Topical compositions and methods of determining cooling capacity of compositions

Abstract

A composition for topical application to the penis for the treatment of erectile dysfunction is provided, wherein the composition is free of glyceryl trinitrate (GTN), sildenafil and acetylcholinesterase inhibitors, but comprises a volatile and a non-volatile solvent, the volatile solvent comprising a lower alcohol and water, the non-volatile solvent comprising a polyol and a glycol. Preferably, the composition is free of any pharmaceutically active ingredient for the treatment of erectile dysfunction. A method of determining the cooling capacity of a test composition, e.g. the above-mentioned composition, is also provided.

Description

Technical Field

[0001] This invention relates to compositions for treating or improving conditions susceptible to vascular smooth muscle relaxation, particularly erectile dysfunction. Background Technology

[0002] WO 2019 / 034878, in the name of the applicant, Futura Medical Developments Ltd, includes a comprehensive review of the pathology, patent and non-patent literature on erectile dysfunction, as well as previous attempts to provide solutions. Specifically, it describes and claims a composition for topical application, particularly for the glans penis, comprising trinitroglycerin (GTN) as an active ingredient, dissolved in a blend of volatile and non-volatile solvents with different solvation capabilities for GTN, wherein the volatile solvent comprises water and a lower alcohol, and the non-volatile solvent comprises a polyol and a diol. The weight ratio of the polyol to the diol is from 1.5:1 to 6.0:1, and the pH of the composition is from 5.1 to 7.0.

[0003] As described in WO 2019 / 034878, the composition provides rapid initial absorption of GTN and continued slow absorption as the volatile solvent evaporates during use, thereby dynamically maintaining GTN concentration even when absorption is depleted. GTN promotes the formation of exogenous nitric oxide (NO) in the corpora cavernosa of the penis to supplement the endogenous NO synthesized internally after stimulation of the glans penis by manual application of the composition, resulting in swelling and a firm and self-sustaining erection. (See “Development of a novel topical trinitroglycerin formulation for the treatment of erectile dysfunction,” Davis, Adrian, and Reisman, Yacov, accepted for publication in IJIR: Your Sexual Medicine Journal, 27 / 11 / 19).

[0004] The clinical trial results for the compositions of WO 2019 / 034878 are very encouraging: compared to baseline data, these compositions provided statistically significant improvements at all three major endpoints (IIEF, SEP2, and SEP3) using industry-standard assessment techniques, with over 60% of all subjects experiencing a noticeable difference in improved erections. Over 60% of subjects saw an onset of action within 10 minutes of administration, significantly faster than sildenafil, and with significant spontaneity. Furthermore, no serious side effects were reported in any subjects, and the overall side effect profile was very favorable across all doses.

[0005] Despite a generally favorable spectrum of side effects, some minor drawbacks remain that would be best eliminated. For example, a small number of users experience headaches, which, while not a serious side effect in itself, are undeniably a concern in the context of use. More importantly, GTN-containing compositions are unsuitable for men with medical conditions requiring the use of nitrate-containing medications. Therefore, despite the clinical success of GTN-containing compositions as disclosed in WO 2019 / 034878, there remains a need for effective formulations that do not contain GTN. In any case, there is a general desire to provide compositions that do not contain synthetic chemicals as active ingredients, in line with the current trend toward the use of “natural” medicines.

[0006] WO 2010 / 044094 describes a topical composition for treating erectile dysfunction and pulmonary hypertension, comprising sildenafil citrate, lidocaine, and pharmaceutically acceptable excipients. In contrast, the compositions according to the invention do not contain sildenafil or lidocaine.

[0007] US 2014 / 0227342 describes a composition comprising an acetylcholinesterase inhibitor, a solvent, and a penetration enhancer in a pharmaceutically acceptable carrier. In contrast, the compositions according to the present invention do not contain an acetylcholinesterase inhibitor. Summary of the Invention

[0008] Unexpectedly, the excipient blends described in WO 2019 / 034878, when used for the treatment of erectile dysfunction without the addition of GTN, provided results indicating that the efficacy of the excipient blends was comparable to that of equivalent compositions containing GTN.

[0009] On one hand, the present invention provides a composition for topical application to the penis to treat erectile dysfunction, the composition being free of GTN and comprising volatile and non-volatile solvents, the volatile solvent comprising lower alcohols and water, and the non-volatile solvent comprising polyols and diols.

[0010] Preferably, the weight ratio of the polyol to the diol is from 1.5:1 to 6.0:1. Preferably, the pH of the composition is higher than 5.0 and lower than 7.0.

[0011] It is speculated that although the composition according to the invention cannot stimulate the production of exogenous NO (due to the absence of an active ingredient), it can enhance the production of endogenous NO by, for example, locally stimulating nerves through the latent heat of cooling generated by the evaporation of the volatile solvent components, thereby producing endogenous nitric oxide. Therefore, in highly debilitated organs or parts, such as the glans penis, there are a series of sensors responsive to bodily senses (e.g., touch, pressure, and temperature). Topical application of the composition according to the invention to these organs can stimulate more than one of these sensors, causing them to synergistically react and induce penile swelling and erection without the presence of an active ingredient. However, topical application of gel formulations or personal lubricants containing sildenafil, as known examples, has been found to have no effect on erectile function.

[0012] The composition is GTN-free, meaning it contains no GTN. Furthermore, preferably, the composition does not contain any GTN derivatives or prodrugs.

[0013] Preferably, the composition also does not contain sildenafil and acetylcholinesterase inhibitors. "Sildenafil" also includes its salt form, such as sildenafil citrate. The acetylcholinesterase inhibitor can be any acetylcholinesterase inhibitor, such as Δ9-tetrahydrocannabinol (THC), physostigmine, neostigmine, pyridostigmine, ammonium chloride, demacamides, rivastigmine, galantamine, caffeine, donepezil, tetrahydroaminoacridine, ederomonidine, huperzine A, bishuperzine A, bishuperzine B, huperzine A-tacrine, derivatives of huperzine A, ladostigil, ungeremine, and lactucopicrin.

[0014] The composition may also be lidocaine-free. The term "lidocaine" also includes its salt form, such as its hydrochloride salt.

[0015] In some embodiments, the composition does not contain any pharmaceutically active ingredients for the treatment of erectile dysfunction, such as phosphodiesterase type 5 (PDE5) inhibitors like tadalafil and sildenafil, and vasodilators like alprostadil and phentolamine mesylate. In some embodiments, the composition does not contain any pharmaceutically active ingredients.

