PHARMACEUTICAL FORMULATION FOR INHIBITING BODY MALODOUR

Abstract

There is provided a pharmaceutical formulation comprising an anticholinergic agent and a ternary solvent comprising 5% to 15% v/v glycol, 60% to 70% v/v alcohol and 5% to 20% v/v water. There is also provided a method of preparing the pharmaceutical formulation as disclosed herein, comprising the step of mixing the anticholinergic agent to a mixture containing alcohol, glycol, water, humectant and pH buffering agent at room temperature. There is also provided a method of inhibiting non-pathological body malodour in a mammal. There is also provided a method of treating apocrine secretion causing odour and reduction of microbial overgrowth in a mammalian subject, and uses of a pharmaceutical formulation.

Claims

1. A pharmaceutical formulation comprising an anticholinergic agent and a ternary solvent comprising 5% to 15% v/v glycol, 60% to 70% v/v alcohol and 5% to 20% v/v water.

2. The pharmaceutical formulation of claim 1, wherein the anticholinergic agent is selected from the group consisting of glycopyrronium bromide, hyoscyamine, atropine, scopolamine, benzatropine, clidinium bromide, cyclopentolate, darifenacin, dicylomine, fesoterodine, homatropine hydrobromide, ipratropium, orphenadrine, oxybutynin, propantheline, methscopolamine, solifenacin, tiotropium, tolterodine, trihexphenidyl, trospium and mixtures thereof.

3. The pharmaceutical formulation of claim 1 or 2, wherein the alcohol is selected from the group consisting of ethanol and isopropanol.

4. The pharmaceutical formulation of any one of claims 1 to 3, wherein the glycol is selected from the group consisting of propylene glycol, butylene glycol and pentylene glycol.

5. The pharmaceutical formulation of any one of claims 1 to 4, wherein the anticholinergic agent is in an amount of 1.0% w/v, 2.0% w/v, 3.0% w/v, 4.0% w/v, 5.0% w/v or 6.0% w/v of the pharmaceutical formulation.

6. The pharmaceutical formulation of any one of claims 1 to 5, wherein the concentrations of the components in the ternary solvent are: glycol at 1.0% w/v, 2.0% w/v, 3.0% w/v, 4.0% w/v, 5.0% w/v or 6.0% w/v of the pharmaceutical formulation; alcohol at 60.0% v/v, 61.0% v/v, 62.0% v/v, 63.0% v/v, 64.0% v/v, 65.0% v/v, 66.0% v/v, 67.0% v/v, 68.0% v/v, 69.0% v/v or 70.0% v/v of the pharmaceutical formulation; and water at 5.0% v/v, 6.0% v/v, 7.0% v/v, 8.0% v/v, 9.0% v/v, 10.0% v/v, 11.0% v/v, 12.0% v/v, 13.0% v/v, 14.0% v/v, 15% v/v, 16% v/v, 17% v/v, 18% v/v, 19% v/v or 20.0% v/v of the pharmaceutical formulation.

7. The pharmaceutical formulation of any one of claims 1 to 6, wherein when the anticholinergic agent is glycopyrronium bromide and the alcohol is isopropanol, the ratio of the components in the ternary solvent is such that the ratio of propylene glycol: isopropanol: water is 2:13:2.5 v/v.

8. The pharmaceutical formulation of any one of claims 1 to 7, further comprising an excipient material suitable for topical administration.

9. The pharmaceutical formulation of claim 8, wherein the excipient material is selected from the group consisting of anti-bacterials, anti-fungals, humectants, emulsifiers, preservatives, dispersants, emollients, surfactants, structurants, absorption promoters, antiseptics, anaesthetics, keratolytics, wound healing agents, lubricants, anti-perspirants, depilatories, UV-protectants, anti-inflammatories, steroids, antioxidants, antihistamines, skin and hair conditioners, fragrances, essential oils and natural plant extracts.

10. The pharmaceutical formulation of claim 9, wherein the humectant is selected from the group consisting of glycerine, glycerol, lecithin, gelatin, lactic acid, hyaluronic acid, glyceryl triacetate, hexylene glycol, butylene glycol, sorbitol, allantoin, sodium hyaluronate, sodium lactate, ammonium lactate, sodium pyrrolidine and urea.

11. The pharmaceutical formulation of any of one of claims 1 to 10, wherein said pharmaceutical formulation is for topical use.

