Treatment of erectile dysfunction and other indications

Abstract

To provide a treatment of erectile dysfunction and other indications.SOLUTION: The present invention generally relates to the transdermal delivery of various compounds. In some aspects, transdermal delivery may be facilitated by the use of a hostile biophysical environment. One set of embodiments provides a composition for topical delivery comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof, and optionally, a hostile biophysical environment and / or a nitrogen monoxide donor. In some cases, the composition may be stabilized using a combination of a stabilization polymer (such as xanthan gum, KELTROL TM BT and / or KELTROL TM RD), propylene glycol, and a polysorbate surfactant such as Polysorbate 20, which combination unexpectedly provides temperature stability to the composition, e.g., at elevated temperatures such as at least 40°C, as compared with compositions lacking one or more of these.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 61 / 427,999, filed December 29, 2010, by E.T. Fossel, entitled "Treatment of Erectile Dysfunction and Other Indications," and U.S. Provisional Patent Application No. 61 / 428,213, filed December 29, 2010, by E.T. Fossel, entitled "Methods and Compositions for Preparing Emulsions for Topical Drug Delivery," each of which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION FIELD OF THE INVENTION The present invention relates generally to transdermal delivery, and in particular to the transdermal delivery of type 5 phosphodiesterase inhibitors and other compounds. [Background technology]

[0003] background Type 5 phosphodiesterase inhibitors are drugs used to block the degradative action of type 5 phosphodiesterase on cyclic GMP in the smooth muscle cells lining the blood vessels that supply the corpus cavernosum of the penis. These drugs are commonly used to treat erectile dysfunction.

[0004] Phosphodiesterase type 5 inhibitors are generally delivered orally. Currently, no transdermal formulation of phosphodiesterase type 5 inhibitors has been approved by the FDA. Therefore, there is a need for a system and method for transdermal delivery of a clinically useful amount of phosphodiesterase type 5 inhibitors. Summary of the Invention [Means for solving the problem]

[0005] Summary of the Invention The present invention relates generally to transdermal delivery of phosphodiesterase type 5 inhibitors and other compounds. The subject matter of the present invention, in some cases, involves interrelated products, alternative solutions to a particular problem, and / or multiple different uses of one or more systems and / or articles.

[0006] Disclosed herein are several methods of administering to a subject a composition for the prevention or treatment of a particular condition. In each such aspect of the invention, it should be understood that the invention also specifically includes the composition for use in the treatment or prevention of that particular condition, and the use of the composition for the manufacture of a medicament for the treatment or prevention of that particular condition.

[0007] In some embodiments, aspects of the present invention relate to compositions for delivering a type 5 phosphodiesterase inhibitor and / or a salt thereof to a subject. In some embodiments, the composition comprises a type 5 phosphodiesterase inhibitor and / or a salt thereof in a hostile biophysical environment for topical delivery to the skin of a subject. In some embodiments, the composition also comprises a nitric oxide donor. In some embodiments, the composition further comprises one or more compounds that stabilize and / or otherwise enhance storage and / or delivery effectiveness (e.g., with or without a nitric oxide donor).

[0008] In some embodiments, the compositions of the present invention increase the efficiency of compound delivery directly to the target site by using transdermal delivery, thereby significantly reducing systemic exposure and reducing potential side effects. For example, transdermal delivery according to the present invention can reduce systemic exposure to less than 10% (e.g., less than 5%, or between 0.1% and 1%, or even less) of the systemic exposure resulting from oral dosing required for effective compound delivery. For example, the systemic exposure of a type 5 phosphodiesterase inhibitor (e.g., sildenafil) delivered locally according to the present invention can be about 0.3% of the systemic exposure resulting from an oral formulation. In some embodiments, the compositions of the present invention also provide an unexpectedly fast rate of action of the compound being delivered (e.g., compared to oral delivery or other delivery techniques used for the compound). Thus, in some embodiments, aspects of the present invention are useful for rapid therapy when delivery of a therapeutic amount of a compound is required within a short period of time. The local delivery formulations described herein can deliver compounds to target tissues more rapidly than, for example, oral formulations. Local delivery formulations also enable targeted, localized delivery of a therapeutically effective amount of a compound without requiring a significant systemic increase in the amount of the compound. However, it should be understood that the topical formulations can be used for systemic delivery if so desired.

[0009] One aspect of the present invention is generally directed to compositions, e.g., compositions for topical delivery to the skin of a subject. According to one set of embodiments, the composition includes a nitric oxide donor, a hostile biophysical environment, a stabilizing polymer, propylene glycol, a polysorbate surfactant, and a type 5 phosphodiesterase inhibitor and / or a salt thereof.

[0010] In another set of embodiments, at least about 80% by weight of the composition comprises water, at least one chloride salt, a nitric oxide donor, a stabilizing polymer, propylene glycol, a polysorbate surfactant, and a type 5 phosphodiesterase inhibitor and / or a salt thereof.

[0011] According to yet another set of embodiments, the composition comprises a nitric oxide donor, a hostile biophysical environment, and a type 5 phosphodiesterase inhibitor and / or a salt thereof.

[0012] According to yet another set of embodiments, the composition comprises, or consists essentially of, water, sodium chloride, a nitric oxide donor, glyceryl stearate, cetyl alcohol, magnesium chloride, squalane, a stabilizing polymer, isopropyl myristate, oleic acid, propylene glycol, a polysorbate surfactant, and a type 5 phosphodiesterase inhibitor and / or a salt thereof.

[0013] In yet another set of embodiments, the composition comprises the following compounds at concentrations of no more than ±20% of the recited concentrations: water at a concentration of about 35% to about 55% by weight, sodium chloride at a concentration of about 2.5% to about 15% by weight, a nitric oxide donor at a concentration of about 2.5% to about 15% by weight, glyceryl stearate at a concentration of about 4% to about 10% by weight, cetyl alcohol at a concentration of about 4% to about 10% by weight, magnesium chloride at a concentration of about 0.1% to about 5% by weight, and hydroxybenzoates at a concentration of about 1% to about 10% by weight. The composition comprises squalane at a concentration of about 8% by weight, a polysorbate surfactant at a concentration of about 0.2% to about 2% by weight, isopropyl myristate at a concentration of about 0.1% to about 5% by weight, oleic acid at a concentration of about 0.1% to about 5% by weight, propylene glycol at a concentration of about 1% to about 10% by weight, a stabilizing polymer at a concentration of about 1% to about 10% by weight, and a type 5 phosphodiesterase inhibitor and / or a salt thereof at a concentration of about 1% to about 10% by weight.

[0014] In some embodiments, the composition comprises approximately 5% by weight (e.g., about 1% to 15% by weight) of an inhibitor (e.g., sildenafil or other inhibitor) in an oil / water emulsion, and further comprises about 10% sodium chloride, 5% potassium chloride, and about 2.5% magnesium chloride. For example, the inhibitor may be a type 5 phosphodiesterase inhibitor and / or a salt thereof.

[0015] In some embodiments, the pH of the composition is optimized to ionize the inhibitor while maintaining compatibility with an acceptable pH range for skin contact (e.g., within a range of about pH 5 to about pH 8). In some embodiments, a pH of less than 10 is sufficient to ionize an inhibitor, such as sildenafil or related compounds. In some embodiments, a pH of 5 to 8 (+ / - 0.5) is effective. In some embodiments, a pH of 6.5 (e.g., + / - 0.5) is particularly effective. In some embodiments, a pH at least about 1 pH unit higher or lower (e.g., at least about 2 pH units higher or lower) than the pKa of the inhibitor can be used, particularly if the pH is within the range of about pH 5.0 to 8.0, which is compatible with topical direct contact with skin. The inhibitor can be, for example, a type 5 phosphodiesterase inhibitor and / or a salt thereof, or any of the inhibitors discussed herein.

[0016] According to aspects of the present invention, relatively high salt concentrations, e.g., at least about 2% (e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 25-50%, by weight), are useful for providing a hostile biophysical environment that promotes transdermal transport of the inhibitor (e.g., sildenafil). In some embodiments, emulsions described herein containing, for example, stabilizing polymers and / or polysorbate surfactants and / or propylene glycol (or low molecular weight glycols, or polyglycols such as polyethylene glycol or other polyglycols—however, it should be understood that glycols with even numbers of carbons may be toxic, particularly smaller glycols such as ethylene glycol and butylene glycol, and should be avoided or eliminated) unexpectedly stabilize the inhibitor in a high-salt composition in a form that remains effective for extended periods of time—e.g., effective in maintaining rapid transdermal delivery of the inhibitor for at least weeks or months. In some cases, the inhibitor is a type 5 phosphodiesterase inhibitor and / or a salt thereof.

[0017] In some embodiments, the composition also includes a nitric oxide donor (e.g., L-Arg), which may be useful to increase local blood flow and further enhance delivery of the compound. According to another set of embodiments, the composition includes a stabilizing polymer, propylene glycol, a polysorbate surfactant, and a type 5 phosphodiesterase inhibitor and / or a salt thereof.

[0018] In yet another set of embodiments, at least about 80% by weight of the composition comprises water, at least one chloride salt, a stabilizing polymer, propylene glycol, a polysorbate surfactant, and a type 5 phosphodiesterase inhibitor and / or a salt thereof.

[0019] According to another aspect, the present invention is generally directed to a method.In one set of embodiments, the method is to apply any of the compositions described herein to a subject, for example, to the skin of a subject.According to another set of embodiments, the method comprises applying a delivery vehicle comprising a type 5 phosphodiesterase inhibitor and / or its salt to a portion of the skin of a subject in an unsuitable biophysical environment.

[0020] In another set of embodiments, the method includes applying to at least a portion of the skin of a subject a composition comprising a nitric oxide donor, a hostile biophysical environment, a stabilizing polymer, propylene glycol, a polysorbate surfactant, and a type 5 phosphodiesterase inhibitor and / or a salt thereof.

[0021] In another aspect, the present invention encompasses the method of making a composition comprising one or more of the embodiments described herein, for example, a type 5 phosphodiesterase inhibitor.In yet another aspect, the present invention encompasses the method of using a composition comprising one or more of the embodiments described herein, for example, a type 5 phosphodiesterase inhibitor.In yet another aspect, the present invention encompasses various uses of a composition comprising a type 5 phosphodiesterase inhibitor.For example, the composition can be used to treat erectile dysfunction.

[0022] In some embodiments, aspects of the invention relate to patches comprising compositions of the invention (e.g., with or without a nitric oxide donor and with or without one or more stabilizing compounds). In some embodiments, the compositions are in the form of a cream or ointment that is incorporated into the patch. However, other configurations may be used.

[0023] In some embodiments, aspects of the present invention relate to methods and formulations for locally delivering compounds at a fraction of the systemic dose required using oral delivery. In some embodiments, hostile biophysical environments can be evaluated to enhance local delivery through topical application. Depending on the therapeutic application, appropriate delivery configurations (e.g., combinations of compound concentration, hostile biophysical environment, creams, patches, etc.) can be used to reduce the systemic amount of compound required for effective therapeutic use.