[0016] In some embodiments, the composition does not contain any of the following: PDE-5 inhibitors, amide anesthetics, local anesthetics, natural prostaglandins, synthetic prostaglandins, testosterone, or combinations thereof. Preferably, the composition does not contain PDE-5 inhibitors or amide anesthetics.

[0017] In certain embodiments, the composition does not contain white petrolatum and / or paraffin.

[0018] The composition is not intended for use in hand sanitizers. The composition may have a lower alcohol content of no more than 50%, optionally no more than 45%, optionally no more than 40%, and further optionally no more than 36%. In some embodiments, the composition may have an ethanol content of no more than 50%, optionally no more than 45%, optionally no more than 40%, and further optionally no more than 36%.

[0019] While other forms, such as foams or sprays, may be considered, and suitable excipients, such as propellant gases in foam or spray forms, may be added within the scope of the invention, the composition is preferably in the form of a gel, cream, or serum. More preferably, the formulation is in gel form. In formulations where the composition is in gel form and applied by hand, a viscosity of 125,000 to 600,000 mPas, with the pH controlled between 5.0 and 7.0, ensures optimal control over application. Preferably, the viscosity should be between 200,000 and 450,000 mPas, more preferably, 250,000 to 350,000 mPas, for example, 300,000 mPas, when measured by a Brookfield viscometer, spindle E, 0.3 RPM, at 25°C.

[0020] It has been found that pH affects not only viscosity but also stability and appearance. Regarding viscosity, when the pH is below 5.0 and the composition is gel-like, the viscosity is too low and the composition is too fluid to be applied to the glans penis without spreading or spontaneously dissipating from it. Viscosity is acceptable at pH values ​​greater than 5.0, preferably greater than 5.2, although at pH values ​​above about 5.8, depending on other components present in the composition, the risk of thickeners or gelling agents forming precipitates increases, making the composition visually unacceptable. It has been found that the tendency to flocculate, caused or exacerbated by thickeners or gelling agents, can be mitigated by pH. In particular, viscosity is unacceptable at pH values ​​significantly below 5.2, while at pH values ​​greater than 5.8, there is a significant risk of flocculation, which may result in the product being unacceptable to consumers.

[0021] Viscosity and flocculation are acceptable within a wide pH range of 5.0 to 7.0, preferably 5.2 to 6, and more preferably 5.25 to 5.75.

[0022] The pH values ​​mentioned above refer to the composition at the time of preparation; however, the pH value may tend to drift upwards by approximately 0.25 pH units over the weeks of preparation. Nevertheless, any increase in pH value after preparation is acceptable due to the tolerance for higher viscosity.

[0023] Due to the tendency of the pH value to drift upward after preparation, the pH value range of the composition according to the present invention should preferably be 5.25 to 6.0, and the upper limit of other ranges should also be adjusted accordingly.

[0024] Depending on its physical form, the compositions according to the invention may further include at least one additional ingredient selected from the following: agents for enhancing skin feel, such as silicone oil compositions like polydimethylsiloxane 200; thickeners or gelling agents, such as polyacrylate-based compositions; pH control agents, such as triethanolamine or inorganic bases; and antimicrobial preservatives, such as methylparaben and / or propylparaben.

[0025] The concentration of the other components is preferably less than 5% by weight, more preferably less than 2% by weight, for example 1.0%. However, a pH control agent is added until the pH value is within the desired target range of 5.0 to 7.0, preferably 5.1 to 6.0, or more preferably 5.25 to 5.75, all of which are during preparation.

[0026] Regarding thickeners or gelling agents, it has been found ideal to use polyacrylate-based compositions that are readily dispersed in solvent blends and facilitate rapid evaporation of volatile solvents, so as to reach a skin penetration equilibrium rate preferably within one minute of application to the penis or more preferably within thirty seconds thereafter. Suitable thickeners or gelling agents comprise high molecular weight interpolymers of crosslinked unsaturated carboxylic acid polymers (which may be homopolymers or copolymers) and copolymer space stabilizers having hydrophilic and hydrophobic moieties. Preferably, the monomers of the unsaturated carboxylic acid polymer comprise acrylic acid or its alkyl ester derivatives, and the space stabilizer preferably comprises block copolymers and / or random copolymers, wherein the block copolymers preferably comprise polyesters such as 12-hydroxystearic acid as the hydrophobic moiety and polyethylene glycol as the hydrophilic moiety. Preferably, the unsaturated carboxylic acid comprises acrylic acid crosslinked with allyl sucrose. Such interpolymers containing space stabilizers are rapidly wetted and readily dispersed during polymerization, and will be referred to as “easily dispersible interpolymers of the type described herein” throughout the remainder of this specification, including the claims. Commercially available representative examples include Ultrez 10, 20, 21, and 30. Homopolymers such as Neither 934P nor 937P is a “dispersible interpolymer of the type described” because they do not contain steric stabilizers.

[0027] Preferably, the thickener or gelling agent is present in the composition at 0.5% to 2% by weight. In some embodiments, the composition contains 0.5% to 1.5% by weight of thickener or gelling agent. In other embodiments, the composition contains 0.7% to 1.5% by weight of thickener or gelling agent. In several embodiments, the composition contains 0.8% to 1.2% by weight of thickener or gelling agent. In some specific embodiments, the composition contains about 1% by weight of thickener or gelling agent.

[0028] The compositions according to the invention can be considered as single-phase solutions comprising a volatile solvent pair such as ethanol and water, and a non-volatile solvent pair such as glycerol and propylene glycol. It has been found that the use of a gelling agent containing readily dispersible interpolymers of this type and having the desired pH value in such a system allows for precise application of the composition to the glans penis. Furthermore, the use of such readily dispersible interpolymers, especially... Ultrez 10 unexpectedly produces a more favorable and acceptable viscosity than previously thought because this type of interpolymer imparts rheological properties to the composition, causing a temporary decrease in viscosity during use and when applied by hand to the glans penis. This allows for even faster evaporation of the volatile solvent, thus establishing equilibrium within a target time of less than 1 minute, preferably less than 30 seconds. Simultaneously, under non-shear conditions, penetration is unaffected by the increased viscosity.

[0029] The molecular weight of volatile solvents can be from 15 to 75 g / mol. The molecular weight of non-volatile solvents can be from 40 to 200 g / mol, preferably from 50 to 150 g / mol, and more preferably from 60 to 120 g / mol.

[0030] The weight ratio of volatile solvent to non-volatile solvent can be from 0.5:1 to 4:1. Preferably, the weight ratio of volatile solvent to non-volatile solvent is from 1:1 to 3:1. More preferably, the weight ratio of volatile solvent to non-volatile solvent is from 2:1 to 2.5:1.

