of Embodiment 40, wherein the one or more fatty acids comprise linoleic acid.

[00315] Embodiment 53. The transdermal delivery formulation of Embodiment 40, wherein the one or more fatty acids comprise oleic acid.

[00316] Embodiment 54. The transdermal delivery formulation of Embodiment 40, wherein the one or more fatty acids comprise stearic acid.

[00317] Embodiment 55. The transdermal delivery formulation of Embodiment 40, wherein the one or more fatty acids are derived from a seed oil and are about 0.5 - 55 % w/w of the transdermal delivery formulation. [00318] Embodiment 56. The transdermal delivery formulation of Embodiment 40, wherein the one or more fatty acids are derived from a seed oil and are about 5 - 35 % w/w of the transdermal delivery formulation.

[00319] Embodiment 57. The transdermal delivery formulation of Embodiment 40, wherein the one or more fatty acids are derived from a safflower oil and are about 0.5 - 55 % w/w of the transdermal delivery formulation.

[00320] Embodiment 58. The transdermal delivery formulation of Embodiment 40, wherein the one or more fatty acids are derived from a safflower oil and are about 5 - 35 % w/w of the transdermal delivery formulation.

[00321] Embodiment 59. The transdermal delivery formulation of Embodiment 40, wherein the one or more fatty acids are derived from an almond oil in and are about 0.5 - 55 % w/w of the transdermal delivery formulation.

[00322] Embodiment 60. The transdermal delivery formulation of Embodiment 40, wherein the one or more fatty acids are derived from an almond oil and are about 5 - 35 % w/w of the transdermal delivery formulation.

[00323] Embodiment 61. The transdermal delivery formulation of Embodiment 40, wherein the one or more fatty acids comprise one or more fatty acids derived from soy lecithin.

[00324] Embodiment 62. The transdermal delivery formulation of Embodiment 40, wherein the glucose is between about 0.05 - 10 % w/w of the transdermal delivery formulation.

[00325] Embodiment 63. The transdermal delivery formulation of Embodiment 40, wherein the glucose is anhydrous dextrose and about 0.05 - 10 % w/w of the transdermal delivery formulation.

[00326] Embodiment 64. The transdermal delivery formulation of Embodiment 40 further comprising a nonionic surfactant in an amount between about 2 - 25 % w/w of the transdermal delivery formulation.

[00327] Embodiment 65. The transdermal delivery formulation of Embodiment 64 further comprising a polar solvent in molar excess of the nonionic surfactant.

[00328] Embodiment 66. The transdermal delivery formulation of Embodiment 65, wherein the nonionic surfactant is a pol oxamer and the polar solvent is water.

[00329] Embodiment 67. The transdermal delivery formulation of Embodiment 40 further comprising a polar solvent that is less than 5 % w/w of the formulation.

[00330] Embodiment 68. The transdermal delivery formulation of Embodiment 40, wherein the transdermal delivery formulation further comprises a detergent portion of about 1 - 30 % w/w of the transdermal delivery formulation.

[00331] Embodiment 69. The transdermal delivery formulation of Embodiment 68, wherein the detergent portion comprises a nonionic surfactant of about 2 - 25 % w/w of the transdermal delivery formulation and apolar solvent of less than 5 % w/w of the transdermal delivery formulation. [00332] Embodiment 70. The transdermal delivery formulation of Embodiment 40, wherein the transdermal delivery formulation further comprises an alcohol in an amount less than 10 % w/w.

[00333] Embodiment 71. The transdermal delivery formulation of Embodiment 40, wherein the transdermal delivery formulation further comprises an alcohol, a surfactant and a polar solvent.

[00334] Embodiment 72. The transdermal delivery formulation of Embodiment 40, wherein the transdermal delivery formulation comprises cetyl alcohol of less than 5 % w/w.

[00335] Embodiment 73. The transdermal delivery formulation of Embodiment 40, wherein the transdermal delivery formulation further comprises ethanol of 5 % w/w.

[00336] Embodiment 74. The transdermal delivery formulation of Embodiment 40, wherein the transdermal delivery formulation comprises glycerine of less than 5 % w/w of the formulation.

[00337] Embodiment 75. The transdermal delivery formulation of Embodiment 40, wherein the transdermal delivery formulation further comprises propylene glycol of less than 8 % w/w of the formulation.

[00338] Embodiment 76. The transdermal delivery formulation of Embodiment 40, wherein the formulation comprises a gelling agent of less than 20 % w/w of the formulation.

[00339] Embodiment 77. The transdermal delivery formulation of Embodiment 40, wherein the formulation comprises menthol of about 0.05 - 5 % w/w of the formulation.

[00340] Embodiment 78. The transdermal delivery formulation of Embodiment 40 further comprising tranexamic acid of less than 5 % w/w of the formulation.

[00341] Embodiment 79. The transdermal delivery formulation of Embodiment 40 further comprising a humectant, an emulsifier, an emollient or a combination thereof

[00342] Embodiment 80. The transdermal delivery formulation of Embodiment 40, wherein the formulation has a pH of 9 - 11.

