Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Definitions

• the skin is a natural barrier of the body that can be the seat of various conditions such as inflammatory disorders, allergic reactions of varying intensity, infections by microorganisms such as bacteria, microscopic fungi or viruses. . It is a fabric made up of different cellular layers which assures in particular a role of protection vis-à-vis the internal tissues.
• the skin can be the seat of different affections, it has the advantage, unlike other tissues of the body to allow some ease of access, so that most drugs that are intended to treat disorders dermas such as dermatoses are administered directly on the skin (cutaneous application).
• the latter may have recourse to various galenic forms such as pulverulent presentations (cutaneous powders), liquid preparations (lotions, liniments) or semisolids (creams and skin ointments) so as to obtain the best possible therapeutic effect.
• some therapeutic agents administered locally have very low efficacy when applied cutaneously, which in some cases significantly limits their local use.
• the skin being made of cell layers of very different compositions, this one can significantly limit the diffusion of certain therapeutic agents within said cell layers, and in particular with regard to therapeutic agents having a very low solubility in water (poorly soluble therapeutic agents, in particular characterized by an aqueous solubility of less than 10 mg / ml at room temperature ).
• the therapeutic molecules that are poorly soluble in water refer to any molecule with an action pharmacological agent that can be applied to the skin for a local action whose solubility in water is less than 10 mg / ml and more particularly less than 1 mg / ml at room temperature):
• ketoconazole The low aqueous solubilities of these therapeutic agents may, in certain cases, lead to two types of restriction on their administration by dermal application:
• Therapeutics are administered locally, which requires the use of an alternative route of administration, such as the oral route.
• an alternative route of administration such as the oral route.
• certain therapeutic agents whose site of action (pharmacodynamic target) is located in the dermis, reach their targets in very small amounts due to a very low solubility.
• these therapeutic agents need to be administered orally despite all the interest that would present a cutaneous application.
• the administration of oral therapeutic agents for the treatment of cutaneous pathologies necessarily involves a digestive absorption of the product and its dissemination throughout the body systemically. This point can become
• ciclosporin A an immunosuppressant belonging to the family of calcineurin inhibitors - used in dermatology to treat some forms of psoriasis. Due to insufficient efficacy of galenic forms of ciclosporin A
• aciclovir in the treatment of cutaneous and genital herpes. Indeed, insofar as the local administration of this molecule does not provide sufficient efficacy in the treatment of the aforementioned indications, the prescriber uses galenic forms of aciclovir administrable orally, such as tablets which can contain between 200 mg and 800 mg of aciclovir for dosages of 1 to 5 tablets per day, which makes the observance of these treatments particularly heavy.
• organic solvents such as ethanol, glycol ethers, pyrrolidone derivatives, dimethyl sulfoxide, natural or modified vegetable oils as well as surfactants such as
• compositions not including such potentially irritating substances for dermatological purposes and composed mainly of water.
• Water is indeed the ideal solvent for dermatological compositions with local action because of its safety and its excellent physiological compatibility with cutaneous tissues.
• compositions envisaged containing very poorly soluble therapeutic agents must, however, be stable enough to be compatible with a pharmaceutical use.
• compositions within the meaning of the invention are therefore intended to mean a composition whose stability is sufficient for its application on the skin, in particular as regards the solubility of the therapeutic agent, which must not be not show traces of precipitation in the composition after several months of storage.
• aqueous compositions of local aqueous action comprising a salt (soluble) of the condensation product of a specific amino acid with at least one fatty acid included in the coconut oil and a therapeutically weakly water-soluble therapeutic agent within the meaning of the invention were likely to facilitate the administration of said therapeutic agents by cutaneous route, by respecting the previously developed problems while ensuring a stability compatible with a use
• N-acyl amino acids may be used in "anti-aging" cosmetic compositions, cf. PCT applications WO 2010/026325 and WO 2010/023390, which disclose regulatory properties of these compounds with respect to certain cells of the skin in order to obtain the desired cosmetic effects, whereas the state of the art does not disclose, nor suggest, the use of a condensation product between a given amino acid and at least one fatty acid included in the coconut oil in order to increase the aqueous solubility of poorly soluble therapeutic agents in water, while respecting the previously developed issues.
• the French patent application FR-A-2935379 discloses firstly the use of N-Acyl amino acids as cosmetic and pharmaceutical active principles for regulating the proportion of basal keratinocytes in the epidermis of human skin and, secondly, anti-aging cosmetic compositions containing such N-acyl amino acids.
• These cosmetic compositions may furthermore comprise numerous other constituents such as emollient agents (glycerine, squalane), emulsifying additives (MONTANOV TM, MONTANOX TM) as well as preservatives (SEPICIDE TM LD, chlorphenesin).
