Patent Description:
Phosphodiesterase type <NUM> inhibitors are drugs used to block the degradative action of phosphodiesterase type <NUM> on cyclic GMP in the smooth muscle cells lining the blood vessels supplying the corpus cavernosum of the penis. These drugs are commonly used in the treatment of erectile dysfunction.

Phosphodiesterase type <NUM> inhibitors are commonly delivered orally. Currently, no transdermal formulations of phosphodiesterase type <NUM> inhibitors have been approved by the FDA. Accordingly, systems and methods for transdermally delivering clinically useful amounts of phosphodiesterase type <NUM> inhibitors are needed.

<CIT> discloses a treatment enhancing the ability of the body to heal wounds. A topical cream is described which improves blood flow by the transdermal delivery of the nitric oxide precursor L-Arginine either alone or with an adjunct, theophylline. The delivery of the active agents is accomplished by use of a vehicle which contains a hostile biophysical environment which is also hostile to hydrogen bond formation.

The present invention generally relates to the transdermal delivery of phosphodiesterase type <NUM> inhibitors and other compounds. The subject matter of the present invention involves, in some cases, interrelated products, alternative solutions to a particular problem, and/or a plurality of different uses of one or more systems and/or articles.

Several methods are disclosed herein of administering a subject with a composition for prevention or treatment of a particular condition. It is to be understood that in each such aspect of the invention, the invention specifically relates to the composition for use in the treatment or prevention of that particular condition.

In some embodiments, aspects of the disclosure relate to compositions for delivering a phosphodiesterase type <NUM> inhibitor and/or a salt thereof to a subject. In some embodiments, a composition comprises a phosphodiesterase type <NUM> inhibitor and/or a salt thereof in a hostile biophysical environment for topical delivery to the skin of a subject. In some embodiments, a composition also comprises a nitric oxide donor. In some embodiments, a composition further comprises one or more compounds that stabilize and/or otherwise promote the efficacy of storage and/or delivery (e.g., with or without a nitric oxide donor).

In some embodiments, compositions disclosed herein increase the efficiency of direct compound delivery to a target site by using transdermal delivery thereby significantly lowering the systemic exposure and reducing potential side effects. For example, a transdermal delivery according to the disclosure can reduce systemic exposure to less than <NUM>% (e.g., less than <NUM>%, or between <NUM>% and <NUM>%, or even less) of the systemic exposure resulting from an oral dosage required for effective delivery of the compound. For example, the systemic exposure of a phosphodiesterase type <NUM> inhibitor (e.g., sildenafil) that is delivered topically according to the disclosure can be about <NUM>% of the systemic exposure resulting from oral formulations. Also, in some embodiments, compositions disclosed herein provide for unexpectedly high speeds of action of the compound being delivered (e.g., relative to oral delivery or other delivery techniques used for the compound). Accordingly, in some embodiments, aspects of the disclosure are useful for rapid therapy when delivery of a therapeutic amount of a compound within a short period of time is required. Topical delivery formulations described herein can deliver a compound to a target tissue more rapidly than an oral formulation, for example. Topical delivery formulations also allow for targeted local delivery of a therapeutically effective amount of compound without requiring a significant systemic increase in the amount of compound. However, it should be appreciated that topical formulations can be used for systemic delivery if so required.

According to a first aspect of the invention, a composition for use in a method of effectively treating sexual dysfunction according to claim <NUM>.

In some embodiments, at least about <NUM>% by weight of the composition comprises water, at least one chloride salt, a nitric oxide donor, a stabilization polymer, propylene glycol, a polysorbate surfactant, and a phosphodiesterase type <NUM> inhibitor and/or a salt thereof.

The composition, in accordance with yet another set of embodiments, includes a nitric oxide donor, a hostile biophysical environment, and a phosphodiesterase type <NUM> inhibitor and/or a salt thereof.

According to still 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 stabilization polymer, isopropyl myristate, oleic acid, propylene glycol, a polysorbate surfactant, and a phosphodiesterase type <NUM> inhibitor and/or a salt thereof.

In yet another set of embodiments, the composition comprises each of the following compounds at concentrations of no more than ±<NUM>% of the stated concentrations: water at a concentration of about <NUM>% to about <NUM>% by weight, sodium chloride at a concentration of about <NUM>% to about <NUM>% by weight, a nitric oxide donor at a concentration of about <NUM>% to about <NUM>% by weight, glyceryl stearate at a concentration of about <NUM>% to about <NUM>% by weight, cetyl alcohol at a concentration of about <NUM>% to about <NUM>% by weight, magnesium chloride at a concentration of about <NUM> % to about <NUM> % by weight, squalane at a concentration of about <NUM> % to about <NUM>% by weight, a polysorbate surfactant at a concentration of about <NUM>% to about <NUM>% by weight, isopropyl myristate at a concentration of about <NUM>% to about <NUM>% by weight, oleic acid at a concentration of about <NUM>% to about <NUM>% by weight, propylene glycol at a concentration of about <NUM>% to about <NUM>% by weight, a stabilization polymer at a concentration of about <NUM>% to about <NUM>% by weight, and a phosphodiesterase type <NUM> inhibitor and/or a salt thereof at a concentration of about <NUM>% to about <NUM>% by weight.

In some embodiments, a composition comprises approximately <NUM>% (e.g., <NUM>% to <NUM>%, or more or less) by weight of inhibitor (e.g., sildenafil or other inhibitor) in an oil/water emulsion further comprising about <NUM>% sodium chloride, <NUM>% potassium chloride, and about <NUM>% magnesium chloride. For example, the inhibitor may be a phosphodiesterase type <NUM> inhibitor and/or a salt thereof.

In some embodiments, the pH of a composition is optimized to ionize the inhibitor while remaining compatible with acceptable pH ranges for contact with the skin (e.g., within a range of about pH <NUM> to about pH <NUM>). In some embodiments, a pH below <NUM> is sufficient to ionize an inhibitor such as sildenafil or related compounds. In some embodiments, a pH of <NUM>-<NUM> (+/- <NUM>) is effective. In some embodiments, a pH of <NUM> (e.g., +/- <NUM>) is particularly effective. In some embodiments, a pH at least about <NUM> pH unit above or below (e.g., at least about <NUM> pH units above or below) the pKa of an inhibitor may be used, particularly if the pH is within the range of about pH <NUM>-<NUM> that is particularly compatible for direct topical contact with skin. The inhibitor may be, for instance, a phosphodiesterase type <NUM> inhibitor and/or a salt thereof, or any inhibitor discussed herein.