[00343] Embodiment 81. The transdermal delivery formulation of Embodiment 40, wherein the formulation has a pH of 7 - 10.5.

[00344] Embodiment 82. The transdermal delivery formulation of Embodiment 40, wherein the formulation has a pH of 4.5 - 10.5.

[00345] Any aspect or embodiment described herein can be combined with any other aspect or embodiment as disclosed herein.

DEFINITIONS

[00346] Unless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art. [00347] Reference in this specification to "one embodiment/aspect" or "an embodiment/aspect" means that a particular feature, structure, or characteristic described in connection with the embodiment/aspect is included in at least one embodiment/aspect of the disclosure. The use of the phrase "in one embodiment/aspect" or "in another embodiment/aspect" in various places in the specification are not necessarily all referring to the same embodiment/aspect, nor are separate or alternative embodiments/ aspects mutually exclusive of other embodiments/aspects. Moreover, various features are described which may be exhibited by some embodiments/aspects and not by others. Similarly, various requirements are described which may be requirements for some embodiments/aspects but not other embodiments/aspects. Embodiment and aspect can in certain instances be used interchangeably.

[00348] As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise.

[00349] As used herein, the phrases “at least one”, “one or more”, and “and/or” are open-ended expressions that are both conjunctive and disjunctive in operation. For example, each ofthe expressions “at least one of A, B and C”, “at least one of A, B, or C”, “one or more of A, B, and C”, “one or more of A, B, or C” and “A, B, and/or C” mean A alone, B alone, C alone, A and B together, A and C together, B and C together, or A, B and C together.

[00350] As used herein, “or” may refer to “and”, “or,” or “and/ of’ and may be used both exclusively and inclusively. For example, the term “A or B” may refer to “A or B”, “A but not B”, “B but not A”, and “A and B”. In some cases, context may dictate a particular meaning.

[00351] As used herein, the term “about” a number refers to that number plus or minus 10% of that number and/or within one standard deviation (plus or minus) from that number. The term “about” a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value and that range minus one standard deviation its lowest value and plus one standard deviation of its greatest value. [00352] Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[00353] The terms “increased”, “increasing”, or “increase” are used herein to generally mean an increase by a statically significant amount relative to a reference level. In some aspects, the terms “increased,” or “increase,” mean an increase of at least 10% as compared to a reference level, for example an increase of at least about 10%, at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level. Other examples of “increase” include an increase of at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 1000-fold or more as compared to a reference level.

[00354] The terms “decreased”, “decreasing”, or “decrease” are used herein generally to mean a decrease in a value relative to a reference level. In some aspects, “decreased” or “decrease” means a reduction by at least 10% as compared to a reference level, for example a decrease by at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% decrease (e.g., absent level or non- detectable level as compared to a reference level), or any decrease between 10-100% as compared to a reference level.

[00355] The term “subject” or "patient" refers to any single animal, more preferably a mammal (including suchnon-human animals as, for example, dogs, cats, horses, rabbits, zoo animals, cows, pigs, sheep, and non-human primates) for which treatment is desired. Most preferably, the patient herein is a human.

[00356] The term “medicament,” “active agent” or “active ingredient” refers to a substance, compound, or molecule, which is biologically active or otherwise, induces a biological or physiological effect on a subject to which it is administered to. In other words, “active agent” or “active ingredienf’ refers to a component or components of a composition to which the whole or part of the effect of the composition is attributed. An active agent can be a primary active agent, or in other words, the component(s) of a composition to which the whole or part of the effect of the composition is attributed An active agent can be a secondary agent, or in other words, the component(s) of a composition to which an additional part and/or other effect of the composition is attributed.

[00357] In an embodiment, a “pharmaceutical composition” is intended to include the combination of a PDE5 inhibitor with a carrier, inert or active, in a sterile composition suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo. In one aspect, the pharmaceutical composition is substantially free of endotoxins or is non-toxic to recipients at the dosage or concentration employed.

[00358] The term “phosphodiesterase type 5” or “PDE5” refers to an enzyme in the walls of blood vessels that affects blood flow and how cells signal within the body.

[00359] The term “phosphodiesterase type 5 inhibitor” or “PDE5 inhibitor” refers to a drug used to block the degradative action of cGMP-specific phosphodiesterase type 5 (PDE5) on cyclic GMP in the smooth muscle cells lining the blood vessels supplying various tissues. People may take PDE5 inhibitors to treat erectile dysfunction (ED) or pulmonary hypertension. These drugs dilate the corpora cavernosa of the penis, facilitating erection with sexual stimulation. In people with pulmonary hypertension, PDE5 inhibitors can help by controlling blood flow to the arteries in the lungs, increasing blood flow to the lungs and lowering blood pressure. Illustrative PDE5 inhibitors include sildenafil, vardenafil, avanafil, tadalafil, lodenafil, mirodenafil, udenafil, gisadenafil, and dipyridamole. [00360] In an embodiment, a “pharmaceutical composition” is intended to include the combination of an active agent with a carrier, inert or active, in a sterile composition suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo. In one aspect, the pharmaceutical composition is substantially free of endotoxins or is non-toxic to recipients at the dosage or concentration employed.

