COMPOSITION COMPRISING AT LEAST 3 DIFFERENT DIOLES
FIELD OF THE INVENTION The present invention relates to a composition comprising at least 3 different diols, wherein the diols have the general structure (CH2) nH202, wherein n is the number of CH2 and is between 3 to 10, in one total amount from about 0.1 to about 50% (v / v), a method for producing the composition and its use, such as in therapy. The composition can be a pharmaceutical, cosmetic, antimicrobial or preservative composition. The composition is useful in inactivating microorganisms or preventing their growth. BACKGROUND OF THE INVENTION Microbes can be inactivated in different ways depending on the purpose to inactivate them. The procedure differs depending on whether the purpose is to prevent the growth of microorganisms, inhibit further growth or reduce and eliminate the microorganism. Additionally, the method differs depending on where the microorganism is located such as in a liquid, on a surface, within a mammalian body, etc. However, there are certain conditions that need to be met which are independent of the criteria mentioned R? F. 181730
previously. In addition to being highly effective, the composition to be used should be non-toxic, non-allergenic, environmentally friendly and possible to manufacture at a reasonable cost. An example of such an agent is propan-1,2-diol
(propylene glycol), which is the only diol widely used to inactivate microorganisms in dermatology. In addition, pentan-1,5-diol has been used as a component in topical pharmaceutical compositions, where it has been shown to increase the percutaneous absorption of active substances more efficiently than propan-1,2-diol. The water binding capacity of pentan-1, 5-diol is greatly comparable to that of propan-1,2-diol, but it penetrates more efficiently into the deeper parts of the stratum corneum of the skin. In addition, pentan-1,5-diol is cosmetically attractive, has a low risk of skin and eye irritation compared to other diols, has low toxicity and is odorless. WO 03/035021 describes a topical composition for skin care or administration of a pharmacologically active agent in the form of a lotion, cream or the like comprising from 5% to 70% by weight of pentan-1,5-diol in a cosmetically or pharmaceutically acceptable carrier. The multi-resistance of bacteria to antibiotics is becoming increasingly common. In the sector of
health there is now a high global interest regarding the future use of traditional antimicrobials. Alternative methods and procedures have been used to manufacture effective antimicrobial agents. PCT / SE2004 / 001001 describes the in vitro effect of pentan-1,5-diol against both gram-positive and gram-negative bacteria both sensitive and multi-resistant to antibiotics. Pentan-1,5-d? Ol was highly effective with minimal inhibitory concentrations (MIC) in the range of 5 to 12.5% against aerobic bacteria both sensitive and multi-resistant. The exact mechanism of the inhibitory action is unknown; possibly pentan-1, 5-d? ol removes water from the bacterial cytoplasm, which causes the cell to collapse. Importantly, it seems to be difficult for bacteria to develop resistance against pentan-1, 5-d-ol. The high antimicrobial activity against multi-resistant bacteria has made pentan-1,5-d? Ol an interesting agent for topical antimicrobial therapy in humans and animals. The use of 2-met? L-pentan-2, -d? Ol in pharmaceutical compositions for transdermal delivery is described in US 4855294 A, US 5026556 A, US 5041 439 A, 6271219 Bl. However, there is an increased medical need to identify new antimicrobial compositions, which can be effectively used to inactivate microorganisms. In particular there is a list
growing microorganisms, such as bacteria, viruses and fungi, which are becoming resistant to antibiotics. Additionally, there is an increased population of individuals that become allergenic against a variety of antibiotics or preservative components used in antibacterial preparations, which also demands the development of new compositions which can be used as alternatives to conventional technologies. BRIEF DESCRIPTION OF THE INVENTION The invention relates to a composition, such as an antimicrobial composition having improved properties such as being highly effective, non-toxic, non-allergenic, environmentally friendly and possible to manufacture at reasonable costs. By combining different specific diols, it has surprisingly been found that it is possible to reduce / inhibit the growth of microorganisms to a greater degree compared when using diols alone or combinations of similar diols. The present invention relates to a composition comprising at least 3 different diols, wherein the diols have the general structure (CH2) nH202, wherein n is the number of CH2 and is between 3 to 10, in a total amount from about 0.1 to approximately 50% (v / v), it is
