Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
  • A61K38/13—Cyclosporins
• • 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
  • A61K9/0017—Non-human animal skin, e.g. pour-on, spot-on
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders

Definitions

• compositions dermal and for the local treatment of atopic canine dermatitis
• the present invention relates to pharmaceutical compositions and more particularly to the use of ciclosporin A in a veterinary composition intended for the local treatment of canine atopic dermatitis, also called atopic dermatitis of dogs.
• Canine atopic dermatitis is a pruriginous, corticosensitive dermatitis, characterized by involvement of the limbs and the face, genetic predisposition and frequent sensitization to environmental factors. It presents the second cause of pruritus after flea infestations, characteristic of flea allergy dermatitis (DAPP), and may affect more than 50% of animals in predisposed breeds.
• AD atopic dermatitis
• Canine atopic dermatitis predisposes to sensitization to flea salivary allergens and therefore allergic dermatitis to bites chips (DAPP). It has been shown that four-fifths of dogs with DAPP are atopic and that one-third of atopic dogs develop DAPP. Dogs with exclusive DAPP are rare and atopic dogs are four times more likely to develop DAPP than non-atopic dogs.
• Atopic dermatitis also promotes the occurrence of staphylococcal or Malassezia sp. since their adhesion is facilitated on weathered skin. However, it must be distinguished from clinically related dermatoses, such as ectoparasitoses (sarcoptic mange, trombiculosis, demodicosis), allergic dermatitis (DAPP) and others.
• ectoparasitoses sarcoptic mange, trombiculosis, demodicosis
• DAPP allergic dermatitis
• pathogenesis and origin of canine atopic dermatitis are very specific and complex. Numerous factors such as genetic predisposition, immune response abnormality, biochemical abnormality, skin barrier alteration, behavioral disorders, atopenes, fleas, infectious agents, and diet, can cross-mediate and influence the onset and progression of disease.
• the first aims to control pruritus and infections
• the second aims to limit the frequency or severity of attacks of atopic dermatitis.
• Hygiene with daily brushing and the use of emollient shampoos can limit the allergenic pressure on the skin surface.
• the control of associated dermatoses including flea infestation and infectious complications can limit the aggravation of canine atopic dermatitis.
• Antihistamines have 20 to 30% effectiveness. They are inexpensive but show varying results.
• Essential fatty acids have about 25% efficiency. They allow the improvement of the state of the skin and the hairs but require high doses to obtain variable results and a slow efficiency.
• Immunotherapy directly targets the cause of the disease. However, there are few data available on this point and the results obtained are also variable. This therapy requires a good monitoring of the animal and its effectiveness is observed only from 6-12 months.
• Topicals such as sprays and shampoos have variable and temporary effectiveness. They reduce allergenic contact with the skin and reduce the itchiness of contact. They lead to temporary and variable local improvement, which is not necessarily practical for homeowners.
• Steroids are very effective in dogs. They cause quick relief but often cause many side effects. Moreover, their effectiveness decreases over time.
• ciclosporin A administration of ciclosporin A has now become a possible alternative and the use of ciclosporin A orally as an alternative to corticosteroids for the treatment of atopic dermatitis canine is more and more used.
• 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 A is highly lipophilic and hydrophobic which makes it poorly soluble in water. Much work has been done to increase the uptake of ciclosporin after oral administration, which is the primary route of administration for transplant rejection in transplant patients. Thus, a series of patents, issued from a priority GB 2 257 359 dating from 1991, including 2 initial patent applications FR 2 678 169 and EP 539319 gave rise to two divisional applications having the same priority, FR 2,685,706 and EP 953630.
• FR 2,678,169 and EP 539319 disclose ciclosporin pharmaceutical compositions using a vehicle comprising 1,2-propylene glycol, a mixture of mono-, di- and triglycerides and a hydrophilic surfactant. . These patents specify that this composition is in microemulsion form and makes it possible to increase the bioavailability of ciclosporin A during oral administration.
• Another series of patents, FR 2 685 706 and EP 953630 more particularly describes compositions comprising a trans-esterification product of corn oil and glycerol in order to improve the stability of the composition, to increase its bioavailability during oral administration and to reduce variability in intra- and inter-individual bioavailability.
• compositions based on solvents and surfactants are essentially the products marketed under the tradenames Transcutol® (2- (2-ethoxyethoxy) ethanol) and Glycofurol® as well as 1,2-propyleneglycol.
• the preferred components for the lipophilic phase are medium chain fatty acid triglycerides marketed under the trade names Miglyol® (caprylic / capric triglyceride), Captex® (propylene glycol dicaprate), Myritol® (caprylic / capric triglyceride), Capmul® ( Glyceryl caprilate), Neobee® (caprylic / capric triglyceride) and Mazol® (glycerol ester).
