WO2010138099A1

WO2010138099A1 - Dermal medicament delivery system causing an exothermic reaction

Info

Publication number: WO2010138099A1
Application number: PCT/US2009/003262
Authority: WO
Inventors: Leonard Mackles; William Bess
Original assignee: Individual
Current assignee: Individual
Priority date: 2009-05-28
Filing date: 2009-05-28
Publication date: 2010-12-02
Anticipated expiration: 2011-11-28

Abstract

There is provided a self heating composition containing at least one medicament, a kit for the components, methods for making it, and methods of applying it to the skin whereby the skin is hydrated and the efficacy of administration of the medicament is raised.

Description

DERMAL MEDICAMENT DELIVERY SYSTEM CAUSING AN EXOTHERMIC REACTION

Field of the invention

[0001] This invention relates to a method for increasing the efficacy of medicaments delivered to the skin of mammals.

Background

[0002] It is well known in the art that the efficacy of topically delivered medicaments can be improved by warming the medicament and/or skin just prior to application. It is also well known in the art that the efficacy can be improved by insuring that the skin is well hydrated just prior to application of the medicament.

Summary of the Invention [0003] The present invention provides a means of applying a heated medicament to the skin and concurrently hydrating the skin thus raising the efficacy of administration. In the present invention there is provided a dual phase aqueous based system which self-heats when the two phases are combined. The medicament(s) can be included in either or both phases. Self-warming is achieved through the use of an oxidation-reduction reaction alone or in combination thereof with an acid-base reaction.

[0004] The invention provides an improved method of applying at least one dermally or transdermal^ physiologically active medicament to the skin of a mammal in need of same consisting essentially of a first dermally acceptable phase and a second dermally acceptable phase mixable therewith, wherein at least one of said phases has an aqueous component.

[0005] The medicament may be present in either phase. In one embodiment, 5 the first phase consists essentially of at least one component capable of producing an exothermic reaction of dermally acceptable magnitude when contacted with the second phase and promptly applying the mixture to the skin of the subject.

0 [0006] The first phase may be a reducing phase and the second phase is then an oxidizing phase. Alternatively where first phase is a basic phase, the second phase is an acidic phase. The invention however is not so limited. The first phase, when reducing, may additionally comprises a basic component and said second phase when acid will comprise an acidic component

S reactable with said basic component. Similarly first reducing phase may additionally comprise an acidic component and then the second phase comprises a basic component reactable with said acidic component.

[0007] The invention also provides a kit for applying at least one dermally or 10 transdermal^ physiologically active medicament to the skin of a mammal in need of same, consisting essentially of a first dermally acceptable phase and a separate second dermally acceptable phase mixable therewith.

[0008] The medicament may be present in either phase. The first phase !5 consists essentially of at least one component capable of producing an exothermic reaction of dermally acceptable magnitude when contacted with said second phase and wherein at least one of said phases has an aqueous component . [0009] In the kit, where the first phase is a reducing phase the second phase is an oxidizing phase. Alternatively, where the first phase is a basic phase, the said second phase is an acidic phase.

[0010] Where the first phase is a reductive phase it may additionally comprise a basic component, then the said second, oxidative phase comprises an acidic component reactable with said basic component. Similarly when the first reductive phase additionally comprises an acidic component and the second phase oxidative comprises a basic component reactable with said acidic component.

[0011] When the two phases are combined, the reaction(s) which occur, result in a dramatic increase in temperature. The increased temperature combined with the aqueous vehicle hydrates the skin and heats the medicament(s). The result is improved product efficacy.

