Composition comprising at least 3 different diols

Abstract

The present invention relates to a composition comprising at least 3 different diols, wherein said diols have the general structure (CH.sub.2).sub.nH.sub.2O.sub.2, wherein n is the number of CH.sub.2 and being between 3 to 10, in a total amount of from about 0.1 to about 50% (v/v), a method for producing the composition and its use, such as in therapy. The composition may be a pharmaceutical, cosmetic, antimicrobial or preservative composition. The composition is useful in inactivating microorganisms or preventing their growth.

Claims

1. An antimicrobial composition for reducing growth of microorganisms, the antimicrobial composition consisting of active antimicrobial diols and pharmaceutically acceptable salts, diluents, excipients, carriers, or adjuvants, wherein the active antimicrobial diols are selected from 2-methyl-pentane-2,4-diol, propane-1,2-diol, pentane-1,5-diol, and butane-1,3-diol, wherein the composition include at least 3 different diols, and wherein the diols are present at 0.25 to 5% (v/v) of the total composition, and wherein the antimicrobial composition is able to reduce the growth of microorganisms to a higher degree than the diols used alone.

2. The composition according to claim 1, wherein the diols consist of 2-methyl-pentane-2,4-diol, propane-1,2-diol and pentane-1,5-diol.

3. The composition according to claim 1, wherein the diols are present in an amount from 0.25 to 4% (v/v).

4. The composition according to claim 2, wherein the diols are present in an amount from 0.25 to 4% (v/v).

5. The composition according to claim 1, wherein the diols are present in an amount from 0.25 to 3% (v/v).

6. The composition according to claim 2, wherein the diols are present in an amount from 0.25 to 3% (v/v).

7. The composition according to claim 1, wherein the diols are present in an amount of 0.5, 1, 2, 3, 4, or 5% (v/v).

8. The composition according to claim 2, wherein the diols are present in an amount of 0.5, 1, 2, 3, 4, or 5% (v/v).

9. The composition of claim 1, wherein the composition is formulated as a pharmaceutical composition, and wherein the composition further comprises a pharmaceutically acceptable salt, diluent, excipient, carrier or adjuvant.

10. The composition of claim 1, wherein the composition is formulated as a cosmetic composition.

11. The composition of claim 1, wherein the composition is formulated as a preservative composition.

12. A composition according to claim 1, wherein the composition is in an ointment, lotion, paste, cream, gel, talc, spray, solution, emulsion soap, shampoo, wet towel, hygiene dish, patch or diaper.

13. The composition of claim 1, wherein the butane-1,3-diol is present at 0.25 to 2% (v/v).

14. The composition of claim 1, wherein 2-methyl-pentane-2,4-diol, propane-1,2-diol, and pentane-1,5-diol are present at a concentration that results in a greater than additive antimicrobial effect.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) In the context of the present invention the following definitions apply:

(2) The term “inactivate” is intended to mean that the antimicrobial composition is capable of preventing and/or inhibiting and/or eliminating and/or reducing the amount of living microorganism.

(3) The term “pharmaceutically active agent” is intended to mean any active agent, which could be used to treat a disorder or a disease. Examples are cortisone, antimicrobial agents, immuno modulating agents and acne agents.