[0031] Preferably, the carbon to oxygen atom ratio of the polyol is 2:1 to 1:1. Preferably, the carbon to oxygen atom ratio of the diol is 2:1 to 1:1.

[0032] Preferably, the lower alcohol has a boiling point below 150°C. Preferably, the polyol has a boiling point below 150°C. Preferably, the diol has a boiling point below 250°C.

[0033] The compositions according to the invention can be completely soluble in water. Both volatile and non-volatile solvents can be soluble in water.

[0034] The compositions according to the present invention can be transparent and / or colorless.

[0035] Preferably, the weight ratio of polyol to diol is 2:1 to 6:1. More preferably, the weight ratio of polyol to diol is 2.5:1 to 5.5:1. Even more preferably, the weight ratio of polyol to diol is 3:1 to 5:1. Still more preferably, the weight ratio of polyol to diol is 3.5:1 to 4.5:1.

[0036] Regarding the concentration of components, the compositions according to the invention may include the following, the range of which is expressed as a weight percentage of the total composition:

[0037] - Lower alcohols: 30-45%

[0038] Water: 20-40%

[0039] - Polyols: 22-26%

[0040] - Ethylene glycol: 4-12%.

[0041] The concentration of water is preferably 30 to 40% by weight. The 20% mentioned above is the minimum preferred value for achieving a gelling effect. Similarly, the concentration of the lower alcohol is preferably 30 to 35% by weight, but concentrations up to 45% can be provided without compromising the potency of the composition, depending on the tolerance of the subjects. Ethanol is more volatile than water, and the ratio of ethanol to water in the volatile solvent pair can be adjusted to change the evaporation rate, up to a maximum of about 1:1. As a skin irritant, the limiting concentration of ethanol, as an example of a lower alcohol, is guided by local intolerance.

[0042] Preferably, the total amount of polyols and diols does not exceed 35% by weight.

[0043] In this specification, the term "lower alcohol" refers to aliphatic alcohols having 1 to 5 carbon atoms, such as ethanol and isopropanol. Ethanol is generally preferred.

[0044] "Polyols" refers to aliphatic polyols, such as glycerol, although sorbitol, erythritol, aritol and xylitol are other examples of water-soluble polyols that may be used in conjunction with or in place of glycerol.

[0045] "Diol" refers to primary or secondary diols or polyol compounds, such as propylene glycol (propylene-1,2-diol), butanediol (butane-1,3-butanediol), pentanediol (pentane-1,5-diol), or hexanediol (2-methyl-2,4-pentanediol). Preferably, the diol is a primary or secondary diol.

[0046] Preferably, the composition according to the invention has the following concentrations by weight percentage:

[0047] - Lower alcohols: 30-35%

[0048] Water: 33-37%

[0049] - Polyols: 22-26%

[0050] - Ethylene glycol: 4-8%.

[0051] For example, a formulation according to the present invention has the following components by weight percentage:

[0052] - Ethanol: 33%

[0053] - Water: 35%

[0054] - Glycerin: 24%

[0055] -Propylene glycol: 6%.

[0056] For example, another formulation according to the invention has the following components by weight percentage:

[0057] - Ethanol: 33%

[0058] - Water: 35%

[0059] - Glycerin: 24%

[0060] -Propylene glycol: 6%

[0061] - Ultrez 10:1%.

[0062] In the above formulation, the ratio of glycerol to propylene glycol is 4:1. The above formulation may also contain an alkali to maintain a pH value in the range of 5.0 to 7.0.

[0063] The compositions according to the invention can be prepared by mixing the components together. Conventional process principles can be applied, for example, by... Ultrez 10 is dispersed in an aqueous phase, ethanol is added, and then optionally, the remaining solvent is added simultaneously with or before pH adjustment. While organic bases such as triethanolamine can be used to adjust the pH, inorganic bases such as potassium hydroxide, sodium hydroxide, or liquid ammonia are preferred to avoid the possibility of nitrosamine formation. Such bases, preferably potassium hydroxide, are particularly advantageous in solvent-rich systems such as those according to the invention, because potassium, for example, has the potential to form salts with gelling agents that may be insoluble at the concentrations used, leading to phase separation after preparation. Easily dispersible interpolymers of this type show less susceptibility to phase separation, likely due to increased solvent affinity of the block copolymer backbone segments. Nevertheless, it is still considered preferable to control the pH in the range of 5.25 to 5.75 to achieve precise application and prevent phase separation. Salt phase separation (e.g., using) Ultrez 10, 20, 21 or 30) and the gel viscosity does not affect the loss rate of volatile solvents.

[0064] According to a second aspect of the invention, a composition for treatment is provided (as described above).

[0065] According to a third aspect of the invention, a composition (as described above) for treating or improving erectile dysfunction is provided. Use of the composition (as described above) in the preparation of a medicament for treating or improving erectile dysfunction is also provided.

[0066] According to a fourth aspect of the invention, a method for treating or improving erectile dysfunction is provided, the method comprising applying a biologically effective amount of a composition (as described above) topically to the penis, preferably to the glans penis of a male subject. Optionally, the method may further comprise artificial stimulation of the penis.

[0067] Subjects may have pre-existing medical conditions that preclude the use of the active ingredient for treating erectile dysfunction. Subjects may have pre-existing medical conditions whose treatment may preclude the use of the active ingredient for treating erectile dysfunction.

[0068] Existing medical symptoms can be any condition that prevents the use of the active ingredient used to treat erectile dysfunction. For example, existing medical symptoms may include angina, low blood pressure, high blood pressure, benign prostatic hyperplasia, or retinitis pigmentosa.

[0069] Treatment for symptoms that prevent the use of active ingredients for treating erectile dysfunction may include the administration of active ingredients selected from PDE-5 inhibitors, nitrates, and alpha-blockers. For example, active ingredients for treating existing medical symptoms may be selected from GTN, isosorbide mononitrate, isosorbide nitrate, alfuzosin, doxazosin, indopramine, prazosin, tamsulosin, and terazosin.

[0070] The method may further include administering to a subject at least one active agent for treating or improving erectile dysfunction, wherein the method does not involve topical application of GTN, sildenafil, or an acetylcholinesterase inhibitor to the subject's penis. The at least one active agent for treating or improving erectile dysfunction may be selected from PDE-5 inhibitors, alprostadil, and phentolamine mesylate. In one embodiment, the at least one active agent for treating or improving erectile dysfunction is administered orally.

[0071] Male participants may have severe erectile dysfunction.