According to some embodiments, a relatively high salt concentration, for example at least about <NUM>% (e.g., about <NUM>%, about <NUM>% about <NUM>%, about <NUM>% about <NUM>%, about <NUM>-<NUM>%, weight %) is useful to provide a hostile biophysical environment that promotes transdermal migration of an inhibitor (e.g., sildenafil). In some embodiments, emulsions described herein, for example, containing a stabilization polymer and/or a polysorbate surfactant and/or propylene glycol (or a low molecular weight glycol, or a polyglycol such as polyethylene glycol or other polyglycol - however it should be appreciated that glycols with even numbers of carbons can be toxic, particularly for smaller glycols such as ethylene glycol and butylene glycol, and should be avoided or excluded) are unexpectedly effective at stabilizing the inhibitor in the high salt composition in a form that remains effective for an extended period - for example, retaining rapid transdermal delivery of the inhibitor for at least several weeks or months. In some cases, the inhibitor is a phosphodiesterase type <NUM> inhibitor and/or a salt thereof.

In some embodiments, a composition also includes a nitric oxide donor (e.g., L-Arg) that can be useful to increase local blood flow and further promote delivery of the compound. In accordance with another set of embodiments, the composition comprises a stabilization polymer, propylene glycol, a polysorbate surfactant, and a phosphodiesterase type <NUM> inhibitor and/or a salt thereof.

In still another set of embodiments, at least about <NUM>% by weight of the composition comprises water, at least one chloride salt, a stabilization polymer, propylene glycol, a polysorbate surfactant, and a phosphodiesterase type <NUM> inhibitor and/or a salt thereof.

In another aspect, the present disclosure encompasses methods of making one or more of the embodiments described herein, for example, a composition comprising a phosphodiesterase type <NUM> inhibitor. In still another aspect, the present disclosure encompasses methods of using one or more of the embodiments described herein, for example, a composition comprising a phosphodiesterase type <NUM> inhibitor. In yet another aspect, the present disclosure encompasses various uses of a composition including a phosphodiesterase type <NUM> inhibitor. For example, the composition may be used to treat erectile dysfunction.

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

In some embodiments, aspects of the disclosure relate to methods and formulations for delivering a compound locally at a fraction of the systemic dose required using oral delivery. In some embodiments, a hostile biophysical environment may be evaluated for enhancing local delivery through a topical application. Depending on the therapeutic application, an appropriate delivery configuration (e.g., a combination of compound concentration, hostile biophysical environment, cream, patch, etc.) can be used to reduce the systemic amount of the compound required for an effective therapeutic application.

In some embodiments, aspects of the invention relate to reducing or avoiding the side effects (in males and in females where side effects have caused the FDA to refuse approval) associated with systemic levels of phosphodiesterase type <NUM> inhibitors required to produce a desired local effect when administered orally. In some embodiments, aspects of the invention can be used to treat sexual dysfunction in males and/or females by providing a topical formulation of one or more phosphodiesterase type <NUM> inhibitors. The topical formulation can be used to provide local levels that are effective (e.g., by applying topically to the male or female genitalia) without causing high systemic levels that are associated with the dosages required for effective oral administration. Aspects of the invention provide a topical delivery formulation that is effective within less than <NUM> minutes after topical application as opposed to waiting for <NUM> minutes to <NUM> hour or more for an oral administration to have an effect.

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.

The present disclosure 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 <NUM> inhibitor and/or a salt thereof, and optionally, a hostile biophysical environment and/or a nitric oxide donor. In some cases, the composition may be stabilized using a combination of a stabilization polymer (such as xanthan gum, KELTROL® BT and/or KELTROL® RD), propylene glycol, and a polysorbate surfactant such as Polysorbate <NUM>, which combination unexpectedly provides temperature stability to the composition, e.g., at elevated temperatures such as at least <NUM> (at least about <NUM> °F), as compared to compositions lacking one or more of these.

According to some embodiments, compositions comprising a relatively high salt composition (e.g., high chloride content) are unexpectedly effective for topical delivery of a phosphodiesterase type <NUM> inhibitor (e.g., sildenafil or other inhibitor, including salts thereof). In some embodiments, a salt-enhanced delivery (e.g., in a composition having at least <NUM>% salt, at least <NUM>% salt, at least <NUM>% salt, at least <NUM>% salt, or higher as described herein) is particularly effective when the pH of the composition is optimized to ionize the compound being delivered (e.g., at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, or about <NUM>% or more) is ionized. It should be appreciated that depending on the pKa of the compound and the pH of the composition, the ionized form may be anionic or cationic (e.g., due to protonation). In some embodiments, a compound may contain several ionizable groups each having a different pKa. In some embodiments, it is sufficient for at least <NUM>, <NUM>, or <NUM> of the groups to be ionized for the salt-enhanced delivery to be effective. In some embodiments, an ionizable group is sufficiently ionized if the pH of the composition is at least <NUM> pH unit, or at least <NUM> pH units (e.g., <NUM>, <NUM>-<NUM>, <NUM>-<NUM>, or more pH units) below the pKa of the group and it is cationic (due to protonation) below its pKa. Similarly, in some embodiments, an ionizable group is sufficiently ionized if the pH of the composition is at least <NUM> pH unit, or at least <NUM> pH units (e.g., <NUM>, <NUM>-<NUM>, <NUM>-<NUM>, or more pH units) above the pKa of the group and it is anionic (due to deprotonation) above its pKa. In some embodiments, the presence of magnesium chloride, for example at <NUM>-<NUM>% by weight, can help stabilize composistions containing compounds with relatively high pKas (e.g., above <NUM>, above <NUM>, above <NUM> or higher). In some embodiments, the pH of a composition may be maintained using a buffer. However, the pH of compositions of the invention are surprisingly stable without a buffer. In some embodiments, a 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., sufficiently for the composition to be effective for transdermal delivery) for extended periods of time (e.g., weeks, months, or <NUM> or more years).

According to some embodiments, a high salt composition containing a phosphodiesterase type <NUM> inhibitor is unexpectedly stable when formulated as an emulsion (e.g., a water in oil emulsion or an oil in water emulsion, for example, including one or more of a stabilization polymer and/or a polysorbate surfactant and/or propylene glycol (or other low molecular weight glycol, or a polyglycol) as described herein). In some embodiments, the pH of the composition comprising the emulsion and high salt concentration is selected to ionize the compound being delivered as described herein.

