Use of amitriptyline and / or one of its pharmaceutically acceptable salts as a preservative

Abstract

The present invention relates to the use of amitriptyline and / or one of its pharmaceutically acceptable salts as a preservative in a pharmaceutical composition.

Description

Title of the invention: Use of amitriptyline and / or one of its pharmaceutically acceptable salts as a preservative agent

[0001] The present invention relates to the use of amitriptyline and / or one of its pharmaceutically acceptable salts as a preservative in a pharmaceutical composition.

[0002] Pharmaceutical compositions and the substances they contain are subject to important standards, particularly in terms of the presence of microorganisms, such as bacteria, yeasts or fungi, in order to avoid the risks of infections for the user and the deterioration of the pharmaceutical compositions.

[0003] In Europe, Chapter 5.1.4 "Microbiological quality of pharmaceutical preparations" of the European Pharmacopoeia states that formulations administered topically do not need to be sterile. However, they must not contain more than one hundred microorganisms per gram of composition and they must not contain Staphylococcus aureus or Pseudomonas aeruginosa.

[0004] In order to verify their proper compliance with these standards before being placed on the market, the compositions must be subjected to tests such as those specified by monographs 2.6.12 and 2.6.13 requiring a count of germs and microorganisms and setting a limit threshold not to be exceeded.

[0005] To meet these standards and maintain such a low microorganism population, it is often necessary to incorporate preservatives or antimicrobial agents into pharmaceutical compositions. Chapter 5.1.3 "Effectiveness of antimicrobial preservation" of the European Pharmacopoeia clearly defines how the effectiveness of an antimicrobial preservative in a pharmaceutical product should be assessed.

[0006] Such standards and tests are also in force in the United States (USP specifications, Chapter 51).

[0007] Among the preservatives commonly used in pharmaceutical compositions, we find in particular parabens, such as methyl paraben. However, these compounds are suspected of interacting with the receptors of certain hormones and therefore of having a role as endocrine disruptors.

[0008] There is therefore a real need to provide new antimicrobial preservatives that can be used in pharmaceutical compositions, in particular topical pharmaceutical compositions.

[0009] It has been surprisingly discovered that amitriptyline and / or one of its pharmaceutically acceptable salts provides an antimicrobial effect equivalent to a paraben-type preservative in pharmaceutical compositions.

[0010] The subject of the present invention is therefore the use of ramitriptyline and / or one of its pharmaceutically acceptable salts as a preservative in a pharmaceutical composition.

[0011] The use of ramitriptyline and / or one of its salts makes it possible to formulate pharmaceutical compositions with a low or even zero amount of paraben-type preservative. Such use therefore makes it possible to limit the presence of potential endocrine disruptors or preservatives that present risks of causing allergies or irritations.

[0012] Other objects, characteristics, aspects and advantages of the invention will appear even more clearly on reading the description and the example which follows.

[0013] In this description, and unless otherwise indicated:

[0014] - the expression "at least one" is equivalent to the expression "one or more" and can be substituted for it;

[0015] - the expression "between...and..." is equivalent to the expression "ranging from...to..." and may be substituted therefor, and implies that the terminals are included;

[0016] - the expression “polyoxyalkylenated” corresponds, within the meaning of the invention, to a unit -(O-alkyl)n-, where n is an integer ranging from 2 to 200, preferably from 2 to 40, more preferably from 2 to 20;

[0017] - the expression “polyoxyethylenated” corresponds, within the meaning of the invention, to a unit -(O-CH2CH2)n-, where n is an integer ranging from 2 to 200, preferably from 2 to 40, more preferably from 2 to 20.

[0018] Amitriptyline and its salts

[0019] The use according to the present invention uses at least amitriptyline and / or one of its pharmaceutically acceptable salts in a pharmaceutical composition.