[00361] In an embodiment, “an effective amount” refers to the amount of the defined component sufficient to achieve the desired chemical composition or the desired biological and/or therapeutic result. In an embodiment, that result can be the desired pH or chemical or biological characteristic, eg, stability of the formulation. In other embodiments, the desired result is the alleviation or amelioration of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. When the desired result is a therapeutic response, the effective amount will vary depending upon the specific disease or symptom to be treated or alleviated, the age, gender and weight of the subject to be treated, the dosing regimen of the formulation, the severity of the disease condition, the manner of administration and the like, all of which can be determined readily by one of skill in the art. A desired effect may, without necessarily being therapeutic, also be a cosmetic effect, in particular for treatment for disorders of the skin or muscles.

[00362] In an embodiment, as used herein, the terms “treating,” “treatment” and the like are used herein to mean obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disorder or sign or symptom thereof, and/or may be therapeutic in terms of amelioration of the symptoms of the disease or infection, or a partial or complete cure for a disorder and/or adverse effect attributable to the disorder.

[00363] The term “bioavailability” refers to the fraction of an administered dose of unchanged drug that reaches the systemic circulation. For example, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes (such as orally), its bioavailability generally decreases due to incomplete absorption and first-pass metabolism Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be considered when calculating dosages for non-intravenous routes of administration.

[00364] The term “lecithin organogel” or “LO” refers to a micellar system for the delivery of bioactive agents through the skin. LOs can be composed of hydrated phospholipids and appropriate organic liquid. Several therapeutic agents have been formulated as LOs for their facilitated transport through topical route (for dermal or transdermal effect). The improved topical drug delivery has mainly been attributed to the biphasic drug solubility, the desired drug partitioning, and the modification of skin barrier function by the organogel components.

[00365] For purposes herein, the terms lecithin and lecithin organogel are used interchangeably and both refer to, include and cover a lecithin organogel that comprises any group of yellow-brownish fatty substances occurring in animal and plant tissues which are amphiphilic and include a mixture of one or more of glycerophospholipids including phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, and phosphatidic acid. [00366] Additionally, the use of particular formulations can disrupt the balance of electrolytes and cations, including those such as the Na/K ratio. For example, the administration of formulations containing calcium carbonate can reduce the amount of sodium or other ions which can decrease the potential for reaching a hyponatremic state. Also, the use of calcium carbonate can also increase the serum levels of calcium which can reduce the amount of calcium leeched from the body by high sodium concentrations.

[00367] The formulations and methods of use provided herein take these complexities of electrolyte balance into account. One approach utilized herein in making formulations that avoid electrolyte imbalance and cation overload is to use non-metal buffers or buffers without counterions. Suitable buffering agents for these embodiments include Lysine (free base), TRIS, and IEPA.

[00368] For transdermal topical administration in particular for agents other than buffer, a suitable formulation typically involves a penetrant that enhances penetration of the skin and is, in some embodiments, composed of chemical permeation enhancers (CPEs). In some cases, it can also include peptides designed to penetrate cells i. e. cell penetrating peptides (CPPs) also known as skin penetrating peptides (SPPs). The formulation can be applied for example in the form of topi cal lotions, creamy and the like, as described herein.

[00369] Many known and useful compounds and the like can be found in Remington’s Pharmaceutical Sciences (13th Ed), Mack Publishing Company, Easton, PA — a standard reference for various types of administration. As used herein, the term “formulation(s)” means a combination of at least one active ingredient with one or more other ingredient, also commonly referred to as excipient^ which may be independently active or inactive. The term “formulation” may or may not refer to a pharmaceutically acceptable composition for administration to humans or animals and may include compositions that are useful intermediates for storage or research purposes.

[00370] For purposes herein, a formulation, aformulationfortransdermaldelivery and atransdermal delivery formulation are each a formulation for transdermal delivery, including, the transdermal delivery of an active ingredient for the treatment of a syndrome and or a disease in an individual.

[00371] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

INCORPORATION BY REFERENCE

[00372] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

EXAMPLES

[00373] The following non-limiting examples are provided for illustrative purposes only in order to facilitate a more complete understanding of representative embodiments now contemplated. These examples are intended to be a mere subset of all possible contexts in which the components of the formulation may be combined. Thus, these examples should not be construed to limit any of the embodiments described in the present specification, including those pertaining to the type and amounts of components of the formulation and/or methods and uses thereof. Ultimately, the formulations ma be utilized in virtually any context where buffering therapy with or without a therapeutic agent(s) is desired.