(4) Antimicrobial Composition

(5) The present invention relates to a composition comprising at least 3 different diols, wherein said diols have the general structure (CH.sub.2).sub.nH.sub.2O.sub.2, wherein n is the number of CH.sub.2 and being between 3 to 10, in a total amount of from about 0.1 to about 50% (v/v), such as n being 3, 4, 5, 6, 7, 8, 9 or 10 or a mixture thereof. N may be different between the three different diols and at least one OH-group may be at different carbon atoms in the different diols or both at different carbon atoms. The composition may contain diols having different length. Furthermore, the diols may be selected from the group consisting of propane-1,2-diol, propane-1,3-diol, butane-1,2-diol, butane-1,3-diol, butane-1,4-diol, 2-methylpropane-1,2-diol, 2-methylpropane-1,3-diol, pentane-1,2-diol, pentane-1,3-diol, pentane-1,4-diol, pentane-1,5-diol, pentane-2,3-diol, pentane-2,4-diol, 2-methyl-pentane-2,4-diol, hexane-1,2-diol, hexane-1,3-diol, hexane-1,4-diol, hexane-1,5-diol, hexane-1,6-diol, hexane-2,3-diol, hexane-2,4-diol, hexane-2,5-diol, hexane-3,4-diol, heptane-1,2-diol, heptane-1,3-diol, heptane-1,4-diol, heptane-1,5-diol, heptane-1,6-diol, heptane-1,7-diol, heptane-2,3-diol, heptane-2,4-diol, heptane-2,5-diol, heptane-2,6-diol, heptane-3,4-diol, heptane-3,5-diol, octane-1,2-diol, octane-1,3-diol, octane-1,4-diol, octane-1,5-diol, octane-1,6-diol, octane-1,7-diol, octane-1,8-diol, octane-2,3-diol, octane-2,4-diol, octane-2,5-diol, octane-2,6-diol, octane-2,7-diol, octane-3,4-diol, octane-3,5-diol, octane-3,6-diol and octane-4,5-diol such as a group consisting of diols having a length of from 3 to 6 carbon atoms, such from the group consisting of 2-methyl-pentane-2,4-diol, propane-1,2-diol, pentane-1,5-diol and butane-1,3-diol. One example being a mixture of 2-methyl-pentane-2,4-diol, propane-1,2-diol and pentane-1,5-diol.

(6) The composition may contain at least 4 or 5 different diols.

(7) The stereochemistry of the diols is not important to the present invention, and enantiomers, diastereomers, tautomers and racemic mixtures of diols may all be used with good results. Indeed, the requirement that the diols be “different” should be understood to mean that they differ in the connectivity of the atoms (regioisomerism) and not in whether they are e.g. R/S or +/−.

(8) Additionally the composition may comprise at least 4 or 5 different diols. If the composition is used as an antimicrobial composition the number of the diols is depending on which microbe is to be inactivated. The diols may be present in an amount of from about 0.25-50% v/v, such as from about 0.25 to about 20% v/v. For example 0.25, 0.5, 1, 2, 3, 4, 5 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20% v/v.

(9) The percentages given in this text should be understood as amounts calculated on a volume/volume basis.

(10) Additionally, the composition may comprise at least one additional component such as an alcohol, for example ethanol.

(11) Accordingly, the composition if it is to be used as an antimicrobial composition, comprises an additional agent or mixture of agents, such as one or more antimicrobial agents. Examples of such agents are fusidic acid, gentamycin, neomycin, allylamines, ciclopirox, amorolfine, nystatin, amphotericin, i.e., antibacterial, antiviral and antifungal agents, such as imidazoles, acyclovir, and vectavir.

(12) The composition of the invention may take the form of a liquid, semi-liquid or solid disinfectant preparation, a bacteriostatic solution, lotion, cream, soap, shampoo, ointment, paste, wet towel, hygiene dish, patch, diaper or similar personal hygiene article. One form of the composition is a topical composition useful for all kind of topical administration, including dry skin repair, treatment of different disorders including microbial ones as well as applied to mucous membranes such as the membranes of the eye and the ear. The invention also relates to a pharmaceutical composition comprising the above-defined composition, including a pharmaceutically acceptable salt, diluent, excipient, carrier or adjuvant

(13) Pharmaceutical compositions of the invention are typically administered in a composition that includes one or more pharmaceutically acceptable adjuvants or excipients. Such pharmaceutical compositions may be prepared in a manner known in the art and are sufficiently storage-stable and suitable for administration to humans and animals.

(14) “Pharmaceutically acceptable” means an adjuvant or excipient that—at the dosage and concentrations employed—does not cause any unwanted effects in the patients to whom it is administered. Such pharmaceutically acceptable carriers or excipients are well-known in the art (see Remington's Pharmaceutical Sciences, 18th edition, A. R Gennaro, Ed., Mack Publishing Company (1990) and handbook of Pharmaceutical Excipients, 3rd edition, A. Kibbe, Ed., Pharmaceutical Press (2000).