[0020] Amitriptyline has the following formula (I):

[0022] In the context of the present invention, the term “pharmaceutically acceptable amitriptyline salts” means salts compatible with a pharmaceutical composition pharmaceutical, i.e. intended for administration to humans. In particular, the term “pharmaceutically acceptable salt of amitriptyline” means the hydrates, solvates, acid salts such as hydrochlorides and clathrates of amitriptyline.

[0023] As a particularly preferred salt of amitriptyline, amitriptyline hydrochloride will be used.

[0024] Preferably, the total content of amitriptyline and / or one of its pharmaceutically acceptable salts is between 1 and 25% by weight, more preferably between 5 and 20% by weight, even more preferably between 5 and 15% by weight, relative to the total weight of the composition.

[0025] More preferably, the total content of amitriptyline hydrochloride is between 1 and 25% by weight, more preferably still between 5 and 20% by weight, even better still between 5 and 15% by weight, relative to the total weight of the composition.

[0026] The presence of amitriptyline and / or one of its pharmaceutically acceptable salts in the pharmaceutical composition according to the invention makes it possible to obtain a composition in accordance with the criteria of the European and American Pharmacopoeia, in particular with regard to the presence of microorganisms in the composition. In particular, the presence of amitriptyline and / or one of its pharmaceutically acceptable salts makes it possible to limit, or even prevent, the growth of microorganisms such as Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Candida albicans, Aspergillus brasiliensis.

[0027] The composition may optionally further comprise at least one additional preservative agent, different from amitriptyline and its salts, such as methyl paraben. In this case, the content of additional preservative agent(s) is preferably less than or equal to 10% by weight, more preferably less than or equal to 5% by weight, more preferably still less than or equal to 1% by weight, better still less than or equal to 0.5% by weight, relative to the total weight of the composition.

[0028] The composition according to the invention may optionally further comprise one or more additional preservatives, different from amitriptyline and its salts, such as methyl paraben, ethyl paraben, propyl paraben, butyl paraben, benzalkonium chloride, potassium sorbate, phenoxyethanol, chlorhexidine, benzyl alcohol, boric acid, butylene glycol, cetrimide, chlorobutanol, sodium benzoate.

[0029] In a particular embodiment, the composition according to the invention is free of additional preservative agent. In particular, preferably, the composition according to the invention is free of methyl paraben, ethyl paraben, propyl paraben, butyl paraben, benzalkonium chloride, potassium sorbate, phenoxyethanol, chlorhexidine, benzyl alcohol, boric acid, butylene glycol, cetrimide, chlorobutanol, sodium benzoate.

[0030] Water

[0031] The composition according to the present invention may comprise water.

[0032] Preferably, the total water content is greater than or equal to 75% by weight, plus preferably between 75 and 95% by weight; more preferably still between 75 and 90% by weight, relative to the total weight of the composition.

[0033] Polyols

[0034] Preferably, the composition according to the present invention may further comprise at least one C2-C8 polyol.

[0035] For the purposes of the present invention, the term "C2-C8 polyol" means an organic compound consisting of a C2-C8 hydrocarbon chain, optionally interrupted by one or more oxygen atoms, and carrying at least two free hydroxyl groups (-OH) carried by different carbon atoms, this compound being able to be cyclic or acyclic, linear or branched, saturated or unsaturated, and in the liquid state at room temperature (25°C) and at atmospheric pressure (i.e. 1,013.105 Pa).

[0036] Preferably, the C2-C8 polyol(s) according to the invention are acyclic and non-aromatic.

[0037] The C2-C8 polyols according to the invention comprise in their structure from 2 to 8 carbon atoms, preferably from 2 to 6 carbon atoms, more preferably from 2 to 5 carbon atoms.

[0038] More particularly, the polyol(s) which can be used according to the invention comprise from 2 to 10 hydroxy groups, more preferably from 2 to 5 hydroxy groups, even more preferably from 2 to 3 hydroxy groups.

[0039] Preferably, the said C2-C8 polyol(s) which can be used according to the invention are chosen from C3-C6 polyols, ethylene glycol, and mixtures thereof.