Example 1: Murine pharmacokinetic study evaluating the efficacy of topical sildenafil with and without pH adjustment

[00374] In this experiment, two topical sildenafil formulations with active ingredient sildenafil citrate were tested in a murine pharmacokinetic study. The formulations were identified as Sildenafil Citrate A and Sildenafil Citrate B. The difference between the two formulations revolved primarily around the pH of the final formulation because pH was believed to play a role in transdermal penetration of sildenafil. Specifically, Sildenafil Citrate A contained 3.6% (w/w) sildenafil citrate, 10% (w/w) sodium carbonate, 2% (w/w) sodium bicarbonate, and 1% (w/w) sodium hydroxide, resulting in the formulation having apH of 10.07. Sildenafil Citrate B contained 3.6% (w/w) sildenafil citrate, but did not have the buffering or pH adjusting components, resulting in a final pH of 4. 17.

[00375] For each study arm, nine mice were administered a 100 mg dose of the topical, resulting in approximately 3.6 mg sildenafil citrate applied to the skin. Blood samples were taken at various time points following application: 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours. The blood samples were analyzed for plasma sildenafil citrate concentration (ng/mL).

[00376] The mean plasma sildenafil citrate concentration and standard deviation were calculated for every time point (FIG. 1). FIG. 1 shows PK data showing resulting mean plasma concentration, displayed as mean ± SD, from applied topical sildenafil, measured at 0.5, 1, 2, 4, 8, and 24 hours. Sildenafil Citrate A was the pH adjusted formulation and Sildenafil Citrate B was not pH adjusted.

[00377] These results werethen used to determinethe half-life (ti/2), maximum plasma concentration (CMax), and time to maximum concentration (tMax) for each topical (Table 6).

Table 6. Half-life (ti/2), maximum concentration (CMax), time to maximum concentration (tMa ), and area under the curve (AUCini) observed in the pharmacokinetic study comparing the two topical sildenafil formulations. (Applied dose: 3.6 mg sildenafil citrate).

[00378] The results demonstrate that the difference in ingredients and resulting final pH of the formulationshad a significant impact on the pharmacokinetic behavior ofthe topi cals. Sildenafil Citrate A had a 50% longer half-life and was 15% more bioavailable than Sildenafil Citrate B. Alternatively, Sildenafil Citrate B obtained a maximum concentration 32% higher than Sildenafil Citrate A and in one-fourth of the time.

[00379] Although Sildenafil Citrate A delivered sildenafil to the bloodstream more efficiently, the pharmacokinetic profile of Sildenafil Citrate B may be more suitable for the indication of erectile dysfunction. The shorter time to maximum concentration of 0.5 hours, combined with a strong peak at maximum concentrations, suggests that Sildenafil Citrate B could bring about the target effects relatively quickly.

[00380] These PKresults for Sildenafil Citrate A and B were converted to the equivalent human dose and dose-adjusted to allow for comparison with human pharmacokinetic datafor 50 mg of intravenously and orally delivered sildenafil. The resulting values are presented in Table 7 along with the pharmacokinetic parameters reported in literature for intravenous and oral delivery of sildenafil in humans.

Table 7. Pharmacokinetic parameters of sildenafil following intravenous and oral administration of 50 mg sildenafil as well as the dose-adjusted parameters for 50 mg of topically applied Sildenafil Citrate A and Sildenafil Citrate B calculated from the values presented in Table 1. The values presented are half-life (ti/2), maximum concentration (CMSX), time to maximum concentration (tMax), area under the curve (AUCinf), and absolute bioavailability (F _a b _S ).

[00381] Based on the dose-adjustment calculations, Sildenafil Citrate A and Sildenafil Citrate B achieved a 46% and 27% increase in bioavailability of sildenafil compared to oral dosing, respectively. The improved bioavailability implies that the topical delivery system is more efficient. This may be attributed to the fact that topical delivery avoids the hepatic first pass metabolism that oral doses are subjected to. As a result, the concentration of the active could be reduced without negatively affecting efficacy, ultimately allowing for a decrease in cost of goods sold.

[00382] Additionally, topically applied Sildenafil Citrate B achieved maximum concentration in nearly one-third the amount of time as orally delivered sildenafil. When considering the indication of erectile dysfunction, rapid and predictable onset of effects is beneficial. The higher maximum concentration achieved by Sildenafil Citrate B, combined with the short time taken to achieve that concentration, suggests the surety one could have in the effective dose being successfully achieved within 30 minutes following application. [00383] Sildenafil Citrate B may also satisfy two other qualifications for a desirable ED treatmait of being well tolerated and associated with minimal side effects because it is a topical formulation. The application of a topical cream can allow for augmented delivery to a localized area. A smaller dose ma be required when delivered locally to achieve the desired effect, and as a result, a further decreased dose will be delivered systemically. A reduced concentration in the blood stream may help to avoid or minimize the side effects and adverse events related to sildenafil.