In some embodiments, topical delivery according to the invention (e.g., topical delivery of phosphodiesterase type <NUM> inhibitor, for example sildenafil) provides a surprisingly rapid effect (within about <NUM>-<NUM> minutes). In contrast, an oral counterpart requires about <NUM> minutes or more to produce an effect. Accordingly, aspects of the invention provide compositions for delivering an effective treatment to a subject to treat or prevent erectile dysfunction. In some embodiments, a topical composition provided that can be applied to a genital region of a female or male subject (e.g., the penis of a male subject) to treat an erectile dysfunction (e.g., promote an erection) within less than <NUM> minutes, less than <NUM> minutes, less than <NUM> minutes, or less than <NUM> minutes of application.

One aspect of the invention provides compositions for the topical delivery of substances such as pharmaceutical agents (e.g., drugs, biological compounds, etc.). The pharmaceutical agents may be applied to the skin of a subject, e.g. a human, to aid in treatment of medical conditions or diseases, and/or the symptoms associated thereof. In some embodiments, the disclosure provides for the treatment of medical conditions or diseases and/or ailments using pharmaceutical agents (for example, to treat a subject diagnosed with a medical condition or disease, as described herein), and in some cases, the disclosure provides for the delivery of a minimum amount of pharmaceutical agents to provide effective levels of medication to an effected area topically 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.

For example, in one set of embodiments, the pharmaceutical agent is a phosphodiesterase type <NUM> inhibitor and/or a salt thereof. A phosphodiesterase type <NUM> inhibitor is a drug that blocks the degradative action of phosphodiesterase type <NUM> on cyclic GMP, e.g., in the smooth muscle cells lining the blood vessels supplying the corpus cavernosum of the penis. Part of the physiological process of erection involves the release of nitric oxide (NO) in vasculature of the corpus cavernosum as a result of sexual stimulation. NO activates the enzyme guanylate cyclase which results in increased levels of cyclic guanosine monophosphate (cGMP), leading to smooth muscle relaxation in blood vessels supplying the corpus cavernosum, resulting in increased blood flow and an erection. Accordingly, PDE5 inhibitors inhibit the degradation of cGMP by phosphodiesterase type <NUM>, increasing bloodflow to the penis during sexual stimulation.

Non-limiting examples of phosphodiesterase type <NUM> inhibitors include, but are not limited to, avanafil, lodenafil, mirodenafil (pKa of <NUM>), sildenafil (or analogs thereof, for example, actetildenafil, hydroxyacetildenafil, or dimethylsildenafil), tadalafil (pKa of <NUM>), vardenafil (pKas of <NUM>, <NUM>, <NUM>, and <NUM>), udenafil (pKa of <NUM>), acetildenafil, or thiomethisosildenafil. The structures of these compounds are respectively shown below:
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>.

Accordingly, various aspects of the invention are directed to compositions including a phosphodiesterase type <NUM> inhibitor for transdermal delivery or topical application to a subject. Other compounds such as salts or derivatives of phosphodiesterase type <NUM> inhibitors (including salts or derivatives of the above compounds) are also included in other embodiments; thus, it should be understood that in any embodiment described herein using a phosphodiesterase type <NUM> inhibitor, this is by way of example only, and other embodiments of the invention are directed to phosphodiesterase type <NUM> inhibitor salts, phosphodiesterase type <NUM> inhibitor derivatives, etc., instead of and/or in addition to phosphodiesterase type <NUM> inhibitors.

Phosphodiesterase type <NUM> inhibitors or other pharmaceutical agents (e.g., salts or derivatives of phosphodiesterase type <NUM> inhibitors, etc.) may be present at any suitable concentration. For instance, in some cases, the pharmaceutical agent may be present at a concentration of at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, or at least about <NUM>% by weight of the composition. In certain embodiments, the pharmaceutical agent may be present at a concentration of no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, or no more than about <NUM>% by weight of the composition. In addition, the pharmaceutical agent may be present in native form and/or as one or more salts. For example, if a phosphodiesterase type <NUM> inhibitor is present, it may be used in its native form, and/or as one or more salts, e.g., the sodium salt, the potassium salt, the magnesium salt, the lysine salt, the arginine salt, the lactate salt, or the citrate salt of a phosphodiesterase type <NUM> inhibitor, e.g., avanafil, lodenafil, mirodenafil, sildenafil, tadalafil, vardenafil, udenafil, acetildenafil, thiomethisosildenafil, etc. For salt forms of the pharmaceutical agent, "by weight of the composition" includes the entire salt form of the pharmaceutical agent, e.g., the agent itself as well as any counterions such as sodium, potassium, etc. The amount of the pharmaceutical agent may be determined in a composition, for example, using techniques such as HPLC or HPLC/MS that are known to those of ordinary skill in the art.

Many phosphodiesterase type <NUM> inhibitors are readily commercially available. In some cases, the phosphodiesterase type <NUM> inhibitor may be obtained as a racemic mixture, for example, of tadalafil (e.g., (R,R)-tadalafil, (R,S)-tadalafil, (S,R)-tadalafil, and (S,S)-tadalafil). However, in other cases, one of the enantiomers may be present in an amount greater than the other. For example, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, or at least about <NUM>% of the phosphodiesterase type <NUM> inhibitor within the composition may be present as one of the enantiomers. Techniques for preparing or separating racemic phosphodiesterase type <NUM> inhibitors are known; see, for example, <NPL>.

The composition may also comprise a nitric oxide donor in some embodiments, for example, L-arginine and/or L-arginine hydrochloride. In some cases, such a nitric oxide donor may be used to increase localized blood flow at the site where the composition is applied, which may enhance delivery of the pharmaceutical agent. The nitric oxide donor may be present at any suitable concentration within the composition. For instance, in some cases, the nitric oxide donor is present at a concentration of at least about <NUM> %, at least about <NUM>%, at least about <NUM> %, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, or at least about <NUM>% by weight of the composition. In some cases, one or more nitric oxide donors (e.g., <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, etc. nitric oxide donors) may be used. In some cases, there may be no more than <NUM>, <NUM>, <NUM>, or <NUM> nitric oxide donors present within the composition.

A "nitric oxide donor," as used herein, is a compound that is able to release nitric oxide and/or chemically transfer the nitric oxide moiety to another molecule, directly or indirectly, for example, through a biological process. The nitric oxide donor may release nitric oxide into the skin, and/or tissues such as muscles and/or elements of the circulatory system in close proximity to the surface of the skin. 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, <NUM>,<NUM>-(nitrooxymethyl)phenyl-<NUM>-hydroxybenzoate, etc., and/or any combination of these and/or other compounds.