[0072] According to a fifth aspect of the invention, a condom comprising the composition is provided (as previously described).

[0073] According to a sixth aspect of the invention, a kit is provided comprising a composition (as described above) and an active agent for treating or improving erectile dysfunction, wherein the kit does not contain GTN, sildenafil, or acetylcholinesterase inhibitors in its composition. Preferably, the active agent is administered separately from the composition, for example, not added to the topical composition (as described above). The active agent may be selected from PDE-5 inhibitors, alprostadil, and phentolamine mesylate. In one embodiment, the active agent for treating or improving erectile dysfunction is administered orally, i.e., it is an oral dosage form.

[0074] According to a seventh aspect of the present invention, a method for determining the cooling capacity of a test composition is provided, the method comprising:

[0075] A layer of test composition is applied to a temperature probe, wherein the test composition and the temperature probe are at a preset temperature between about 25°C and about 50°C;

[0076] The temperature probe is placed in an environment with a temperature that is the same as and relatively constant as the preset temperature;

[0077] Monitor the temperature change of the temperature probe over time; and

[0078] Optionally, the weight of the temperature probe can be monitored over time.

[0079] In the application step of the method, when the test composition layer is applied to the temperature probe, the temperature probe and the test composition are at substantially the same temperature.

[0080] In some embodiments, about 30 mg to about 120 mg of the test composition is applied to the temperature probe. Preferably, about 40 mg to about 100 mg of the test composition is applied to the temperature probe. More preferably, about 50 mg to about 90 mg of the test composition is applied to the temperature probe. Preferably, the test composition is applied to the temperature probe such that the layer of the test composition has a substantially uniform thickness.

[0081] In several embodiments, the temperature change of the temperature probe is monitored, and optionally, the weight change of the temperature probe is monitored for at least about 5 minutes. Preferably, the temperature change of the temperature probe is monitored, and optionally, the weight change of the temperature probe is monitored for about 20 minutes to about 30 minutes. More preferably, the temperature change of the temperature probe is monitored, and optionally, the weight change of the temperature probe is monitored for about 10 minutes to about 40 minutes. Still more preferably, the temperature change of the temperature probe is monitored, and optionally, the weight change of the temperature probe is monitored for about 15 minutes to about 35 minutes. Even more preferably, the temperature change of the temperature probe is monitored, and optionally, the weight change of the temperature probe is monitored for about 20 minutes to about 30 minutes. In some embodiments, the temperature change of the temperature probe is monitored, and optionally, the weight change of the temperature probe is monitored for about 25 minutes.

[0082] In some embodiments, prior to the application step, the test composition and the temperature probe are incubated in an environment with a relatively constant temperature and at the preset temperature, such that the test composition and the temperature probe are at the preset temperature for use in the application step.

[0083] In several embodiments, the preset temperature can be between about 25°C and about 40°C. In some embodiments, the preset temperature can be between about 25°C and about 30°C. In some embodiments, the preset temperature can be between about 30°C and about 35°C. In other embodiments, the preset temperature can be between about 35°C and about 40°C. In specific embodiments, the preset temperature is 27°C ± 1°C, 32°C ± 1°C, or 37°C ± 1°C.

[0084] The method is preferably carried out at atmospheric pressure, for example at about 1 atm or about 100 kPa.

[0085] In some embodiments, the method is performed at a relative humidity of about 40% to 60%.

[0086] In some embodiments, the weight of the temperature probe is measured before the test composition is applied.

[0087] In some embodiments, the method includes:

[0088] The test composition and the temperature probe are incubated in an environment with a relatively constant temperature and at a preset temperature of about 25°C to about 40°C.

[0089] A layer of test composition having a concentration of about 40 mg to about 100 mg is applied to the temperature probe, the test composition and the temperature probe being at the preset temperature;

[0090] The temperature probe is placed in an environment with a relatively constant temperature and at the preset temperature; and

[0091] The temperature and weight changes of the temperature probe are monitored for approximately 20 to 30 minutes.

[0092] In one specific embodiment, a method for determining the cooling capacity of a test composition is provided, the method comprising the following steps:

[0093] 1. Drill a hole approximately 5 mm in diameter in the cap of a 15 mL centrifuge tube. Weigh the empty centrifuge tube on an analytical balance.

[0094] 2. Place approximately 14 mL of sample gel into the 15 mL centrifuge tube. Seal with a standard cap and centrifuge at approximately 1500 rpm for about 30 seconds to collect the gel.

[0095] 3. Place the tube containing the sample gel, the calibration temperature probe, and the analytical balance into a benchtop oven set to 32℃±1℃.

[0096] 4. Weigh the tube containing the sample gel. (Weight check 1).

[0097] 5. Place all instruments (including the tubes containing the sample gel) overnight for incubation.

[0098] 6. After incubation, weigh the tube containing the sample gel. (Weight check 2).

[0099] 7. Place the cap with the 5mm hole cut into it onto the centrifuge tube containing the sample gel. Plug the hole to prevent evaporation until ready to collect the sample. Return the centrifuge tube to the benchtop oven.

[0100] 8. Calibrate the balance using the temperature probe. Ensure the temperature of the probe is within the range of 32℃±1℃.

[0101] 9. Remove the temperature probe from the balance and insert it into the centrifuge tube containing the sample gel until the bottom of the probe contacts the tube cap. Administer approximately 70 mg (±20 mg). (Note: Time-sensitive step)

[0102] 10. In a smooth motion, remove the probe from the gel, being careful not to touch the side of the centrifuge lid. Place the probe back on the balance, close the oven door, and start the stopwatch. (Note: This is a time-sensitive step.)

[0103] 11. Continuously record the weight and temperature of the probe for 25 minutes.

[0104] The above method can also be carried out at a temperature of 27℃±1℃ or 37℃±1℃.

[0105] The present invention also provides a composition in which, when tested using the above method, the maximum temperature drop is at least 5°C. The maximum temperature drop is calculated by subtracting the lowest temperature (°C) reached by the temperature probe from a preset temperature (°C) (also referred to as ambient temperature in the detailed description below). When tested using the above method, the maximum temperature drop of the composition can be at least 6°C. The maximum temperature drop of the composition can be at least 7°C. The maximum temperature drop of the composition can be at least 8°C. The maximum temperature drop of the composition can be at least 9°C. The maximum temperature drop of the composition can be at least 10°C. The maximum temperature drop of the composition can be at least 11°C.