[0024] In some embodiments, aspects of the present invention relate to reducing or avoiding side effects associated with the systemic levels of type 5 phosphodiesterase inhibitors required to produce the desired local effect when administered orally (side effects that have led to FDA denial of approval in men and women). In some embodiments, aspects of the present invention can be used to treat male and / or female sexual dysfunction by providing a topical formulation of one or more type 5 phosphodiesterase inhibitors. The topical formulation can be used (e.g., by topical application to the male or female genitalia) to produce effective local levels without causing the high systemic levels associated with the dosage required for effective oral administration. In some embodiments, aspects of the present invention provide a topical delivery formulation that takes effect within about 5 minutes (e.g., less than about 30 minutes, less than about 20 minutes, less than about 15 minutes, less than about 10 minutes, or less than about 5 minutes) after topical application, compared to waiting 30 minutes to an hour or more for oral administration to take effect.

[0025] Other advantages and novel features of the present invention will become apparent from the following detailed description of various non-limiting embodiments of the invention when considered in conjunction with the accompanying figures. In cases where the present specification and a document incorporated by reference include conflicting and / or inconsistent disclosure, the present specification shall control in the absence of clear error. If two or more documents incorporated by reference include conflicting and / or inconsistent disclosure with respect to each other, the document having the later effective date shall control. In one embodiment, for example, the following items are provided: (Item 1) 1. A composition for topical delivery to the skin of a subject, comprising: an unsuitable biophysical environment; a stabilizing polymer; Propylene glycol, a polysorbate surfactant; a type 5 phosphodiesterase inhibitor and / or its salt, and optionally Nitric oxide donor and A composition comprising: (Item 2) 2. The composition of claim 1, wherein each of the nitric oxide donor, the hostile biophysical environment, the xanthan gum, the propylene glycol, the polysorbate surfactant, and the type 5 phosphodiesterase inhibitor and / or its salt is contained within a delivery vehicle. (Item 3) 3. The composition of any one of items 1 to 2, which is stable when exposed to a temperature of 40° C. for at least about 1 day. (Item 4) 4. The composition of any one of items 1 to 3, which is stable when exposed to a temperature of 40° C. for at least about 1 week. (Item 5) 5. The composition of any one of items 1 to 4, which is stable when exposed to a temperature of 40° C. for at least about 4 weeks. (Item 6) 6. The composition according to any one of items 1 to 5, which is a cream. (Item 7) 6. The composition of any one of items 1 to 5, which is a gel. (Item 8) 6. The composition according to any one of items 1 to 5, which is a lotion. (Item 9) 6. The composition of any one of items 1 to 5, contained within a transdermal patch. (Item 10) 10. The composition of any one of items 1 to 9, wherein the nitric oxide donor comprises L-arginine. (Item 11) 11. The composition of any one of items 1 to 10, wherein the nitric oxide donor comprises an L-arginine salt. (Item 12) 12. The composition of any one of items 1 to 11, wherein the nitric oxide donor comprises L-arginine HCl. (Item 13) 13. The composition of any one of items 1 to 12, wherein the nitric oxide donor is present in a concentration of at least about 0.5% by weight of the composition. (Item 14) 14. The composition of any one of items 1 to 13, wherein the nitric oxide donor is present in a concentration of at least about 5% by weight of the composition. (Item 15) 15. The composition of any one of the preceding claims, wherein the nitric oxide donor is present in a concentration of at least about 7% by weight of the composition. (Item 16) 16. The composition according to any one of items 1 to 15, wherein the hostile biophysical environment is capable of transporting the type 5 phosphodiesterase inhibitor and / or its salt through the stratum corneum. (Item 17) 17. The composition of any one of items 1 to 16, wherein the hostile biophysical environment comprises ionic salts. (Item 18) 18. The composition of claim 17, wherein the ionic salt is present at a concentration of at least about 5% by weight of the composition. (Item 19) 19. The composition of any one of items 17 or 18, wherein the ionic salt is present at a concentration of at least about 7% by weight of the composition. (Item 20) 20. The composition of any one of items 17 to 19, wherein the ionic salt is present at a concentration of at least about 10% by weight of the composition. (Item 21) 21. The composition of any one of items 1 to 20, wherein the hostile biophysical environment comprises choline chloride. (Item 22) 22. The composition according to any one of items 1 to 21, wherein the hostile biophysical environment comprises magnesium chloride. (Item 23) 23. The composition of claim 22, wherein the magnesium chloride is present in a concentration of between about 0.1% and about 5% by weight of the composition. (Item 24) 24. The composition according to any one of items 1 to 23, wherein the hostile biophysical environment comprises calcium chloride. (Item 25) 25. The composition of any one of items 1 to 24, wherein the hostile biophysical environment has an ionic strength of at least about 0.25 M. (Item 26) 26. The composition of any one of items 1 to 25, wherein the hostile biophysical environment has an ionic strength of at least about 1 M. (Item 27) 27. The composition of any one of items 1 to 26, having a pH between about 5 and about 9. (Item 28) 28. The composition of any one of items 1 to 27, having a pH between about 5 and about 8.5. (Item 29) 29. The composition of any one of items 1 to 28, wherein the hostile biophysical environment comprises a component having an octanol-water partition coefficient of at least about 1000. (Item 30) 30. The composition of any one of items 1 to 29, wherein the hostile biophysical environment is capable of causing the nitric oxide donor to migrate from the composition to the skin of the subject when the composition is applied to the subject. (Item 31) 31. The composition of any one of items 1 to 30, wherein the subject is a human. (Item 32) 32. The composition of any one of items 1 to 31, further comprising packaging containing the nitric oxide donor, said packaging being selected from the group consisting of liposomes, emulsions of collagen, collagen peptides, and combinations thereof. (Item 33) 33. The composition of any one of the preceding claims, wherein the stabilizing polymer comprises xanthan gum. (Item 34) 34. The composition of any one of the preceding claims, wherein the stabilizing polymer comprises KELTROL® BT. (Item 35) 33. The composition of any one of the preceding claims, wherein the stabilizing polymer consists essentially of KELTROL® BT and / or KELTROL® RD. (Item 36) 36. The composition of claim 35, wherein the ratio of KELTROL® BT to KELTROL® RD in the composition is 3:5. (Item 37) 37. The composition of any one of items 35 or 36, wherein the KELTROL® BT is present in a concentration of about 0.3% by weight of the composition and the KELTROL® RD is present in a concentration of 0.5% by weight of the composition. (Item 38) 38. The composition of any one of the preceding claims, wherein the stabilizing polymer is present at a concentration of at least about 0.5% by weight of the composition. (Item 39) 39. The composition of any one of the preceding claims, wherein the stabilizing polymer is present at a concentration of at least about 0.8% by weight of the composition. (Item 40) 40. The composition of any one of the preceding claims, wherein the propylene glycol is present in a concentration of at least about 3% by weight of the composition. (Item 41) 41. The composition of any one of the preceding items, wherein the propylene glycol is present in a concentration of at least about 5% by weight of the composition. (Item 42) 42. The composition of any one of the preceding claims, wherein the polysorbate surfactant comprises polysorbate 20. (Item 43) 43. The composition of any one of the preceding claims, wherein the polysorbate surfactant comprises a polysorbate comprising a sorbitan monolaurate moiety. (Item 44) 44. The composition of any one of the preceding claims, wherein the polysorbate surfactant is present in a concentration of at least about 1% by weight of the composition. (Item 45) 45. The composition of any one of the preceding claims, wherein the polysorbate surfactant is present in a concentration of at least about 2% by weight of the composition. (Item 46) The polysorbate surfactant has the formula: [ka] 46. ​​The composition according to any one of items 1 to 45, comprising a compound having the formula: (Item 47) 47. The composition according to item 46, wherein w+x+y+z is 20. (Item 48) 48. The composition of any one of the preceding claims, having a ratio of the stabilizing polymer to propylene glycol to the polysorbate surfactant of about 1:6.25:2.5. (Item 49) 49. The composition according to any one of items 1 to 48, comprising a type 5 phosphodiesterase inhibitor. (Item 50) 50. The composition according to any one of items 1 to 49, comprising a salt of a type 5 phosphodiesterase inhibitor. (Item 51) 51. The composition according to item 50, comprising a sodium salt of a type 5 phosphodiesterase inhibitor. (Item 52) 52. The composition of any one of items 50 or 51, comprising a citrate salt of a type 5 phosphodiesterase inhibitor. (Item 53) 53. The composition of any one of items 1 to 52, wherein the type 5 phosphodiesterase inhibitor is avanafil. (Item 54) 53. The composition of any one of items 1 to 52, wherein the type 5 phosphodiesterase inhibitor is lodenafil. (Item 55) 53. The composition of any one of items 1 to 52, wherein the type 5 phosphodiesterase inhibitor is mirodenafil. (Item 56) 53. The composition of any one of items 1 to 52, wherein the type 5 phosphodiesterase inhibitor is sildenafil. (Item 57) 53. The composition of any one of items 1 to 52, wherein the type 5 phosphodiesterase inhibitor is tadalafil. (Item 58) 53. The composition of any one of items 1 to 52, wherein the type 5 phosphodiesterase inhibitor is vardenafil. (Item 59) 53. The composition of any one of items 1 to 52, wherein the type 5 phosphodiesterase inhibitor is udenafil. (Item 60) 53. The composition of any one of items 1 to 52, wherein the type 5 phosphodiesterase inhibitor is acetyldenafil. (Item 61) 53. The composition of any one of items 1 to 52, wherein the type 5 phosphodiesterase inhibitor is thiomethisosildenafil. (Item 62) 62. The composition of any one of the preceding items, wherein the type 5 phosphodiesterase inhibitor and / or salt thereof is present in a concentration of at least about 1% by weight of the composition. (Item 63) 63. The composition of any one of items 1 to 62, wherein the type 5 phosphodiesterase inhibitor and / or salt thereof is present in a concentration of at least about 5% by weight of the composition. (Item 64) 64. The composition of any one of items 1 to 63, wherein the type 5 phosphodiesterase inhibitor and / or salt thereof is present in a concentration of at least about 7% by weight of the composition. (Item 65) 65. The composition of any one of items 1 to 64, wherein the type 5 phosphodiesterase inhibitor and / or salt thereof is present in a concentration of between about 1% and about 10% by weight of the composition. (Item 66) 66. A method comprising the step of applying to a subject the composition of any one of items 1 to 65. (Item 67) 1. A composition for topical delivery to the skin of a subject, wherein at least about 80% by weight of the composition comprises: Water and at least one chloride salt; a stabilizing polymer; Propylene glycol, a polysorbate surfactant; a type 5 phosphodiesterase inhibitor and / or its salt, and optionally Nitric oxide donor and A composition comprising: (Item 68) 68. The composition of claim 67, further comprising glyceryl stearate. (Item 69) The composition according to any one of items 67 or 68, further comprising cetyl alcohol. (Item 70) 70. The composition of any one of items 67 to 69, further comprising squalane. (Item 71) 71. The composition of any one of items 67 to 70, further comprising isopropyl myristate. (Item 72) 72. The composition of any one of items 67 to 71, further comprising oleic acid. (Item 73) 73. The composition of any one of items 67 to 72, wherein the water is present in a concentration of at least about 35% by weight of the composition. (Item 74) 74. The composition of any one of items 67 to 73, wherein the water is present in a concentration of at least about 40% by weight of the composition. (Item 75) 75. The composition of any one of items 67 to 74, having a pH of between about 5 and about 8.5. (Item 76) 76. The composition of any one of items 67 to 75, wherein the at least one chloride salt comprises magnesium chloride. (Item 77) 77. The composition of claim 76, wherein the magnesium chloride is present in a concentration of between about 0.1% and about 5% by weight of the composition. (Item 78) 78. The composition according to any one of items 67 to 77, wherein the at least one chloride salt creates a hostile biophysical environment. (Item 79) 79. The composition of any one of items 67 to 78, wherein the at least one chloride salt comprises sodium chloride. (Item 80) 80. The composition of any one of items 67 to 79, wherein the at least one chloride salt is present in a concentration of at least about 5% by weight of the composition. (Item 81) 81. The composition of any one of items 67 to 80, wherein the at least one chloride salt is present in a concentration of at least about 10% by weight of the composition. (Item 82) 82. The composition of any one of items 67 to 81, wherein the at least one chloride salt is present in a concentration of at least about 15% by weight of the composition. (Item 83) 83. The composition of any one of items 67 to 82, wherein the nitric oxide donor comprises L-arginine. (Item 84) 84. The composition of any one of items 67 to 