Besides 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., a methyl ester, an ethyl ester, a propyl ester, a butyl ester, etc.) and/or salts thereof, as well as other derivatives of arginine and other nitric oxide donors. For instance, non-limiting examples of pharmaceutically acceptable salts include hydrochloride, glutamate, butyrate, or glycolate (e.g., resulting in L-arginine glutamate, L-arginine butyrate, L-arginine glycolate, D-arginine hydrochloride, D-arginine glutamate, etc.). Still other examples of nitric oxide donors include L-arginine-based compounds such as, but not limited to, L-homoarginine, N-hydroxy-L-arginine, nitrosylated L-arginine, nitrosylated L-arginine, nitrosylated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, citrulline, ornithine, finsidomine, nipride, glutamine, etc., and salts thereof (e.g., hydrochloride, glutamate, butyrate, glycolate, etc.), and/or any combination of these and/or other compounds. Still other non-limiting examples of nitric oxide donors include S-nitrosothiols, nitrites, <NUM>-hydroxy-<NUM>-nitrosohydrazines, or substrates of various forms of nitric oxide synthase. In some cases, the nitric oxide donor may be a compound that stimulates 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 endothelein, and/or any combination of these and/or other compounds.

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

In some cases, the concentration of the nitric oxide donor within the composition may be tailored to have a duration of effective treatment of at least about <NUM> hours, at least about <NUM> hours, or at least about <NUM> hours or more in certain instances. The duration may also be controlled, for instance, by controlling the concentration of a penetrating agent used in conjunction with the nitric oxide donor. Penetration agents are discussed in detail herein. The actual concentration for a particular application can be determined by those of ordinary skill in the art using no more than routine experimentation, for example, by measuring the amount of transport of the nitric oxide donor as a function of concentration in vitro across cadaver skin or suitable animal models, skin grafts, synthetic model membranes, human models, or the like.

As a particular non-limiting example, in certain embodiments, nitric oxide is provided using L-arginine, for example, at a concentration of at least about <NUM>% by weight (wt% or w/v) of L-arginine (optionally with one or more penetrating agents as discussed herein, for example, a penetrating agent able to create a hostile biophysical environment), at least about <NUM> wt%, at least about <NUM> wt%, at least about <NUM> wt%, at least about <NUM> wt%, at least about <NUM> wt%, at least about <NUM> wt%, at least about <NUM> wt%, or at least about <NUM> wt%. The L-arginine may be present in a suitable delivery vehicle, such as a cream or a lotion. L-arginine may be particularly useful in some cases due to its low toxicity, its high solubility, and/or its low cost. Other examples of nitric oxide donors are discussed in International Patent Application No. <CIT>, entitled "Topical Delivery of a Nitric Oxide Donor to Improve Body and Skin Appearance," by E. Fossel, published as <CIT>.

Without wishing to be bound to any theory, it is generally believed that the flow of the pharmaceutical agent across the skin may slow as it builds up within the tissue. Fick's first law of diffusion suggests that when the concentration inside becomes substantially equal to that outside, passive flow stops. The increased local blood flow may prevent or at least decrease the stoppage of the flow of the pharmaceutical agent. Thus, when the composition is applied to the skin, the pharmaceutical agent exits the vehicle into the tissue more readily, as the pharmaceutical agent is dispersed by flow and does not build up in concentration in the tissue. Thus, in certain embodiments, pharmaceutical agents may be introduced into the skin, for example, a phosphodiesterase type <NUM> inhibitor and/or a salt or derivative of a phosphodiesterase type <NUM> inhibitor, such as avanafil, lodenafil, mirodenafil, sildenafil, tadalafil, vardenafil, udenafil, acetildenafil, or thiomethisosildenafil. Accordingly, the composition may be delivered locally and/or systemically; initially, much of the delivery is at first local (i.e., through the skin), but in some cases, the pharmaceutical agents may also be distributed systemically, e.g., upon reaching the blood supply.

The composition may also comprise a hostile biophysical environment to a phosphodiesterase type <NUM> inhibitor in some embodiments. In a hostile biophysical environment, the environment surrounding the pharmaceutical agent (e.g., a phosphodiesterase type <NUM> inhibitor, etc.) may be such that the pharmaceutical agent is in a chemically and/or energetically unfavorable environment, relative to the skin (e.g., the chemical potential and/or the free energy of the pharmaceutical agent within the hostile biophysical environment is significantly greater than the chemical potential and/or the free energy of the pharmaceutical agent within the skin, thus energetically favoring transport into the skin), especially the stratum corneum.

Examples of such compositions are discussed in International Patent Application No. <CIT>, entitled "Transdermal Delivery of Beneficial Substances Effected by a Hostile Biophysical Environment," by<CIT>. Other techniques for hostile biophysical environments are discussed in detail herein. Accordingly, certain embodiments of the 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 phosphodiesterase type <NUM> inhibitor, or a salt or a derivative of a phosphodiesterase type <NUM> inhibitor, or the like.

A hostile biophysical environment of the invention can comprise, in various embodiments, high ionic strength, a high concentration of osmotic agents such as ureas, sugars, or carbohydrates, a high pH environment (e.g., greater than about <NUM>, greater than about <NUM>, greater than about <NUM>, greater than about <NUM>, greater than about <NUM>, greater than about <NUM>, or greater than about <NUM>), a low pH environment (less than about <NUM>, less than about <NUM>, less than about <NUM> or less than about <NUM>), 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. A hydrophobic component may, in some embodiments, have an octanol-water partition coefficient of at least about <NUM>, at least about <NUM>, at least about <NUM><NUM>, at least about <NUM><NUM>, or more in some cases. Similarly, a hydrophilic component may have an octanol-water partition coefficient of less than about <NUM>, less than about <NUM>-<NUM>, less than about <NUM>-<NUM>, or less than about <NUM>-<NUM> in some cases.

In some cases, the composition defines the biophysical hostile environment. In other cases, a pharmaceutical agent may be packaged in such a way that it is carried into tissue and/or its charge is neutralized by derivitization and/or by forming a neutral salt. Examples of biophysically hostile environments include, but are not limited to, high ionic strength environments (e.g., by the addition of ureas, 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 combinations of these and/or other agents, for instance at high ionic strengths (for example, greater than about <NUM>, greater than about <NUM>, greater than about <NUM>, greater than about <NUM>, greater than about <NUM>, greater than about <NUM>, greater than about <NUM>, greater than about <NUM>, greater than about <NUM>, etc., or in some cases, between about <NUM> and about <NUM>, between about <NUM> and about <NUM>, between about <NUM> and about <NUM>, etc.); high or low pH environments (e.g., by adding pharmaceutically acceptable acids or bases, for example, such that the pH is between about <NUM> and about <NUM>, between about <NUM> and about <NUM>, between about <NUM> and about <NUM>, between about <NUM> and <NUM>, between about <NUM> and about <NUM>, between about <NUM> and <NUM>, between about <NUM> and about <NUM>, between about <NUM> and about <NUM>, between about <NUM> and about <NUM>, etc.); or highly hydrophobic environments (e.g., by decreasing water content and increasing lipid, oil and/or wax content of the environment). In some embodiments, the ionic strength is any amount greater than two times the physiological ionic strength of blood. The ionic strength of a composition can be readily controlled in certain embodiments by controlling the amounts or concentrations of one or more of the salts present in the composition, e.g., by controlling the amount of sodium chloride, magnesium chloride, choline chloride, etc., and/or other salts.