[00384] These two topical sildenafil formulations showed positive yet different PK results. The formulation with a higher pH, Sildenafil Citrate A, has a pharmacokinetic profile which shows a slower and more sustained delivery of sildenafil. Alternatively, the formulation with a lower pH, Sildenafil Citrate B, achieves more rapid delivery allowing for a quicker onset of effect with a shorter total duration. As a result, Sildenafil Citrate B provides a preferable pharmacokinetic profile for the application of erectile dysfunction.

Example 2: Topical Application of Sildenafil for Treatment of ED

[00385] The treatment of ED has been shown to improve the quality of life and overall satisfaction for both patients and their partners. In this example, a middle-aged patient suffers from recurrent ED Attempts at lifestyle changes were ineffective as he continued to suffer from ED. As in most cases, the ED was a product of a combination of unhealthy behaviors rather than from a single cause (e.g. unhealthy diet, lack of exercise, smoking, and alcohol use).

[00386] The patient takes daily medication to help lower his blood pressure. Because of this, he cannot tolerate oral phosphodiesterase type 5 (PDE5) inhibitors due to systemic side effects and drugdrug interactions. The patient wishes to avoid intracavernosal therapies due to their invasive nature. Other second line therapies (e.g. vacuum erection devices, intraurethral alprostadil, and topical alprostadil cream) are undesired and not well tolerated.

[00387] A transdermal PDE5 inhibitor is the ideal alternative for several reasons. The lack of interference with food and alcohol is one advantage. Topical delivery avoids the GI tract. Increased bioavailability permits lower doses which reduce the risk of side effects. Suldinafil topical cream obviates the need for the invasive nature and side effects of the intracavemous/transurethral administration of drugs. Topical administration also allows for a higher degree of sexual spontaneity.

[00388] In this example, the patient uses a topical cream that contains 3.6% w/w of suldinafil (formulated to deliver 100 mg of sildenafil) based on the formulation of Table 1. Prior to sexual activity (e.g. 15 to 30 minutes), the patient applies the cream to the genital area. The patient can increase the dose with a second application if the response is suboptimal.

[00389] Although Sildenafil is used in this example, the formulation can be used with other PDE5 inhibitors including vardenafil, avanafil, tadalafil, lodenafil, mirodenafil, udenafil, gisadenafil, and dipyridamole that are conventionally taken orally. Example 3 Transdermal formulations of the present disclosure provide systemic administration of active agents

[00390] In various embodiments, a transdermal delivery formulation comprises the components of the below table:

[00391] In the above table, where an ingredient has weight percent that ranges from 5 to 20% (e.g, for the Fatty acid ester and viscosity -improving agent), as an example, that ingredient may be present in the formulation at any percentage (w/w or w/v) from about 5% to about 20%. The weight percentage may be about 5 % to about 20 %. The weight percentage may 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 %, 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 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 about 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 may 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 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 may be at most 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 %. Moreover, the weight percentage may be about

5 % to about 6 %. The weight percentage may be 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. 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 %, about5.4 %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 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 may 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 may 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 may be at most 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 %. Further, the weight percentage may be about 5 % to about 5. 1 %. The weight percentage may be 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 %, about 5.01 % to about 5.06 %, 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 about5.04 %, about5.02 %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 5.03 % to about 5.05 %, about 5.03 % to about 5.06 %, about 5.03 % to about5.07 %, about5.03 %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 5.07 %, 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 may be about 5 %, about 5.01 %, about 5.02 %, about5.03 %, about 5.04 %, about 5.05 %, about5.06 %, about 5.07 %, about 5.08 %, about 5.09 %, or about 5.1 %. The weight percentage may 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 may be at most 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 %.

[00392] The other ranges (e.g., 3 - 15% for the phospholipids; 0.1 - 10% for the Long-chain fatty acids; 30 - 90% for the water; 0.05% - 5% for the PDE5 inhibitor; 0.5-5% for the penetration enhancer; and 0.5-10% for the emulsifier) recited in the above table include similar ranges and subranges and values within ranges. The present disclosure contemplates all similar ranges and subranges and values within ranges for each ingredient included in a formulation.

[00393] In some cases, the PDE5 inhibitor is in an amount from about 0.05% to about 0. 1% w/w of the formulation. In some embodiments, the PDE5 inhibitor is in an amount from about 0. 1 % to about 1% w/w of the formulation. In other embodiments, the PDE5 inhibitor is in an amount from about 1% to about 5% w/w of the formulation. The present disclosure contemplates all similar ranges and subranges and values within ranges for the PDE5 inhibitor or inhibitors included in a formulation [00394] The PDE5 inhibitor is at least one of sildenafil, vardenafil, avanafil, tadalafil, lodenafil, mirodenafil, udenafil, gisadenafil, and dipyridamole.

[00395] In some cases, more than one PDE5 inhibitor is included in a transdermal formulation In these cases, the first and the second medicament are sildenafil, vardenafil, avanafil, tadalafil, lodenafil, mirodenafil, udenafil, gisadenafil, and dipyridamole. Example 4: Topical application of a PDE5 inhibitor for treatment of cognitive decline

[00396] In some embodiments, a formulation of the present disclosure is administered to a subject with a neurologic disease, e.g., a neurologic disease that is characterized by age-related cognitive decline.