(15) The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilisation and/or may contain conventional adjuvants such as preservatives, stabilisers, wetting agents, emulsifiers, buffers, fillers, etc., such as disclosed herein.

(16) The pharmaceutical composition according to the invention may be administered topically such as ointments, lotions, pastes, creams, gels, talc, sprays, solutions and emulsions. The ointments, lotions, creams and gels can contain, in addition to the antimicrobial agent or agents, excipients such as animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicons, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances. Talc and sprays can contain, in addition to the antimicrobial agent or agents, excipients such as lactose, talc, silica acid, aluminium hydroxide, calcium silicate and polyamide powders or mixtures thereof. Sprays may also contain propellants such as chloroflourohydrocarbons. Solutions and emulsions may contain excipients such as solvents, solubilising agents and emulsifiers such as water, ethyl alcohol, isopropylalcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene alcohol, dimethylformamide, oils such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, glycerol formal, tetrahydrofurfuyl alcohol, polyethylene glycols and fatty acid esters such as sorbitan or mixtures thereof.

(17) The pharmaceutical composition will be administered to a patient in a pharmaceutically effective dose. By “pharmaceutically effective dose” is meant a dose that is sufficient to produce the desired effects in relation to the condition for which it is administered. The exact dose is dependent on the, activity of the compound, manner of administration, nature and severity of the disorder, age and body weight of the patient, and different doses may be needed. The administration of the dose can be carried out both by single administration in the form of an individual dose unit or by several smaller dose units or by multiple administration of subdivided doses at specific intervals.

(18) The pharmaceutical composition of the invention may be administered alone or in combination with other therapeutic agents. These agents may be incorporated as part of the same pharmaceutical composition.

(19) The “patient” for the purposes of the present invention includes both humans and other mammal. Thus the methods are applicable to both human therapy and veterinary applications.

(20) The invention also relates to a cosmetic composition or in topical formulations comprising the antimicrobial composition as defined above and a gel, cream, ointment, suspension, aerosol, paste, powder, lotion.

(21) The invented composition, pharmaceutical composition, cosmetic composition, antimicrobial composition or preservative composition can be used to inactivate microorganisms selected from the group consisting of gram positive and gram negative bacteria, fungi, including yeasts, moulds and dermatophytes and virus. Examples include but are not limited to Staphylococcus aureus, Streptococci, gram negative rodes, Candida albicans, Candida glabrata, Malassezia, M. furfur, the mould Aspergillus flavus and the dermatophytes Trichophyton rubrum, T. mentagrophytes, Epidermophyton floccusum, Microsporum canis, papilloma virus, herpes virus and pox virus. Other useful uses are repair of dry skin.

(22) The invention also relates to a method of manufacturing a composition as defined above comprising the steps of; providing at least 3 different diols as mentioned above, adding a liquid or solid agent, mixing and obtaining a composition, such as an antimicrobial composition having a total amount of from about 0.1 to about 50 (v/v) of the diols.

(23) Accordingly, the invention relates to a method of treating an antimicrobial infection comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition as defined above.

(24) Finally, the invention relates to use of the above, mentioned diols as a preservative, without use of other preservatives such as parabenes, sodium lauryl sulphate, sorbic acid etc. A preservative may be used, for example, in contact lens solutions, shampoo, tooth paste, liquid soap, washing solutions, creams, ointments, pasta or cleaning solutions.

(25) Following examples are intended to illustrate but not to limit the invention in any manner, shape, or form, either explicitly or implicitly.

(26) Material and Methods.

(27) Microorganisms.

(28) Staphylococcus aureus number 515×6352 and Candida albicans H 29 were obtained from the Collection in the Department of Microbiology, Sahigrenska University Hospital, Gothenburg, Sweden. The isolates were maintained on blood agar at 37° C. M. sympodialis CBS 7222 and M. globosa CBS 7966

(29) Compounds.