[0106] In some embodiments, when tested using the above method, the maximum temperature drop of the composition is from about 5°C to about 15°C. The maximum temperature drop of the composition can be from about 6°C to about 15°C. The maximum temperature drop of the composition can be from about 7°C to about 15°C. The maximum temperature drop of the composition can be from about 8°C to about 14°C. The maximum temperature drop of the composition can be from about 9°C to about 13°C. The maximum temperature drop of the composition can be from about 10°C to about 12°C.

[0107] In several embodiments, when tested using the above method, the maximum temperature drop of the composition is at most 15°C. The maximum temperature drop of the composition can be at most 14°C. The maximum temperature drop of the composition can be at most 13°C. The maximum temperature drop of the composition can be at most 12°C.

[0108] In some embodiments, when tested using the method described above, the temperature of the composition decreases by at least 5°C after 1 minute of monitoring. The temperature decrease is calculated by subtracting the temperature reached after 1 minute of monitoring from the preset temperature (°C). When tested using the method described above, the temperature of the composition can decrease by at least 6°C after 1 minute of monitoring. The temperature of the composition can decrease by at least 7°C after 1 minute of monitoring. The temperature of the composition can decrease by at least 8°C after 1 minute of monitoring. The temperature of the composition can decrease by at least 9°C after 1 minute of monitoring. The temperature of the composition can decrease by at least 10°C after 1 minute of monitoring. The temperature of the composition can decrease by at least 11°C after 1 minute of monitoring.

[0109] In some embodiments, when tested using the above method, the temperature of the composition decreases by about 5°C to about 15°C after 1 minute of monitoring. The temperature of the composition decreases by about 6°C to about 15°C after 1 minute of monitoring. The temperature of the composition decreases by about 7°C to about 15°C after 1 minute of monitoring. The temperature of the composition decreases by about 8°C to about 14°C after 1 minute of monitoring. The temperature of the composition decreases by about 9°C to about 13°C after 1 minute of monitoring. The temperature of the composition decreases by about 10°C to about 12°C after 1 minute of monitoring.

[0110] In some embodiments, when tested using the above method, the temperature of the composition recovers to at least 4°C after 25 minutes of monitoring. The recovery temperature is calculated by subtracting the lowest temperature (°C) reached by the temperature probe after 25 minutes of monitoring from the temperature (°C) of the temperature probe. When tested using the above method, the temperature of the composition can recover to at least 5°C after 25 minutes of monitoring. The temperature of the composition can recover to at least 6°C after 25 minutes of monitoring. The temperature of the composition can recover to at least 7°C after 25 minutes of monitoring. The temperature of the composition can recover to at least 8°C after 25 minutes of monitoring.

[0111] In some embodiments, when tested using the above method, the temperature of the composition recovers to approximately 4°C to approximately 15°C after 25 minutes of monitoring. The temperature of the composition may recover to approximately 4°C to approximately 14°C after 25 minutes of monitoring. The temperature of the composition may recover to approximately 4°C to approximately 13°C after 25 minutes of monitoring. The temperature of the composition may recover to approximately 4°C to approximately 12°C after 25 minutes of monitoring. The temperature of the composition may recover to approximately 5°C to approximately 11°C after 25 minutes of monitoring. The temperature of the composition may recover to approximately 6°C to approximately 10°C after 25 minutes of monitoring. The temperature of the composition may recover to approximately 7°C to approximately 9°C after 25 minutes of monitoring.

[0112] In some specific embodiments, when the composition is tested at a preset temperature of 32°C ± 1°C,

[0113] 1) The maximum temperature drop of the composition is at least 9°C;

[0114] 2) The maximum temperature drop of the composition is from about 9°C to about 13°C;

[0115] 3) The temperature of the composition decreases by at least 9°C after 1 minute of monitoring;

[0116] 4) The temperature of the composition decreased by approximately 9°C to approximately 13°C after 1 minute of monitoring;

[0117] 5) The temperature of the composition recovers by at least 6°C after 25 minutes of monitoring; and / or

[0118] 6) The temperature of the composition recovers to about 6°C to about 10°C after 25 minutes of monitoring.

[0119] In some embodiments, when tested using the above method, the weight of the composition changes by at least -10% after 1 minute of monitoring. The percentage change in weight is calculated as follows: Weight percentage change = -100 + ((reading interval weight (g) / initial weight (g)) * 100). The weight change of the composition after 1 minute of monitoring can be at least -12%. The weight change of the composition after 1 minute of monitoring can be at least -14%. The weight change of the composition after 1 minute of monitoring can be at least -15%. The weight change of the composition after 1 minute of monitoring can be at least -16%. The weight change of the composition after 1 minute of monitoring can be at least -17%. The weight change of the composition after 1 minute of monitoring can be at least -18%.

[0120] In some embodiments, when tested using the methods described above, the weight change of the composition after 1 minute can be between about -10% and about -30%. The weight change of the composition after 1 minute can be between about -12% and about -28%. The weight change of the composition after 1 minute can be between about -14% and about -26%. The weight change of the composition after 1 minute can be between about -15% and about -25%. The weight change of the composition after 1 minute can be between about -16% and about -24%. The weight change of the composition after 1 minute can be between about -17% and about -23%. The weight change of the composition after 1 minute can be between about -18% and about -22%.

[0121] In some embodiments, when tested using the above method, the weight change of the composition after 5 minutes of monitoring is at least -20%. The weight change of the composition after 5 minutes of monitoring can be at least -25%. The weight change of the composition after 5 minutes of monitoring can be at least -30%. The weight change of the composition after 5 minutes of monitoring can be at least -32%. The weight change of the composition after 5 minutes of monitoring can be at least -34%. The weight change of the composition after 5 minutes of monitoring can be at least -35%. The weight change of the composition after 5 minutes of monitoring can be at least -36%. The weight change of the composition after 5 minutes of monitoring can be at least -37%. The weight change of the composition after 5 minutes of monitoring can be at least -38%.

[0122] In some embodiments, when tested using the methods described above, the weight change of the composition after 5 minutes of monitoring can be between about -20% and about -60%. The weight change of the composition after 5 minutes of monitoring can be between about -25% and about -55%. The weight change of the composition after 5 minutes of monitoring can be between about -30% and about -50%. The weight change of the composition after 5 minutes of monitoring can be between about -32% and about -48%. The weight change of the composition after 5 minutes of monitoring can be between about -34% and about -46%. The weight change of the composition after 5 minutes of monitoring can be between about -35% and about -45%. The weight change of the composition after 5 minutes of monitoring can be between about -36% and about -44%.