83, wherein the nitric oxide donor comprises an L-arginine salt. (Item 85) 85. The composition of any one of items 67 to 84, wherein the nitric oxide donor is present in a concentration of at least about 3% by weight of the composition. (Item 86) 86. The composition of any one of items 67 to 85, wherein the nitric oxide donor is present in a concentration of at least about 7% by weight of the composition. (Item 87) 87. The composition of any one of items 67 to 86, wherein the type 5 phosphodiesterase inhibitor and / or salt thereof is present in a concentration of at least about 1% by weight of the composition. (Item 88) 88. The composition of any one of items 67 to 87, wherein the type 5 phosphodiesterase inhibitor and / or salt thereof is present in a concentration of between about 1% and about 10% by weight of the composition. (Item 89) 89. The composition of any one of items 67 to 88, comprising a type 5 phosphodiesterase inhibitor. (Item 90) 90. The composition according to any one of items 67 to 89, comprising a salt of a type 5 phosphodiesterase inhibitor. (Item 91) 91. The composition of claim 90, comprising a sodium salt of a type 5 phosphodiesterase inhibitor. (Item 92) 92. The composition of any one of items 90 or 91, comprising a citrate salt of a type 5 phosphodiesterase inhibitor. (Item 93) 93. The composition of any one of items 67 to 92, wherein the stabilizing polymer consists essentially of KELTROL® BT and / or KELTROL® RD. (Item 94) 94. The composition of any one of items 67 to 93, wherein the stabilizing polymer is present in a concentration of at least about 0.5%. (Item 95) 95. The composition of any one of items 67 to 94, wherein the stabilizing polymer is present in a concentration of at least about 0.8%. (Item 96) 96. The composition of any one of items 67 to 95, wherein the propylene glycol is present in a concentration of at least about 3%. (Item 97) 97. The composition of any one of items 67 to 96, wherein the propylene glycol is present in a concentration of at least about 5%. (Item 98) 98. The composition of any one of items 67 to 97, wherein the polysorbate surfactant is present in a concentration of at least about 1% by weight of the composition. (Item 99) 99. The composition of any one of items 67 to 98, wherein the polysorbate surfactant is present in a concentration of at least about 2% by weight of the composition. (Item 100) 99. The composition of any one of items 67 to 99, wherein the polysorbate surfactant comprises polysorbate 20. (Item 101) 101. A method comprising applying to a subject the composition of any one of items 67 to 100. (Item 102) 1. A composition for topical delivery to the skin of a subject, comprising: an unsuitable biophysical environment; a type 5 phosphodiesterase inhibitor and / or its salt, and optionally Nitric oxide donor and A composition comprising: (Item 103) 103. The composition of claim 102, wherein the hostile biophysical environment has an ionic strength of at least about 0.25M. (Item 104) 104. The composition of any one of items 102 to 103, wherein the hostile biophysical environment has an ionic strength of at least about 1 M. (Item 105) 105. The method of any one of items 102 to 104, wherein the hostile biophysical environment has an ionic strength of between about 0.25M and about 15M. (Item 106) 106. The composition according to any one of items 102 to 105, wherein the hostile biophysical environment is capable of transporting the type 5 phosphodiesterase inhibitor and / or its salt through the stratum corneum. (Item 107) 107. The composition of any one of items 102 to 106, wherein the hostile biophysical environment comprises ionic salts. (Item 108) 108. The composition of any one of items 102 to 107, wherein the hostile biophysical environment comprises one or more of sodium chloride, choline chloride, magnesium chloride, calcium chloride. (Item 109) 109. The composition of any one of items 102 to 108, wherein the hostile biophysical environment comprises magnesium chloride. (Item 110) 110. The composition of claim 109, wherein the magnesium chloride is present in a concentration of between about 0.1% and about 5% by weight of the composition. (Item 111) 111. The composition of any one of items 102 to 110, having a pH of between about 5 and about 8.5. (Item 112) 112. The composition of any one of items 102 to 111, wherein the nitric oxide donor comprises L-arginine. (Item 113) 113. The composition of any one of items 102 to 112, wherein the nitric oxide donor is present in an amount effective to increase blood flow in the skin. (Item 114) 114. The composition according to any one of items 102 to 113, which is a cream. (Item 115) 114. The composition of any one of items 102 to 113, which is a gel. (Item 116) 114. The composition according to any one of items 102 to 113, which is a lotion. (Item 117) 117. The composition of any one of items 102 to 116, wherein the type 5 phosphodiesterase inhibitor and / or salt thereof is present in a concentration of between about 1% and about 10% by weight of the composition. (Item 118) 118. A method comprising applying to a subject the composition of any one of items 102 to 117. (Item 119) A method comprising applying to a portion of a subject's skin a delivery vehicle comprising a type 5 phosphodiesterase inhibitor and / or a salt thereof in a hostile biophysical environment. (Item 120) 120. The method of claim 119, wherein the hostile biophysical environment has an ionic strength of at least about 1 M. (Item 121) 121. The method of any one of items 119 or 120, wherein the hostile biophysical environment has an ionic strength of between about 0.25M and about 15M. (Item 122) 122. The method according to any one of items 119 to 121, wherein the hostile biophysical environment is capable of transporting the type 5 phosphodiesterase inhibitor and / or salt thereof through the stratum corneum. (Item 123) 123. The method of any one of items 119 to 122, wherein the hostile biophysical environment comprises ionic salts. (Item 124) 124. The method of any one of items 119 to 123, wherein the hostile biophysical environment comprises one or more of sodium chloride, choline chloride, magnesium chloride, calcium chloride. (Item 125) 125. The method of any one of items 119 to 124, wherein the hostile biophysical environment comprises magnesium chloride. (Item 126) Item 126. The method of item 125, wherein the magnesium chloride is present at a concentration of between about 0.1% and about 5% by weight of the delivery vehicle. (Item 127) 127. The method of any one of items 119 to 126, wherein the delivery vehicle has a pH of between about 5 and about 8.5. (Item 128) 128. The method of any one of items 119 to 127, wherein the delivery vehicle further comprises a nitric oxide donor. (Item 129) 129. The method of claim 128, wherein the nitric oxide donor comprises L-arginine. (Item 130) 130. The method of any one of items 128 or 129, wherein the nitric oxide donor is present in an amount effective to increase blood flow in the skin. (Item 131) 131. The method of any one of items 119 to 130, wherein the delivery vehicle is a cream. (Item 132) Item 133. The method of any one of items 119 to 130, wherein the delivery vehicle is a gel. 131. The method of any one of items 119 to 130, wherein the delivery vehicle is a lotion. (Item 134) 134. The method of any one of items 119 to 133, wherein the type 5 phosphodiesterase inhibitor and / or salt thereof is present in a concentration of between about 1% and about 10% by weight of the delivery vehicle. (Item 135) 1. A composition for topical delivery to the skin of a subject, comprising: Water and Sodium chloride, a nitric oxide donor; Glyceryl stearate, Cetyl alcohol and Magnesium chloride, Squalane and a stabilizing polymer; Isopropyl myristate, Oleic acid and Propylene glycol, a polysorbate surfactant; Type 5 phosphodiesterase inhibitors and / or their salts A composition consisting essentially of: (Item 136) Item 136. The composition of item 135, wherein the water is present in a concentration of about 40.9% by weight of the composition. (Item 137) 137. The composition of any one of items 135 or 136, wherein the sodium chloride is present in a concentration of about 10% by weight of the composition. (Item 138) 138. The composition of any one of items 135 to 137, wherein the nitric oxide donor comprises L-arginine HCl. (Item 139) 139. The composition of any one of items 135 to 138, wherein the nitric oxide donor is present in a concentration of about 7.5% by weight of the composition. (Item 140) 139. The composition of any one of items 135 to 139, comprising a type 5 phosphodiesterase inhibitor. (Item 141) 141. The composition according to any one of items 135 to 140, comprising a sodium salt of a type 5 phosphodiesterase inhibitor. (Item 142) 142. The composition according to any one of items 135 to 141, comprising a citrate salt of a type 5 phosphodiesterase inhibitor. (Item 143) 143. The composition of any one of items 135 to 142, wherein the type 5 phosphodiesterase inhibitor and / or salt thereof is present in a concentration of between about 1% and about 10% by weight of the composition. (Item 144) 144. The composition of any one of items 135 to 143, wherein the glyceryl stearate is present in a concentration of about 7% by weight of the composition. (Item 145) 145. The composition of any one of items 135 to 144, wherein the cetyl alcohol is present in a concentration of about 7% by weight of the composition. (Item 146) 146. The composition of any one of items 135 to 145, wherein the magnesium chloride is present in a concentration of between about 0.1% and about 5% by weight of the composition. (Item 147) 147. The composition of any one of items 135 to 146, wherein the squalene is present in a concentration of about 4% by weight of the composition. (Item 148) 148. The composition of any one of items 135 to 147, wherein the stabilizing polymer comprises xanthan gum. (Item 149) 149. The composition of any one of items 135 to 148, wherein the stabilizing polymer consists essentially of KELTROL® BT and / or KELTROL® RD. (Item 150) 150. The composition of any one of items 135 to 149, wherein the stabilizing polymer is present in a concentration of about 0.8% by weight of the composition. (Item 151) 151. The composition of any one of items 135 to 150, wherein the isopropyl myristate is present in a concentration of about 1% by weight of the composition. (Item 152) 152. The composition of any one of items 135 to 151, wherein the oleic acid is present in a concentration of about 1% by weight of the composition. (Item 153) 153. The composition of any one of items 135 to 152, wherein the propylene glycol is present in a concentration of 5%. (Item 154) 154. The composition of any one of items 135 to 153, wherein the polysorbate surfactant comprises polysorbate 20. (Item 155) 155. The composition of any one of items 135 to 154, having a pH of between about 5 and about 8.5. (Item 156) 156. A method comprising applying to a subject the composition of any one of items 135 to 155. (Item 157) 1. A composition for topical delivery to the skin of a subject, comprising the following compound at a concentration of no more than ±20% of the stated concentration: Water at a concentration of about 35% to about 55% by weight Sodium chloride at a concentration of about 2.5% to about 15% by weight Nitric oxide donor at a concentration of about 2.5% to about 15% by weight Glyceryl stearate at a concentration of about 4% to about 10% by weight Cetyl alcohol at a concentration of about 4% to about 10% by weight Magnesium chloride at a concentration of about 0.1% to about 5% by weight Squalane at a concentration of about 1% to about 8% by weight Polysorbate surfactant at a concentration of about 0.2% to about 2% by weight isopropyl myristate at a concentration of about 0.1% to about 5% by weight Oleic acid at a concentration of about 0.1% to about 5% by weight Propylene glycol at a concentration of about 1% to about 10% by weight a stabilizing polymer at a concentration of about 1% to about 10% by weight, and A type 5 phosphodiesterase inhibitor and / or a salt thereof at a concentration of about 1% to about 10% by weight A composition comprising each of the above. (Item 158) Item 158. The composition of item 157, wherein the stabilizing polymer comprises xanthan gum. (Item 159) 159. The composition of any one of items 157 to 158, wherein the stabilizing polymer consists essentially of KELTROL® BT and / or KELTROL® RD. (Item 160) 159. The composition of any one of items 157 to 159, wherein the polysorbate surfactant comprises polysorbate glucose. (Item 161) 161. The composition of any one of items 157 to 160, comprising the compound described in the preceding items at a concentration not exceeding ±10% of the stated concentration. (Item 162) 162. The composition of any one of items 157 to 161, having a pH between about 5 and about 8.5. (Item 163) 163. The composition of any one of items 157 to 162, wherein the type 5 phosphodiesterase inhibitor and / or salt thereof comprises sildenafil. (Item 164) 163. The composition of any one of items 157 to 162, wherein the type 5 phosphodiesterase inhibitor and / or salt thereof comprises tadalafil. (Item 165) 163. The composition of any one of items 157 to 162, wherein the type 5 phosphodiesterase inhibitor and / or salt thereof comprises vardenafil. (Item 166) 166. A method comprising applying to a subject the composition of any one of items 157 to 165. (Item 167) on at least a portion of the skin of the subject, an unsuitable biophysical environment; a stabilizing polymer; Propylene glycol, a polysorbate surfactant; a type 5 phosphodiesterase inhibitor and / or its salt, and optionally a nitric oxide donor; applying a composition comprising: (Item 168) 1. A composition for topical delivery to the skin of a subject, comprising: a stabilizing polymer; Propylene glycol, a polysorbate surfactant; Type 5 phosphodiesterase inhibitors and / or their salts A composition comprising: (Item 169) 1. A composition for topical delivery to the skin of a subject, wherein at least about 80% by weight of the composition comprises: Water and at least one chloride salt; a stabilizing polymer; Propylene glycol, a polysorbate surfactant; Type 5 phosphodiesterase inhibitors and / or their salts A composition comprising: DETAILED DESCRIPTION OF THE INVENTION