Medicaments

[0012] Acceptable medicaments include any drug suitable for topical delivery, whether intended for systemic treatment via transdermal delivery or intended to treat a topical skin condition. Non-limiting examples include analgesic drugs, analgesic anti-inflammatory drugs, central nervous system drugs, antihistaminic or antiallergic drugs, acitonide anti-inflammatory drugs, androgenic and estrogenic steroids, -respiratory drugs, sympathomimetic drugs, antimicrobial drugs, antihypertensive drugs, cardiotonic drugs, coronary vasodilators, vasoconstrictors, beta blocking and antiarrhythemic drugs, calcium antagonistic and other circulatory anticonvulsants, anti-vertigo- tranquilizing drugs, antipsychotic drugs, muscle-reactants drugs, anti- Parkinson drugs, non-steroidal hormones, anti-hormones, vitamins, antitumor, enzymes, herb medicines or crude extracts, miotics, cholinergic agonists, antimuscarinic or muscarinic cholinergic blocking drugs, mydriatics, psychic energizers, humoral agents, antispasmodic drugs, antidepressants, antidiabetics, anorexic drugs, anti-allergic«drugs, decongestants, antipyretics, antimigraine drugs, antimalarial, antiulcer drugs, peptides, and anti-estrogens. Additional acceptable medicaments include cosmeceutical agents. Non- limiting examples include, moisturizers, hydroxy-acids, bleaching agents, and skin protectants.

[0013] The concentration range will vary by medicament, but it is to be understood that the acceptable range would encompass all concentrations of a particular medicament or combination of medicaments, which demonstrate acceptable efficacy.

Heat-Producing Reactants

[0014] Heat production can be achieved by using an oxidation-reduction reaction either as the sole reaction, or in combination with an acid-base reaction. Quantities mention herein should be considered as parts by weight of the phase in which they are initially provided, unless otherwise indicated

[0015] Acceptable reducing agents include but are not limited to alkali metal or alkaline earth metal sulfites, bisulfites, thiosulfates, and metabisulfites. The acceptable range of reducing agent(s) utilized will be from 1-20%, preferably 2-15 w/w% based on total solution.

[0016] Acceptable oxidizing agents include but are not limited to peroxides. Suitably they include include hydrogen peroxide and urea peroxide. The acceptable range of peroxide(s) will depend on the concentration of reducing agent(s), and the composition of the reducing agent(s) utilized. It is to be understood that the acceptable range of peroxide will include concentrations which will result in at least a 5 degree (Fahrenheit) rise in temperature when the two phases are mixed. [0017] Acceptable acidic reactants inciude but are not limited to, inorganic mineral acids, suitably sulphuric, hydrochloric, nitric and phosphoric acids preferably phosphoric acid.. The range for inorganic acids is 0.05-10 w/w% preferably 0.5-5.0 w/w%, based on the aqueous diluted form selected. Similarly water soluble organic acids with an equivalent weight of less than 100, but not limited thereto, such as lactic, glycolic and citric acids may be used. In both cases the given percentages are bases on the diluted form, if present, relative to total weight of the phase.

[0018] Acceptable basic reactants include hydroxides, amines, and ammonia. The range for basic reactants will vary according to the concentration of inorganic acid used in the oxidizing phase, the particular basic reactant(s) utilized, and the final desired pH of the product. It is to be understood that the acceptable range of basic reactant(s) will encompass the range that will result in a final product pH in the range of 2-13, preferably 4- 12.

Dosage Forms

[0019] Acceptable dosage forms include any dosage form capable of delivering the medicament to a topical area. These would include liquids, lotions, gels, creams, pastes, ointments, foams, and aerosols.

Examples

Example 1

[0020] Lotion formulation containing diphenhydramine HCI an antihistamine. and utilizing only the oxidation-reduction reaction to produce heat.

Reducing Phase

Ingredient

Sodium Sulfite Water

Hydroxypropyl Methylcellulose

Propylene Glycol

Alcohol 95%

Diazolidinyl Urea Xanthan Gum

Diphenhydramine HCI

Total

Oxidizing Phase Ingredient %bv weight

Hydrogen Peroxide (50%) 5.40

Water _{93 60}

Xanthan Gum -_j QQ

^Total . 100.00

Combine approx. equal weights of each phase, mix and apply to skin. The mean rise in temperature upon mixing is CJL 50° F. Example 2

[0021] A lotion formulation utilizing both an oxidation-reduction reaction and an acid base reaction to produce heat. This product contains methyl salicylate, a topical anti-inflammatory medicament.