[0123] In some embodiments, when tested using the above method, the weight change of the composition after 25 minutes of monitoring is at least -40%. The weight change of the composition after 25 minutes of monitoring can be at least -45%. The weight change of the composition after 25 minutes of monitoring can be at least -50%. The weight change of the composition after 25 minutes of monitoring can be at least -52%. The weight change of the composition after 25 minutes of monitoring can be at least -54%. The weight change of the composition after 25 minutes of monitoring can be at least -55%. The weight change of the composition after 25 minutes of monitoring can be at least -56%. The weight change of the composition after 25 minutes of monitoring can be at least -57%. The weight change of the composition after 25 minutes of monitoring can be at least -58%. The weight change of the composition after 25 minutes of monitoring can be at least -59%. The weight change of the composition after 25 minutes of monitoring can be at least -60%.

[0124] In some embodiments, when tested using the methods described above, the weight change of the composition after 25 minutes can be between about -40% and about -90%. The weight change of the composition after 25 minutes can be between about -45% and about -85%. The weight change of the composition after 25 minutes can be between about -50% and about -80%. The weight change of the composition after 25 minutes can be between about -52% and about -78%. The weight change of the composition after 25 minutes can be between about -54% and about -76%. The weight change of the composition after 25 minutes can be between about -55% and about -75%. The weight change of the composition after 25 minutes can be between about -56% and about -74%. The weight change of the composition after 25 minutes can be between about -57% and about -73%. The weight change of the composition after 25 minutes can be between about -58% and about -72%. The weight change of the composition after 25 minutes of monitoring can be between approximately -59% and approximately -71%. The weight change of the composition after 25 minutes of monitoring can be between approximately -60% and approximately -70%.

[0125] In some embodiments, when tested using the methods described above, the weight change of the composition upon reaching the maximum cooling temperature is at least -10%. The weight change of the composition upon reaching the maximum cooling temperature may be at least -12%. The weight change of the composition upon reaching the maximum cooling temperature may be at least -14%. The weight change of the composition upon reaching the maximum cooling temperature may be at least -15%. The weight change of the composition upon reaching the maximum cooling temperature may be at least -16%. The weight change of the composition upon reaching the maximum cooling temperature may be at least -17%. The weight change of the composition upon reaching the maximum cooling temperature may be at least -18%.

[0126] In some embodiments, when tested using the methods described above, the weight change of the composition when reaching the maximum cooling temperature is between about -10% and about -35%. The weight change of the composition when reaching the maximum cooling temperature may be between about -12% and about -33%. The weight change of the composition when reaching the maximum cooling temperature may be between about -14% and about -31%. The weight change of the composition when reaching the maximum cooling temperature may be between about -15% and about -30%. The weight change of the composition when reaching the maximum cooling temperature may be between about -16% and about -29%. The weight change of the composition when reaching the maximum cooling temperature may be between about -17% and about -28%. The weight change of the composition when reaching the maximum cooling temperature may be between about -18% and about -27%. The weight change of the composition when reaching the maximum cooling temperature may be between about -18% and about -26%. The weight change of the composition when reaching the maximum cooling temperature may be between about -18% and about -25%.

[0127] In one specific embodiment, the weight change of the composition when the maximum reduction temperature is reached is between about -15% and about -25%.

[0128] In the above embodiments involving changes in the weight of the composition, the composition can be tested at a preset temperature of 32°C ± 1°C.

[0129] In some embodiments, the composition provides a faster cooling rate during the cooling phase than it provides a faster heating rate during the temperature recovery phase.

[0130] In some embodiments, when the composition is tested at a higher preset temperature, the composition provides a faster cooling rate during the cooling phase.

[0131] In various embodiments, the cooling rate provided by the composition during the cooling phase is substantially proportional to the weight loss rate of the composition during the cooling phase.

[0132] Brief description of the attached figures

[0133] The invention will now be described in detail by way of embodiments with reference only to the accompanying drawings, wherein:

[0134] Figure 1 A graph showing the change in average temperature (°C) of the sample gel over time (minutes) at each ambient temperature (27°C, 32°C, 37°C) is presented.

[0135] Figure 2 A graph showing the change in the average weight percentage of the sample gel over time (minutes) at each ambient temperature (27°C, 32°C, 37°C) is presented.

[0136] Figure 3 A graph showing the change in the average weight percentage of the sample gel as a function of temperature (°C) at each ambient temperature (27°C, 32°C, 37°C) is presented.

[0137] Detailed Description of the Invention

[0138] Efficacy of the composition

[0139] Clinical trial results of the compositions according to the present invention indicate that they are functionally equivalent to compositions containing GTN as an active ingredient, as described above. The compositions of the present invention contain: ethanol: 33%; water: 35%; glycerol: 24%; propylene glycol: 6%; Ultrez 10:1%. Adjust the pH to 5.25 using potassium hydroxide solution. The ethanol used to prepare the composition is anhydrous ethanol (i.e., 100% anhydrous ethanol), so the final composition contains 33% pure ethanol. If a lower grade of ethanol containing impurities (e.g., 96% ethanol) is used, the amount used must be adjusted to ensure that the final composition contains the appropriate amount of components, i.e., 33% pure ethanol and 35% water.

[0140] The availability of an effective composition for treating erectile dysfunction that does not contain GTN or any other active ingredient means fewer contraindications compared to other treatments, thus allowing its use even by men taking nitrate medications. Furthermore, its high safety profile allows for its use with other treatments such as sildenafil. In summary, the composition according to the invention represents a significant improvement over known treatments in providing rapid onset of action, sustained erectile quality, and high safety, and offers further treatment opportunities for patients who have been unable or contraindicated to currently available treatments.

[0141] The appendix shows clinical trial results of the compositions according to the invention compared to equivalent compositions containing GTN and commercially available Cialis and Vitaros. In the results, IIEF data were based on questionnaires related to male sexual function assessment, with SEP2 and SEP3 relating to the ability to insert the penis into the vagina and the ability to maintain an erection long enough to complete intercourse, respectively.

[0142] Comparison of major endpoints with baseline at 12 weeks

[0143]

[0144] Clinical significance difference at 12 weeks (Rosen & Araujo) - percentage of patients with observed significant differences

[0145]

[0146] Comparison of the primary endpoints and baselines of the compositions of the present invention and Cialis & Vitaros

[0147] Main efficacy parameters This invention Cialis 5mg Vitaros 100, 200 & 300 μg IIEF 3.6 4.6 1.6 / 2.5 / 2.4 SEP2 13.8％ 16.5％ 2.9％ / 5.1％ / 7.2％ SEP3 23.2％ 21.5％ 7.0％ / 13.8％ / 9.1％

[0148] Side effects - Comparison of this invention with Cialis

[0149]

[0150] Cooling effect of the composition

[0151] As described above, when the volatile solvent component evaporates, the composition according to the invention is believed to generate latent heat of cooling through the evaporation of the volatile solvent component, stimulating local nerves and generating endogenous nitric oxide to enhance the production of endogenous NO. For example, the glans penis has a series of sensors that respond to bodily senses (e.g., touch, pressure, and temperature), and the composition according to the invention is applied topically to these sensors. The rapid cooling caused by the composition and the subsequent recovery of temperature are believed to act as a stimulant, thereby causing the sensors to respond synergistically and inducing swelling and erection without containing an active ingredient.