[0026] Detailed Description The present invention generally relates to the transdermal delivery of various compounds. In some embodiments, transdermal delivery can be facilitated by the use of a hostile biophysical environment. One set of embodiments provides a composition for topical delivery, comprising a type 5 phosphodiesterase inhibitor and / or its salt, and optionally a hostile biophysical environment and / or a nitric oxide donor. In some cases, the composition can be stabilized using a combination of a stabilizing polymer (such as xanthan gum, KELTROL® BT and / or KELTROL® RD), propylene glycol, and a polysorbate surfactant such as polysorbate 20, which unexpectedly provides the composition with temperature stability at elevated temperatures, for example, at least 40°C (at least about 104°F), compared to a composition lacking one or more of these.

[0027] According to aspects of the present invention, compositions comprising a relatively high salt composition (e.g., high chloride content) are unexpectedly effective for the local delivery of type 5 phosphodiesterase inhibitors (e.g., sildenafil or other inhibitors, including salts thereof). In some embodiments, salt-enhanced delivery (e.g., in compositions having at least 2% salt, at least 5% salt, at least 10% salt, at least 15% salt, or more, as described herein) is particularly effective when the pH of the composition is optimized to ionize (e.g., at least about 80%, at least about 90%, at least about 95%, or greater than about 99%) the compound being delivered. It should be understood that, depending on the pKa of the compound and the pH of the composition, the ionized form may be anionic or cationic (e.g., by protonation). In some embodiments, the compound may contain several ionizable groups, each with a different pKa. In some embodiments, it is sufficient for at least one, two, or three ionizable groups to be effective for salt-enhanced delivery. In some embodiments, an ionizable group is sufficiently ionized if the pH of the composition is at least 1 pH unit, or at least 2 pH units (e.g., 1, 1-2, 2-3, or more pH units) below the pKa of the group and is cationic (by protonation) below that pKa. Similarly, in some embodiments, an ionizable group is sufficiently ionized if the pH of the composition is at least 1 pH unit, or at least 2 pH units (e.g., 1, 1-2, 2-3, or more pH units) above the pKa of the group and is anionic (by deprotonation) above that pKa. In some embodiments, the presence of, for example, 0.1-5 wt. % magnesium chloride can help stabilize compositions containing compounds with relatively high pKas (e.g., greater than 8.0, greater than 9.0, greater than 10.0, or more). In some embodiments, the pH of the composition can be maintained using a buffer. However, the pH of the compositions of the present invention is surprisingly stable even without a buffer.In some embodiments, the desired pH can be established by titrating the mixture with an acid (e.g., HCl) or a base (e.g., NaOH). The pH of the resulting composition (e.g., when formulated as an emulsion as described herein) can be stable (e.g., sufficient for the composition to be effective for transdermal delivery) for extended periods of time (e.g., weeks, months, or a year or more).

[0028] According to another aspect of the present invention, high salt compositions containing a type 5 phosphodiesterase inhibitor are unexpectedly stable when formulated as emulsions (e.g., water-in-oil emulsions or oil-in-water emulsions, including one or more of the stabilizing polymers and / or polysorbate surfactants and / or propylene glycol (or other low molecular weight glycols or polyglycols) described herein). In some embodiments, the pH of the emulsion and the composition including the high salt concentration is selected to ionize the compound being delivered as described herein.

[0029] In some embodiments, topical delivery of the present invention (e.g., topical delivery of a type 5 phosphodiesterase inhibitor, such as sildenafil) surprisingly provides a rapid effect (within about 1 to 5 minutes). In contrast, oral counterparts require about 60 minutes or more to provide an effect. Accordingly, aspects of the present invention provide methods and compositions for delivering to a subject a treatment effective for treating or preventing erectile dysfunction. In some embodiments, topical compositions are provided that can be applied to the genital area of ​​a female or male subject (e.g., the penis of a male subject) to treat erectile dysfunction (e.g., promote erection) within less than 60 minutes, less than 45 minutes, less than 30 minutes, or less than 15 minutes of application.

[0030] One aspect of the present invention provides compositions for the local delivery of substances such as pharmaceutical agents (e.g., drugs, biological compounds, etc.). The pharmaceutical agents can be applied to the skin of a subject, e.g., a human, to aid in the treatment of a medical condition or disease and / or symptoms associated therewith. In some embodiments, the present invention provides treatments for medical conditions or diseases and / or illnesses using pharmaceutical agents (e.g., to treat a subject diagnosed with a medical condition or disease as described herein), and in some cases, the present invention provides for the delivery of minimal amounts of pharmaceutical agents to provide effective levels of medication locally to the affected area while limiting side effects. In some cases, the effective dosage of the pharmaceutical agent may be lower than the effective dosage of the pharmaceutical agent when taken orally.

[0031] For example, in one set of embodiments, the pharmaceutical agent is a type 5 phosphodiesterase inhibitor and / or its salt.Type 5 phosphodiesterase inhibitor is a drug that blocks the decomposition of cyclic GMP by type 5 phosphodiesterase, for example, in the smooth muscle cells that line the blood vessels that supply blood to the corpus cavernosum of the penis.Part of the physiological process of erection involves the release of nitric oxide (NO) in the vasculature of the corpus cavernosum as a result of sexual stimulation.NO activates the enzyme guanylate cyclase, thereby increasing the level of cyclic guanosine monophosphate (cGMP), relaxing the smooth muscle in the blood vessels that supply blood to the corpus cavernosum, leading to increased blood flow and erection.Therefore, PDE5 inhibitors inhibit the decomposition of cGMP by type 5 phosphodiesterase, and increase blood flow to the penis during sexual stimulation.

[0032] Non-limiting examples of type 5 phosphodiesterase inhibitors include, but are not limited to, avanafil, lodenafil, mirodenafil (pKa 6.0), sildenafil (or an analog thereof, e.g., acetyldenafil, hydroxyacetyldenafil, or dimethylsildenafil), tadalafil (pKa 18), vardenafil (pKa 3.4, 6.7, 8.8, and 14), udenafil (pKa 10.53), acetyldenafil, or thiomethisosildenafil. The structures of these compounds are each shown below.

[0033] [ka]

[0034] [ka] Thus, various aspects of the present invention are directed to compositions comprising a type 5 phosphodiesterase inhibitor for transdermal delivery or topical application to a subject. Other compounds, such as salts or derivatives of a type 5 phosphodiesterase inhibitor (including salts or derivatives of the foregoing compounds), are also included in other embodiments. Thus, in any embodiment described herein that uses a type 5 phosphodiesterase inhibitor, it should be understood that the type 5 phosphodiesterase inhibitor is merely exemplary, and other embodiments of the present invention are directed to salts of a type 5 phosphodiesterase inhibitor, derivatives of a type 5 phosphodiesterase inhibitor, etc., instead of and / or in addition to a type 5 phosphodiesterase inhibitor.

[0035] The type 5 phosphodiesterase inhibitor or other pharmaceutical agent (e.g., a salt or derivative of a type 5 phosphodiesterase inhibitor, etc.) can be present at any suitable concentration. For example, in some cases, the pharmaceutical agent can be present at a concentration of at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.7%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 7.5%, at least about 8%, at least about 9%, or at least about 10% by weight of the composition. In certain embodiments, the pharmaceutical agent can be present at a concentration of about 1% or less, about 2% or less, about 3% or less, about 4% or less, about 5% or less, about 6% or less, about 7% or less, about 8% or less, about 9% or less, about 10% or less, about 12% or less, about 15% or less, or about 20% or less by weight of the composition. In addition, pharmaceutical agents can be present in their natural form and / or as one or more salts. For example, if a type 5 phosphodiesterase inhibitor is present, the type 5 phosphodiesterase inhibitor can be used in its natural form and / or as one or more salts of the type 5 phosphodiesterase inhibitor, such as sodium, potassium, magnesium, lysine, arginine, lactate, or citrate salts, such as avanafil, lodenafil, mirodenafil, sildenafil, tadalafil, vardenafil, udenafil, acetyldenafil, thiomethisosildenafil, etc. For salt forms of pharmaceutical agents, "by weight of the composition" includes the entire salt form of the pharmaceutical agent, e.g., the agent itself, and any counterions, such as sodium, potassium, etc. The amount of pharmaceutical agent can be determined in the composition using, for example, techniques known to those skilled in the art, such as HPLC or HPLC / MS.