Reducing Phase

Ingredient %by weight

Sodium Sulfite 8.00

Sodium Metabisulfite 2.00 Monafax 785 4.00

Span 80 5.00

Cetyl Alcohol 2.50

Methyl Salicylate 20.00

Germaben 2 0.20 Calcium Hydroxide 2.00

Water 56.30

Total 100.00

Oxidizing Phase

Ingredient

Phosphoric Acid (85%)

Hydrogen Peroxide (50%)

Water

Arlacel 165

Cetyl Alcohol

Total

Combine approx. equal weights, mix and apply to skin. The mean rise in temperature upon mixing is Ca₁65 ° F. Example 3

A foam product containing a hvdroxy-acid and utilizing an oxidation-reduction reaction to produce heat.

Reducing Phase

Ingredient %bv weight

Sodium Sulfite 12.00

Lactic Acid 3.00

Lonzaine C 10.00 Glycerin 10.00

Euxyl 90/10 0.50

Water 64.50

Total 100.00

Oxidizing Phase

Ingredient %bv weight

Hydrogen Peroxide (50%) 7.75

Pluronic F-127 2.50

Water 89.75 Total 100.00

Package in Rexam® Airspray Dual Foamer with Nitronic® Stainless Steel. This package dispenses equal volumes of each phase, as such, the concentration of hydrogen peroxide has been adjusted to compensate for differences in the density of the two phases. The mean rise in temperature upon mixing is ca,.57° F. Example 4

A lotion formula utilizing both oxidation-reduction and acid-base reactions to produce heat. This formula contains dimethicone. a skin protectant medicament-

Reducing Phase

Ingredient by weight

Sodium Sulfite 8.00

Dimethicone 500cps 2.00 Span 80 5.00

Stearyl Alcohol 3.50

Monafax 785 4.00

Mineral Oil 4.00

Xanthan Gum 1.00 Germaben 2 0.25

TEA, 99% 7.65

Water 64.60

Total 100.00

Oxidizing Phase

Ingredient %bv weight

Phosphoric Acid (85%) 2.00

Hydrogen Peroxide (50%) 4.30

Xanthan Gum 1.00 Water 92.70

Total 100.00

The mean rise in temperature upon mixing is ca. 50° F.

Claims

12.09.08 RV4 10Claims

1. An improved method of applying at least one dermally or transdermal^ physiologically active medicament to the skin of a mammal in need of same consisting essentially of a) mixing a first dermally acceptable phase with a second dermally acceptable phase to provide a mixture, wherein at least one of said phases has an aqueous component , wherein said medicament is present in either phase, and said first phase consists essentially of at least one component capable of producing an exothermic reaction of dermally acceptable magnitude when contacted with said second phase and wherein at least one of said phases has an aqueous component and a) promptly applying said mixture to the skin of said subject.

2. The method of claim 1 wherein said first phase is a reducing phase and said second phase is an oxidizing phase.

3. The method of claim 1 wherein said first phase is a basic phase and said second phase is an acidic phase.

4. The method of claim 2 wherein said first phase additionally comprises a basic component and said second phase comprises an acidic component reactable with said basic component

5. The method of claim 2 wherein said first phase additionally comprises an acidic component and said second phase comprises a basic component reactable with said acidic component.

6. The method of claim 4 wherein the acidic phase is selected from the group consisting of sulfuric, hydrochloric, nitric, phosphoric, and water soluble organic acids with an equivalent weight of less than 100 , the bases are selected from the group consisting of alkali and alkaline earth metal hydroxides, aqueous ammonia and amines, and the reducing agents are selected from the group consisting of alkali metal sulfites, thiosulphites and metabisulphites and the oxidizing agents is selected from dermally acceptable peroxides.

7. The method of claim 5 wherein the acidic phase is selected from the group consisting of sulfuric, hydrochloric, nitric, phosphoric, and water soluble organic acids with an equivalent weight of less than 100 selected from the group consisting of alkali and alkaline earth metal hydroxides, aqueous ammonia and amines, and the reducing agents are selected from the group consisting of alkali metal sulfites, thiosulphites and metabisulphites metabisulphites and the oxidizing agents is selected from dermally acceptable peroxides.