[0152] The cooling effect of the compositions used in the above clinical trials was tested (ethanol: 33%; water: 35%; glycerol: 24%; propylene glycol: 6%). Ultrez 10:1%. (The pH was adjusted to 5.25 using a potassium hydroxide solution) and a scheme was developed to compare the cooling effects of different compositions.

[0153] 1. Principles

[0154] The cooling effect and recovery rate of the gel composition were measured by applying the gel to a calibrated temperature probe that had been weighed on an analytical balance. This allowed for simultaneous monitoring of temperature changes and weight loss over time. Different cooling / recovery "curves" could be generated when incubated at different ambient temperatures (e.g., 27°C, 32°C, and 37°C).

[0155] 2. Summary

[0156] A suitable method for evaluating the cooling profiles of the compositions according to the invention was performed at three different ambient temperatures: 27°C, 32°C, and 37°C. This method is disclosed to describe the process for obtaining the cooling profiles.

[0157] The results of the validation study confirmed that the method is suitable for purposes of repeatability (precision), reproducibility (intermediate precision), and accuracy.

[0158] 3. Instruments and apparatus

[0159] • Temperature probe (e.g., Fisherbrand Traceable Flip-Stick thermometer, P / N: 14-648-45). Total probe surface area: 11.64 cm² 2

[0160] · 15mL plastic centrifuge tubes or equivalent

[0161] • An electric drill or equivalent capable of drilling holes with a diameter of 5mm.

[0162] • Analytical balance (e.g., a Sartorius analytical balance or equivalent that measures to four decimal places)

[0163] Stopwatch

[0164] • Tabletop ovens capable of maintaining temperatures of 27°C, 32°C, and 37°C ± 1°C

[0165] Benchtop centrifuge

[0166] Video recorder / camera

[0167] 4. Sample

[0168] The following example is used for verification:

[0169] The gel contains ethanol: 33%; water: 35%; glycerol: 24%; propylene glycol: 6%. Ultrez 10:1%. Adjust the pH to 5.25 using potassium hydroxide solution.

[0170] 5. Method Development

[0171] This method was developed using three different ambient temperatures: 27°C, 32°C, and 37°C, to evaluate the cooling profiles of the sample gels. A description of the method can be found in Section 6 (only the 32°C version is described). The temperature and weight of the gel were recorded over a 25-minute run. Six replicate preparations were performed, and the average data was calculated at each ambient temperature. The following cooling profiles were generated: temperature versus time (…). Figure 1 ), weight percentage change over time ( Figure 2) and weight percentage change with temperature ( Figure 3 These cooling profiles are used to uniquely characterize the cooling properties of the sample gel.

[0172] During development, we observed that the first replicate of each day at each ambient temperature deviated the most from the average results compared to the other five replicates. This was likely due to temperature fluctuations when the oven door was first opened after overnight incubation. For this reason, we decided to omit the first replicate of each day in the validation study to allow the oven to stabilize before proceeding with further replicates.

[0173] The results of the development work show that different cooling profiles can be obtained when analyzing under different ambient temperatures. When plotting temperature (°C) versus time (minutes)... Figure 1 This difference in cooling profiles was most pronounced at 37°C. At all three ambient temperatures, the gel temperature reached its lowest point after approximately 1 to 1.5 minutes, then began to recover to ambient temperature. The temperature drop at 37°C was approximately 13°C, compared to approximately 8°C at 27°C, and the temperature drop appeared to increase with increasing ambient temperature. After 25 minutes, the sample gel recovered to within approximately 3°C of its initial starting temperature (ambient). For 37°C, the temperature recovery plateau occurred at approximately 15 minutes, while for 32°C and 27°C, both tended to plateau at approximately 25 minutes.

[0174] Figure 2 Cooling curves are shown for each ambient temperature when plotting weight percentage change against time (minutes). Generally, for all three ambient temperatures, the weight percentage change is fastest at the beginning of the curve, and begins to plateau after approximately 5 minutes. Second decreases in weight percentage change were observed at approximately 15 minutes at 32°C and approximately 20 minutes at 37°C. Overall, a significant difference is visible between the 27°C and 32°C / 37°C curves, while the 32°C curve shows only minor differences compared to the 37°C curve.

[0175] The cooling curve obtained by plotting temperature (°C) versus weight percentage change is as follows: Figure 3 As shown. Similarly, similar curve shapes were obtained at each ambient temperature. Overall, these curves are U-shaped. As the ambient temperature increases, as... Figure 1 As shown, the amount of temperature drop / recovery also increases. Maximum temperature drop was achieved at approximately 24% weight change for all three ambient temperatures. For 32°C and 37°C, a full recovery temperature required approximately 70% weight change, while returning to the ambient temperature of 27°C required only 60% weight change.

[0176] 6. Analysis and Guidance

[0177] Perform the following steps to test the sample gel.

[0178] Notice The first run of the day will be ignored and treated as a simulation run to allow the oven to stabilize after the first run.

[0179] 1. Drill a hole approximately 5 mm in diameter in the cap of a 15 mL centrifuge tube. Weigh the empty centrifuge tube on an analytical balance. Record the weight and calibrate the balance.

[0180] 2. Using a syringe, transfer approximately 14 mL of sample gel into a 15 mL centrifuge tube. Seal with a standard cap and centrifuge at 1500 rpm for 30 seconds to collect the gel.

[0181] 3. Place the tube containing the sample gel, the calibration temperature probe, and the analytical balance into a benchtop oven set to 32℃±1℃.

[0182] 4. Weigh the tube containing the sample gel. Record the weight of the gel (Weight Check 1).

[0183] 5. Place another calibrated temperature probe (for ambient temperature monitoring only) in the balance room. Incubate all instruments (including tubes containing sample gels) overnight.

[0184] 6. After incubation, weigh the tube containing the sample gel. (Weight check 2). Calculate the weight change and check for any significant weight loss (NMT 2%).