say, the first OH group can be on the first carbon atom in all the diols and the second on different carbon atoms, such as on 2, 3, 4 or 5 carbon atoms. Additionally, the invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable salt, diluent, excipient, carrier or adjuvant and the antimicrobial composition. Additionally, the invention relates to a cosmetic or preservative composition. Accordingly, the invention relates to the use of the composition, the pharmaceutical composition, the cosmetic composition, the antimicrobial composition or the preservative composition. Additionally, the invention relates to a method for manufacturing a composition comprising the steps of: providing at least 3 different diols, adding a liquid or solid agent, mixing and obtaining a composition having a total amount from about 0.1 to about 50% (v / v) of the diols. Finally, the invention relates to a method for treating an antimicrobial infection comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition as mentioned above. Providing such a new composition, which has a
Wide use such as being an antimicrobial composition, the list of useful compounds to inactivate microorganisms will be increased. Additionally, due to the unique properties (i.e., being able to inactivate more than one microorganism) the new antimicrobial composition of the invention will be suitable in cases where there is a need to inactivate more than one microorganism. Accordingly, the composition of the invention shows an increased effect compared to other combinations of diols or when one and the same diol is used alone. It has also been found that by using the unique combination of diols as defined above it is possible to use a lower concentration of the different diols. DETAILED DESCRIPTION OF THE INVENTION In the context of the present invention the following definitions apply: The term "inactive" is proposed to mean that the antimicrobial composition is capable of preventing and / or inhibiting and / or eliminating and / or reducing the amount of living microorganism. The term "pharmaceutically active agent" is intended to mean any active agent, which may be used to treat a disorder or disease. Examples are cortisone, antimicrobial agents, immunomodulation agents and anti-acne agents.
ANTIMICROBIAL COMPOSITION The present invention relates to a composition comprising at least 3 different diols, wherein the diols have the general structure (CH2) nH2? 2, wherein n is the number of CH2 and is between 3 to 10, in a total amount 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 on different carbon atoms in the different diols or both on different carbon atoms. The composition may contain diols having different length. In addition, the diols can be selected from the group consisting of propan-1,2-diol, propan-1,3-diol, butan-1,2-diol, butan-1,3-diol, butan-1,4- diol, 2-methylpropan-l, 2-diol, 2-methylpropan-l, 3-diol, pentan-1,2-diol, pentan-1,3-diol, pentan-1,4-diol, pentan-1, 5-diol, pentan-2, 3-diol, pentan-2,4-diol, 2-methyl-pentan-2, -diol, hexan-1,2-diol, hexane-1,3-diol, hexan-1 , 4-diol, hexane-1,5-diol, hexane-1,6-diol, hexane-2,3-diol, hexan-2,4-diol, hexan-2,5-diol, hexan-3, - diol, heptan-1, 2-diol, heptan-1,3-diol, heptan-1,4-diol, heptan-1,5-diol, heptan-1,6-diol, heptan-1,7-diol, heptan-2, 3-diol, heptan-2,4-diol, heptan-2, 5-diol, heptan-2, β-diol, heptan-3,4-diol, heptan-3,5-diol, octan- 1,2-diol, octan-1,3-diol, octan-1,4-diol, octan-1,5-diol, octane-1,6-diol, octan-1,7-diol, octan-1, 8-diol, octan-2, 3-diol,