[00397] One example of such a neurologic disease is Alzheimer's disease.

[00398] Other examples of such neurologic diseases include ADHD, AIDS — Neurological Complications, Absence of the Septum Pellucidum, Acquired Epileptiform Aphasia, Acute Disseminated Encephalomyelitis, Adrenoleukodystrophy, Agenesis of the Corpus Callosum, Agnosia, Aicardi Syndrome, Alexander Disease, Alpers' Disease, Alternating Hemiplegia, Alzheimer's Disease. Amyotrophic Lateral Sclerosis, Anencephaly, Aneurysm, Angelman Syndrome, Angiomatosis, Anoxia, Aphasia, Apraxia, Arachnoid Cysts, Arachnoiditis, Arnold-Chiari Malformation, Arteriovenous Malformation, Aspartame, Asperger Syndrome, Ataxia Telangiectasia, Ataxia, Attention Deficit- Hyperactivity Disorder, Autism, Autonomic Dysfunction, Back Pain, Barth Syndrome, Batten Disease, Behcet's Disease, Bell's Palsy, Benign Essential Blepharospasm, Benign Focal Amyotrophy, Benign Intracranial Hypertension, Bernhardt-Roth Syndrome, Binswanger's Disease, Blepharospasm, Bloch- Sulzberger Syndrome, Brachial Plexus Birth Injuries, Brachial Plexus Injuries, Bradbury -Eggleston Syndrome, Brain Aneurysm, Brain Injury, Brain and Spinal Tumors, Brown-Sequard Syndrome, Bulbospinal Muscular Atrophy, Canavan Disease, Carpal Tunnel Syndrome, Causalgia, Cavernoma^ Cavernous Angioma, Cavernous Malformation, Central Cervical Cord Syndrome, Central Cord Syndrome, Central Pain Syndrome, Cephalic Disorders, Cerebellar Degeneration, Cerebellar Hypoplasia, Cerebral Aneurysm, Cerebral Arteriosclerosis, Cerebral Atrophy, Cerebral Beriberi, Cerebral Gigantism, Cerebral Hypoxia, Cerebral Palsy, Cerebro-Oculo-Facio-Skeletal Syndrome, Charcot-Marie-Tooth Disorder, Chiari Malformation, Chorea, Choreoacanthocytosis, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Chronic Orthostatic Intolerance, Chronic Pain, Cockayne Syndrome Type II, Coffin Lowry Syndrome, Coma, including Persistent Vegetative State, Complex Regional Pain Syndrome, Congenital Facial Diplegia, Congenital Myasthenia, Congenital Myopathy, Congenital Vascular Cavernous Malformations, Corti cobasal Degeneration, Cranial Arteritis, Craniosynostosis, Creutzfeldt- Jakob Disease, Cumulative Trauma Disorders, Cushing's Syndrome, Cytomegalic Inclusion Body Disease (CIBD), Cytomegalovirus Infection, Dancing Eyes- Dancing Feet Syndrome, Dandy-Walker Syndrome, Dawson Disease, De Morsier's Syndrome, Dejerine-Klumpke Palsy, Dementia — Multi-Infarct, Dementia — Subcortical, Dementia With Lewy Bodies, Dermatomyositis, Developmental Dyspraxia, Devic's Syndrome, Diabetic Neuropathy, Diffuse Sclerosis, Dravefs Syndrome, Dysautonomia, Dysgraphia, Dyslexia, Dysphagia, Dyspraxia, Dystonia^ Early Infantile Epileptic Encephalopathy, Empty Sella Syndrome, Encephalitis Lethargica, Encephalitis and Meningitis, Encephaloceles, Encephalopathy, Encephalotrigeminal Angiomatosis, Epilepsy, Erb's Palsy, Erb-Duchenne and Dejerine-Klumpke Palsies, Fabry's Disease, Fahr's Syndrome, Fainting, Familial Dysautonomia, Familial Hemangioma, Familial Idiopathic Basal Ganglia Calcification, Familial Spastic Paralysis, Febrile Seizures (e.g., GEFS and GEFS plus), Fisher Syndrome, Floppy Infant Syndrome, Friedreich's Ataxia, Gaucher's Disease, Gerstmann's Syndrome, Gerstmann- Straussler-Scheinker Disease, Giant Cell Arteritis, Giant Cell Inclusion Disease, Globoid Cell Leukodystrophy, Glossopharyngeal Neuralgia, Guillain-Barre Syndrome, HTLV-1 Associated Myelopathy, Hallervorden-Spatz Disease, Head Injury, Headache, Hemi crania Continua, Hemifacial Spasm, Hemiplegia Alterans, Hereditary Neuropathies, Hereditary Spastic Paraplegia, Heredopathia Atactica Polyneuritiformis, Herpes Zoster Oticus, Herpes Zoster, Hirayama Syndrome, Holoprosencephaly, Huntington's Disease, Hydranencephaly, Hydrocephalus — Normal Pressure, Hydrocephalus, Hydromyelia, Hypercortisolism, Hypersomnia, Hypertonia, Hypotonia, Hypoxia, Immune-Mediated Encephalomyelitis, Inclusion Body Myositis, Incontinentia Pigmenti, Infantile Hypotonia, Infantile Phytanic Acid Storage Disease, Infantile Refsum Disease, Infantile Spasms, Inflammatory Myopathy, Intestinal Lipodystrophy, Intracranial Cysts, Intracranial Hypertension, Isaac's Syndrome, Joubert Syndrome, Kearns-Sayre Syndrome, Kennedy's Disease, Kinsboume syndrome, Kleine-Levin syndrome, Klippel Feil Syndrome, Klippel -Trenaunay Syndrome (KTS), Kluver-Bucy Syndrome, Korsakoffs Amnesic Syndrome, Krabbe Disease, Kugelberg-Welander Disease, Kuru, Lambert-Eaton Myasthenic Syndrome, Landau-Kleffner Syndrome, Lateral Femoral Cutaneous Nerve Entrapment, Lateral Medullary Syndrome, Learning Disabilities, Leigh's