Topical composition

Abstract

There is provided a composition for topical application to the penis for the treatment of erectile dysfunction, the composition being free of glyceryl trinitrate (GTN), sildenafil and an acetylcholinesterase inhibitor, and comprising volatile and non-volatile solvents, the volatile solvents comprising a lower alcohol and water and the non-volatile solvents comprising a polyhydric alcohol and a glycol. Preferably, the composition does not contain any pharmaceutically active ingredients for the treatment of erectile dysfunction. Also provided is a method of determining the cooling ability of a test composition, such as the composition described above.

Claims

1. A composition for topical application to the penis for the treatment of erectile dysfunction, the composition consisting of the following ingredients being expressed in percentages by weight of the overall composition: ethanol: 30-35%, water: 33-37%, glycerol: 22-26%, propylene glycol: 4-8%, a thickening or gelling agent: 0.5-1.5%, and a pH control agent, wherein the thickening or gelling agent consists of high molecular weight interpolymers of a crosslinked unsaturated carboxylic acid polymer, which may be a homopolymer or a copolymer, and a copolymeric steric stabilizer having hydrophilic and hydrophobic moieties.

2. The composition of claim 1, wherein the composition has a manufactured pH in the range of 5.25 to 5.75.

3. The composition according to claim 1, wherein the composition has the form of a gel.

4. The composition according to claim 3, wherein the composition has the form of a gel having a viscosity in the range 125,000 to 600,000 mPas.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The invention will now be described in detail by way of example only with reference to the figures in which:

(2) FIG. 1 is a graph showing the average temperature ( C.) of the sample gel over time (min) at each ambient temperature (27 C., 32 C., 37 C.).

(3) FIG. 2 is a graph showing the average % weight change of the sample gel over time (min) at each ambient temperature (27 C., 32 C., 37 C.).

(4) FIG. 3 is a graph showing the average % weight change of the sample gel over temperature ( C.) at each ambient temperature (27 C., 32 C., 37 C.).

DETAILED DESCRIPTION OF THE INVENTION

Efficacy of Composition

(5) The results of a clinical trial of compositions according to the invention show that they are equivalent in performance to compositions containing GTN as active ingredient, as set out hereinbefore. The composition of the invention contained: ethanol: 33%; water: 35%; glycerol: 24%; propylene glycol: 6%; Carbopol Ultrez 10: 1%. pH was adjusted to 5.25 with potassium hydroxide solution. The ethanol used in the manufacture of the composition was absolute ethanol (i.e. 100% ethanol free from water) such that the final composition contained 33% of pure ethanol. If a lower grade of ethanol was used which contained impurity amounts of water (e.g. 96% ethanol), then the amount used would have to be adjusted to ensure the final composition contained the correct amount of the components, i.e. 33% pure ethanol and 35% water.

(6) The availability of an efficacious composition for treatment of erectile dysfunction, without the inclusion of GTN or any other active ingredient, means that the composition has reduced contraindications compared with other treatments, thus for example enabling the composition to be used by men taking nitrate medication. Furthermore, the high safety profile enables the compositions to be used in conjunction with other treatments such as sildenafil. In summary, compositions according to the invention, in providing fast onset time and sustained erection quality, together with a high safety profile, represent a significant improvement to known treatments and offer further treatment opportunities to patients who hitherto have been unable to or are contra-indicated to use currently-available treatments.

(7) The appended Tables show clinical trial results for compositions according to the invention, compared with equivalent compositions containing GTN and with commercially-available Cialis and Vitaros. In the results, the IIEF figures are on the basis of questionnaire responses relating to the evaluation of male sexual function and SWEP2 and SEP3 respectively relate to the ability to insert the penis into the vagina and the ability of the erection to sustain long enough for completion of intercourse.

(8) Primary Endpoints at 12 Weeks Vs Baseline

(9) TABLE-US-00001 0.6 mg 1.2 mg 1.8 mg Primary (0.2%) (0.4%) (0.6%) Endpoint Invention P-values GTN P-values GTN P-values GTN P-values IIEF-EF 3.60 <0.001 3.39% <0.001 3.42% <0.001 3.66% <0.001 Domain SEP2 13.8% <0.001 9% <0.001 13.27% <0.001 10.67% <0.001 SEP3 23.16% <0.001 20.76% <0.001 22.63% <0.001 23.27% <0.001

(10) Clinically Important Differences at 12 Weeks (Rosen & Araujo)Percentage of Patients Who Noticed a Meaningful Difference

(11) TABLE-US-00002 Overall responders Responders in patients using with Mild/Moderate/ Rosen/Araujo Severe ED using Invention (%) Rosen/Araujo (%) IIEF 63 61/59/80 SEP2 75 83/57/77 SEP3 68 71/61/71

(12) Primary Endpoints Vs Baseline for Composition of the Invention, Cialis & Vitaros