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

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

In one set of embodiments, the composition may be present as an emulsion. As known by those of ordinary skill in the art, an emulsion typically includes a first phase (e.g., a discontinuous phase) contained within a second fluid phase (e.g., a continuous phase). The pharmaceutical agent (e.g., a phosphodiesterase type <NUM> inhibitor) may be present in either or both phases. In addition, other materials such as those described herein may be present in the same phase as the pharmaceutical agent.

In some embodiments, an emulsion may be prepared to contain a drug (or other pharmaceutical agent) of interest in a hostile biophysical environment, and optionally one or more of a stabilization polymer, propylene glycol, and/or a polysorbate surfactant. An emulsion may also comprise a nitric oxide donor in some embodiments, for example, L-arginine and/or L-arginine hydrochloride.

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

In some embodiments, an emulsion is prepared by mixing a first aqueous preparation (e.g., a water phase) with a second non-aqueous preparation (e.g., an oil or lipid phase). Drugs or other pharmaceutical agents that are water-soluble may be added to the first aqueous preparation (e.g., prior to mixing with the second non-aqueous preparation). Drugs or other pharmaceutical agents that are water insoluble (or relatively water insoluble) may be added to the second non-aqueous preparation (e.g., prior to mixing with the first aqueous preparation). Drugs or other pharmaceutical agents that are partially water soluble may be added to one phase, or may be split between the two phases prior to mixing. The split between the two phases will depend on the amount of drug (or other pharmaceutical agent) that is being added, the composition (e.g., the nature and the amount of other chemicals or agents) of the first and second preparations, the pH, the temperature, other physical or chemical factors, and/or a combination thereof. For example, if a drug of interest is soluble at a <NUM> % level in the aqueous (e.g., water or buffer) phase, but a <NUM>% level of the drug is required in the emulsion, then the drug may also be added to the non-aqueous (e.g., lipid) phase at a <NUM> % level. In some embodiments, a drug that is less than <NUM>% soluble in an aqueous phase is provided in the non-aqueous phase prior to mixing. However, it should be appreciated that other percentages and/or splits between the two phases may be used.

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. In order to prevent a high salt concentration from breaking down an emulsion, one or more emulsifying agents may be used in some cases. In some embodiments, the mixing time may be adjusted to promote appropriate mixing and/or emulsion formation.

In some embodiments, the temperature of the first and/or second preparation may be controlled to promote solubility, mixing, and/or emulsion formation. In some embodiments, the temperature of one or both preparations and/or of the mixing may be set at <NUM> or higher (e.g., <NUM> or higher, <NUM> or higher, <NUM> or higher, <NUM> or higher, <NUM> or higher, or <NUM> or higher). For example, the temperature may be at between <NUM> and <NUM>, between <NUM> and <NUM>, at around <NUM>, at around <NUM>, or at around <NUM>.

It should be appreciated that compositions for use according to the invention may be used with any suitable drug or pharmaceutical agent. In some embodiments, for example, an oral drug may be formulated for topical delivery using one or more compositions or methods described herein. A topical formulation may be useful to deliver 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 systemic levels required for effectiveness when the drug is administered orally. Accordingly, a topical formulation may be useful to deliver an amount of a drug that is sufficient to cause a desired effect (e.g., a therapeutic effect) but that is lower than the total amount of the drug that would be administered to a subject (e.g., a human) if it were provided orally.

Emulsions of the invention may be packaged using any suitable format (e.g., in a tube, a pump-actuated container, or any other suitable form), in certain embodiments of the invention. For example, in some embodiments, an emulsion may be added to a surface of a patch or bandage. The emulsion may also be applied to the skin of a subject as a cream, gel, liquid, lotion, spray, aerosol, or the like.

Methods and compositions such as any of those discussed herein may be used to prepare a composition that is sterile or that has a low microbial content, in some embodiments.

In some aspects of the invention, a composition of the invention is administered to a subject using a delivery vehicle such as a cream, gel, liquid, lotion, spray, aerosol, or transdermal patch. In one set of embodiments, a composition of the invention may be applied or impregnated in a bandage or a patch applied to the skin of a subject. In some embodiments, a patch has a skin contacting portion made of any suitable material that is covered or impregnated with a cream or emulsion described herein, wherein the skin contacting portion may be supported by a backing, one or both of which may have an adhesive segment or other configuration for attaching to the skin surface of a subject. A "subject," as used herein, means a human or non-human animal. Examples of subjects include, but are not limited to, a mammal such as a dog, a cat, a horse, a donkey, a rabbit, a cow, a pig, a sheep, a goat, a rat (e.g., Rattus Norvegicus), a mouse (e.g., Mus musculus), a guinea pig, a hamster, a primate (e.g., a monkey, a chimpanzee, a baboon, an ape, a gorilla, etc.), or the like. Such delivery vehicles may be applied to the skin of a subject, such as a human subject. Examples of delivery vehicles are discussed herein. The delivery vehicle may promote transfer into the skin of an effective concentration of the nitric oxide donor and/or the pharmaceutical agent, directly or indirectly. For instance, the delivery vehicle may include one or more penetrating agents, as further described herein. Those of ordinary skill in the art will know of systems and techniques for incorporating a nitric oxide donor and/or a pharmaceutical agent within delivery vehicles such as a cream, gel, liquid, lotion, spray, aerosol, or transdermal patch. In some cases, the concentration of the nitric oxide donor, and/or a pharmaceutical agent in the delivery vehicle can be reduced with the inclusion of a greater amount or concentration of penetrating agent, or increased to lengthen the beneficial effect. In one set of embodiments, the nitric oxide donor and/or the pharmaceutical agent may be used in conjunction with an adjunct, such as theophylline (for example, at <NUM>% weight by volume).

Other materials may be present within the delivery vehicle, for example, buffers, preservatives, surfactants, etc. For instance, the 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 <NUM>, propylene glycol, oleic acid, tocopherol acetate, collagen, sorbitan stearate, vitamin A and D, triethanolamine, methylparaben, aloe vera extract, imidazolidinyl urea, propylparaben, PND, and/or BHA.

