TOPICAL COMPOSITION

Abstract

There is described a composition for topical application to the penis for treatment of erectile dysfunction, the composition comprising glyceryl trinitrate (GTN) as active ingredient dissolved in a blend of volatile and non-volatile solvents of different solvating capacities for the GTN, in which the volatile solvents comprise water and a lower alcohol and the non-volatile solvents comprise a polyhydric alcohol and a glycol having a ratio by weight of from 1.5:1 to 6.0:1, in which the composition has a pH as manufactured in the range 5.1 to 7.0. Also described is the use of the composition and methods involving the composition for treating or ameliorating erectile dysfunction.

Claims

1. A composition for topical application to the penis for treatment of erectile dysfunction, the composition comprising glyceryl trinitrate (GTN) as active ingredient dissolved in a blend of volatile and non-volatile solvents of different solvating capacities for the GTN, in which the volatile solvents comprise water and a lower alcohol and the non-volatile solvents comprise a polyhydric alcohol and a glycol having a ratio by weight of from 1.5:1 to 6.0:1, in which the composition has a pH as manufactured in the range 5.1 to 7.0.

2. A composition according to claim 1, having a pH as manufactured in the range 5.25 to 5.75.

3. A composition according to claim 1, having the form of a gel, cream or serum.

4. A 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.

5. A composition according to claim 4, including at least one additional ingredient selected from agents for enhancing skin feel, a thickening or gelling agent, a pH control agent and an antimicrobial preservative.

6. A composition according to claim 5, wherein the additional ingredient is a thickening or gelling agent which comprises an easy to disperse interpolymer of the type described.

7. A composition according to claim 6, wherein the easy to disperse interpolymer of the type described is a high molecular weight interpolymer of a crosslinked unsaturated carboxylic acid polymer and a copolymeric steric stabiliser having hydrophilic and hydrophobic moieties.

8. A composition according to claim 7, wherein the monomer of the unsaturated carboxylic acid polymer comprises acrylic acid or an alkyl ester derivate thereof.

9. A composition according to claim 7, wherein the unsaturated carboxylic acid comprises acrylic acid crosslinked with allyl sucrose.

10. A composition according to claim 7, wherein the steric stabiliser comprises either a block copolymer and/or a random copolymer, the block copolymer comprising a polyester such as 12-hydroxystearic acid as the hydrophobic moiety and polyethylene glycol as the hydrophilic moiety.

11. A composition according to claim 6, wherein the thickening or gelling agent is present in the composition at 0.5% to 2% by weight.

12. A composition according to claim 1, wherein the lower alcohol is ethanol or isopropanol.

13. A composition according to claim 1, wherein the polyhydric alcohol is selected from glycerol, zorbitol, erythritol, arabitol and xylitol.

14. A composition according to claim 1, wherein the glycol is selected from propylene glycol, butylene glycol, pentylene glycol and hexylene glycol.

15. A composition according to claim 1, wherein the polyhydric alcohol to glycol weight ratio is from 3:1 to 5:1.

16. A composition according to claim 1, comprising the following ingredients, the ranges being expressed in percentages by weight of the overall composition: lower alcohol: 30-45% water: 20-40% polyhydric alcohol: 22-26% glycol: 4-12%

17. A composition according to claim 1, wherein the water is in the range 30-40% by weight.

18. A composition according to claim 1, wherein the lower alcohol is in the range 30-35% by weight.

19. A composition according to claim 1, wherein the combined amount of the polyhydric alcohol and the glycol is not more than 35% by weight.

20. A composition according to claim 1, wherein the composition comprises a neutralising agent selected from potassium hydroxide, sodium hydroxide or liquid ammonia.

21. A composition according to claim 1, wherein the composition comprises a neutralising agent selected from potassium hydroxide, sodium hydroxide or liquid ammonia, and wherein the composition comprises a thickening or gelling agent which comprises an easy to disperse interpolymer of the type described.