(30) Propane-1,2-diol, pentane-1,5-diol and 2-methylpentane-2,4-diol and butan-1,3-diol were obtained from Merck Schuchardt, Hohenbrunn, Germany in a purity of 98 to 98.5%.

Example 1

(31) Test for bacteriostatic effect (MIC=minimal inhitory concentration).

(32) Each of the diols and their combination (1:1:1 volume/volume) was diluted directly with the test culture medium, Diagnostic Sensitivity test agar (DST) (Oxoid, UK) to obtain concentrations, in the test medium, of 2, 3, 4, 6, 9, and 12% volume percent of the respective diol and of 2, 3, and 4% of the respective diol in the combination.

(33) S. aureus cells were added to the agar medium in concentrations of 10.sup.3 and 10.sup.5 cells/ml while C. albicans cells were added in a concentration of 10.sup.6 cells/ml and M. sympodialis and M. globosa in a concentration of 10.sup.7 cells/ml. Plates were incubated at 37° C. and analysed after 1 and 2 days. Each experiment was repeated. MIC (Minimum Inhibitory Concentration) was defined as the lowest concentration that totally inhibited growth. The MIC's for propane-1,2-diol, pentane-1,5-diol, 2-methylpentane-2,4-diol and the combination of these 3 diols are shown in the table 1.

(34) The table shows the effect (MIC in %) of propane-1,2-diol, pentane-1,5-diol, 2-methylpentane-2,4-diol and their combination on the growth of Staphylococcus aureus and Candida albicans in vitro.

(35) The combination of 3% of each of the 3 diols completely inhibited the growth of S. aureus and a combination of 2% completely inhibited the growth of C. albicans and a concentration of 0.5% completely inhibited the growth of M. sympodialis and M. globosa. With a combination of 4 diols a combination of 2% completely inhibited the growth of S aureus and a combination of 1% completely inhibited the growth of C. albicans and a concentration of 0.25% completely inhibited the growth of M. sympodialis and M. globosa. For S. aureus, the same activity was only obtained with a total of 12% pentane-1,5-diol and 2-methylpentane-2,4-diol when they were tested alone. Propane-1,2-diol, butane-1,3-diol and ethanol were not able to inhibit the growth of S. aureus, even at 12%.

(36) TABLE-US-00001 TABLE 1 S. aureaus S. aureaus C. albicans Diol 10.sup.3 10.sup.5 10.sup.6 M. sympodialis M. globosa Propane-1,2-diol >12% >12% 9% 10 10 Butane-1,3-diol >12% >12% 8% 10 10 Pentane-1,5-diol    12%    12% 4% 3 3 2-Methyl pentane-2,4-    12%    12% 4% 3 3 diol Propane-1,2-diol +     3%     3% 2% 0.5% 0.5% pentane-1,5-diol + 2- methyl pentane-2,4-diol in equal amounts Ethanol >12% >12% 8% 10 10 Propane-1,2-diol +     2%     2% 1% 0.25 0.25 butane-1,3-diol + pentane-1,5-diol + 2- methyl pentane-2,4-diol in equal amounts

Example 2

(37) Preparation of a Bacteriostatic Topical Pharmaceutical Composition

(38) A mixture of equal amount of propane-1,2-diol+pentane-1,5-diol+2-methyl pentane-2,4-diol were mixed with the Essex® cream base (Schering Plough) to a final concentration of 2 or 3%.

Example 3

(39) Example 3 was performed as example 1.

(40) TABLE-US-00002 Mixtures Effect against Effect against Final 3% S aureus C. Albicans butane-1.3-diol, + + pentane-1,5-diol heptan-1.2-diol propan-1,2-diol + + pentane-1,5-diol heptan-1.3-diol pentane-1,5-diol + + 2-methyl pentane-2,4 diol hexan-1.2-diol butan-1.4-diol + + pentane-1,5-diol 2-methyl pentane-2,4 diol butan-1.3diol + + propane-1,2-diol heptan-1.5-diol etan-1.2 diol − − butan-1.2 diol propane-1.2 diol + indicates that the composition shows an effect − indicates that the composition show less effect or no effect