octan-2, 4-diol, octan-2, 5-diol, octan-2, 6-diol, octan-2,7-diol, octan-3,4-diol, octan-3, 5-diol, octan- 3,6-diol and octan-4,5-diol such as a group consisting of diols having a length of from 3 to 6 carbon atoms, such as from the group consisting of 2-methyl-pentan-2, 4- diol, propan-1,2-diol, pentan-1,5-diol and butan-1,3-diol. An example is a mixture of 2-methyl-pentan-2,4-diol, propan-1,2-diol and pentan-1,5-diol. The composition may contain at least 4 or 5 different diols. The stereochemistry of the diols is not important for the present invention, and enantiomers, diastereomers, tautomers and racemic mixtures of diols can 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, for example, R / S or +/-. Additionally, the composition may comprise at least 4 or 5 different diols. If the composition is used as an antimicrobial composition, the number of diols is dependent on which microbe will be inactivated. The diols may be present in an amount 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. The percentages given in this text should be understood as quantities calculated on a volume / volume basis. Additionally, the composition may comprise at least one additional component such as an alcohol, for example ethanol. Accordingly, the composition if it will be used as an antimicrobial composition, comprises an additional agent or mixture of agents, such as one or more anti-microbial agents. Examples of such agents are fusidic acid, gentamicin, neomycin, allylamines, cyclopirox, amorolfine, nystatin, amphotericin, ie antibacterial, antiviral and antifungal agents, such as imidazoles, acyclovir, and vectavir. The composition of the invention can take the form of a liquid, semi-liquid or solid disinfectant preparation, a bacteriostatic solution, lotion, cream, soup, shampoo, ointment, paste, wet towel, toilet bowl, patch, diaper or hygiene article similar staff. One form of the composition is a topical composition useful for all types of topical administration, including dry skin restoration, treatment of different disorders including microbial as well as applied to mucous membranes such as the membranes of the eye and the ear. The invention
it also relates to a pharmaceutical composition comprising the composition defined above, including a pharmaceutically acceptable salt, diluent, excipient, carrier or adjuvant. The pharmaceutical compositions of the invention are typically administered in a composition that includes one or more pharmaceutically acceptable adjuvants or excipients. Such pharmaceutical compositions can be prepared in a manner known in the art and are sufficiently stable in storage and suitable for administration to humans and animals. "Pharmaceutically acceptable" means an adjuvant or excipient which - in the dosage and concentrations employed - does not cause some undesired 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, AR Gennaro, Ed., Mack Publishing Company (1990) and manual of Pharmaceutical Excipients, 3rd edition, A. Kibbe, Ed., Pharmaceutical Press (2000) The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and / or they can contain conventional adjuvants such as preservatives, stabilizers, agents
humectants, emulsifiers, buffers, fillers, etc., as described herein. The pharmaceutical composition according to the invention can be administered topically such as ointments, lotions, pastes, creams, gels, talc, aerosols, solutions and emulsions. Ointments, lotions, creams and gels may contain, in addition to the antimicrobial agent or agents, excipients such as animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and rust. of zinc or mixtures of these substances. Talc and aerosols may contain, in addition to the antimicrobial agent or agents, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powders or mixtures thereof. The aerosols may also contain propellants such as florofluorohydrocarbons. The solutions and emulsions may contain excipients such as solvents, solubilizing agents and emulsifiers such as water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene alcohol, d-methylformamide, oils such as oil cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, glycerol formal, alcohol
tetrahydrofurfuryl, polyethylene glycols and fatty acid esters such as sorbitan and mixtures thereof. 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, the manner of administration, nature and severity of the disorder, age and body weight of the patient, and different doses may be necessary. Administration of the dose can be carried out by single administration in the form of a single dose unit or by various small dose units or by multiple administration of subdivided doses at specific intervals. The pharmaceutical composition of the invention can be administered alone or in combination with other therapeutic agents. These agents can be incorporated as part of the same pharmaceutical composition. The "patient" for the purposes of the present invention includes both humans and other mammals. Accordingly, the methods are applicable for both human therapy and veterinary applications. The invention also relates to a cosmetic composition or topical formulations comprising the