• FR-A-2935379 does not disclose, nor does it suggest, the possibility of using said N-Acyl amino acids in order to promote the solubilization of therapeutic molecules (active ingredients) that are poorly soluble in water, with a view to obtain a local action after dermal administration.
• these dispersed systems are systemically acting and in no case locally acting (see WO 02/076506, page 3, lines 21-24 and Example 4, the latter relating to a transdermal dispersed system, that is, to say one dispersed system to cross the skin and spread throughout the body for therapeutic purposes).
• Examples 1 to 8 relate to dispersed systems including surfactants (such as PEG30).
• polyhydroxystearate and solvents (such as propylene glycol or its derivatives), as well as lipophilic compounds (such as soybean oil or oleic acid), and this in significant proportions (on average, the total of these compounds exceeds 50% of the weight of the composition).
• solvents such as propylene glycol or its derivatives
• lipophilic compounds such as soybean oil or oleic acid
• An object of the present invention is therefore a topically administrable, aqueous skin-action pharmaceutical composition
• a topically administrable, aqueous skin-action pharmaceutical composition comprising: at least one salt of a condensation product of an amino acid of general formula (I)
• R represents a hydrogen atom or a methyl group and said therapeutic agent is selected from the group consisting of therapeutic molecules intended for local application.
• said composition comprises a therapeutic agent which has a solubility in water at room temperature equal to or less than 10 mg / ml.
• the therapeutic agent has a solubility equal to or less than 1 mg / ml, preferably less than 1 mg / ml.
• aqueous pharmaceutical composition for local action means a composition intended to act locally on the skin (topical action) in which water represents at least 20% of the weight of the excipient.
• “Local action” means that the pharmacological activity of the therapeutic agent occurs locally, ie without any systemic effect.
• “Cutaneous application” means an application of the therapeutic agent to all or part of the skin of a patient.
• the condensation product of an amino acid of general formula (I) with at least one fatty acid included in coconut oil can be defined as an N-Acyl amino acid (in this case N-Acyl glycine or N-acyl glycine).
• N-Acyl amino acid in this case N-Acyl glycine or N-acyl glycine.
• Acyl alanine that is to say a product resulting from the condensation of the amino function carried by the amino acid referred to above (respectively glycine or alanine, and preferably L-glycine or L-alanine) with the carboxylic acid function carried by one or more of the fatty acids included in the coconut oil.
• the N-Acyl amino acid is an N-Acyl L-amino acid, namely an N-Acyl L-glycine or an N-Acyl L-alanine.
• the coconut oil generally contains a mixture of fatty acids whose length of the carbon chain can be between 6 and 18 carbon atoms (mixture of fatty acids in Ce - Cis).
• the condensation product of an amino acid of general formula (I) with the mixture of fatty acids constituting coconut oil in their proportion is used. respectively.
• This condensation product can therefore be defined as a N-cocoyl amino acid (in this case N-cocoyl glycine or N-cocoyl alanine).
• the invention therefore also relates to any topical pharmaceutical composition, administrable by cutaneous application, comprising at least one N-acyl component Ce-Cis amino acid, the "acyl" portion being constituted by a fatty chain present in coconut oil.
• the naturally occurring fatty acids in coconut oil are generally caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, coconut palmitoleic acid, stearic acid, oleic acid, linoleic acid and linolenic acid.
• the acyl part will exclusively consist of the fatty chain of lauric, myristic, caprylic or capric acid.
• the above-mentioned condensation product (also referred to as N-acyl amino acid) is N-cocoyl alanine (preferably N-cocoyl L-alanine), which consists of the mixture of N-Lauroyl Alanine, N-myristoyl alanine, N-capryl alanine and N-capryloyl alanine according to the proportions of fatty acid derivatives usually present in coconut oil.
• N-cocoyl alanine preferably N-cocoyl L-alanine
• N-cocoyl L-alanine which consists of the mixture of N-Lauroyl Alanine, N-myristoyl alanine, N-capryl alanine and N-capryloyl alanine according to the proportions of fatty acid derivatives usually present in coconut oil.
• the above-mentioned condensation product is N-Lauroyl Alanine, and preferably N-Lauroyl L-Alanine.
• Said condensation product is used in a salified form.
• This salified form is soluble in water and can easily be obtained using an organic amino base such as monoethylamine, diethylamine or an inorganic base such as sodium hydroxide or potassium hydroxide.
• the amino acid is alanine, and preferably L-alanine, this particular derivative allowing, surprisingly, to obtain compositions which have excellent skin tolerance as well as sufficient stability. This allows to consider the use of these compositions for the cutaneous application of one or more drugs.
• Example 2 As indicated in Example 2 (see below), a stability study demonstrated that the cocoyl alanine salt pharmaceutical composition of Example 1 was able to administer a drug topically. for cutaneous applications.
• compositions according to Example 1 were prepared using a different amino acid: valine.