(13) TABLE-US-00003 Primary Efficacy Vitaros 100, 200 & Parameters Invention Cialis 5 mg 300 ug 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%

(14) Side Effect ProfileInvention vs. Cialis

(15) TABLE-US-00004 Adverse events - Invention Adverse events - Cialis 5 mg Invention (N = 250) Cialis (N = 151) Headache 3% Headache 11% Flushing 0% Flushing 2% Nasal congestion 0% Nasal congestion 2% Back pain 0% Back pain 3% Dizziness 0% Myalgia 2% Penile burning 1% Pain in limb 1%
Cooling Effect of Composition

(16) As indicated above, the compositions of the invention are believed to enhance production of endogenous NO by virtue of the latent heat of cooling as the volatile solvent component evaporates, stimulating the nerves locally and resulting in generation of endogenous NO. In the glans of the penis, there are sensors which are reactive to a range of physical sensations, such as and including touch, pressure and temperature, and topical application of compositions of the invention stimulate such sensors. It is thought that the rapid cooling brought about by the composition followed by the recovery in temperature acts as a stimulant so that the sensors react synergistically and result in tumescence and erection without the inclusion of an active ingredient.

(17) The cooling effect of the composition used in the clinical trial above (ethanol: 33%; water: 35%; glycerol: 24%; propylene glycol: 6%; Carbopol Ultrez 10: 1%. pH adjusted to 5.25 with potassium hydroxide solution) was tested and a protocol developed to enable the comparison of the cooling effect of different compositions.

(18) 1. Principle

(19) The cooling effect and rate of recovery of the gel composition is measured by applying the gel to a calibrated temperature probe that is weighed on an analytical balance. This allows the temperature change to be monitored simultaneously with weight loss over time. Different cooling/recovery profiles can be generated when incubating the setup at different ambient temperatures (i.e. 27 C., 32 C. and 37 C.).

(20) 2. Summary

(21) A suitable method to assess the cooling profiles of the composition of the invention was developed at three different ambient temperatures: 27 C., 32 C. and 37 C. The method was issued to describe the process used to obtain the cooling profiles.

(22) The results of the validation studies confirm that the method is fit for purpose regarding the repeatability (precision), reproducibility (intermediate precision) and accuracy.

(23) 3. Instruments & Apparatus

(24) Temperature probe (e.g. Fisherbrand Traceable Flip-Stick Thermometer, P/N: 14-648-45). Total probe surface area: 11.64 cm.sup.2 15 mL plastic centrifuge tubes or equivalent Power drill capable of drilling a 5 mm diameter hole or equivalent Analytical balance (e.g. Sartorius 4 decimal place Analytical Balance or equivalent) Stopwatch Bench top oven capable of maintaining 27 C., 32 C. and 37 C.1 C. Bench top centrifuge Video recorder/Camera
4. Sample

(25) The following sample was used for the validation:

(26) Gel comprising ethanol: 33%; water: 35%; glycerol: 24%; propylene glycol: 6%; Carbopol Ultrez 10: 1%. pH adjusted to 5.25 with potassium hydroxide solution.

(27) 5. Method Development

(28) Development of the method utilised three different ambient temperatures: 27 C., 32 C. and 37 C., to assess the cooling profile of the sample gel. A description of the method can be found in section 6 (32 C. described only). The temperature and weight of the gel was recorded over a run time of 25 minutes. Six replicate preparations were performed and the average of the data calculated at each ambient temperature. The following cooling profiles were generated: Temperature vs Time (FIG. 1), % Weight Change vs Time (FIG. 2) and % Weight Change vs Temperature (FIG. 3). It is intended that these cooling profiles can be used to uniquely characterise the cooling properties of the sample gel.

(29) During development, it was observed that the first replicate on each day at each ambient temperature was further from the mean result when compared to the other five replicates of data. This could be caused by fluctuations in oven temperature when opening the oven door for the first time after overnight incubation. For this reason, it was decided for the validation studies to disregard the first replicate on each day in order to allow the oven to stabilise before further replicates were performed.

(30) The results obtained for the development work show that a different cooling profile is achieved when analysing at different ambient temperatures. This difference in the cooling profile is most apparent when plotting Temperature ( C.) against Time (minutes) (FIG. 1). At all three ambient temperatures, the temperature of the gel reached the lowest point after 1-1.5 minutes and then began to recover back to the ambient temperature. The temperature drop appeared to increase as the ambient temperature increased with an ambient temperature of 37 C. showing a temperature drop of 13 C. compared to 8 C. at an ambient temperature of 27 C. After 25 minutes, the sample gel had recovered to within 3 C. of the initial starting temperature (ambient). The plateau of the temperature recovery occurred at 15 minutes for 37 C. ambient and at 32 C. and 27 C., both levelled off at 25 minutes.