As specific non-limiting examples, a cream may have one or more of (w/v): water (<NUM>-<NUM>%), white oil (<NUM>-<NUM>%), glyceryl stearate (<NUM>-<NUM>%), squalene (<NUM>-<NUM>%), cetyl alcohol (<NUM>-<NUM>%), propylene glycol stearate (<NUM>-<NUM>%), wheat germ oil (<NUM>-<NUM>%), polysorbate <NUM> (<NUM>-<NUM>%), propylene glycol (<NUM>-<NUM>%), collagen (<NUM>-<NUM>%), sorbitan stearate (<NUM>-<NUM>%), vitamin A (<NUM>-<NUM>%), vitamin D (<NUM>-<NUM>%), vitamin E (<NUM>-<NUM>%), triethanolamine (<NUM>-<NUM>%), methylparaben (<NUM>-<NUM>%), aloe vera extract (<NUM>-<NUM>%), imidazolidinyl urea (<NUM>-<NUM>%), propylparaben (<NUM>-<NUM>%), BHA (<NUM>-<NUM>%), L-arginine hydrochloride (<NUM>-<NUM>%), sodium chloride (<NUM>-<NUM>%), magnesium chloride (<NUM>-<NUM>%), and/or choline chloride (<NUM>-<NUM>%). The percentages of each compound can vary (or the compound may be absent in some cases), for example, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, etc..

In another embodiment, the cream may include a pharmaceutical agent, for instance, a phosphodiesterase type <NUM> inhibitor such as those described herein, and one or more of the following, in any suitable amount: water (e.g., <NUM>-<NUM>%), L-arginine hydrochloride (e.g., <NUM>-<NUM>%), sodium chloride (e.g., <NUM>-<NUM>%), potassium chloride (e.g., <NUM>-<NUM>%), glyeryl steareate (e.g., <NUM>-<NUM>%), cetyl alcohol (e.g., <NUM>-<NUM>%), squalene (e.g., <NUM>-<NUM>%), isopropyl mysterate (e.g., <NUM>-<NUM>%), oleic acid (e.g., <NUM>-<NUM>%), Tween <NUM> (e.g., <NUM>-<NUM> %), and/or butanediol (e.g., <NUM>-<NUM>%). The percentages of each compound can vary (or the compound may be absent in some cases), for example, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, etc..

In some embodiments, the cream may include a pharmaceutical agent, and one or more ionic salts at a concentration at least sufficient to produce a hostile biophysical environment with respect to the pharmaceutical agent. For example, the cream may include one or more of (w/v): a charged and/or hydrogen bonding entity (<NUM>-<NUM>%), choline chloride (<NUM>-<NUM>%), sodium chloride (<NUM>-<NUM>%), and/or magnesium chloride (<NUM>-<NUM>% w/v). In another example, the cream may include one or more of (w/v): L-arginine hydrochloride (<NUM>-<NUM>%), choline chloride (<NUM>-<NUM>%), sodium chloride (<NUM>-<NUM>%), and/or magnesium chloride (<NUM>-<NUM>%). In still another example, the cream may include one or more of (w/v): creatine (<NUM>-<NUM>%), inosine (<NUM>-<NUM>%), choline chloride (<NUM>-<NUM>%), sodium chloride (<NUM>-<NUM>%), magnesium chloride (<NUM>-<NUM>%), L-arginine (<NUM>-<NUM>%), and/or theophylline (<NUM>-<NUM>%). In some cases, the cream may also contain L-arginine hydrochloride (<NUM>-<NUM>% w/v) and/or theophylline (<NUM>-<NUM>% w/v). The percentages of each compound can vary (or the compound may be absent in some cases), for example, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, etc. In these examples, choline chloride, sodium chloride, and/or magnesium chloride can be used to provide a high ionic strength environment.

In some embodiments, the composition may include an antioxidant, which may be able to reduce or inhibit the oxidation of other molecules within 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 in any suitable concentration. For example, the antioxidant may be present at a concentration of at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, or at least about <NUM>% by weight of the composition. In certain embodiments, the pharmaceutical agent may be present at a concentration of no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, or no more than about <NUM>% by weight of the composition.

Another set of embodiments is generally directed to compositions having relatively high temperature stability. For example, the composition may be stable at elevated temperatures such as at least <NUM> (at least about <NUM> °F) for periods of time of at least about a day. In some embodiments, for instance, a composition of the present invention may further include a stabilization polymer, propylene glycol, and a polysorbate surfactant. Non-limiting examples of stabilization polymers include xanthan gum, KELTROL® BT and/or KELTROL® RD; an example of a polysorbate surfactant is Polysorbate <NUM>. Additional examples are discussed herein.

Such a combination of components to create high temperature stability are surprising, since compositions involving any two of these components (but not the third) were found to lack such high temperature stabilization properties. It is not currently known why this combination of components is remarkably effective at facilitating relatively high temperature stability of the compositions discussed herein, as these components are not known to participate in any significant chemical reactions with each other, and high temperature stability is greatly reduced when one of the components is removed. In addition, propylene glycol is not known to work in pharmaceutical compositions as a stabilizing agent.

For instance, in one set of embodiments, a composition may be determined to be one that has high temperature stability by determining whether the composition exhibits phase separation over a relatively long period of time, e.g., over at least an hour, at least about <NUM> hours, at least a day, at least about a week, at least about <NUM> weeks, etc. For example, in some embodiments, a composition is exposed to ambient temperature and pressure for at least <NUM> hour, and the composition is then analyzed to determine whether the composition exhibits phase separation or a change in phase. A stable compound is one that exhibits no phase separation, whereas an unstable compound may exhibit phase separation. Such stability may be useful, for example, for storage of the composition, transport of the composition, shelf life, or the like.

As used herein, a "stabilization polymer" is a polymer that comprises xanthan gum, a xanthan gum derivative, and/or a xanthan gum equivalent, for example, KELTROL® BT and/or KELTROL® RD, KELZAN® XC, KELZAN® XCD, KELZAN® D, KELZAN® CC, XANTURAL® <NUM>, XANTURAL® <NUM>, or the like, all of which can be obtained commercially from various suppliers. In some embodiments, combinations of these and/or other polymers are also possible. In some cases, the stabilization polymer is chosen to be one which is at least generally regarded as safe for use in humans. In addition, in certain embodiments, the stabilization polymer is produced synthetically, and/or one which has been purified to some degree. The stabilization polymer may have any suitable molecular weight, for example, at least about <NUM> million, at least about <NUM> million, at least about <NUM> million, at least about <NUM> million, at least about <NUM> million, or at least about <NUM> million.