8. The method of claim 6 wherein the amount of reducing agent is between about 2- about 5 w/w%, the amount of acid is between about 0.5- about 5.0 w/w% both calculated on total weight of the phase and the amount of base is sufficient to result in a final mixture of pH between about 2- about 12.

9. The method of claim 6 wherein the amount of reducing agent is between about 2- about 5 w/w%, the amount of acid is between about 0.5- about 5.0 w/w% both calculated on total weight of the phase and the amount of base is sufficient to result in a final mixture of pH between about 2- about 12

10. A kit for applying at least one dermally or transdermal^ physiologically active medicament to the skin of a mammal in need of same consisting essentially of: a first dermally acceptable phase and a separate second dermally acceptable phase mixable therewith, wherein said medicament is present in either phase, and said first phase consists essentially of at least one component capable of producing an exothermic reaction of dermally acceptable magnitude when contacted with said second phase and wherein at least one of said phases has an aqueous component .

11.The kit of claim 6 wherein said first phase is a reducing phase and said second phase is an oxidizing phase.

12. The kit of claim 6 wherein said first phase is a basic phase and said second phase is an acidic phase.

13. The kit of claim 7 wherein said first phase additionally comprises a basic component and said second phase comprises an acidic component reactable with said basic component

14. The kit of claim 7 wherein said first phase additionally comprises an acidic component and said second phase comprises a basic component reactable with said acidic component.

15. An improved method of forming a self warming composition for the application of at least one dermally or transdermally physiologically active medicament to the skin of a mammal in need of same consisting essentially of: mixing a first dermally acceptable phase with a second dermally acceptable phase to provide a. mixture, wherein at least one of said phases has an aqueous component , wherein said medicament is present in either phase, and said first phase consists essentially of at least one component capable of producing an exothermic reaction of dermally acceptable magnitude when contacted with said second phase and wherein at least one of said phases has an aqueous component

16.The method of claim 15 wherein said first phase is a reducing phase and said second phase is an oxidizing phase.

17.The method of claim 15 wherein said first phase is a basic phase and said second phase is an acidic phase.

18.The method of claim 16 wherein said first phase additionally comprises a basic component and said second phase comprises an acidic component reactable with said basic component.

19. The method of claim 16 wherein said first phase additionally comprises an acidic component and said second phase comprises a basic component reactable with said acidic component.

20. The method of claim 18 wherein the acidic phase is selected from the group consisting of sulfuric, hydrochloric, nitric, phosphoric, and water soluble organic acids with an equivalent weight of less than 100 , the bases are selected from the group consisting of alkali and alkaline earth metal hydroxides, aqueous ammonia and amines, and the reducing agents are selected from the group consisting of alkali metal sulfites, thiosulphites and metabisulphrtes and the oxidizing agents is selected from dermally acceptable peroxides.

21. The method of claim 19 wherein the acidic phase is selected from the group consisting of sulfuric, hydrochloric, nitric, phosphoric, and water soluble organic acids with an equivalent weight of less than 10 selected from the group consisting of alkali and alkaline earth metal hydroxides, aqueous ammonia and amines, and the reducing agents are selected from the group consisting of alkali metal sulfites, thiosulphites and metabisulphites metabisulphites and the oxidizing agents is selected from dermally acceptable peroxides.

22. The method of claim 20 wherein the amount of reducing agent is between about 2- about 5 w/w%, the amount of acid is between about 0.5- about 5.0 w/w% both calculated on total weight of the phase and the amount of base is sufficient to result in a final mixture of pH between about 2- about 12.

23. The method of claim 20 wherein the amount of reducing agent is between about 2- about 5 WΛΛ/%, the amount of acid is between about 0.5- about 5.0 w/w% both calculated on total weight of the phase and 25 the amount of base is sufficient to result in a final mixture of pH between about 2- about 12.

24. The composition formed by the method of Claim 15.

25. The composition formed by the method of Claim 16.

26. The composition formed by the method of Claim 17.

27. The composition formed by the method of Claim 18.

28. The composition formed by the method of Claim 19.