TOPICAL CONJUGATES AND COMPOSITIONS

Abstract

The present invention relates to a conjugate suitable for topical application to the skin of a user, the conjugate comprising at least one volatile active coupled directly or indirectly to a carrier substance, wherein the carrier substance is substantially resistant to permeation through the skin of a user under ambient conditions, and wherein the coupling between the active and the carrier substance is such that said coupling is cleaved under said ambient conditions when said conjugate has been applied to the skin of a user, so as to release said volatile active from said carrier substance in a sustained release manner. The present invention also relates to a composition including such a conjugate and also processes of preparing such conjugates and compositions.

Claims

1. A conjugate suitable for topical application to the skin of a user, the conjugate comprising at least one volatile active coupled directly or indirectly to a carrier substance, wherein the carrier substance is substantially resistant to permeation through the skin of a user under ambient conditions, and wherein the coupling between the active and the carrier substance is such that said coupling is cleaved under said ambient conditions when said conjugate has been applied to the skin of a user, so as to release said volatile active from said carrier substance in a sustained release manner.

2. A composition suitable for topical application to the skin of a user, the composition comprising a conjugate and at least one inert diluent or excipient therefor, said conjugate comprising at least one volatile active coupled directly or indirectly to a carrier substance, wherein the carrier substance is substantially resistant to permeation through the skin of a user under ambient conditions, and wherein the coupling between the active and the carrier substance is such that said coupling is cleaved under said ambient conditions when said composition has been applied to the skin of a user, so as to release said volatile active from said carrier substance in a sustained release manner.

3. A conjugate for releasing at least one volatile active in a sustained release manner when said conjugate has been applied to the skin of a user, the conjugate comprising the at least one volatile active coupled directly or indirectly to a carrier substance, wherein the carrier substance is substantially resistant to permeation through the skin of a user under ambient conditions, and wherein the coupling between the active and the carrier substance is such that said coupling is cleaved under said ambient conditions when said conjugate has been applied to the skin of a user.

4. A composition for releasing at least one volatile active in a sustained release manner when said composition has been applied to the skin of a user, the composition comprising a conjugate and at least one inert diluent or excipient therefor, said conjugate comprising the at least one volatile active coupled directly or indirectly to a carrier substance, wherein the carrier substance is substantially resistant to permeation through the skin of a user under ambient conditions, and wherein the coupling between the active and the carrier substance is such that said coupling is cleaved under said ambient conditions when said composition has been applied to the skin of a user.

5. A conjugate for repelling insects, wherein said conjugate releases at least one volatile insect repellent in a sustained release manner when said conjugate has been applied to the skin of a user, the conjugate comprising the at least one volatile insect repellent coupled directly or indirectly to a carrier substance, wherein the carrier substance is substantially resistant to permeation through the skin of a user under ambient conditions, and wherein the coupling between the insect repellent and the carrier substance is such that said coupling is cleaved under said ambient conditions when said conjugate has been applied to the skin of a user.

6. A composition for repelling insects, wherein the composition comprises a conjugate and at least one inert diluent or excipient therefor, said conjugate comprising at least one volatile insect repellent coupled directly or indirectly to a carrier substance, wherein the carrier substance is substantially resistant to permeation through the skin of a user under ambient conditions, and wherein the coupling between the insect repellent and the carrier substance is such that said coupling is cleaved under said ambient conditions when said composition has been applied to the skin of a user, so as to release said volatile insect repellent from said carrier substance in a sustained release manner.

7. A conjugate for providing a desirable fragrance, wherein said conjugate releases at least one volatile fragrance in a sustained release manner when said conjugate has been applied to the skin of a user, the conjugate comprising at least one volatile fragrance coupled directly or indirectly to a carrier substance, wherein the carrier substance is substantially resistant to permeation through the skin of a user under ambient conditions, and wherein the coupling between the fragrance and the carrier substance is such that said coupling is cleaved under said ambient conditions when said conjugate has been applied to the skin of a user.

8. A composition for providing a desirable fragrance, wherein the composition comprises a conjugate and at least one inert diluent or excipient therefor, said conjugate comprising at least one volatile fragrance coupled directly or indirectly to a carrier substance, wherein the carrier substance is substantially resistant to permeation through the skin of a user under ambient conditions, and wherein the coupling between the fragrance and the carrier substance is such that said coupling is cleaved under said ambient conditions when said composition has been applied to the skin of a user, so as to release said volatile fragrance from said carrier substance in a sustained release manner.

9. A method of releasing at least one volatile active in a sustained release manner when said active has been applied to the skin of a user, wherein said active is present in a conjugate and said conjugate comprises the at least one volatile active coupled directly or indirectly to a carrier substance, wherein the carrier substance is substantially resistant to permeation through the skin of a user under ambient conditions, wherein said method comprises the steps of: applying the conjugate to the skin of the user; effecting cleavage of the coupling between the active and the carrier substance, so that said sustained release of said active occurs.

10. A method according to claim 9, wherein said conjugate is present in a composition that further comprises at least one inert diluent or excipient for said conjugate.

11. A conjugate according to claim 1, a composition according to claim 2, a method according to claim 9 or 10, wherein said volatile active comprises an insect repellent.

12. A conjugate according to claim 1, a composition according to claim 2, a method according to claim 9 or 10, wherein said volatile active comprises a desirable fragrance.

13. A conjugate according to any of claims 1, 3, 5, 7; a composition according to any of claims 2, 4, 6, 8; a method according to claim 9 or 10; wherein said sustained release is a release period of at least 6 hours, more preferably at least 8 hours, more preferably at least 9 hours, more preferably at least 10 hours, more preferably at least 11 hours and in some instances most preferably for at least 12 hours.