[0185] 7. Place the cap with the 5mm hole cut into it onto the centrifuge tube containing the sample gel. Plug the hole to prevent evaporation until ready to collect the sample. Return the centrifuge tube to the benchtop oven.

[0186] 8. Calibrate the balance using a temperature probe. Ensure the probe temperature is within the range of 32℃±1℃.

[0187] 9. Start recording and ensure temperature and weight are visible. (Note: Video recording does not need to exceed 5 minutes. Readings exceeding this time can be recorded manually.)

[0188] 10. Remove the temperature probe from the balance and insert it into the centrifuge tube containing the sample gel until the bottom of the probe touches the cap. Administer approximately 70 mg (±20 mg). (Note: Time-sensitive step).

[0189] 11. In a smooth motion, remove the probe from the gel, being careful not to touch the side of the centrifuge lid. Place the probe back on the balance, close the oven door, and start the stopwatch. Cap the centrifuge tube and centrifuge at 1500 rpm for 15 seconds to collect the gel. Seal the tube with a regular cap and return it to the oven. (Note: This is a time-sensitive step).

[0190] 12. Continuously record the probe weight and temperature for 25 minutes. The reading interval is shown in Table 2.

[0191] 13. If an ambient temperature drift is observed, the oven can be kept at 32℃±1℃ by adjusting the oven control knob or leaving a small gap on the oven door opposite the balance.

[0192] After 14.25 minutes, remove the temperature probe from the balance and clean it with a dry, lint-free paper towel. Place the temperature probe back on the balance, which should be maintained at 32°C ± 1°C. For the next repetition, repeat steps 7 through 14.

[0193] 15. Repeat all steps for other ambient temperatures of 27℃±1℃ and 37℃±1℃.

[0194] Read interval

[0195] Time (minutes) Read interval 0 to 1.5 Every 5 seconds 1.5 to 4 Every 30 seconds 4 to 15 Every minute 15 to 25 Every 5 minutes

[0196] 7. Results

[0197] Calculate the percentage change in weight for each reading interval using the following formula:

[0198] Weight percentage change = -100 + ((reading interval weight (g) / initial weight (g)) * 100)

[0199] Calculate the following:

[0200] Maximum temperature drop = Ambient temperature (°C) - Minimum temperature (°C)

[0201] Recovery temperature (T = 25 minutes) = Final temperature (°C) - Minimum temperature (°C)

[0202] According to the validation study protocol given in Section 6, conducted at an ambient temperature of 32℃±1℃, the test samples showed the following results:

[0203]

Claims

1. A composition for topical application to the penis for the treatment of erectile dysfunction, said composition consisting of ingredients in the following amounts, ranges being expressed in weight percent of the total composition: - ethanol: 30 to 45% - water: 20 to 40% - glycerol: 22 to 26% - propylene glycol: 4 to 12% - a thickening or gelling agent: 0.5-1.5% - a pH control agent for adjusting the pH of the composition as made to 5.25-5.75, wherein said thickening or gelling agent comprising a high molecular weight interpolymer of a crosslinked unsaturated carboxylic acid polymer, which is a homopolymer or copolymer, and a copolymeric steric stabilizer having hydrophilic and hydrophobic portions.

2. The composition of claim 1, wherein, said composition being in the form of a gel.

3. The composition of claim 2, wherein, said composition being in the form of a gel having a viscosity of 125,000 to 600,000 mPas.

4. The composition according to any one of claims 1-2, wherein, said glycerol and propylene glycol being in a weight ratio of 1.5:1 to 6.0:

1.

5. The composition according to any one of claims 1-2, wherein, said glycerol and propylene glycol being in a weight ratio of 3:1 to 5:

1.

6. The composition according to any one of claims 1-2, wherein, said water being 30-40% by weight.

7. The composition according to any one of claims 1-2, wherein, said ethanol being 30-35% by weight.

8. The composition according to any one of claims 1-2, wherein, the total amount of said glycerol and said propylene glycol not exceeding 35% by weight.

9. The composition according to any one of claims 1-2, wherein, said ranges being expressed in weight percent of the total composition: - ethanol: 30 to 35% - water: 33 to 37% - glycerol: 22 to 26% - propylene glycol: 4 to 8%.

10. A composition for topical application to the penis for the treatment of erectile dysfunction, said composition consisting of ingredients in the following amounts, ranges being expressed in weight percent of the total composition: - ethanol: 33% - water: 35% - glycerol: 24% - propylene glycol: 6% - Carbopol® Ultrez 10: 1% - a pH control agent, an agent for enhancing the skin feel and / or an antimicrobial preservative, wherein said pH control agent for adjusting the pH of the composition to 5.

25.

11. A composition for use in the treatment or amelioration of erectile dysfunction in a male subject, said composition for topical application to the penis for the treatment of erectile dysfunction, said composition consisting of ingredients in the following amounts, ranges being expressed in weight percent of the total composition: - ethanol: 30 to 45% - water: 20 to 40% - glycerol: 22 to 26% - propylene glycol: 4 to 12% - a thickening or gelling agent: 0.5-1.5% - a pH control agent for adjusting the pH of the composition as made to 5.25-5.75, wherein said thickening or gelling agent comprising a high molecular weight interpolymer of a crosslinked unsaturated carboxylic acid polymer, which is a homopolymer or copolymer, and a copolymeric steric stabilizer having hydrophilic and hydrophobic portions.

12. Use of a composition according to any one of claims 1-11 for the manufacture of a medicament for the treatment or amelioration of erectile dysfunction in a male subject.

13. Use according to claim 12, wherein, said subject having a pre-existing medical condition which precludes the taking of active ingredients for the treatment of erectile dysfunction, said pre-existing medical condition being selected from the group consisting of angina pectoris, hypotension, hypertension, benign prostatic hyperplasia and retinitis pigmentosa.

14. The use according to claim 12, wherein, The subject has an existing medical condition, treatment of which precludes the taking of active ingredients for the treatment of erectile dysfunction, the existing medical condition being selected from the group consisting of angina, low blood pressure, high blood pressure, benign prostatic hyperplasia and retinitis pigmentosa.

15. Use according to claim 14, wherein, Treatment of the existing medical condition comprises administration of an active ingredient selected from the group consisting of PDE-5 inhibitors, nitrates and alpha blockers.

16. The use according to claim 15, wherein, The active ingredient used to treat the existing medical condition is selected from the group consisting of GTN, isosorbide mononitrate, isosorbide dinitrate, alfuzosin, doxazosin, indoramin, prazosin, tamsulosin and terazosin.

17. The use according to any one of claims 12-16, wherein, The male subject has severe erectile dysfunction.

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