Disease, Lennox-Gastaut Syndrome, Lesch-Nyhan Syndrome, Leukodystrophy, Levine- Critchley Syndrome, Lewy Body Dementia, Lissencephaly, Locked-In Syndrome, Lou Gehrig's Disease, Lupus — Neurological Sequelae, Lyme Disease — Neurological Complications, Machado-Joseph Disease, Macrencephaly, Megalencephaly, Melkersson-Rosenthal Syndrome, Meningitis, Menkes Disease, Meralgia Paresthetica, Metachromatic Leukodystrophy, Microcephaly, Migraine, Miller Fisher Syndrome, Mini-Strokes, Mitochondrial Myopathies, Mobius Syndrome, Monomelic Amyotrophy, Motor Neuron Diseases, Moyamoya Disease, Mucolipidoses, Mucopolysaccharidoses, Multi-Infarct Dementia, Multifocal Motor Neuropathy, Multiple Sclerosis, Multiple System Atrophy with Orthostatic Hypotension, Multiple System Atrophy, Muscular Dystrophy, Myasthenia — Congenital, Myasthenia Gravis, Myelinoclastic Diffuse Sclerosis, Myoclonic Encephalopathy of Infants, Myoclonus^ Myopathy — Congenital, Myopathy — Thyrotoxic, Myopathy, Myotonia Congenita, Myotonia, Narcolepsy, Neuroacanthocytosis, Neurodegeneration with Brain Iron Accumulation, Neurofibromatosis, Neuroleptic Malignant Syndrome, Neurological Complications of AIDS, Neurological Manifestations of Pompe Disease, Neuromyelitis Optica, Neuromyotonia, Neuronal Ceroid Lipofuscinosis, Neuronal Migration Disorders, Neuropathy — Hereditary, Neurosarcoidosis. Neurotoxicity, Nevus Cavernosus, Niemann-Pick Disease, O'Sullivan-McLeod Syndrome, Occipital Neuralgia, Occult Spinal Dysraphism Sequence, Ohtahara Syndrome, Olivopontocerebellar Atrophy, Opsoclonus Myoclonus, Orthostatic Hypotension, Overuse Syndrome, Pain — Chronic, Paraneoplastic Syndromes, Paresthesia, Parkinson's Disease, Parnyotonia Congenita, Paroxysmal Choreoathetosis. Paroxysmal Hemi crania, Parry -Romberg, Pelizaeus-Merzbacher Disease, Pena Shokeir II Syndrome, Perineural Cysts, Periodic Paralyses, Peripheral Neuropathy, Periventricular Leukomalacia, Persistent Vegetative State, Pervasive Developmental Disorders, Phytanic Acid Storage Disease, Pick's Disease, Piriformis Syndrome, Pituitary Tumors, Polymyositis, Pompe Disease, Porencephaly, Post-Polio Syndrome, Postherpetic Neuralgia, Postinfectious Encephalomyelitis, Postural Hypotension, Postural Orthostatic Tachycardia Syndrome, Postural Tachycardia Syndrome, Primary Lateral Sclerosis, Prion Diseases, Progressive Hemifacial Atrophy, Progressive Locomotor Ataxia, Progressive Multifocal Leukoencephalopathy, Progressive Sclerosing Poliodystrophy, Progressive Supranuclear Palsy, Pseudotumor Cerebri, Pyridoxine Dependent and Pyridoxine Responsive Siezure Disorders, Ramsay Hunt Syndrome Type I, Ramsay Hunt Syndrome Type II, Rasmussen's Encephalitis and other autoimmune epilepsies, Reflex Sympathetic Dystrophy Syndrome, Refsum Disease — Infantile, Refsum Disease, Repetitive Motion Disorders, Repetitive Stress Injuries, Restless Legs Syndrome, Retrovirus- Associated Myelopathy, Rett Syndrome, Reye's Syndrome, Riley-Day Syndrome, SUNCT Headache, Sacral Nerve Root Cysts, Saint Vitus Dance, Salivary Gland Disease, Sandhoff Disease, Schilder's Disease, Schizencephaly, Seizure Disorders, Septo-Optic Dysplasia, Severe Myoclonic Epilepsy of Infancy (SMEI), Shaken Baby Syndrome, Shingles, Shy -Drager Syndrome, Sjogren's Syndrome, Sleep Apnea, Sleeping Sickness, Soto's Syndrome, Spasticity, Spina Bifida, Spinal Cord Infarction, Spinal Cord Injury, Spinal Cord Tumors, Spinal Muscular Atrophy, Spinocerebellar Atrophy, Steele- Richardson-Olszewski Syndrome, Stiff-Person Syndrome, Striatonigral Degeneration, Stroke, Sturge- Weber Syndrome, Subacute Sclerosing Panencephalitis, Subcortical Arteriosclerotic Encephalopathy, Swallowing Disorders, Sydenham Chorea, Syncope, Syphilitic Spinal Sclerosis, Syringohydromyelia, Syringomyelia, Systemic Lupus Erythematosus, Tabes Dorsalis, Tardive Dyskinesia, Tarlov Cysts, Tay-Sachs Disease, Temporal Arteritis, Tethered Spinal Cord Syndrome, Thomsen Disease, Thoracic Outlet Syndrome, Thyrotoxic Myopathy, Tic Douloureux, Todd's Paralysis, Tourette Syndrome, Transient Ischemic Attack, Transmissible Spongiform Encephalopathies, Transverse Myelitis^ Traumatic Brain Injury, Tremor, Trigeminal Neuralgia, Tropical Spastic Paraparesis, Tuberous Sclerosis, Vascular Erectile Tumor, Vasculitis including Temporal Arteritis, Von Economo's Disease, Von Hippel-Lindau disease (VHL), Von Recklinghausen's Disease, Wallenberg's Syndrome, Werdnig- Hoffman Disease, Wernicke-Korsakoff Syndrome, West Syndrome, Whipple's Disease, Williams Syndrome, Wilson's Disease, X-Linked Spinal and Bulbar Muscular Atrophy, and Zellweger Syndrome.