[0040] According to a preferred embodiment of the invention, the said C2-C8 polyol(s) which can be used according to the invention are chosen from propylene glycol, 1,3-propanediol, 1,3-butylene glycol, pentane-1,2-diol, dipropylene glycol, hexylene glycol, pentylene glycol, glycerol, ethylene glycol, and a mixture of these compounds; more preferably the composition comprises at least propylene glycol.

[0041] Preferably, when the composition according to the invention comprises at least one C2-C8 polyol, the total content of C2-C8 polyol(s) is between 0.1 and 15% by weight, more preferably between 0.5 and 10% by weight, even more preferably between 1 and 6% by weight, and even better between 3 and 6% by weight, relative to the total weight of the composition.

[0042] Preferably, when the composition according to the invention comprises at least one C2-C8 polyol, the total propylene glycol content is between 0.1 and 15% by weight, more preferably between 0.5 and 10% by weight, even more preferably between 1 and 6% by weight, and even better between 3 and 6% by weight, relative to the total weight of the composition.

[0043] Thickening agents

[0044] The composition according to the invention may further comprise at least one thickening agent.

[0045] More preferably, the thickening agent(s) are thickening polymers.

[0046] By "thickening polymer" is meant according to the present invention polymers which increase, by their presence at a concentration of 0.05% by weight, the viscosity of the cosmetic compositions into which they are introduced by at least 20 cps (20 mPa.s), preferably by at least 50 cps (50 mPa.s), at room temperature (25°C), at atmospheric pressure and at a shear rate of 1s 1 (the viscosity can be measured using a cone / plate viscometer, Haake R600 Rheometer or the like).

[0047] By way of example, the following thickening agents may be mentioned: crosslinked homopolymers or copolymers of acrylic or methacrylic acid, crosslinked homopolymers of 2-acrylamido-2-methyl-propanesulfonic acid and their crosslinked acrylamide copolymers, homopolymers of ammonium acrylate or copolymers of ammonium acrylate and acrylamide, cellulose polymers, and mixtures thereof.

[0048] Among the crosslinked acrylic acid homopolymers, mention may be made of those crosslinked by an allyl ether of alcohol of the sugar series, such as for example the products sold under the names CARBOPOLS 980, 981, 954, 2984 and 5984 by the company NOVEON or the products sold under the names SYNTHALEN M and SYNTHALEN K by the company 3 VS A. These polymers have the INCI name Carbomer. The thickening polymers may also be crosslinked (meth)acrylic acid copolymers such as the polymer sold under the name AQUA SF1 by the company NOVEON.

[0049] More preferably still, the composition according to the invention further comprises at least one cellulose polymer.

[0050] According to the invention, the term “cellulosic” polymer means any polysaccharide compound, substituted or not, having in its structure chains of glucose residues united by [3-1,4] bonds; in addition to unsubstituted celluloses, cellulose derivatives can be anionic, cationic, amphoteric or non-ionic.

[0051] Thus, the cellulose polymers which can be used according to the invention can be chosen from unsubstituted celluloses including in a microcrystalline form and substituted celluloses.

[0052] More preferably, the cellulosic polymers that can be used according to the invention do not comprise a Cio-C3O side fatty chain in their structure.

[0053] Preferably, the cellulose polymer(s) usable according to the invention have an average molecular weight of between 5,000 and 1,500,000, more preferably potentially between 50,000 and 800,000, more preferably still between 400,000 and 800,000.

[0054] Among the cellulose polymers according to the invention, one can distinguish cellulose ethers, cellulose esters and cellulose ether esters.

[0055] Among the cellulose esters, there are inorganic cellulose esters (nitrates, sulfates or phosphates of cellulose, etc.), organic cellulose esters (monoacetates, triacetates, amidopropionates, acetatebutyrates, acetatepropionates or acetatetrimellitates of cellulose, etc.) and mixed organic / inorganic cellulose esters such as cellulose acetatebutyrate sulfates and acetatepropionate sulfates. Among the cellulose ether esters, there are hydroxypropylmethylcellulose phthalates and ethylcellulose sulfates.