12. The pharmaceutical formulation of any of one of claims 1 to 11, wherein said pharmaceutical formulation is antichlolinergic and antimicrobial or antichlolinergic and antibacterial.

13. The pharmaceutical formulation of any of one of claims 1 to 12, wherein said pharmaceutical formulation is the form selected from the group consisting of solution, lotion, cream, ointment, gel, paste, aerosol, foam and spray.

14. The pharmaceutical formulation of any of one of claims 1 to 13, wherein when the pharmaceutical formulation is in the form of a spray for use in human, the pharmaceutical formulation is sprayed on the axilla 1 or 2 sprays per administration at a frequency of at least once in a day, wherein once in the morning and optionally once in the afternoon, depending on a person's requirement.

15. The pharmaceutical formulation of any of one of claims 1 to 13, wherein when the pharmaceutical formulation is in the form of a spray for use in dog, the pharmaceutical formulation is sprayed on the affected skin at a frequency of 1 to 3 times a day and 4 to 8 hours between sprays.

16. The pharmaceutical formulation of any of one of claims 1 to 15, wherein when the pharmaceutical formulation is in the form of a spray, the amount of anticholinergic agent in each spray administered is 2.00 mg, 2.10 mg, 2.20 mg, 2.30 mg, 2.40 mg, 2.50 mg, 2.60 mg, 2.70 mg or 2.80 mg.

17. A method of preparing the pharmaceutical formulation of any one of claims 1 to 16, comprising the step of mixing the anticholinergic agent to a mixture containing alcohol, glycol, water, humectant and pH buffering agent at room temperature.

18. The method of claim 17, wherein said alcohol is selected from the group consisting of ethanol and isopropanol.

19. The method of claim 17 or 18, wherein said pH buffering agent is selected from the group consisting of organic acids, amino acids, polyaminocarboxylic acids, citrate salts, polyphosphates and combinations thereof.

20. The method of any one of claims 17 to 19, wherein said pH buffering agent is selected from the group consisting of citric acid, acetic acid, tartaric acid, ethylenediaminetetraacetic acid, 2,3-dimercaptopropanesulfonic acid, thiamine tetrahydrofurfuryl acid, alpha lipoic acid, glycine, sodium citrate, potassium citrate, sodium phosphate and combinations thereof.

21. The method of any one of claims 17 to 20, wherein said humectant is in an amount of 5.0% w/v, 6.0% w/v, 7.0% w/v, 8.0% w/v, 9.0% w/v, 10.0% w/v, 11.0% w/v, 12.0% w/v, 13.0% w/v, 14.0% w/v, 15.0% w/v, 16.0% w/v, 17.0% w/v, 18.0% w/v, 19.0% w/v or 20.0% w/v of the pharmaceutical formulation.

22. The method of any one of claims 17 to 21, wherein said pH buffering agent is in an amount in the range of 0.05% w/v to 1.00% w/v of the pharmaceutical formulation.

23. A method of inhibiting non-pathological body malodour in a mammal, comprising the step of administrating a pharmaceutical formulation to an area on said mammal, to inhibit apocrine secretion and inhibit the activity or prevent the overgrowth of the microorganism resident on said area, wherein said pharmaceutical formulation comprises an anticholinergic agent and a ternary solvent comprising 5% to 15% v/v glycol, 60% to 70% v/v alcohol and 5% to 20% v/v water.

24. The method of claim 23, wherein said mammal is selected from the group consisting of primates, caniformia and artiodactyla.

25. The method of claim 23 or 24, wherein said microorganism is selected from the group consisting of Corynebacterium spp., Corynebacterium minutissimum, Corynebacterium striatum, Corynebacterium jeikeium, Staphylococcus spp., Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus pseudintermedius, Streptococcus spp., Micrococcus spp, Propionbacterium spp., Propionbacterium acnes, Anaerococcus spp., Candida spp., Escherichia coli, Malassezia pachydermatis and Sphingomonas paucimobilis.

26. A method of treating apocrine secretion causing odour and reduction of microbial overgrowth in a mammalian subject, comprising administrating the pharmaceutical formulation to an area on said mammalian subject exhibiting said microbial overgrowth, wherein said pharmaceutical formulation comprises an anticholinergic agent and a ternary solvent comprising 5% to 15% v/v glycol, 60% to 70% v/v alcohol and 5% to 20% v/v water.