[0036] Many type 5 phosphodiesterase inhibitors are readily available commercially. In some cases, the type 5 phosphodiesterase inhibitor can be obtained as a racemic mixture of, for example, tadalafil (e.g., (R,R)-tadalafil, (R,S)-tadalafil, (S,R)-tadalafil, and (S,S)-tadalafil). However, in other cases, one enantiomer can be present in an amount greater than the other. For example, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% of the type 5 phosphodiesterase inhibitor in the composition can be present as one of the enantiomers. Techniques for preparing or separating racemic type 5 phosphodiesterase inhibitors are known. See, e.g., Gao et al., "Chiral Separation of Two Pairs of Enantiomers of Tadalafil by High-Performance Liquid Chromatography," J. Chromatogr. Sci., 45:540-543, 2007.

[0037] In some embodiments, the composition may also include a nitric oxide donor, such as L-arginine and / or L-arginine hydrochloride. In some cases, such a nitric oxide donor can be used to increase local blood flow at the site where the composition is applied, thereby enhancing the delivery of pharmaceutical agents. The nitric oxide donor can be present in the composition at any suitable concentration. For example, in some cases, the nitric oxide donor is present at a concentration of at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 7.5%, at least about 8%, at least about 9%, or at least about 10% by weight of the composition. In some cases, one or more nitric oxide donors (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, etc. nitric oxide donors) can be used. In some cases, no more than 3, 5, 7, or 10 nitric oxide donors can be present in the composition.

[0038] As used herein, a "nitric oxide donor" is a compound that can directly or indirectly, e.g., via a biological process, release nitric oxide and / or chemically transfer a nitric oxide moiety to another molecule. The nitric oxide donor can release nitric oxide to tissues such as the skin and / or muscle and / or elements of the circulatory system in close proximity to the skin surface. Non-limiting examples of nitric oxide donors include arginine (e.g., L-arginine and / or D-arginine), arginine derivatives (e.g., L-arginine hydrochloride and / or D-arginine hydrochloride), nitroglycerin, polysaccharide-bound nitric oxide-nucleophile adducts, N-nitroso-N-substituted hydroxylamines, 1,3-(nitrooxymethyl)phenyl-2-hydroxybenzoates, etc., and / or any combination of these and / or other compounds.

[0039] In addition to L-arginine and L-arginine hydrochloride, other non-limiting examples of nitric oxide donors include D,L-arginine, D-arginine, or alkyl (e.g., ethyl, methyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.) esters of L-arginine and / or D-arginine (e.g., methyl ester, ethyl ester, propyl ester, butyl ester, etc.) and / or salts thereof, as well as other derivatives of arginine and other nitric oxide donors. For example, non-limiting examples of pharmaceutically acceptable salts include hydrochlorides, glutamate, butyrate, or glycolate salts (e.g., to yield L-arginine glutamate, L-arginine butyrate, L-arginine glycolate, D-arginine hydrochloride, D-arginine glutamate, etc.). Further examples of nitric oxide donors include L-arginine-based compounds and their salts (e.g., hydrochloride, glutamate, butyrate, glycolate, etc.), such as, but not limited to, L-homoarginine, N-hydroxy-L-arginine, nitrosylated L-arginine, nitrosylated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, citrulline, ornithine, linsidomine, nipride, glutamine, and / or any combination of these and / or other compounds. Further non-limiting examples of nitric oxide donors include S-nitrosothiols, nitrite, 2-hydroxy-2-nitrosohydrazine, or various forms of substrates of nitric oxide synthase. In some cases, the nitric oxide donor may be a compound that stimulates the endogenous production of nitric oxide in vivo. Examples of such compounds include, but are not limited to, L-arginine, substrates of various forms of nitric oxide synthase, certain cytokines, adenosine, bradykinin, calreticulin, bisacodyl, phenolphthalein, OH-arginine or endothelin, and / or any combination of these and / or other compounds.

[0040] Thus, in any of the embodiments described herein that describe L-arginine and / or L-arginine hydrochloride, it should be understood that other nitric oxide donors may be used instead of or in combination with L-arginine and / or L-arginine hydrochloride in other embodiments of the invention.

[0041] In some cases, the concentration of the nitric oxide donor in the composition can be tailored to provide a duration of effective treatment of at least about 3 hours, at least about 5 hours, or at least about 8 hours or more in certain cases. The duration can also be controlled, for example, by controlling the concentration of the penetrant used in conjunction with the nitric oxide donor. Penetrants are discussed in detail herein. The actual concentration for a particular application can be determined by one of ordinary skill in the art without more than routine experimentation, for example, by measuring the transport of the nitric oxide donor as a function of concentration in vitro across cadaver skin or a suitable animal model, skin graft, synthetic model membrane, human model, etc.

[0042] As a specific, non-limiting example, in certain embodiments, nitric oxide is provided at at least about 0.75 wt%, at least about 1 wt%, at least about 2 wt%, at least about 3 wt%, at least about 5 wt%, at least about 7 wt%, at least about 10 wt%, or at least about 15 wt%, using L-arginine, e.g., at a concentration of at least about 0.5% by weight (wt% or w / v) (optionally with one or more penetrants discussed herein, e.g., penetrants that can create a hostile biophysical environment). L-arginine can be present in a suitable delivery vehicle, such as a cream or lotion. L-arginine can be particularly useful in some cases due to its low toxicity, high solubility, and / or low cost. Other examples of nitric oxide donors are discussed in International Patent Application No. PCT / US2005 / 005726, filed February 23, 2005, entitled "Topical Delivery of a Nitric Oxide Donor to Improve Body and Skin Appearance," by E.T. Fossel, published September 9, 2005 as WO2005 / 081964, which is incorporated herein by reference.

[0043] Although not wishing to be bound by any theory, it is generally believed that the flow of pharmaceutical agents across the skin may slow down as they increase in tissue.Fick's first law of diffusion suggests that passive flow stops when the internal concentration is substantially equal to that outside.Increased local blood flow can prevent or at least reduce the cessation of the flow of pharmaceutical agents.Therefore, when the composition is applied to the skin, the pharmaceutical agents are dispersed by flow and do not increase in concentration in the tissue, so the pharmaceutical agents can more easily exit the vehicle and enter the tissue.Therefore, in certain embodiments, the pharmaceutical agents can be introduced into the skin by a type 5 phosphodiesterase inhibitor and / or a salt or derivative of a type 5 phosphodiesterase inhibitor, such as avanafil, lodenafil, mirodenafil, sildenafil, tadalafil, vardenafil, udenafil, acetyldenafil, or thiomethisosildenafil. Thus, the compositions can be delivered locally and / or systemically, and although initially most delivery is initially local (i.e., via the skin), in some cases the pharmaceutical agent may be distributed systemically, for example, upon reaching the blood supply.

[0044] The composition, in some embodiments, can also include a biophysical environment hostile to a type 5 phosphodiesterase inhibitor. In a hostile biophysical environment, the environment surrounding a pharmaceutical agent (such as a type 5 phosphodiesterase inhibitor) can be such that the pharmaceutical agent is in a chemically and / or energetically unfavorable environment compared to the skin (e.g., the chemical potential and / or free energy of the pharmaceutical agent in the hostile biophysical environment is significantly greater than the chemical potential and / or free energy of the pharmaceutical agent in the skin, thus energetically favoring transport into the skin), particularly the stratum corneum.

[0045] Examples of such compositions are discussed in International Patent Application No. PCT / US2005 / 013228, filed April 19, 2005, entitled "Transdermal Delivery of Beneficial Substances Effected by a Hostile Biophysical Environment," by E. Fossel, published November 3, 2005 as WO2005 / 102282, which is incorporated herein by reference. Other techniques for hostile biophysical environments are discussed in detail herein. Accordingly, certain embodiments of the present invention are generally directed to compositions for topical delivery to the skin of a subject, comprising a nitric oxide donor, a hostile biophysical environment, and a pharmaceutical agent, such as a type 5 phosphodiesterase inhibitor, or a salt or derivative of a type 5 phosphodiesterase inhibitor.

[0046] The hostile biophysical environment of the present invention can, in various embodiments, include high ionic strength, high concentrations of osmotic agents such as urea, sugars, or carbohydrates, a high pH environment (e.g., greater than about 7, greater than about 8, greater than about 9, greater than about 10, greater than about 11, greater than about 12, or greater than about 13), a low pH environment (less than about 5, less than about 4, less than about 3, or less than about 2), highly hydrophobic components, or highly hydrophilic components, or other substances that cause an increase in the chemical potential and / or free energy of the pharmaceutical agent, or any combination of two or more of these and / or other compounds. The hydrophobic component, in some embodiments, has a pH of at least about 100, at least about 1000, at least about 10 4 , at least about 10 5 Similarly, hydrophilic components may have an octanol-water partition coefficient of less than about 0.01, about 10, or greater in some cases. -3 Less than, about 10 -4 Less than or about 10 -5 In some cases, the compound may have an octanol-water partition coefficient of less than 10%.

[0047] In some cases, the composition defines a biophysical hostile environment. In other cases, the pharmaceutical agent may be packaged in such a way that the agent is transported into the tissue and / or its charge is neutralized by derivatization and / or by forming a neutral salt. Examples of biophysically hostile environments include high ionic strength environments (e.g., by addition of urea, sugars, carbohydrates, and / or ionic salts such as lithium chloride, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, choline chloride, sodium fluoride, lithium bromide, etc.), as well as high ionic strength environments (e.g., greater than about 0.25M, greater than about 1M, greater than about 2M, greater than about 3M, greater than about 5M, greater than about 10M, greater than about 15M, greater than about 20M, greater than about 25M, etc., or in some cases, between about 0.25M and about 15M). , between about 5M and about 15M, between about 10M and about 15M, etc.); high or low pH environments (e.g., by adding a pharmaceutically acceptable acid or base such that the pH is between about 3 and about 7, between about 3 and about 6, between about 3 and about 5, between about 4 and about 8, between about 5 and about 8, between about 5 and about 8.5, between about 7 and about 11, between about 8 and about 11, between about 9 and about 11, etc.); or highly hydrophobic environments (e.g., by decreasing the water content of the environment and increasing the lipid, oil, and / or wax content). In some embodiments, the ionic strength is any amount greater than two times the physiological ionic strength of blood. The ionic strength of the composition can, in certain embodiments, be readily controlled by controlling the amount or concentration of one or more salts present in the composition, for example, by controlling the amount of sodium chloride, magnesium chloride, choline chloride, etc., and / or other salts.

[0048] In certain embodiments, other highly charged molecules, such as polylysine, polyglutamine, polyaspartate, or copolymers of such highly charged amino acids, may also be used to create a hostile biophysical environment. Non-limiting examples of delivery vehicles that can be carried into tissue include collagen liposomes or emulsions, collagen peptides, or other components of the skin or basement membrane. Non-limiting examples of charge neutralization include delivery of pharmaceutical agents in an electronically neutral form or in an ester or salt form. In some embodiments, the hostile biophysical environment can include any two or more of these conditions. For example, the hostile biophysical environment can include high ionic strength and high or low pH, a highly hydrophobic environment and high or low pH, a highly hydrophobic environment containing liposomes, etc.

[0049] A hostile biophysical environment can also be created in some embodiments by placing a relatively highly charged pharmaceutical agent in a hydrophobic, oily environment, such as in an oil-based cream or lotion that contains little or no water. Absorption can be further aided by combining the use of a hostile biophysical environment with the use of a penetrating agent, as further described herein.

[0050] In one set of embodiments, the composition can be present as an emulsion.As known to those skilled in the art, emulsions typically comprise a first phase (e.g., a discontinuous phase) contained in a second fluid phase (e.g., a continuous phase).Pharmaceutical active substances (e.g., type 5 phosphodiesterase inhibitors) can be present in either or both phases.In addition, other materials, such as those described herein, can be present in the same phase as the pharmaceutical active substance.