[0056] Among the non-ionic cellulose ethers, mention may be made of (Ci-C4)alkylcelluloses such as methylcelluloses and ethylcelluloses (for example Ethocel standard 100 Premium from DOW CHEMICAL); (poly)hydroxy(Ci-C4)alkylcelluloses such as hydroxymethylcelluloses, hydroxyethylcelluloses (for example Natrosol 250 HHR offered by AQUALON) and hydroxypropylcelluloses (for example Klucel EF from AQUALON); mixed celluloses (poly)hydroxy(Ci-C4)alkyl-(Ci-C4 )alkylcelluloses such as hydroxypropyl-methylcelluloses (for example Methocel E4M from DOW CHEMICAL), hydroxyethyl-methylcelluloses, hydroxyethyl-ethylcelluloses (for example Bermocoll E 481 FQ from AKZO NOBEL) and hydroxybutyl-methylcelluloses.

[0057] Among the anionic cellulose ethers, mention may be made of (poly)carboxy(CrC4)alkylcelluloses and their salts. By way of example, mention may be made of carboxymethylcelluloses, carboxymethylmethylcelluloses (for example Blanose 7M from the company AQUALON) and carboxymethylhydroxyethylcelluloses and their sodium salts.

[0058] Among the cationic cellulose ethers, mention may be made of cationic cellulose derivatives such as cellulose copolymers or cellulose derivatives grafted with a water-soluble quaternary ammonium monomer, and described in particular in US patent 4,131,576, such as (poly)hydroxy(Ci-C4)alkyl celluloses, such as hydroxymethyl-, hydroxyethyl- or hydroxypropyl celluloses grafted in particular with a methacryloylethyl-trimethylammonium, methacrylmidopropyl-trimethyl-ammonium, or dimethyl-diallylammonium salt. The marketed products meeting this definition are more particularly the products sold under the name "Celquat® L 200" and "Celquat® H 100" by the National Starch Company.

[0059] According to a preferred embodiment of the invention, the cellulose polymer(s) are chosen from cellulose polymers not comprising a Cio-C3O side fatty chain in their structure; more preferably from cellulose ethers; even more preferably from non-ionic cellulose ethers; even better among (a) (Ci-C4)alkylcelluloses such as methylcelluloses and ethylcelluloses, (b) (poly)hydroxy(Ci-C4)alkylcelluloses such as hydroxymethylcelluloses, hydroxyethylcelluloses and hydroxypropylcelluloses, (c) mixed celluloses (poly)hydroxy(Ci-C4)alkyl-(Ci-C4)alkylcelluloses such as hydroxypropylmethylcelluloses, hydroxypropylethylcelluloses, hydroxyethylmethylcelluloses, hydroxyethylethylcelluloses and hydroxybutylmethylcelluloses, and (d) mixtures thereof.

[0060] More preferably, the composition according to the invention comprises at least one (poly)hydroxy(Ci-C4)alkylcellulose such as hydroxymethylcelluloses, hydroxyethylcelluloses and hydroxypropylcelluloses; even better at least hydroxyethylcellulose.

[0061] Preferably, when the composition according to the invention comprises at least one thickening agent, the total content of thickening agent(s) is between 0.1 and 10% by weight, more preferably between 0.5 and 5% by weight, even more preferably between 1 and 2.5% by weight, relative to the total weight of the composition.

[0062] Preferably, when the composition according to the invention comprises at least one cellulose polymer, the total content of cellulose polymer(s) is between 0.1 and 10% by weight, more preferably between 0.5 and 5% by weight, even more preferably between 1 and 2.5% by weight, relative to the total weight of the composition.