The stabilization polymer may be present at any suitable concentration within the composition. For example, the stabilization polymer may be present at a concentration of at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, or at least about <NUM>% by weight of the composition. In some embodiments, the stabilization polymer may be present at a concentration of no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, or no more than about <NUM>% by weight of the composition. In some cases, more than one stabilization polymer may be present, and each stabilization polymer may be present in any suitable amount. As a specific example, in certain embodiments, the stabilization polymer consists essentially of KELTROL® BT and/or KELTROL® RD. In certain instances, the stabilization polymer may have a fixed ratio of KELTROL® BT and/or KELTROL® RD, for example, <NUM>:<NUM> or <NUM>:<NUM> by weight. In another example, the KELTROL® BT may be present at a concentration of about <NUM>% by weight and the KELTROL® RD may be present at a concentration of <NUM>% by weight of the composition, or one or both of these may be present at one of the other concentrations described above. Combinations of these and/or other stabilization polymers are also contemplated in other embodiments, e.g., KELTROL® BT and xanthan gum, KELTROL® RD and xanthan gum, etc. In some cases, thickening agents can be used instead of, or in conjunction with a stabilization polymer. Many thickening agents can be obtained commercially. Thickening agents include those used in the food industry, or are GRAS agents (generally regarded as safe), e.g., alginin, guar gum, locust bean gum, collagen, egg white, furcellaran, gelatin, agar, and/or carrageenan, as well as combinations of these and/or other stabilization polymers. It should thus be appreciated that, in the specification herein, references to stabilization polymers, in other embodiments, should be understood to also include thickening agents in conjunction or instead of stabilization polymers,.

Propylene glycol can be obtained commercially, and can be present as any stereoisomer or racemic mixture of isomers. It may also be present at any suitable concentration. For instance, propylene glycol may be present at a concentration of at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, or at least about <NUM>% by weight of the composition. In some embodiments, propylene glycol may be present at a concentration of no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, or no more than about <NUM>% by weight of the composition. In some cases, other glycols can be used in conjunction or instead of propylene glycol, such as butylene glycol. Accordingly, it should thus be appreciated that, in the specification herein, references to propylene glycol, in other embodiments, should be understood to also include other glycols (e.g., a low molecular weight glycol, or a polyglycol, as described herein) in conjunction or instead of propylene glycol.

In addition, a polysorbate surfactant can also be present any suitable concentration within the composition. For instance, in some cases, the polysorbate surfactant may be present at a concentration of at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, at least about <NUM>%, or at least about <NUM>% by weight of the composition. In certain embodiments, the polylsorbate surfactant may be present at a concentration of no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, no more than about <NUM>%, or no more than about <NUM>% by weight of the composition A "polysorbate surfactant," as used herein, is a surfactant comprising a polysorbate. For example, the surfactant may comprise sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, or another sorbitan salt. In some cases, the polysorbate surfactant has a molecular formula:
<CHM>
where w, x, y, and z are any suitable positive integers. w, x, y, and z may also each be independently the same or different. In one set of embodiments, w+x+y+z is <NUM> (e.g., as in Polysorbate <NUM>). In some cases, other polymeric sugars can be used instead of, or in conjunction with, a polysorbate surfactant. Thus, it should be appreciated that, in the specification herein, references to a polysorbate surfactant are by way of example, and in other embodiments, it should be understood that references to a polysorbate surfactant may include other polymeric sugars in conjunction or instead of a polysorbate surfactant.

In some cases, the composition may have a fixed ratio of the stabilization polymer to propylene glycol to the polysorbate surfactant. For instance, the ratio of these may be about <NUM>:<NUM>:<NUM>, about <NUM>:<NUM>:<NUM>, about <NUM>:<NUM>:<NUM>, about <NUM>:<NUM>:<NUM>, about <NUM>:<NUM>:<NUM>, about <NUM>:<NUM>:<NUM>, about <NUM>:<NUM>:<NUM>, about <NUM>:<NUM>:<NUM>, about <NUM>:<NUM>:<NUM>, about <NUM>:<NUM>:<NUM>, about <NUM>:<NUM>:<NUM>, etc. As mentioned above, such ratios may be useful, in certain embodiments of the invention, in providing temperature stability to the composition.

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, relative 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 its constituents, or certain molecules containing heterocyclic rings to which are attached hydrocarbon chains.

Non-limiting examples of penetrating 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., dimethylsulfoxide); terpenes (e.g., cyclohexene); ureas; sugars; carbohydrates or other agents. In certain embodiments, the penetrating agent includes a salt, e.g., as described herein.

Thus, another aspect provides for the delivery of pharmaceutical agents (e.g., drugs, biological compounds, etc.) into the body, and such treatments may be systemic or localized, e.g., directed to a specific location of the body of a subject, such as the head, one or more specific muscles, an arm, a leg, the genitals, etc., depending on the specific application.

In one set of embodiments, pharmaceutical agents are introduced to aid in treatment of medical conditions or diseases, and the symptoms associated thereof. In some embodiments, the invention provides compositions for the treatment of medical conditions or diseases and/or ailments using pharmaceutical agents (for example, to treat a subject diagnosed with a medical condition or disease), and in some cases, the invention provides for the delivery of a minimum amount of pharmaceutical agents to provide effective levels of medication to an effected area topically 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. Other embodiments of the invention provide compositions for treating erectile dysfunction. Accordingly, in some embodiments, a composition may be topically applied to a specific location of the body, e.g., to the penis. Also, in certain cases, a composition as described herein may be used in the preparation of a medicament for treatment of erectile dysfunction, or other diseases or conditions as discussed herein.

In another aspect, the present disclosure is directed to a kit including one or more of the compositions discussed herein. A "kit," as used herein, typically defines a package or an assembly including one or more of the compositions of the invention, and/or other compositions associated with the invention, for example, as described herein. Each of the compositions of the kit may be provided in liquid form (e.g., in solution), or in solid form (e.g., a dried powder). In certain cases, some of the compositions may be constitutable or otherwise processable (e.g., to an active form), for example, by the addition of a suitable solvent or other species, which may or may not be provided with the kit. Examples of other compositions or components associated with the invention include, but are not limited to, solvents, surfactants, diluents, salts, buffers, emulsifiers, chelating agents, fillers, antioxidants, binding agents, bulking agents, preservatives, drying agents, antimicrobials, needles, syringes, packaging materials, tubes, bottles, flasks, beakers, dishes, frits, filters, rings, clamps, wraps, patches, containers, and the like, for example, for using, administering, modifying, assembling, storing, packaging, preparing, mixing, diluting, and/or preserving the compositions components for a particular use, for example, to a sample and/or a subject.