antimicrobial composition as defined above and a gel, cream, ointment, suspension, aerosol, paste, powder, lotion. The composition of the invention, pharmaceutical composition, cosmetic composition, antimicrobial composition or conversational composition can be used to inactivate microorganisms selected from the group consisting of gram positive and gram negative bacteria, fungi, including yeasts, molds and dermatophytes and viruses. Examples include, but are not limited to, Staphylococcus aureus, Streptococci, Gram negative bacilli, Candida albi cans, Candida glabra ta, Malassezia, M. fúrfur, Aspergillus flavus mold and Dermatophytes Tri chophyton rubrum, T. men tagrophytes, Epidermophyton floccusum, My crosporum canis, papilloma virus, herpes virus, and pox virus. Other useful uses are the restoration of dry skin. The invention also relates to a method for 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, blends and obtaining a composition, such as a composition antimicrobial having a total amount from about 0.1 to about 50 (v / v) of the diols. Accordingly, the invention relates to a
method for treating an antimicrobial infection comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition as defined above. Finally, the invention relates to the use of the diols mentioned above as a preservative, without the use of other preservatives such as parabens, sodium lauryl sulfate, ascorbic acid, etc. A preservative may be used, for example, in contact lens solutions, shampoo, toothpaste, liquid soap, laundry solutions, creams, ointments, paste or cleaning solutions. The following examples are proposed to illustrate but not limit the invention in any way, aspect or form, either explicitly or implicitly. Material and Methods Microorganisms. Staphylococcus aureus number
515x6352 and Candida albicans H 29 were obtained from Collection in the Department of Microbiology, Sahlgrenska University Hospital, Gothenburg, Sweden. The isolates were kept on blood agar at 37 ° C. M.sympodíalis CBS 7222 and M. globosa CBS 7966 Compounds. Propan-1, 2-diol, pentan-1,5-diol and 2-methylpentan-2,4-diol and butan-1,3-diol were obtained from Merck
Schuchardt, Hohenbrum, Germany with a purity of 98 to 98.5%. Example 1 Bactepostatic effect test (MIC = minimum inhibitory concentration) Each of the diols and their combination (1: 1: 1 volume / volume) was diluted directly with the test culture medium:, Diagnostic Sensitivity Test (DST) agar (Oxoid, UK) to obtain concentrations, in the test medium, of 2, 3, 4, 6, 9, and 12% percent by volume of the respective diol and of 2.3, and 4% of the respective diol in the combination. S aureus cells were added to the agar medium at concentrations of 103 and 105 cells / ml while C cells. albicans were added in a concentration of
10fc cells / ml and M sympodialis and M. globosa at a concentration of 10 cells / ml The plates were incubated at 37 ° C and analyzed after 1 and 2 days. Each experiment was repeated. MIC (Minimum Inhibitory Concentration) was defined as the lowest concentration that totally inhibited growth. The MICs for propan-1, 2-d? Ol, pentan-1,5-diol, 2-met? Lpentan-2, 4-d? Ol and the combination of these 3 diols are shown in table 1. The table shows the effect (MIC in%) of propan-1,2-d? ol, pentan-1, 5-d? ol, 2-met? lpentan-2, 4-d? ol and its
combination on the growth of Staphylococcus aureus and Candida albicans in vitro. The combination of 3% of each of the 3 diols completely inhibited S growth. 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. globose 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. sympodial is and M. globosa. For
S. aureus, the same activity was obtained only with a total of 12% pentan-1, 5-diol and 2-me t ipentan-2,4-diol when tested alone. Propan-1,2-diol, butan-1,3-diol and ethanol were not able to inhibit the growth of S. aureus, still at 12%. EXAMPLE 2 Preparation of a topical pharmaceutical composition bac ter ios tica A mixture of equal amount of propan-1,2-diol + pentan-1,5-diol + 2-methyl pentan-2,4-diol was mixed with the Essex® cream base (Schering Plow) at a final concentration of 2 or 3%.
Example 3 Example 3 was carried out as example 1
+ indicates that the composition shows an effect - indicates that the composition shows less effect or no effect It is noted that in relation to this date, the best method known by the applicant to implement the aforementioned invention, is that which is clear of the present description of the invention.