[0063] Preferably, when the composition according to the invention comprises at least one cellulose polymer, the total content of (poly)hydroxy(Ci-C4)alkylcellulose(s) is between 0.1 and 10% by weight, more preferably between 0.5 and 5% by weight, even more preferably between 1 and 2.5% by weight, relative to the total weight of the composition.

[0064] Preferably, when the composition according to the invention comprises at least one cellulose polymer, the total hydroxyethylcellulose content is between 0.1 and 10% by weight, more preferably between 0.5 and 5% by weight, even more preferably between 1 and 2.5% by weight, relative to the total weight of the composition.

[0065] Surfactants

[0066] The composition according to the invention may optionally also comprise at least one surfactant.

[0067] The surfactants that can be used according to the invention can be chosen from anionic surfactants, cationic surfactants, amphoteric and / or zwitterionic surfactants, non-ionic surfactants, and mixtures thereof.

[0068] More preferably, the surfactant(s) which can be used according to the invention are chosen from non-ionic surfactants.

[0069] The nonionic surfactants which can be used can be chosen from alkyl poly- glucosides (APG), oxyalkylenated glycerol esters, optionally oxyalkylenated fatty acid and sorbitan esters, polyoxyalkylenated fatty acid esters (in particular polyoxyethylenated and / or polyoxypropylenated) optionally in association with a fatty acid and glycerol ester such as the PEG-100 Stearate / Glyceryl Stearate mixture marketed for example by the company ICI under the name Arlacel 165, oxyalkylenated sugar esters, and mixtures thereof.

[0070] As alkylpolyglucosides, mention may be made of those containing an alkyl group comprising from 6 to 30 carbon atoms and preferably from 8 to 16 carbon atoms, and containing a glucoside group preferably comprising 1.2 to 3 glucoside units. The alkylpolyglucosides may be chosen, for example, from decylglucoside (Alkyl-Cç / Cn-polyglucoside (1.4)) such as the product marketed under the name Mydol 10® by the company Kao Chemicals or the product marketed under the name Plantacare 2000 UP® by the company Cognis; caprylyl / capryl glucoside such as the product marketed under the name Plantacare KE 3711® by the company Cognis; laurylglucoside such as the product marketed under the name Plantacare 1200 UP® by the company Cognis; cocoglucoside such as the product marketed under the name Plantacare 818 UP® by the company Cognis; caprylylglucoside such as the product marketed under the name Plantacare 810 UP® by the company Cognis; and mixtures thereof.

[0071] The oxyalkylenated glycerol esters are in particular the polyoxyethylenated derivatives of glyceryl esters and fatty acid esters and their hydrogenated derivatives. These oxyalkylenated glycerol esters may be chosen, for example, from hydrogenated and oxyethylenated glyceryl esters and fatty acids such as PEG-200 hydrogenated glyceryl palmate sold under the name Rewoderm LLS 80 by the company Goldschmidt; oxyethylenated glyceryl cocoates such as PEG-7 glyceryl cocoate sold under the name Tegosoft GC by the company Goldschmidt, and PEG-30 glyceryl cocoate sold under the name Rewoderm LL63 by the company Goldschmidt; oxyethylenated glyceryl stearates; and mixtures thereof.

[0072] The oxyalkylenated sugar esters are in particular polyethylene glycol ethers of fatty acid and sugar esters. These oxyalkylenated sugar esters may be chosen, for example, from oxyethylenated glucose esters such as PEG-120 methyl glucose dioleate marketed under the name Glucamate DOE 120 by the company Amerchol.

[0073] Preferably, the number of moles of alkylene oxide of the nonionic surfactants which can be used according to the invention varies from 2 to 400; more preferably from 4 to 250.

[0074] Preferably, the composition according to the invention is free of surfactant.

[0075] According to a variant of the invention, the composition comprises at least one non-ionic surfactant; more preferably a non-ionic surfactant chosen from esters of polyoxyalkylenated glycerol; more preferably still at least one non-ionic surfactant chosen from esters of glyceryl and hydrogenated and polyoxyethylenated fatty acids such as PEG-200 hydrogenated glyceryl palmate, polyoxyethylenated glyceryl cocoates such as PEG-7 glyceryl cocoate and PEG-30 glyceryl cocoate, polyoxyethylenated glyceryl stearates, and mixtures thereof.