[0051] In some embodiments, emulsions can be prepared to contain a drug of interest (or other pharmaceutical agent) in a hostile biophysical environment, and optionally one or more of a stabilizing polymer, propylene glycol, and / or a polysorbate surfactant. The emulsions can also include a nitric oxide donor, such as L-arginine and / or L-arginine hydrochloride, in some embodiments.

[0052] In some embodiments, various aspects of the present invention relate to methods and compositions for preparing and / or manufacturing drug formulations for local delivery. In one set of embodiments, the present invention is generally directed to emulsions containing one or more drugs or other pharmaceutical agents described herein for topical application. In some embodiments, certain aspects of the present invention are useful for preparing emulsions containing one or more drugs (or other pharmaceutical agents) in a hostile biophysical environment. In some embodiments, the hostile biophysical environment is, for example, a high salt concentration (e.g., a high concentration of one or more salts), as described herein.

[0053] In some embodiments, emulsions are prepared by mixing a first aqueous preparation (e.g., an aqueous phase) with a second non-aqueous preparation (e.g., an oil or lipid phase). Water-soluble drugs or other pharmaceutical agents can be added to the first aqueous preparation (e.g., before mixing with the second non-aqueous preparation). Water-insoluble (or relatively water-insoluble) drugs or other pharmaceutical agents can be added to the second non-aqueous preparation (e.g., before mixing with the first aqueous preparation). Partially water-soluble drugs or other pharmaceutical agents can be added to one phase or split into two phases before mixing. The split into two phases will depend on the amount of drug (or other pharmaceutical agent) added, the composition of the first and second preparations (e.g., the nature and amount of other chemicals or agents), pH, temperature, other physical or chemical factors, and / or a combination thereof. For example, if the drug of interest is soluble in the aqueous (e.g., water or buffer) phase at 1% level, but the drug is required to be at 2% level in the emulsion, the drug can be added to the non-aqueous (e.g., lipid) phase at 1% level. In some embodiments, the drug that is less than 1% soluble in the aqueous phase is provided in the non-aqueous phase before mixing. However, it should be understood that other percentages and / or divisions into two phases can be used.

[0054] In some embodiments, the pH of one or both of the first and second preparations is adjusted to optimize the solubility of the drug being used. In some embodiments, a high salt concentration is used. To prevent the high salt concentration from breaking down the emulsion, one or more emulsifiers may be used in some cases. In some embodiments, the mixing time may be adjusted to promote proper mixing and / or emulsion formation.

[0055] In some embodiments, the temperature of the first and / or second preparations may be controlled to facilitate solubility, mixing, and / or emulsion formation. In some embodiments, the temperature of one or both preparations and / or mixing may be set at 25°C or higher (e.g., 30°C or higher, 40°C or higher, 50°C or higher, 60°C or higher, 70°C or higher, or 80°C or higher). For example, the temperature may be between 30°C and 90°C, between 40°C and 80°C, around 50°C, around 60°C, or around 70°C.

[0056] It should be understood that the methods and compositions of the present invention can be used with any suitable drug or pharmaceutical agent. In some embodiments, for example, oral drugs can be formulated for local delivery using one or more compositions or methods described herein. Topical formulations can be useful for delivering a locally effective amount of a drug (or other pharmaceutical agent) to a subject (e.g., a human) without causing unwanted side effects associated with the systemic level required for efficacy when the drug is administered orally. Thus, topical formulations can be useful for delivering a drug in an amount sufficient to cause a desired effect (e.g., a therapeutic effect), but lower than the total amount of drug that would be administered to a subject (e.g., a human) if it were administered orally.

[0057] In certain embodiments of the present invention, the emulsion of the present invention can be packaged using any suitable format (e.g., a tube, a pump-actuated container, or any other suitable form). For example, in some embodiments, the emulsion can be added to the surface of a patch or bandage. The emulsion can be applied to the skin of a subject as a cream, gel, liquid, lotion, spray, aerosol, etc.

[0058] Using methods and compositions such as any of those discussed herein, compositions that are sterile or have low microbial content can be prepared in some embodiments.

[0059] In some aspects of the present invention, the composition of the present invention is administered to a subject using a delivery vehicle such as cream, gel, liquid, lotion, spray, aerosol or transdermal patch.In one set of embodiments, the composition of the present invention can be applied to the skin of a subject or impregnated into a bandage or patch that is applied to the skin of a subject.In some embodiments, the patch has a skin contact portion made of any suitable material that is covered with or impregnated with the cream or emulsion described herein, wherein the skin contact portion can be supported by a backing, one or both of which can have an adhesive section or other shape for adhering to the skin surface of a subject.As used herein, "subject" refers to a human or non-human animal. Examples of subjects include, but are not limited to, mammals such as dogs, cats, horses, donkeys, rabbits, cows, pigs, sheep, goats, rats (e.g., Rattus Norvegicus), mice (e.g., Mus musculus), guinea pigs, hamsters, primates (e.g., monkeys, chimpanzees, baboons, apes, gorillas, etc.). Such delivery vehicles can be applied to the skin of a subject, such as a human subject. Examples of delivery vehicles are discussed herein. The delivery vehicle can directly or indirectly facilitate the transfer of an effective concentration of the nitric oxide donor and / or pharmaceutical agent into the skin. For example, the delivery vehicle can include one or more penetrants, as further described herein. Those skilled in the art will be aware of systems and techniques for incorporating the nitric oxide donor and / or pharmaceutical agent into a delivery vehicle, such as a cream, gel, liquid, lotion, spray, aerosol, or transdermal patch. In some cases, the concentration of the nitric oxide donor and / or pharmaceutical agent in the delivery vehicle may be reduced by including a greater amount or concentration of a penetrating agent, or may be increased to prolong the beneficial effect. In one set of embodiments, the nitric oxide donor and / or pharmaceutical agent may be used in conjunction with an additive such as theophylline (e.g., at 10% weight by volume).

[0060] Other materials may be present in the delivery vehicle, such as buffers, preservatives, surfactants, etc. For example, a cream may include one or more of water, mineral oil, glyceryl stereate, squalene, propylene glycol stearate, wheat germ oil, glyceryl stearate, isopropyl myristate, steryl stearate, polysorbate 60, propylene glycol, oleic acid, tocopheryl acetate, collagen, sorbitan stearate, vitamins A and D, triethanolamine, methylparaben, aloe vera extract, imidazolidinyl urea, propylparaben, PND, and / or BHA.

[0061] As a specific, non-limiting example, the cream may contain (w / v): water (20-80%), white oil (3-18%), glyceryl stearate (0.25-12%), squalene (0.25-12%), cetyl alcohol (0.1-11%), propylene glycol stearate (0.1-11%), wheat germ oil (0.1-6%), polysorbate 60 (0.1-5%), propylene glycol (0.05-5%), collagen (0.05-5%), sorbitan stearate (0.05-5%), vitamin A (0.02-4%), niacin ... %), vitamin D (0.02-4%), vitamin E (0.02-4%), triethanolamine (0.01-4%), methylparaben (0.01-4%), aloe vera extract (0.01-4%), imidazolidinyl urea (0.01-4%), propylparaben (0.01-4%), BHA (0.01-4%), L-arginine hydrochloride (0.25-25%), sodium chloride (0.25-25%), magnesium chloride (0.25-25%), and / or choline chloride (0.25-25%). The percentage of each compound may vary (or the compound may be absent in some cases), for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, etc.

[0062] In another embodiment, the cream may include a pharmaceutical agent (e.g., a type 5 phosphodiesterase inhibitor such as those described herein) and one or more of the following in any suitable amount: water (e.g., 20-80%), L-arginine hydrochloride (e.g., 0-25%), sodium chloride (e.g., 0-25%), potassium chloride (e.g., 0-25%), glyeryl steareate (e.g., 0-15%), cetyl alcohol (e.g., 0-15%), squalene (e.g., 0-15%), isopropyl myristate (e.g., 0-15%), oleic acid (e.g., 0-15%), Tween 20 (e.g., 0-10%), and / or butanediol (e.g., 0-10%). The percentage of each compound may vary (or the compound may be absent in some cases), for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, etc.

[0063] In some embodiments, the cream may include a pharmaceutical agent and one or more ionic salts, at least in concentrations sufficient to create a biophysical environment hostile to the pharmaceutical agent. For example, the cream may include one or more of (w / v): charge and / or hydrogen bonding entities (0.001-30%), choline chloride (1-30%), sodium chloride (2-30%), and / or magnesium chloride (1-20% w / v). In another example, the cream may include one or more of (w / v): L-arginine hydrochloride (2.5-25%), choline chloride (10-30%), sodium chloride (5-20%), and / or magnesium chloride (5-20%). In yet another example, the cream may include one or more of (w / v): creatine (0.001-30%), inosine (0.001-30%), choline chloride (1-30%), sodium chloride (2-30%), magnesium chloride (1-20%), L-arginine (0.1-25%), and / or theophylline (0.1-20%). In some cases, the cream may also contain L-arginine hydrochloride (0-12.5% ​​w / v) and / or theophylline (0-10% w / v). The percentage of each compound may vary (or the compound may be absent in some cases), e.g., 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, etc. In these instances, choline chloride, sodium chloride and / or magnesium chloride can be used to provide a high ionic strength environment.

[0064] In some embodiments, the composition may contain an antioxidant that can reduce or inhibit the oxidation of other molecules in the composition. Examples of suitable antioxidants include, but are not limited to, glutathione, vitamin C, and vitamin E, as well as enzymes such as catalase, superoxide dismutase, and various peroxidases. The antioxidant may be present at any suitable concentration. For example, the antioxidant may be present at a concentration of at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.7%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, or at least about 5% by weight of the composition. In certain embodiments, the pharmaceutical agent may be present at a concentration of about 0.2% or less, about 0.5% or less, about 1% or less, about 2% or less, about 3% or less, about 4% or less, or about 5% or less by weight of the composition.

[0065] Another set of embodiments is generally directed to compositions having relatively high temperature stability. For example, the composition may be stable at high temperatures, such as at least 40°C (at least about 104°F), for at least about one day. In some embodiments, for example, the compositions of the present invention may further comprise a stabilizing polymer, propylene glycol, and a polysorbate surfactant. Non-limiting examples of stabilizing polymers include xanthan gum, KELTROL® BT, and / or KELTROL® RD, and an example of a polysorbate surfactant is polysorbate 20. Additional examples are discussed herein.

[0066] Such a combination of ingredients to create high temperature stability is surprising because compositions involving any two of these ingredients (but not the third) have been found to lack such high temperature stabilizing properties. Because these ingredients are not known to be involved in any significant chemical reaction with each other, and because high temperature stability is greatly reduced when one of the ingredients is removed, it is currently unknown why this combination of ingredients is so effective in promoting the relatively high temperature stability of the compositions discussed herein. In addition, propylene glycol is not known to act as a stabilizer in pharmaceutical compositions.