27. A pharmaceutical formulation for use in the treatment of apocrine secretion causing odour and reduction of microbial overgrowth in a mammalian subject, wherein said pharmaceutical formulation comprises an anticholinergic agent and a ternary solvent comprising 5% to 15% v/v glycol, 60% to 70% v/v alcohol and 5% to 20% v/v water.

28. Use of a pharmaceutical formulation, in the manufacture of a medicament for the treatment of apocrine secretion causing odour and reduction of microbial overgrowth in a mammalian subject, wherein said pharmaceutical formulation comprises an anticholinergic agent and a ternary solvent comprising 5% to 15% v/v glycol, 60% to 70% v/v alcohol and 5% to 20% v/v water.

29. The method of claim 26 or the pharmaceutical formulation for use of claim 27 or the use of claim 28, wherein said mammalian subject is selected from the group consisting of primates, caniformia and artiodactyla.

30. The method of claim 26 or the pharmaceutical formulation for use of claim 27 or the use of claim 28, wherein said microbial overgrowth is caused by a microorganism selected from the group consisting of Corynebacterium spp., Corynebacterium minutissimum, Corynebacterium striatum, Corynebacterium jeikeium, Staphylococcus spp., Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus pseudintermedius, Streptococcus spp., Micrococcus spp, Propionbacterium spp., Propionbacterium acnes, Anaerococcus spp., Candida spp., Escherichia coli and Malassezia pachydermatis.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0094] The accompanying drawings illustrate a disclosed embodiment and serves to explain the principles of the disclosed embodiment. It is to be understood, however, that the drawings are designed for purposes of illustration only, and not as a definition of the limits of the invention.

[0095] FIG. 1

[0096] FIG. 1 is a schematic illustration of the preparation of the pharmaceutical formulation in spray bottles as disclosed herein, with the delivery of 0.10 to 0.14 mL/spray, wherein weighted citric acid (100) and sodium citrate (200) are added to beaker 1 (400) containing purified water (300) to make a buffer solution. Thereafter, glycerine (500) and propylene glycol (600) are added to beaker 1 (400) containing the buffer solution and thoroughly mixed. The resultant mixture in beaker 1 (400) is added to beaker 2 (800) containing isopropanol (700) before the combined mixture is used to dissolve glycopyrronium bromide (900). The final volume of the pharmaceutical formulation in beaker 2 (800) is adjusted 100% (v/v) using purified water (1000) before packaging into individual spray bottles (1100) as samples for human and animal studies.

EXAMPLES

[0097] Non-limiting examples of the invention will be further described in greater detail by reference to specific Examples, which should not be construed as in any way limiting the scope of the invention.

Materials and Methods

[0098] All the reagents were obtained from commercial suppliers as shown in Table 1 and used without further purification.

Example 1: Preparation of the pharmaceutical formulation

[0099] A pharmaceutical formulation was prepared using the following chemical components in the indicated amounts in Table 1.

TABLE-US-00001 TABLE 1 Composition of the pharmaceutical formulation Chemicals Concentration Commercial Suppliers Glycopyrronium 2% (w/v) PCAS, Finland bromide powder Citric acid 0.32% (w/v) Medisca, USA Sodium citrate 0.084% (w/v) Medisca, USA Glycerine 10% (v/v) ICM Pharma Pte. Ltd., Singapore Propylene glycol 10% (v/v) ICM Pharma Pte. Ltd., Singapore Isopropanol 65% (v/v) Merck KGaA, Germany Sterile water ~15% (v/v) B. Braun, Germany (make up formulation to 100% (v/v))

[0100] A schematic of the procedure to prepare the pharmaceutical formulation is as shown in FIG. 1. Briefly, glycopyrronium bromide powder (12 g), citric acid (1.92 g) and sodium citrate (0.504 g) were weighted separately on weighing paper. Citric acid and sodium citrate were dissolved in some purified water (70 ml) to make a buffer solution. Glycerine (60 ml) and propylene glycol (60 ml) were added to the buffer solution and mixed well by stirring. Isopropanol (390 ml) was added to the mixture to create the ternary solvent before using it to dissolve the anticholinergic agent glycopyrronium bromide powder.

[0101] The final volume of the formulation was adjusted to 100% (v/v) using purified water. The pharmaceutical formulation was packed into individual bottles and labelled as samples for the human and animal studies in Example 2 and 3 respectively.