[00399] In these cases, a subject in need thereof is administered a herein disclosed transdermal formulation (e.g., as disclosed in Example 3 and elsewhere herein).

[00400] Notably, the dosage of the PDE5 inhibitor may less than the dosage of a formulation whai used for treating erectile disfunction.

[00401] In this method, the formulation is applied to the to the skin of the subject for 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.

[00402] In this method, the formulation is applied to the to the skin of the subj ect once daily, twice daily, thrice daily, once every few days, or once weekly.

[00403] When treating a neurological disorder, a formulation of the present disclosure may be topically administered nearby blood vessels that feed the affected tissue or organ. As an example, when treating Alzheimer’s, the formulation may be applied to the skin overlaying the carotid arteries; thereby promoting delivery of the PED5 inhibitor to the cortex.

Example 5: Topical application of a PDE5 inhibitor for treatment of other disorders

[00404] In some embodiments, a formulation of the present disclosure is administered to a subject for treating pulmonary hypertension and heart diseases such as congestive heart failure and diastolic dysfunction, as well as Raynaud’s disease.

[00405] Also, the formulations of the present disclosure can be used to improve lung function at high altitudes (e.g., mountain sickness) by reducing pulmonary artery pressure.

[00406] Further, in some embodiments, the formulations may be used to help peripheral blood circulation in diabetic patients.

[00407] There is some evidence showing that PED5 inhibitors may be effective for the treatment of female sexual arousal disorder. Without wishing to be bound by theory, improved blood flow to the female reproductive parts may promote arousal and increase sensitivity and stimulation. Thus, in some embodiments, formulations of the present disclosure may be administered to female subject in need thereof.

[00408] When treating a non-ED disorder, a formulation of the present disclosure may be topically administered nearby blood vessels that feed the affected tissue or organ. As an example, when treating reduced peripheral circulation, e.g., in a diabetic patient, the formulation may be applied to the skin overlaying the arteries feeding the hands or feet; thereby promoting delivery of the PED5 inhibitor where needed.

[00409] In these cases, a subject in need thereof is administered a herein disclosed transdermal formulation (e.g., as disclosed in Example 3 and elsewhere herein).

[00410] Notably, the dosage of the PDE5 inhibitor may less than the dosage of a formulation whai used for treating erectile disfunction.

[00411] In this method, the formulation is applied to the to the skin of the subj ect for 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, 1 1 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[00412] In this method, the formulation is applied to the to the skin of the subj ect once daily, twice daily, thrice daily, once every few days, or once weekly.