[0067] For example, in one set of embodiments, a composition can be determined to have high temperature stability by determining whether the composition exhibits phase separation over a relatively long period of time, e.g., at least 1 hour, at least about 2 hours, at least 1 day, at least about 1 week, at least about 4 weeks, etc. For example, in some embodiments, the composition is exposed to ambient temperature and pressure for at least 1 hour, and then the composition is analyzed to determine whether the composition exhibits phase separation or a phase change. A stable compound is one that does not exhibit phase separation, whereas an unstable compound may exhibit phase separation. Such stability is useful, for example, for storing the composition, transporting the composition, shelf life, etc.

[0068] As used herein, a "stabilizing polymer" refers to a polymer including xanthan gum, xanthan gum derivatives, and / or xanthan gum equivalents, such as KELTROL® BT and / or KELTROL® RD, KELZAN® XC, KELZAN® XCD, KELZAN® D, KELZAN® CC, XANTURAL® 180, XANTURAL® 75, and the like, all of which are commercially available from a variety of suppliers. In some embodiments, combinations of these and / or other polymers are possible. In some cases, the stabilizing polymer is selected to be one that is at least generally considered safe for human use. Additionally, in certain embodiments, the stabilizing polymer is synthetically produced and / or purified to some extent. The stabilizing polymer can have any suitable molecular weight, for example, at least about 1 million, at least about 2 million, at least about 5 million, at least about 10 million, at least about 25 million, or at least about 50 million.

[0069] The stabilizing polymer can be present in any suitable concentration in the composition.For example, the stabilizing polymer can be present at a concentration of at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, or at least about 1% by weight of the composition.In some embodiments, the stabilizing polymer can be present at a concentration of about 0.1% or less, about 0.2% or less, about 0.4% or less, about 0.6% or less, about 0.8% or less, about 1% or less, about 2% or less, about 3% or less, about 4% or less, about 5% or less, about 7% or less, about 10% or less, about 12% or less, about 15% or less, or about 20% or less by weight of the composition.In some cases, more than one stabilizing polymer can be present, and each stabilizing polymer can be present in any suitable amount. As a specific example, in certain embodiments, the stabilizing polymer consists essentially of KELTROL® BT and / or KELTROL® RD. In certain cases, the stabilizing polymer may have a fixed ratio of KELTROL® BT and / or KELTROL® RD, for example, 1:1 or 3:5 by weight. In another example, KELTROL® BT may be present at a concentration of about 0.3% by weight, and KELTROL® RD may be present at a concentration of 0.5% by weight of the composition, or one or both may be present at one of the other concentrations described above. Combinations of these and / or other stabilizing polymers, such as KELTROL® BT and xanthan gum, KELTROL® RD and xanthan gum, etc., are also contemplated in other embodiments. In some cases, a thickening agent may be used in place of or in conjunction with the stabilizing polymer. Many thickening agents are commercially available. Thickening agents include those used in the food industry or are GRAS agents (generally regarded as safe), such as alginin, guar gum, locust bean gum, collagen, egg white, furcellaran, gelatin, agar and / or carrageenan, and combinations of these and / or other stabilizing polymers.It should therefore be understood that references herein to stabilizing polymers in other embodiments should be understood to also include thickeners in addition to or in place of the stabilizing polymer.

[0070] Propylene glycol is commercially available and can be present as a racemic mixture of any stereoisomer or isomer. Propylene glycol can also be present at any suitable concentration. For example, propylene glycol can be present at a concentration of at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, or at least about 10% by weight of the composition. In some embodiments, propylene glycol can be present at a concentration of about 2% or less, about 4% or less, about 6% or less, about 8% or less, about 10% or less, about 12% or less, about 15% or less, about 20% or less, or about 25% or less by weight of the composition. In some cases, other glycols, such as butylene glycol, can be used in combination with or instead of propylene glycol. Thus, it should be understood that references herein to propylene glycol in other embodiments should be understood to include other glycols (e.g., low molecular weight glycols or polyglycols as described herein) in addition to or in place of propylene glycol.

[0071] In addition, polysorbate surfactants can be present in the composition at any suitable concentration. For example, in some cases, polysorbate surfactants can be present at a concentration of at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, or at least about 10% by weight of the composition. In certain embodiments, polysorbate surfactants can be present at a concentration of about 2% or less, about 4% or less, about 6% or less, about 8% or less, about 10% or less, about 12% or less, about 15% or less, about 20% or less, or about 25% or less by weight of the composition. "Polysorbate surfactants" as used herein refers to surfactants containing polysorbates. For example, the surfactant can include sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, or another sorbitan salt. In some cases, the polysorbate surfactant has the molecular formula:

[0072] [ka] where w, x, y, and z are any suitable positive integers. Each of w, x, y, and z may independently be the same or different. In one set of embodiments, w+x+y+z is 20 (e.g., as in polysorbate 20). In some cases, other polymeric sugars may be used in place of or in combination with polysorbate surfactants. Thus, it should be understood that references herein to polysorbate surfactants are by way of example only, and that in other embodiments, references to polysorbate surfactants may be understood to include other polymeric sugars in combination with or in place of polysorbate surfactants.

[0073] In some cases, the composition may have a fixed ratio of stabilizing polymer to propylene glycol to polysorbate surfactant. For example, these ratios may be about 1:1:1, about 1:6:3, about 1:6:2, about 1:7:2, about 1:7:3, about 1.5:1:1, about 1.5:6:3, about 1.5:6:4, about 1:6:2.5, about 1:6.25:2.5, about 1:6.25:2.5, etc. As mentioned above, such ratios may be useful in certain embodiments of the present invention to provide temperature stability to the composition.

[0074] In certain aspects of the invention, a pharmaceutical agent may be combined with a penetrating agent, i.e., an agent that increases transport of the pharmaceutical agent into the skin compared to transport in the absence of the penetrating agent. In some embodiments, the penetrating agent may define and / or be combined with a hostile biophysical environment. Examples of penetrating agents include oleoresin capsicum or components thereof, or certain molecules containing a heterocyclic ring to which a hydrocarbon chain is attached.

[0075] Non-limiting examples of osmotic agents include, but are not limited to, cationic, anionic, or nonionic surfactants (e.g., sodium dodecyl sulfate, polyoxamers, etc.); fatty acids and alcohols (e.g., ethanol, oleic acid, lauric acid, liposomes, etc.); anticholinergic agents (e.g., benzilonium bromide, oxyphenonium bromide); alkanones (e.g., n-heptane); amides (e.g., urea, N,N-dimethyl-m-toluamide); fatty acid esters (e.g., n-butyrate); organic acids (e.g., citric acid); polyols (e.g., ethylene glycol, glycerol); sulfoxides (e.g., dimethyl sulfoxide); terpenes (e.g., cyclohexene); urea; sugars; carbohydrates, or other agents. In certain embodiments, the osmotic agent comprises a salt, for example, as described herein.

[0076] Thus, another aspect of the present invention provides for the delivery of pharmaceutical agents (e.g., drugs, biological compounds, etc.) into the body; such treatment may be systemic or localized, and may be targeted to specific locations on a subject's body, such as the head, one or more specific muscles, arms, legs, genitals, etc., depending on the particular application.

[0077] In one set of embodiments, pharmaceutical agents are introduced to aid in the treatment of medical conditions or diseases and their associated symptoms. In some embodiments, the present invention provides treatment of medical conditions or diseases and / or illnesses using pharmaceutical agents (e.g., to treat a subject diagnosed with a medical condition or disease), and in some cases, the present invention provides delivery of minimal amounts of pharmaceutical agents to provide effective levels of medication locally to the affected area while limiting side effects. In some cases, the effective dosage of the pharmaceutical agent may be lower than the effective dosage of the pharmaceutical agent when taken orally. Another embodiment of the present invention provides a method for treating erectile dysfunction. Thus, in some embodiments, the composition may be applied locally to a specific location on the body, for example, to the penis. In certain cases, the compositions described herein may also be used in the preparation of a medicament for treating erectile dysfunction or other diseases or conditions as discussed herein.

[0078] In another aspect, the present invention is directed to a kit comprising one or more of the compositions discussed herein.As used herein, "kit" typically defines a package or structure comprising one or more of the compositions of the present invention and / or other compositions related to the present invention, for example, as described herein.Each of the compositions of the kit can be provided in liquid form (e.g., in solution) or solid form (e.g., dry powder).In certain cases, some of the compositions can be configured or otherwise processed (e.g., into active form), for example, by adding suitable solvents or other species, which may or may not be included in the kit. Examples of other compositions or components relevant to the present invention include, but are not limited to, solvents, surfactants, excipients, salts, buffers, emulsifiers, chelating agents, fillers, antioxidants, binders, bulking agents, preservatives, desiccants, antimicrobial agents, needles, syringes, packaging materials, tubes, bottles, flasks, beakers, petri dishes, frits, filters, rings, clamps, wraps, patches, containers, etc., for using, administering, modifying, constructing, storing, packaging, preparing, mixing, diluting, and / or preserving composition components, e.g., for a particular use, e.g., to a sample and / or subject.

[0079] In some cases, the kit of the present invention can include any form of instruction provided in connection with the composition of the present invention, in a manner that a person skilled in the art would recognize that the instruction is related to the composition of the present invention.For example, the instruction can include instructions for using, modifying, mixing, diluting, preserving, administering, constructing, storing, packaging, and / or preparing the composition and / or other compositions related to the kit.In some cases, the instruction can also include instructions for a specific use, for example, for delivering and / or administering the composition to a sample and / or subject.The instruction can be provided in any form that a person skilled in the art can recognize as a suitable vehicle for containing such instructions, for example, written or published, verbal, audio (e.g., by telephone), digital, optical, visual (e.g., videotape, DVD, etc.), or electronic communication (including Internet or web-based communication), provided in any manner.

[0080] In some embodiments, the present invention is directed to methods of promoting one or more embodiments of the present invention as discussed herein, e.g., methods of promoting the making or use of compositions such as those discussed above, methods of promoting kits as discussed above, etc. As used herein, "promoted" includes all methods of doing business, including, but not limited to, methods of selling, advertising, transferring, licensing, contracting, teaching, teaching, researching, importing, exporting, negotiating, financing, lending, trading, peddling, reselling, distributing, repairing, bartering, insuring, litigating, patenting, etc., relating to systems, devices, apparatus, articles, methods, compositions, kits, etc. of the present invention as discussed herein. Methods of promotion can be conducted by any party, including, but not limited to, individual parties, businesses (public or private), partnerships, corporations, trusts, contracting or subcontracting organizations, educational institutions such as colleges and universities, research facilities, hospitals or other clinical facilities, government agencies, etc. Promotional activities may include any form of communication specifically related to the present invention (e.g., written, oral, and / or electronic communication, including but not limited to email, telephone, internet, web-based, etc.).

[0081] In one set of embodiments, the promotional method may be accompanied by one or more instructions. As used herein, "instructions" may define the practical components of the instructions (e.g., instructions, guidelines, warnings, labels, notes, FAQs or "frequently asked questions," etc.), and may typically be accompanied by written instructions about or related to the present invention and / or packaging of the present invention. Instructions may also include communication of instructions in any form (e.g., oral, electronic, audio, digital, optical, visual, etc.), provided in any manner that clearly identifies the user that the instructions relate to the present invention, for example, as discussed herein.