• Example 1 The compositions of Example 1 were thus prepared using N-cocoyl valine as the sodium salt.
• the compositions obtained revealed a significant instability (see Example 4 infra), rendering their use as a medicine unfit.
• the expression "ambient temperature” designates a temperature of the order of 20 to 25 ° C.
• said composition does not comprise irritating agents, such as surfactants and organic solvents or co-solvents, which represents a non-essential advantage.
• treating agents substances that may induce inflammatory symptoms at the cutaneous level, which may notably result in edema and redness.
• the therapeutic agent is selected from the group of therapeutic molecules intended for local application belonging to the family:
• antibacterials for dermal purposes such as fusidic acid
• cutaneous antivirals such as aciclovir
• antifungals such as imidazoles such as econazole, miconazole or ketoconazole
• immunomodulators preferably those selected from the group of calcineurin inhibitors such as tacrolimus, pimecrolimus and ciclosporin A
• anti-inflammatory steroids such as prednisolone, betamethasone or dexamathesone;
• analgesics or non-steroidal anti-inflammatory drugs such as diclofenac, ketoprofen or phenylbutazone
• local anesthetics such as lidocaine or xylocaine.
• the therapeutic molecules intended for local application are selected from among the
• immunomodulators preferably from calcineurin inhibitors such as tacrolimus, pimecrolimus and ciclosporin A, or from local anesthetics such as lidocaine or xylocaine;
• the therapeutic molecule is ciclosporin A.
• Another object of the present invention is a composition
• the present invention also relates to the use of a pharmaceutical composition as defined above to obtain a drug.
• Yet another object of said invention is a composition
• the invention also relates to a pharmaceutical composition as defined above for its use as a medicament with local action which can be administered by cutaneous application:
• the therapeutic agent is selected from immunomodulators and preferably from calcineurin inhibitors such as tacrolimus, pimecrolimus and ciclosporin A;
• the therapeutic agent in the treatment of cutaneous infections of bacterial origin when the therapeutic agent is an antibacterial agent such as fusidic acid; in the treatment of cutaneous diseases of viral origin when the therapeutic agent is an antiviral agent such as aciclovir, valaciclovir or ganciclovir;
• the therapeutic agent in the treatment of skin disorders of fungal origin when the therapeutic agent is an antifungal such as imidazole derivatives such as econazole, miconazole or ketoconazole;
• the therapeutic agent is a steroidal anti-inflammatory drug such as prednisolone, betamethasone or dexamathesone;
• a nonsteroidal antalgic or anti-inflammatory drug such as diclofenac, ketoprofen or phenylbutazone
• the therapeutic agent belongs to the family of local anesthetics such as lidocaine or xylocaine.
• ciclosporin A will be used to treat atopic dermatitis and psoriasis.
• ciclosporin A is a macromolecular cyclic peptide compound composed of 11 amino acids. This molecule has a broad spectrum of useful pharmacological activities including immunosuppressive and anti-inflammatory activity. Cyclosporine is highly lipophilic and hydrophobic which makes it poorly soluble in water. Due to its structure and physicochemical properties, ciclosporin A does not penetrate the skin (Stratum corneum). In therefore, it was commonly accepted that cidosporin A could not be administered topically, mainly because this molecule had a very low solubility in water which did not allow sufficient concentration to be obtained. in assets. The use of the locally active aqueous pharmaceutical compositions according to the present invention makes it possible to administer cidosporin A topically and to obtain a sufficient active concentration while maintaining excellent stability.
• the process for obtaining the composition according to the invention comprises the following steps: introduction of a volume of water representing between 50% and 90%, and preferably around 75%, of the total weight of the water of the composition obtained in fine in a container equipped with an agitator;
• light heating is meant heating at a temperature between 30 ° C and 70 ° C.
• the salt of the condensation product is added in an amount of between 1% and 25% of the final weight of the product,
• Example 1 infra The process for preparing the composition that is the subject of Example 1 (see Example 1 infra) is as follows:
• Example 1 a sodium salt of a condensation product of alanine and coconut oil also called N -Cocoyl alanine (ie 12% of the final weight of the product). Cyclosporin A gradually dissolves in the mixture; the solution formed is clear and can be slowly cooled with stirring
• the solution obtained is translucent and can be distributed in bottles provided with delivery system for application to the skin. It should be noted that it is also possible to prepare a solution of sodium cocoyl alaninate from the stirring mixture of a solution of sodium hydroxide and cocoyl alanine in suitable amounts.
• a solution of sodium cocoyl alaninate from the stirring mixture of a solution of sodium hydroxide and cocoyl alanine in suitable amounts.
• composition according to the invention comprises the following compounds, in the weight amounts indicated below:
• Example No. 1 A stability study according to pharmaceutical standards was conducted on the composition described in Example No. 1 to verify that it can be compatible with use as a drug.