22. A composition according to claim 1, comprising the following ingredients, the ranges being expressed in percentages by weight of the overall composition: lower alcohol: 30-35% water: 33-37% polyhydric alcohol: 22-26% glycol: 4-8%

23. A composition according to claim 1, wherein the composition is in the form of a gel and comprises the following ingredients, the ranges being expressed in percentages by weight of the overall composition: lower alcohol: 30-35% water: 33-37% polyhydric alcohol: 22-26% glycol: 4-8% a thickening or gelling agent: 0.5-1.5%, wherein the composition has a pH as manufactured in the range 5.25 to 5.75.

24. A composition according to claim 1, wherein the concentration of GTN is in the range 0.05 to 1.0% by weight.

25. A method for treating or ameliorating erectile dysfunction, the method comprising administering a biologically effective amount of the composition according to claim 1 to the penis of a subject.

26. (canceled)

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0068] The invention will now be described in detail by way of example only with reference to the figures in which:

[0069] FIG. 1a shows the mean plasma concentrations of GTN following topical application of a virtual injection formulation (this formulation corresponds to the compositions of WO2006/016139 and is referred to as MED 2003).

[0070] FIG. 1b shows the mean plasma concentrations of GTN following topical application of a hybrid virtual injection-slow absorption formulation (this formulation corresponds to the compositions of the invention and is referred to as MED 2005).

[0071] FIG. 2.1 shows the effect of GTN dose and formulation type on apparent t.

[0072] FIG. 2.2 shows the effect of GTN dose and formulation type on Cmax plasma.

[0073] FIG. 2.3 shows the effect of GTN dose and formulation type on Tmax plasma.

[0074] FIG. 2.4 shows the effect of GTN dose and formulation type on AUC 0-.

EXPERIMENTAL RESULTS

[0075] A pharmacokinetic study measuring systemic plasma levels of GTN following topical application of virtual injection (MED 2003, 0.075, 0.1, 0.25 and 0.50 mg of GTN) and hybrid virtual injection-slow absorption gel formulations of GTN (MED 2005 1.2 mg of GTN) was conducted in 16 volunteers. The MED 2005 formulation contained: ethanol: 33%; water: 35%; glycerol: 24%; propylene glycol: 6%; Carbopol Ultrez 10: 1%; glyceryl trinitrate: 0.2%. pH was adjusted to 5.25 with potassium hydroxide solution.

[0076] In the laboratory setting of this study, GTN clearance from the penis via the venous return was rapid in the non-erect state. Even so these plasma levels data allow comparison of the pharmacokinetics of GTN from virtual injection and hybrid virtual injection-slow absorption gel formulations. FIGS. 1a and 1b show log individual (n=6) plasma concentrations of GTN with time plots for each volunteer following topical administration of MED 2003, 0.5 mg GTN (virtual injection) and MED 2005, 1.2 mg (hybrid virtual injection-slow absorption) gel formulations, respectively. It is seen that, for some subjects, GTN was present in the plasma for up to 90 minutes following application of the MED2005 gel formulation.

[0077] By eye, and by statistical analysis, the apparent plasma t (the half life of the apparent elimination phase) is longer for MED 2005.

[0078] This finding is consistent with so-called flip-flop pharmacokinetics. Flip-flop pharmacokinetics arise when the absorption rate and elimination rate constants are of similar magnitude, especially when the elimination rate is faster than the absorption rate constant. In this case, the apparent elimination rate is governed by the absorption rate and is thus a characteristic of the formulation. In the Background section, we describe how GTN absorption rate was required to in the same range as the penile clearance rates for GTN.

[0079] Mean plasma level data with time from several dose of GTN in MED 2003 and a single 1.2 mg dose of GTN in MED 2005 were fitted to a one-compartment pharmacokinetic model and the model-derived pharmacokinetic parameters (t, apparent systemic half life, minutes; Cmax. maximum plasma concentration, g/ml; Tmax, time of maximum plasma concentration, minutes and AUC, area under curve 0- pg.Math.min/min) obtained are shown in FIGS. 2.1-2.4. FIG. 2.1 shows that the apparent half life of GTN is increased and FIG. 2.2 that Cmax is decreased in the MED 2005 hybrid virtual injection-slow absorption gel formulation. Both of these pharmacokinetic effects are consistent with slow absorption of GTN from the MED 2005 formulation. FIG. 2.3 shows little effect of MED 2005 formulation on Tmax, which is more typical of a hybrid virtual injection-slow absorption system than one which provides a more steady (slow) absorption. Finally, FIG. 2.4 shows that bioavailability, as measured by AUC 0-/dose, is very similar for MED 2003 and 2005 formulations.