[0076] Even more preferably according to this variant, the composition comprises at least one polyoxyethylenated glyceryl cocoate.

[0077] Preferably, when the composition according to the invention comprises at least one surfactant, the total content of surfactant(s) is between 0.1 and 10% by weight, more preferably between 0.5 and 5% by weight, even more preferably between 1 and 4% by weight, relative to the total weight of the composition according to the invention.

[0078] Preferably, when the composition according to the invention comprises at least one surfactant, the total content of non-ionic surfactant(s) is between 0.1 and 10% by weight, more preferably between 0.5 and 5% by weight, even more preferably between 1 and 4% by weight, relative to the total weight of the composition according to the invention.

[0079] Preferably, when the composition according to the invention comprises at least one surfactant, the total content of (poly)oxyalkylenated glycerol ester(s) is between 0.1 and 10% by weight, more preferably between 0.5 and 5% by weight, even more preferably between 1 and 4% by weight, relative to the total weight of the composition according to the invention.

[0080] Antioxidant agent

[0081] Preferably, the composition according to the invention is free of antioxidant agent.

[0082] According to a variant of the invention, the composition further comprises at least one antioxidant agent; more preferably chosen from tocopherol and its esters, such as tocopherol acetate, propyl gallate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and mixtures thereof.

[0083] Sequestering agent

[0084] Preferably, the composition according to the invention is free of sequestering agent.

[0085] According to a variant of the invention, the composition further comprises at least one sequestering agent; more preferably chosen from (a) ethylenediamine tetraacetic acid (EDTA) and its salts such as the disodium salt of ethylenediaminetetraacetic acid (Disodium EDTA), (b) phosphonic derivatives and their salts such as hexamethylenediaminetetra(methylene phosphonic acid), ethylenediamine tetra(methylene phosphonic acid), 1-hydroxyethylidene-1,1-diphosphonic acid, aminotri(methylenephosphonic acid), diethylenetriamine penta(methylene phosphonic acid), (c) polyamine polymers such as polyalkylene polyamines and their derivatives, in particular polyethyleneimine, (d) dendrimers with activity chelating, (e) proteins such as spermine, spermidine, transferrin, ferritin, (f) carboxylic acids such as phytic acid, citric acid, malic acid, nitriloacetic acid, fumaric acid, tartaric acid, succinic acid, oxalic acid, (g) desferrioxamine mesylate, and mixtures thereof.

[0086] The definition of "sequestering agent" (also called "chelating agent") is well known to those skilled in the art and refers to a compound or mixture of compounds capable of forming a chelate with a metal ion. A chelate is an inorganic complex in which a compound (the sequestering or chelating agent) is coordinated to a metal ion, i.e. it forms one or more bonds with the metal ion (formation of a ring including the metal ion).

[0087] A sequestering (or chelating) agent generally comprises at least two electron donor atoms which allow the formation of bonds with the metal ion.

[0088] According to another variant of the invention, the composition comprises at least one sequestering agent and at least one antioxidant agent.

[0089] According to another variant of the invention, the composition is free of fatty substances, sequestering agents and / or antioxidant agents.

[0090] pH

[0091] Preferably, the pH of the composition according to the invention is between 3 and 8, more preferably between 4 and 7, and even better between 5 and 6.

[0092] The pH of these compositions can be adjusted to the desired value by means of alkalizing agents or acidifying agents commonly used. Among the alkalizing agents, mention may be made, by way of examples, of ammonia, alkanolamines, mineral or organic hydroxides. Among the acidifying agents, mention may be made, by way of examples, of mineral or organic acids such as hydrochloric acid, orthophosphoric acid, carboxylic acids such as, for example, acetic acid, tartaric acid, citric acid, lactic acid, sulfonic acids.