• the protocol used was to place the samples obtained in Example No. 1 under different conditions of temperature and residual moisture in order to comply with pharmaceutical standards (25 ° C / 60% Residual Humidity, and 40 ° C / 75 ° C). % Residual Humidity) for a period of 12 months.
• Example 3 Additional pharmaceutical compositions according to the invention
• compositions were prepared according to the present invention, using other therapeutic agents (active ingredients) and varying the N-Acyl amino acid compound:
• Demineralised water qs 100g (about 82g) The process for preparing the solution is that described in Example 1.
• the final pH of the composition defined above is close to 7.
• the composition formed is translucent immediately after manufacture but is not stable over time. Thus, a stability study revealed that the solution formed shows white precipitates after two months of stability and a corresponding decrease in the titre of the
• ciclosporin revealing instability and inability to use as a drug.
• Biochemical examination a biochemical examination was carried out daily to follow the evolution of the following parameters: - Minerals: sodium, potassium, chlorine, calcium, phosphate,
• Erythrocytes Leukocytes, Packed cell volume (PCV), Mean corpuscular volume (MCV), Hemoglobin, Platelet count, Mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), Fibrinogen.
• PCV Cell volume
• MCV Mean corpuscular volume
• MH Hemoglobin
• MHC mean corpuscular haemoglobin concentration
• Fibrinogen Fibrinogen.
• Results Local signs: the results indicate that there is no significant difference for the sites treated with the product prepared according to the composition of Example No. 1 and with the placebo regardless of the day for each group.
• General signs the results indicate a lack of increase in the scores of the general signs and that there is no significant difference between the groups treated (healthy skin and damaged skin).
• Biochemistry the results show no impact of the tested products on the parameters monitored during the period.
• Hematology the results show no impact of the tested products on the parameters monitored during the period.
• Example 6 efficacy study on dog atopic dermatitis
• the present invention was used in the context of a treatment trial for atopic dermatitis in dogs.
• Example 1 The composition of Example 1 was applied daily to dogs with canine atopic dermatitis.
• Efficacy was assessed 28 days after the first administration using a LICAD and PICAD score system.
• LICAD is a scoring system that has been set up to evaluate erythema, excoriation and lichenification.
• PICAD is another scoring system for the assessment of pruritus.
• Example 1 The effectiveness of the composition described in Example 1 was demonstrated in this preliminary test for the treatment of canine atopic dermatitis after daily topical application for 28 days.
• the present invention can be used in different areas
• compositions for preventive or curative purposes, particularly in the context of acute or chronic conditions, as well as for obtaining locally active anesthetic compositions generally used in the preamble to a diagnostic or surgical gesture (for example for curative purposes or diagnosis).
• immunomodulators and preferably calcineurin inhibitors such as ciclosporin A, tacrolimus and pimecrolimus.
• compositions according to the present invention can be used in human or veterinary therapy. They are
• atopic canine dermatitis also known as atopic dog dermatitis
• Canine atopic dermatitis is the second most common cause of pruritus after flea infestation, characteristic of flea allergy dermatitis (DAPP), and may affect more than 50% of animals in predisposed breeds.
• the composition described according to the invention may comprise, as excipients (in addition to water), various ingredients which may especially promote the application of the product, enhance its effectiveness, improve stability, facilitate dispensing or dosage, limit or on the contrary, depending on the case, facilitate evaporation.
• viscosity or texturing agents such as polymers of natural origin (for example derived from cellulose) or synthetic polymers (for example acrylic polymers) intended for ensure prolonged contact with the skin, agents to stabilize the pH such as acid salts inorganic or organic substances and their conjugate bases, agents
• skin-moisturizing agents such as urea, humectants or emollients such as glycerin, antimicrobial preserving agents such as benzoic acid or sorbic acid derivatives and their salts, agents to prevent the product of a possible oxidation such as sulfites and their derivatives, agents to reduce or otherwise promote the evaporation of the product after its application such as volatile compounds, as well as agents to ensure a protective role of the skin such as fat derivatives, etc.
• antimicrobial preserving agents such as benzoic acid or sorbic acid derivatives and their salts
• agents to prevent the product of a possible oxidation such as sulfites and their derivatives
• agents to reduce or otherwise promote the evaporation of the product after its application such as volatile compounds
• agents to ensure a protective role of the skin such as fat derivatives, etc.
• composition according to the invention can in particular be applied using a suitable multi-dose delivery system such as a bottle provided with a metering pump in order to deliver a reproducible dose of said product.
• a suitable multi-dose delivery system such as a bottle provided with a metering pump in order to deliver a reproducible dose of said product.
• Another presentation may consist of a single-dose packaging optionally having an applicator tip.
• composition may also be administered from a system that can be applied to the skin over a prolonged period such as a patch to provide extended residence time at the application site.

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• 2011
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