A kit of the disclosure may, in some cases, include instructions in any form that are provided in connection with the compositions of the invention in such a manner that one of ordinary skill in the art would recognize that the instructions are to be associated with the compositions of the invention. For instance, the instructions may include instructions for the use, modification, mixing, diluting, preserving, administering, assembly, storage, packaging, and/or preparation of the compositions and/or other compositions associated with the kit. In some cases, the instructions may also include instructions for the delivery and/or administration of the compositions, for example, for a particular use, e.g., to a sample and/or a subject. The instructions may be provided in any form recognizable by one of ordinary skill in the art as a suitable vehicle for containing such instructions, for example, written or published, verbal, audible (e.g., telephonic), digital, optical, visual (e.g., videotape, DVD, etc.) or electronic communications (including Internet or web-based communications), provided in any manner.

In some embodiments, the present disclosure is directed to methods of promoting one or more embodiments of the invention as discussed herein, for example, methods of promoting the making or use of compositions such as those discussed above, methods of promoting kits as discussed above, or the like. As used herein, "promoted" includes all methods of doing business including, but not limited to, methods of selling, advertising, assigning, licensing, contracting, instructing, educating, researching, importing, exporting, negotiating, financing, loaning, trading, vending, reselling, distributing, repairing, replacing, insuring, suing, patenting, or the like that are associated with the systems, devices, apparatuses, articles, methods, compositions, kits, etc. of the invention as discussed herein. Methods of promotion can be performed by any party including, but not limited to, personal parties, businesses (public or private), partnerships, corporations, trusts, contractual or sub-contractual agencies, educational institutions such as colleges and universities, research institutions, hospitals or other clinical institutions, governmental agencies, etc. Promotional activities may include communications of any form (e.g., written, oral, and/or electronic communications, such as, but not limited to, e-mail, telephonic, Internet, Web-based, etc.) that are clearly associated with the invention.

In one set of embodiments, the method of promotion may involve one or more instructions. As used herein, "instructions" can define a component of instructional utility (e.g., directions, guides, warnings, labels, notes, FAQs or "frequently asked questions," etc.), and typically involve written instructions on or associated with the invention and/or with the packaging of the invention. Instructions can also include instructional communications in any form (e.g., oral, electronic, audible, digital, optical, visual, etc.), provided in any manner such that a user will clearly recognize that the instructions are to be associated with the invention, e.g., as discussed herein.

The following documents are referred to herein: International Patent Application No. <CIT>, published as<CIT>; <CIT>, published as <CIT>; and <CIT>, published as <CIT>.

Also referred to herein are International Patent Application No. <CIT>, published as <CIT>; International Patent Application No. <CIT>, published as <CIT>; International Patent Application No. <CIT>, published as <CIT>; <CIT>, published as <CIT>; <CIT>, published as <CIT>; <CIT>, published as <CIT>; <CIT>; <CIT>; <CIT>; and <CIT>.

In addition, referred to herein in their entireties are <CIT>; and <CIT>.

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

This prophetic example illustrates one method of preparing a transdermal formula of the invention including sildenafil, tadalafil, or vardenafil. The final composition is shown in Table <NUM>. Of course, those of ordinary skill in the art will understand that percentages other than the ones listed below are also possible, according to other embodiments of the invention.

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

Initially, it should be appreciated 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., a phosphodiesterase type <NUM> inhibitor), 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 individually be provided in the first preparation, the second preparation, or both.

Ibuprofen sodium salt is water soluble at pH <NUM> and is added to the water phase. Any suitable ibuprofen salt may be used. For example, a commercially available ibuprofen salt may be used. In some embodiments, an ibuprofen preparation is manufactured to have the following relative composition (Table <NUM>).

The basic manufacturing process is to form an emulsion by mixing a water phase and an oil phase at elevated temperature with rapid mixing. Once the two phases are mixed the mixture is cooled to room temperature. While cooling is being accomplished homomixing is accomplished with a vertical colloid mill. For example, in one set of embodiments, the following manufacturing steps can be used:.

The resulting smooth emulsion has a pH of <NUM> to <NUM>. In some cases, the preparation can be manufactured under conditions to minimize microbial content (e.g., completely sterile or with a microbiological content of less than about <NUM> CFU/g).

In some embodiments, a transdermal ibuprofen cream is packaged in <NUM> "Magic Star Dispensers" which are airless pumps. The pump dispenses <NUM> with each depression of the pump head.

Similar procedures may be used for preparing emulsions of other compounds described herein. In some embodiments, the compound is added to the oil phase prior to mixing with the aqueous phase. In some embodiments, the compound is added to the aqueous phase prior to mixing with the oil phase.

Use of a topical sildenafil composition:
A <NUM> year old male with erectile dysfunction was given a cream containing <NUM>% sildenafil in an oil/water emulsion to which was added <NUM>% sodium chloride, <NUM>% potassium chloride and <NUM>% magnesium chloride. The pH was <NUM>. <NUM> minutes before initiating sexual activity he applied <NUM> gram of cream to his penis and gently rubbed it in until absorbed. Upon engaging in sexual activity he achieved a full and functional erection and sexual activity proceeded until successfully concluded.

The formula for the topical composition that was used for sildenafil is provided in Table <NUM> below (shown as % weight). It should be appreciated that the relative amounts of each component may be varied (e.g., by about <NUM> %) in some embodiments. It also should be appreciated that this topical composition may be used for other inhibitors (e.g., one or more examples of phosphodiesterase type <NUM> inhibitors including, but not limited to, avanafil, lodenafil, mirodenafil, tadalafil, vardenafil, udenafil, acetildenafil, or thiomethisosildenafil). In some embodiments, the active compound (e.g., sildenafil) may be added to the oil phase prior to mixing with the aqueous phase. However, other compounds may be added to the aqueous phase prior to mixing with the oil phase.

All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents referred to herein, and/or ordinary meanings of the defined terms.

Claim 1:
A composition for use in a method of effectively treating sexual dysfunction in a subject, preferably a human subject, the composition comprising:
an ionic salt present at a concentration of at least about <NUM>% by weight of the composition;
xanthan gum;
propylene glycol;
a polysorbate surfactant;
sildenafil and/or a salt thereof; and,
a nitric oxide donor comprising L-arginine, an L-arginine salt, and/or L-arginine HCl,
wherein the method comprises topically applying the composition to the genitalia.