[0093] The use of amitriptyline and / or one of its pharmaceutically acceptable salts as a preservative can be carried out in pharmaceutical compositions of different formulations, such as an aqueous gel, an aqueous solution, an oil-in-water emulsion. These compositions can be applied topically, as an oral solution, or even by injection, etc. Preferably, the composition is applied topically.

[0094] The present invention further relates to a pharmaceutical composition as defined above comprising amitriptyline and / or one of its pharmaceutically acceptable salts, preferably in a total content of between 1 and 25% by weight, more preferably between 5 and 20% by weight, even more preferably between 5 and 15% by weight, relative to the total weight of the composition, it being understood that the composition is as defined above.

[0095] The composition may optionally further comprise at least one additional preservative agent, different from amitriptyline and its salts, such as methyl paraben. In this case, the content of additional preservative agent(s) is preferably less than or equal to 10% by weight, more preferably less than or equal to 5% by weight, even more preferably less than or equal to 1% by weight, better still less than or equal to 0.5% by weight, relative to the total weight of the composition.

[0096] In a particular embodiment, the composition according to the invention is free of additional preservative. In particular, preferably, the composition according to the invention is free of methyl paraben.

[0097] The following examples illustrate the composition according to the invention and the advantages of this composition. However, they do not in any way represent a limitation of the present invention but simply illustrate the invention.

[0098] Examples Compositions A (comparative) and B, C and D (according to the invention) were prepared from the ingredients indicated in the table below, the quantities of which are expressed in % by weight:

[0099] [Tables 1] ABCD Amitriptyline hydrochloride 0 5 10 10 Hydroxyethylcellulose 1 1 1 1 Propylene glycol 5 5 5 5 Methyl paraben 0.1 0.1 0.1 0 pH agent Qsp pH 5.5 ± 0.5 Qsp pH 5.5 ± 0.5 Qsp pH 5.5 ± 0.5 Qsp pH 5.5 ± 0.5 Water Qsp 100 Qsp 100 Qsp 100 Qsp 100

[0100] Compositions A, C and D were then subjected to antimicrobial preservation tests in accordance with European (Chapter 5.1.3 “Antimicrobial preservation effectiveness”) and American (USP, Chapter 51) regulations. The microbial strains studied are indicated in the following table:

[0101] [Tables2] European Pharmacopoeia Chapter 5.1.3 USP Chapter 51 Pseudomonas ae-ruginosa XX Staphylococcus aureus XX Escherichia coli X Candida albicans XX Aspergillus brasiliensis XX

[0102] The counting of the growth of microorganisms (or its absence) is carried out at specified time intervals of 2, 7, 14 and 28 days and expressed as a logarithmic reduction compared to the control. The acceptance criteria according to European and American standards are presented in the following tables:

[0103] [Tables3] European Pharmacopoeia Criteria Chapter 5.1.3 T 2 days 7 days 14 days 28 days Microorganisms logarithmic concentration of inoculum Criteria Log Reduction (CFU) P. aeruginosa S. aureus [5-6] A >2 >3 - NI [5-6] B - - >3 NI C. albicans A. brasiliensis [5-6] A - - >2 NI [5-6] B - - > 1 NI

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110] [YES]

[0112]