[0082] The following documents are incorporated herein by reference: International Patent Application No. PCT / US98 / 19429, filed September 17, 1998, by E.T. Fossel, entitled "A Delivery of Arginine to Cause Beneficial Effects," published March 25, 1999 as WO 99 / 13717; U.S. Patent Application No. 11 / 587,323, filed October 19, 2006, by E.T. Fossel, entitled "Transdermal Delivery of Beneficial Substances Effected by a Hostile Biophysical Environment," published November 13, 2008 as U.S. Patent Application Publication No. 2008 / 0280984; and U.S. Patent Application No. 11 / 587,323, filed October 19, 2006, by E.T. Fossel, entitled "Transdermal Delivery of Beneficial Substances Effected by a Hostile Biophysical Environment," published November 13, 2008 as U.S. Patent Application Publication No. 2008 / 0280984. U.S. Patent Application No. 11 / 587,328, published April 23, 2009 as U.S. Patent Application Publication No. 2009 / 0105336, by E.T. Fossel, entitled "A Novel Method for Improving Local Blood Flow in Patients with Diabetic Retinopathy," in which the patient is treated with steroids.

[0083] Also, the application was filed on February 23, 2005, and is entitled "Topical Delivery of International Patent Application No. PCT / US2005 / 005726, filed on September 9, 2005, by E. Fossel, entitled "A Nitric Oxide Donor to Improve Body and Skin Appearance," published as WO2005 / 081964; International Patent Application No. PCT / US2005 / 013228, filed on April 19, 2005, by E. Fossel, entitled "Transdermal Delivery of Beneficial Substances Effected by a Hostile Biophysical Environment," published as WO2005 / 102282; International Patent Application No. PCT / US2005 / 013228, filed on April 19, 2005, by E. Fossel, entitled "Beneficial Effects of International Patent Application No. PCT / US2005 / 013230, filed September 17, 1997, by E. Fossel, entitled "Increasing Local Blood Flow," published as WO2005 / 102307; U.S. Patent Application No. 08 / 932,227, filed September 17, 1997, by E.T. Fossel, entitled "Topical Delivery of Arginine to Cause Beneficial Effects," published as 2002 / 0041903; U.S. Patent Application No. 08 / 932,227, filed July 22, 2002, by E.T. Fossel, entitled "Topical Delivery of L-Arginine to Cause Beneficial Effects," published as 2002 / 0041903; U.S. Patent Application No. 10 / 201,635, entitled "Topical and Oral Arginine to Cause Beneficial Effects," filed on August 5, 2002, by E.T. Fossel, published as 2003 / 0028169; U.S. Patent Application No. 10 / 213,286, entitled "Topical and Oral Arginine to Cause Beneficial Effects," filed on January 23, 2003, by E.T. Fossel, published as 2003 / 0018076; U.S. Patent No. 5,895,658, entitled "Topical Delivery of L-Arginine to Cause Tissue Warming," issued on April 20, 1999, by E.T. Fossel; U.S. Patent No. 5,895,658, entitled "Topical Delivery of L-Arginine to Cause Tissue Warming," issued on July 13, 1999, by E.T. Fossel; U.S. Patent No. 5,922,332 to E.T. Fossel, issued on March 27, 2001, entitled "Topical and Oral Delivery of Arginine to Cause Beneficial Effects"; and U.S. Patent No. 6,207,713 to E.T. Fossel, issued on October 1, 2002, entitled "Topical and Oral Delivery of Arginine to Cause Beneficial Effects." Also incorporated herein by reference is U.S. Patent No. 6,458,841 by ET Fossel, entitled "Arginine to Cause Beneficial Effects."

[0084] Additionally, incorporated herein by reference in their entireties are U.S. Provisional Patent Application No. 61 / 427,999, filed December 29, 2010, by E.T. Fossel, entitled "Treatment of Erectile Dysfunction and Other Indications"; and U.S. Provisional Patent Application No. 61 / 428,213, filed December 29, 2010, by E.T. Fossel, entitled "Methods and Compositions for Preparing Emulsions for Topical Drug Delivery."

[0085] The following examples are intended to illustrate certain embodiments of the present invention, but do not exemplify the full scope of the invention. [Example]

[0086] Example 1 This prophetic example illustrates one method of preparing a transdermal formula of the present invention containing sildenafil, tadalafil, or vardenafil. The final composition is shown in Table 1. Of course, one of ordinary skill in the art will recognize that percentages other than those listed below are possible according to other embodiments of the present invention.

[0087] [Table 1] To prepare the formulation in this example, sodium chloride, potassium chloride, L-arginine, and sildenafil, tadalafil, or vardenafil were mixed in water and then heated to 74°C with rapid mixing. In a separate container, the remaining ingredients were mixed together and heated to 74°C. The other ingredients were then added to the water phase at 74°C with rapid mixing. The mixture was then cooled to room temperature with continued mixing. At this point, an emulsion was formed with a relatively thin consistency. The emulsion was then homogenized at high speed at room temperature to thicken the consistency.

[0088] Example 2 First, it should be understood that the compositions described in this example for the first aqueous and second non-aqueous preparations for use with ibuprofen may be used for other drugs or other pharmaceutical agents, such as those described herein (e.g., type 5 phosphodiesterase inhibitors), or may be modified to contain equivalent or similar compounds (or a subset thereof) for use with different drugs or other pharmaceutical agents, and each drug or other pharmaceutical agent may be provided individually in the first preparation, the second preparation, or both.

[0089] Ibuprofen sodium salt is water-soluble at pH 7.0 and is added to the aqueous phase. Any suitable ibuprofen salt can be used. For example, commercially available ibuprofen salts can be used. In some embodiments, the ibuprofen preparation is prepared to have the following relative composition (Table 2):

[0090] [Table 2] The basic manufacturing process is to form an emulsion by mixing the water phase and the oil phase at high temperature and with rapid mixing. After the two phases are mixed, the mixture is cooled to room temperature. While cooling, homomixing is carried out in a vertical colloid mill. For example, in one set of embodiments, the following manufacturing steps can be used.

[0091] Step 1: Disperse xanthan gum in propylene glycol and water and mix to fully hydrate.

[0092] Step 2: Add ibuprofen and sodium hydroxide to the above mixture to form sodium ibuprofen, then add sodium chloride, potassium chloride and L-arginine HCl. Heat the mixture to 75-80°C.

[0093] Step 3: Glyceryl stearate SE, cetyl alcohol, squalane, isopropyl myristate, oleic acid and polysorbate-20 are added and the mixture is heated to 75-80°C.

[0094] Step 4: The mixtures produced in Steps 2 and 3 are combined and mixed well while maintaining the temperature.

[0095] Step 5: Cool the mixture from Step 4 to 25°C to 30°C while circulating it through a vertical colloid mill.

[0096] The resulting smooth emulsion has a pH of 6.50 to 7.50. In some cases, the preparation may be manufactured under conditions to minimize microbial content (e.g., completely sterile, or with a microbiological content of less than about 100 CFU / g).

[0097] In some embodiments, the transdermal ibuprofen cream is packaged in a 100 ml "Magic Star Dispenser," an airless pump that dispenses 1.45 ml with each depression of the pump head.

[0098] Similar procedures can be used to prepare emulsions of other compounds described herein. In some embodiments, the compound is added to the oil phase before mixing with the aqueous phase. In some embodiments, the compound is added to the aqueous phase before mixing with the oil phase.

[0099] Example 3 Uses of topical sildenafil compositions A 66-year-old man with erectile dysfunction was given a cream containing 5% sildenafil in an oil / water emulsion with added 10% sodium chloride, 5% potassium chloride, and 2.5% magnesium chloride. The pH was 6.5. 15 minutes before initiating sexual activity, one gram of the cream was applied to the penis and gently rubbed in until absorbed. Upon sexual activity, a fully functional erection was achieved, and sexual activity proceeded until successful completion.

[0100] The formulation of the topical composition used for sildenafil is presented below in Table 3 (shown as weight percent). It should be understood that in some embodiments, the relative amount of each component may vary (e.g., by about 10%). It should also be understood that this topical composition can be used for other inhibitors (e.g., one or more examples of type 5 phosphodiesterase inhibitors, including, but not limited to, avanafil, lodenafil, mirodenafil, tadalafil, vardenafil, udenafil, acetyldenafil, or thiomethisosildenafil). In some embodiments, the active compound (e.g., sildenafil) can be added to the oil phase before mixing with the aqueous phase. However, other compounds can be added to the aqueous phase before mixing with the oil phase.

[0101] [Table 3] While several embodiments of the present invention have been described and illustrated herein, those skilled in the art will readily conceive of a variety of other means and / or structures for performing the functions and / or obtaining the results and / or one or more of the advantages described herein, and each such variation and / or modification is deemed to be within the scope of the present invention. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary, and that the actual parameters, dimensions, materials, and / or configurations will depend on the specific application(s) in which the teachings of the present invention are used. Those skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Accordingly, it should be understood that the foregoing embodiments are presented by way of example only, and that, within the scope of the appended claims and their equivalents, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits and / or methods is included within the scope of the present invention, unless such features, systems, articles, materials, kits and / or methods are mutually inconsistent.

[0102] All definitions as defined and used herein should be understood to supersede dictionary definitions, definitions in documents incorporated by reference, and / or ordinary meanings of the defined terms.

[0103] The indefinite articles "a" and "an," as used herein in the specification and claims, unless clearly indicated to the contrary, should be understood to mean "at least one."

[0104] The term "and / or," as used herein in the specification and claims, should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are conjunctive in some cases and disjunctive in other cases. Multiple elements listed with "and / or" should be construed in the same manner, i.e., "one or more" of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the "and / or" clause, whether related to the specifically identified elements or not. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open-ended language such as "comprising," can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0105] As used herein in the specification and claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" shall be interpreted as inclusive, i.e., the inclusion of at least one but more than one element or list of elements, and optionally the inclusion of additional unlisted items. When used only in terms clearly indicating the contrary, such as "only one of" or "exactly one of," or in the claims, "consisting of" shall refer to the inclusion of exactly one element of any element or list of elements. In general, the term "or," when used herein, when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of," shall be interpreted as indicating exclusive alternatives (i.e., "one or the other, but not both"). "Consisting essentially of," when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0106] As used herein in the specification and claims, the phrase "at least one" in reference to a list of one or more elements should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed in the list of elements, and not excluding any combination of elements in the list of elements. This definition also allows for the possibility that elements other than those specifically identified may occasionally be present in the list of elements to which the phrase "at least one" refers, whether related to the specifically identified elements or not. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B" or, equivalently, "at least one of A and / or B") can refer to, in one embodiment, at least one A, optionally including more than one A, and no B (optionally including elements other than B); in another embodiment, at least one B, optionally including more than one B, and no A (optionally including elements other than A); in yet another embodiment, at least one A, optionally including more than one A, and at least one B, optionally including more than one B (optionally including other elements); etc.

[0107] It should also be understood that, unless expressly indicated to the contrary, in any method claimed herein that includes more than one step or act, the order of the method steps or acts is not necessarily limited to the order in which the method steps or acts are described.

[0108] In the claims and in the above specification, all transitional phrases such as "comprising," "including," "possessing," "having," "containing," "with," "holding," "consisting of," and the like, are to be construed as open-ended, i.e., to mean including but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" are used in accordance with the United States Patent Office Manual of Patents Each shall be a closed or semi-closed transitional phrase as explained in Examining Procedures, Section 2111.03.

Claims

[Claim 1] A composition or method as described in the specification.

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