Example 2: Human studies using the pharmaceutical formulation

[0102] The pharmaceutical formulation as prepared in Example 1 was used by a confidential test group of five persons reported to suffer from bromhidrosis as a preliminary evaluation of the formulation efficacy on humans. The profile and the comparative results of the test group before and after use of the pharmaceutical formulation is as indicated in Table 2.

[0103] The severity of the sweating (hyperhidrosis) as self-reported by the test group was rated on a scale of 1 to 4 (HDSS, hyperhidrosis severity scale), 1 being the least severe and 4 being the most severe. The percentage reduction of bromhidrosis after use of the pharmaceutical formulation was as self-reported by the test group and the percentage mean reduction of bromhidrosis was calculated.

TABLE-US-00002 TABLE 2 Profile of human subjects and comparative results before and after use of the pharmaceutical formulation H1 H2 H3 H4 H5 Age (years) 51 24  34 46  22 Gender Female Male Male Male Male Race Indian Indian Chinese Chinese Chinese Prior Aluminium Aluminium Aluminium Aluminium Aluminium treatment(s) salt anti- salt anti- salt anti- salt anti- salt anti- perspirants perspirants perspirants perspirants perspirants (caused itch (ineffective) (ineffective) (caused (caused hot and was and antiseptic itch, hence sensation) ineffective) washes stopped and antiseptic treatment) washes Before Treatment with Pharmaceutical Formula Severity of  2 1  2 2  3 sweating (HDSS scale of 1 to 4) Descriptive Distressed Distressed Bothered Bothered Not severity of bothered bromhidrosis (not bothered, bothered and distressed) Dosage regime The pharmaceutical formulation is sprayed on the axilla 1 or 2 sprays at a frequency of once in the morning and optionally once in the afternoon depending on person's requirement. Two Months After Treatment with Pharmaceutical Formulation Severity of  1 1  1 2  2 sweating (HDSS scale of 1 to 4) Reduction of 50 N.A. 80 0 30 sweatiness (%) Descriptive Not Not Not Bothered Not severity of bothered bothered bothered bothered bromhidrosis (not bothered, bothered and distressed) Reduction of 100% 100% 100% 15% .sup. 50% bromhidrosis (%) Mean reduction 73% of bromhidrosis (%) Side effects None None None None None

[0104] Based on the results in Table 2, it is shown that the pharmaceutical formulation is effective in reducing bromhidrosis in the test group with a 73% overall reduction of bromhidrosis. There was also no irritation and adverse reactions reported on the human body. The pharmaceutical formulation does not case dryness or darkening of the skin.

Example 3: Animal studies using the pharmaceutical formulation

[0105] The pharmaceutical formulation as prepared in Example 1 was applied on a Shetland sheepdog with bromhidrosis as a preliminary evaluation of the formulation efficacy on dogs. The profile and the comparative results of the test dog before and after use of the pharmaceutical formulation is as indicated in Table 3.

TABLE-US-00003 TABLE 3 Profile and comparative results of the test dog before and after use of the pharmaceutical formulation A1 Species Shetland sheepdog Gender Male Age (years) 1 Prior treatment(s) None Before Treatment with Pharmaceutical Formulation Owner's perception of odour 8 severity (scale of 1 to 10) Dosage regime Sprayed on affected skin 1 to 3 times a day, at 4 to 8 hours between sprays After Treatment with Pharmaceutical Formulation Onset of effect 3 days Owner's perception of odour 3 severity (scale of 1 to 10) Reduction of bromhidrosis (%)  62.5% Side effects None
Based on the results in Table 3, it is shown that the pharmaceutical formulation is effective in reducing bromhidrosis in the test dog with a 62.5% % reduction of bromhidrosis. There was also no irritation and adverse reactions reported for the test dog.

INDUSTRIAL APPLICABILITY

[0106] The pharmaceutical formulation may be used as a treatment for pathological or non-pathological body malodour in humans and dogs. The pharmaceutical formulation is applicable in various applications, but not limited to, consumer care, healthcare and cosmetics industries.

[0107] It will be apparent that various other modifications and adaptations of the invention will be apparent to the person skilled in the art after reading the foregoing disclosure without departing from the spirit and scope of the invention and it is intended that all such modifications and adaptations come within the scope of the appended claims.