(31) FIG. 2 shows the cooling profiles at each ambient temperature when plotting % Weight Change against Time (minutes). In general, the % weight change is most rapid at the beginning of the curve for all three ambient temperatures where after 5 minutes the % weight change begins to level off. A second % weight change drop was observed at 15 minutes for 32 C. and at 20 minutes for the 37 C. ambient temperature. Overall, a clear difference between the 27 C. and 32 C./37 C. profiles can be seen with the 32 C. profile only showing subtle differences when compared to the 37 C. profile.

(32) The cooling profiles obtained by plotting Temperature ( C.) against % Weight Change are shown in FIG. 3. Again, a similar profile shape was obtained at each of the ambient temperatures. Overall, the shape of these profiles represent a U shape. As the ambient temperature increases, the amount of temperature drop/recovery is also increased as seen in FIG. 1. At 24% weight change the maximum temperature drop is achieved for all three ambient temperatures. Full temperature recovery requires 70% weight change for 32 C. and 37 C., whereas only 60% weight change is needed to return to 27 C. ambient.

(33) 6. Analytical Guidance

(34) The following steps were carried out to test the sample gel.

(35) Note: the first run on each day of analysis is to be disregarded and treated as a mock run to allow the oven setup to stabilise after the first run. 1. Drill a hole 5 mm in diameter into a 15 mL centrifuge tube lid. Weigh the empty centrifuge tube on an analytical balance. Record the weight and tare the balance. 2. Place 14 mL of sample gel into the 15 mL centrifuge tube using a syringe. Seal with a normal lid and centrifuge at 1500 rpm for 30 seconds to collect the gel. 3. Place the tube containing sample gel, a calibrated temperature probe and an analytical balance into a bench top oven set at 32 C.1 C. 4. Weigh the tube containing the sample gel. Record the weight of the gel (Weight Check 1). 5. Place another calibrated temperature probe inside the balance chamber (for ambient temperature monitoring only). Leave all apparatus including the tube containing sample gel overnight to incubate. 6. After incubation, weigh the tube containing the sample gel. (Weight Check 2). Calculate the weight change and check there is no significant weight loss (NMT 2%). 7. Place the lid with the 5 mm hole cut out onto the centrifuge tube containing sample gel. Stopper the hole to prevent any evaporation until it is ready to be sampled. Place back into the benchtop oven. 8. Tare the balance with the temperature probe. Ensure the temperature of the probe is within 32 C.1 C. 9. Begin video recording ensuring the temperature and weight are visible. (NB: it is not required to video record beyond 5 minutes. Readings after this time may be manually recorded). 10. Remove the temperature probe from the balance and insert it into centrifuge tube containing sample gel until the base of the probe makes contact with the tube lid. Approximately 70 mg is applied (20 mg). (NB: Time sensitive step). 11. In one smooth motion, withdraw the probe from the gel taking care not to make contact with the sides of the centrifuge cap. Place the probe back onto the balance, close the oven door and start the stopwatch. Stopper the centrifuge tube lid and centrifuge the tube for 15 seconds at 1500 rpm to collect the gel. Seal the tube with a regular lid and place back into the oven. (NB: Time sensitive step). 12. Record the weight and temperature of the probe for 25 minutes. See Table 2 for reading intervals. 13. If ambient temperature drift is observed, the oven may be maintained at 32 C.1 C. by adjusting the oven control dial or by venting with a small gap in the oven door on the opposite side of the balance. 14. After 25 minutes, remove the temperature probe from the balance and clean with a dry lint-free tissue. Place the temperature probe back onto the balance maintained at 32 C.1 C. Repeat steps 7-14 for the next replicate. 15. Repeat all steps for the remaining ambient temperatures of 27 C.1 C. and 37 C.1 C.

Reading Intervals

(36) TABLE-US-00005 Time (mins) Reading Interval 0-1.5 Every 5 seconds 1.5-4 Every 30 seconds 4-15 Every 1 minute 15-25 Every 5 minutes
7. Results

(37) Calculate % weight change at each reading interval using the following equation:
% weight change=100+((Reading Interval Weight (g)/Initial Weight (g))*100)
Calculate the following:
Maximum Temperature Reduction=Ambient Temperature( C.)Lowest Temperature ( C.)
Temperature Recovery(T=25 mins)=Final Temperature ( C.)Lowest Temperature ( C.)

(38) In a validation study conducted at an ambient temperature of 32 C.1 C. in accordance with the protocol given in section 6, the test sample gave the following results:

(39) TABLE-US-00006 Target Precision Parameter ( C.) Mean SD % RSD (% RSD) Temperature Drop After 1 min 11.5 0.1 0.7 7.5% RSD Maximum Temperature Drop 11.5 0.1 1.0 Temperature Recovery After 25 min 8.9 0.4 5.0