[0080] These derived pharmacokinetic parameters are consistent with those of a system designed to optimise both onset and duration of activity appropriate to treatment of ED.

Clinical Studies on Erectile Dysfunction (ED) for MED 2005

[0081] Popular culture may regard the successful treatment of ED in terms of the ability to achieve and sustain an erection to enable intercourse to take place. Thus, both onset and duration of activity are important in treatment of ED. In order to assess the degree of severity of ED on a more objective basis, the International Index of Erectile Function (IIEF) has formulated a questionnaire containing questions relating to the evaluation of male sexual function. The erectile function domain of the IIEF questionnaire relates to confidence in achieving and maintaining an erection; whether sexually-stimulated erections are hard enough for penetration; the ability to maintain an erection following penetration; the ability to maintain an erection to completion of intercourse; and how often was the experience of intercourse satisfactory (for the male participant).

[0082] In a clinical study, formulations of the invention, containing glyceryl trinitrate, ethanol to water in a ratio of around 1:1 and the Carbopol Interpolymer Ultrez-10 were remarkably effective, compared to an otherwise identical placebo gel. Particularly, onset of erection occurred with 5 minutes of application. It appears likely that the interpolymer of the type described, for example Carbopol Ultrez-10, acts in some way to optimise volatile solvent evaporation, either by increasing the rate of total solvent evaporation or preferential loss of ethanol. Shear thinning and reduced viscosity, upon application of the gel, may also contribute to the effect.

[0083] In all the above respects, IIEF scores obtained following application of GTN compositions according to the present invention are remarkably high. Also in these clinical studies on compositions of the present invention, subjects reported that time for onset of erection is on a scale of minutes and much shorter than experienced with oral PDE5 inhibitors. We therefore believe that the compositions of the present invention compared with those disclosed in WO2006/016139, provide both initially rapid and yet slowly absorbed delivery of GTN resulting in both rapid onset of erection and appropriate sustainment to the benefit of both sexual partners.

[0084] A further pharmacokinetic study has shown that absorption of GTN through the glans of the penis using a composition including Ultrez 10 as the gelling agent follows the usual initial pattern of rapid absorption but in some subjects a tail of GTN in the PK profile, lasting up to 4 hours (the duration of the study), is demonstrated. This suggests that the compositions of the invention do provide a hybrid virtual injection-slow absorption effect in prolonging the efficacy time following application. This finding reinforces the inference drawn from FIG. 1b concerning the concentration of GTN in plasma up to 90 minutes from application.

[0085] An additional study was carried out to assess the safety and efficacy of compositions according to the invention containing different concentrations of GTN. Doses ranged up to 0.8% (2.4 mg GTN) compared with an orally-administered sub-lingual composition (Nitrostat) at 1.8 mg GTN. Concentrations of GTN and its metabolites were measured in plasma samples using tandem mass spectrometry. In a further study to measure gel absorption, penile swabs were taken for the participants, 5 minutes after application of 0.8% (2.4 mg) of GTN gel in order to measure residual GTN.

[0086] It was found that plasma concentration of GTN and its two major metabolites increased proportionally with increasing dosage level. Pharmokinetic modelling suggested that GTN initially enters the systemic circulation by a rapid zero order process with a Tmax of 10-12 minutes. This is followed by a first order absorption with a lag time, the first appearance of GTN being around 4 minutes after application. Comparison of Cmax and the AUC data between compositions according to the invention and the reference product Nitrostat indicated that, at concentrations up to and including 0.6% (1.8 mg) GTN, the bioavailability of systemically absorbed GTN was less than or equivalent to the reference product, indicative of systemic safety. Adverse events experienced by the participants were generally mild and acceptable and, in particular, incidence of headache did not increase markedly at higher doses.

[0087] Penile swabs taken 5 minutes after application showed that 73% of the dose was absorbed, suggesting that adverse events as a result of transference to partners would be minimal.

[0088] In summary, compositions according to the invention have been shown to have a fast onset of action, low systemic bioavailability and a favourable safety profile for both partners.