[0113] [Tables 4] USP Criteria Chapter 51 T 2 days 7 days 14 days 28 days Microorganisms Log Inoculum Concentration Criteria Log Reduction (CFU) P. aeruginosa S. aureus E. coli [5-6] USP Criteria - - >2 NI C. albicans A. brasiliensis [5-6] - - NI NI - T2, 7, 14, 28 days: results expressed as logarithmic reduction compared to control T - NI: No increase in the number of colonies compared to the previous count - T: logarithmic concentration of microorganisms in the inoculum used to carry out the contamination 10g of each of compositions A, C and D is inoculated with 100 pL of an inoculum of one of the tested microorganisms comprising 107 to 108 CFU / ml of inoculum for bacteria and 106 to 107 CFU / ml of inoculum for fungi. Then, 1g of composition inoculated by a microorganism is diluted in 9mL of buffer solution before undergoing a series of dilutions and being distributed in Petri dishes. Incubate for up to 28 days at a temperature between 30 and 35°C for bacteria and between 20 and 25°C for fungi. The number of colonies is counted at 2, 7, 14 and 28 days. The results are shown in Tables 4 and 5 below: [Tables 5] Microorganisms S. aureus P. aeruginosa Composition Time (D) 2 7 14 28 2 7 14 28 A >4.7 >4.7 >4.7 >4.7 >4.7 >4.7 >4.7 >4.7 C >4.7 >4.7 >4.7 >4.7 >4.7 >4.7 >4.7 >4.7 >4.7 D >4.7 >4.7 >4.7 >4.7 >4.7 >4.7 >4.7 >4.7 >4.7

[0114] [T ableauxô] Microorganisms E. coli C. albicans A. brasiliensis Acceptance at 28 days Composition Time 0) 14 28 14 28 14 28 A >4.7 >4.7 1.7 2.9 -0.4 -0.4 Non-compliant with USP, EP C >4.7 >4.7 >4.7 >4.7 2 2 Complies with USP and EP criteria AD >4.7 >4.7 >4.7 >4.7 1 1 Complies with USP and EP criteria B

[0115] Composition A, comprising methyl paraben but not amitriptyline, does not comply with the European and American Pharmacopoeia tests.

[0116] Composition C, comprising methyl paraben and amitriptyline, complies with the European and American Pharmacopoeia tests. The same is true for composition D, comprising amitriptyline but not methyl paraben.

[0117] Thus, the presence of amitriptyline makes it possible to reduce the populations of microorganisms such as P. aeruginosa, S. aureus, E. coli, C. albicans and A. brasiliensis, in pharmaceutical compositions, even in the absence of a preservative such as methyl paraben.

Claims

Claims

1. Use of amitriptyline and / or one of its pharmaceutically acceptable salts as a preservative in a pharmaceutical composition.

2. Use of amitriptyline and / or one of its pharmaceutically acceptable salts according to claim 1, characterized in that the total content of amitriptyline and / or one of its pharmaceutically acceptable salts is between 1 and 25% by weight, preferably between 5 and 20% by weight, more preferably still between 5 and 15% by weight, relative to the total weight of the composition.

3. Use of amitriptyline and / or one of its pharmaceutically acceptable salts according to any one of the preceding claims, characterized in that the water content of the pharmaceutical composition is greater than or equal to 75% by weight, preferably between 75 and 95% by weight; and more preferably between 75 and 90% by weight, relative to the total weight of the composition.

4. Use of amitriptyline and / or one of its pharmaceutically acceptable salts according to any one of the preceding claims, characterized in that the pH of the pharmaceutical composition is between 3 and 8; preferably between 4 and 7; more preferably between 5 and 6.

5. Use of amitriptyline and / or one of its pharmaceutically acceptable salts according to any one of the preceding claims, characterized in that the composition further comprises at least one C2-C8 polyol.

6. Use of amitriptyline and / or one of its pharmaceutically acceptable salts according to any one of the preceding claims, characterized in that the composition further comprises at least one thickening agent; preferably chosen from cellulose polymers.

7. Use of amitriptyline and / or one of its pharmaceutically acceptable salts according to any one of the preceding claims, characterized in that the composition further comprises at least one surfactant chosen from anionic surfactants, cationic surfactants, amphoteric and / or zwitterionic surfactants, non-ionic surfactants, and mixtures thereof, preferably from non-ionic surfactants and mixtures thereof.

8. Use of amitriptyline and / or one of its pharmaceutically acceptable salts according to any one of the preceding claims, characterized in that the pharmaceutical composition is in topical form.