14. A conjugate, composition or method according to claim 13, wherein the release profile provides protection for a user against biting flies throughout a period of sleep without the need for reapplication.

15. A conjugate, composition or method according to claim 14, wherein the release profile provides protection for a user against biting flies throughout the night.

16. A conjugate, composition or method according to preceding claims, wherein the volatile active, or insect repellent, or fragrance, includes at least one OH group in its structure.

17. A conjugate, composition or method according to claim 16, wherein the volatile active, or insect repellent, or fragrance, forms an ester bond with one or more carboxylic acid groups as present in the carrier substance.

18. A conjugate, composition or method according to preceding claims, wherein the carrier substance comprises one or more polymers.

19. A conjugate, composition or method according to claim 18, wherein the polymer is selected from the group consisting of hyaluronic acid, polycarboxylic acids, other suitable carboxylic acids, and mixtures thereof.

20. A conjugate, composition or method according to claim 19, wherein the polymer is selected from the group consisting of hyaluronic acid, polycarboxylic acid, and mixtures thereof.

21. A conjugate, composition or method according to preceding claims, wherein the volatile active or volatile insect repellent is selected from the group consisting of p-menthane-3,8-diol, geraniol, nerolidol and picararidin.

22. A composition according to preceding claims, which further comprise at least one further volatile active in addition to the at least one volatile active coupled directly or indirectly to the carrier substance.

23. A composition according to claim 22, wherein the further volatile active is the same as the at least one volatile active coupled directly or indirectly to the carrier substance.

24. A composition according to claim 22, wherein the further volatile active is different to the at least one volatile active coupled directly or indirectly to the carrier substance.

25. A composition according to claims 22 to 24, wherein said at least one further volatile active is present in substantially non-bound form.

26. A composition according to claim 25, wherein said at least one further volatile active exhibits an immediate release profile, whereas the at least one volatile active coupled directly or indirectly to the carrier substance exhibits a sustained release profile.

27. A composition according to any of claims 22 to 26, wherein said at least one further volatile active, and said at least one volatile active coupled directly or indirectly to the carrier substance, are both insect repellents.

28. A composition according to claim 27, wherein said at least one volatile active coupled directly or indirectly to the carrier substance is selected from the group consisting of p-menthane-3,8-diol, geraniol, nerolidol and picararidin

29. A process of providing a conjugate according to claim 1, which process comprises coupling at least one volatile active with a carrier substance, under conditions so as to provide a conjugate wherein the coupling between the at least one volatile active and carrier substance is such that it can be cleaved under ambient conditions and when said conjugate has been applied to the skin of a user.

30. A process according to claim 29, wherein the reaction is carried out in the presence of a coupling agent.

31. A process according to claim 30, wherein the coupling agent comprises PyBop.

32. A process according to any of claims 29 to 31, wherein the reaction is carried out in the presence of an esterification reagent.

33. A process according to claim 32, wherein the esterification reagent comprises DIPEA.

34. A process according to any of claims 29 to 33, which is carried out in the presence of a polar aprotic solvent.

35. A process according to claim 34, wherein the solvent comprises DMSO.

36. A process of preparing a composition according to claim 2, which process comprises admixing a conjugate according to claim 1 with at least a suitable diluent or excipient so as to provide a composition according to claim 2.

Description

EXAMPLE 1

[0075] DOWEX ion exchange resin (12.5 g) was washed three times with 250 mL aliquots of distilled water and then treated with 25 mL of tetra-n-butyl ammonium hydroxide (TBA) and left to react at room temperature for 1 hour. The resin (Dowex-TBA) was then filtered and the resin collected. 1 g of hyaluronic acid (HA) was dissolved in 100 mL of distilled water to which 10 g of the DOWEX-TBA resin was added and the reaction was allowed to proceed at room temperature for 18 hours. The reaction mixture was then filtered through a 0.45 μm filter and the supernatant was collected. The supernatant was freeze dried for three days to yield HA-TBA. 500 mg of HA-TBA was dissolved in 60 mL dimethyl sulphoxide (DMSO). 0.5 mL of N,N-diisopropylethylamine (DIPEA) and 0.9 g of benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBop) were added and left stirring at room temperature for 1 hour. 1 g of para-menthane-3,8-diol (PMD) was then added and the mixture left stirring for a further 24 hours at room temperature. The resultant HA-PMD conjugate was then recovered from the reaction mixture by dialysis against an excess amount of 100 mM sodium chloride aqueous solution containing 25% v/v ethanol and distilled water (5 changes over 48 hours) before freeze drying for 3 days to provide the solid HA-PMD conjugate.

EXAMPLE 2

[0076] The HA-PMD conjugate was formulated into a hydroalcoholic gel. Deionised water (47 weight %), denatured ethanol (31.75 weight %), polyethylene glycol with an average molecular weight of 400 Da (10 weight %), 0.5M aqueous sodium hydroxide (0.25 weight %) were mixed until uniform at room temperature. To this mixture was added the HA-PMD conjugate (10 weight %) prepared according to Example 1 and Carbopol Ultrez 10 polymer (1 weight %). The mixture was stirred at 1200 rpm until a clear gel is obtained.

EXAMPLE 3

[0077] The HA-PMD conjugate was formulated into a topical spray. Isopropyl myristate (30 weight %), propylene glycol (15 weight %), distilled water (10 weight %) and denatured ethanol (35 weight %) were mixed until uniform at room temperature. To this mixture was added the HA-PMD conjugate (10 weight %) prepared according to Example 1 and the mixture was stirred until uniform. The resultant formulation was packaged into a spray delivery system.