• Miglyol® caprylic / capric triglyceride
• Captex® propylene glycol dicaprate
• Myritol® caprylic / capric triglyceride
• Capmul® Glyceryl caprilate
• Neobee® caprylic / capric triglyceride
• Mazol® glycerol ester
• Suitable surfactants are in particular the reaction products of ethylene glycol with natural or hydrogenated vegetable oils such as those sold under the trade names Cremophor® RH40 (Polyoxyl 40 Hydrogenated Castor Oil) and Nikkol® (PEG 40 Castor Oil Hydrogenated). It will be appreciated by those skilled in the art that the inventions described above specifically target the improvement of the oral solubility of ciclosporin.
• patent FR 2,636,534 issued from a British priority of 1989 also describes ciclosporin compositions in microemulsion form for oral administration for the treatment of atopic dermatitis.
• Topical application is discussed with an in-vivo preclinical skin allergic contact dermatitis reduction test in guinea pigs.
• the use of these compositions in the dog as part of a local treatment of atopic dermatitis (and not allergic contact dermatitis) is in no way mentioned, nor suggested.
• compositions comprising ciclosporin A in organic solutions based on solvents and intended for oral use have been developed and described in the aforementioned patents.
• compositions disclosed in the patents mentioned above contain significant amounts of solvents and surfactants which can induce local irritation and significant side effects which are likely to aggravate skin lesions present in clinical cases of atopic dermatitis such as pruritus, erythema, excoriation, lichenification and hypermelanosis.
• the said inventions were developed with the aim of improving the oral bioavailability of ciclosporin A and thus enabling a greater action by the systemic route.
• ciclosporin A has numerous general side effects which are notably related to the systemic resorption thereof, the most marked side effect being a very significant renal toxicity. which requires strict biological monitoring of the treatment. Consequently, if the compositions described above actually make it possible to improve the Oral bioavailability of ciclosporin A, they also have the disadvantage of exposing patients to a general toxicity of the product.
• atopic dermatitis favors the appearance of staphylococcal infections or Malassezia sp .
• the pyodermites are accompanied by papules, pustules, erythema, lichenification and squamosis. They can be localized to interdigital spaces, external auditory ducts, lips, fold of the face and inguinal region, or generalized.
• canine atopic dermatitis predisposes to sensitization to flea salivary allergens and therefore to allergic dermatitis flea bite (DAPP) which also causes a weakening of the skin, with a location of very different lesions.
• DAPP allergic dermatitis flea bite
• ciclosporin A is highly lipophilic and hydrophobic which makes it poorly soluble in water. Because of its structure and physicochemical properties, ciclosporin A not penetrate the skin (Stratum corneum). Therefore, it was generally accepted that it was not possible to administer ciclosporin A topically, mainly because this molecule had a very low solubility in water which did not allow for to obtain a sufficient concentration in active.
• An object of the present invention is therefore a topically administrable, skin-administering pharmaceutical composition comprising ciclosporin A for use as a veterinary medicament administrable by cutaneous application in the local treatment of canine atopic dermatitis.
• the invention relates to the use of said pharmaceutical composition for preparing a topical veterinary drug, administrable cutaneously, to treat canine atopic dermatitis.
• said composition is an aqueous composition.
• Another object of the present invention relates to a method for treating canine atopic dermatitis, by administering to a dog affected by this pathology a composition according to the invention comprising ciclosporin A topically (cutaneous application).
• compositions dermal-acting pharmaceutical compositions comprising ciclosporin A and at least one salt of a condensation product of glycine or alanine with at least one fatty acid included in the coconut oil were of interest. particularly to solve the problems developed while ensuring stability compatible with a pharmaceutical (veterinary) use of the product.
• composition with local action is intended to mean a composition intended to act locally on the skin (topical action).
• said composition is an aqueous pharmaceutical composition, ie wherein the water is at least 20% by weight of the excipient.
• “Cutaneous application” means an application of the therapeutic agent to all or part of the skin of a patient.
• 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 international application WO 02/076506 discloses dispersed systems for pharmaceutical use comprising at least one active principle, at least one lipoamino acid consisting of the combination of a fatty acid and an amino acid as intestinal absorption promoters or pulmonary, depending on whether the dispersed system is respectively in a dosage form suitable for oral administration or in a dosage form suitable for administration to the lungs.
• 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, ie a dispersed system allowing to cross the skin and spread it 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
• the pharmaceutical composition according to the invention is a composition (preferably aqueous) comprising: at least one salt of a condensation product of an amino acid of general formula (I)
• 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 alanine), that is to say a product resulting from the condensation of the amine function carried by the aforementioned amino acid (respectively glycine or alanine) with the carboxylic acid function carried by one or more of the fatty acids included in coconut oil.
• N-Acyl amino acid in this case N-Acyl glycine or N -Acyl alanine
• the condensation product of an amino acid of general formula (I) with coconut oil can be defined as a N-cocoyl amino acid (in this case N-cocoyl glycine or N-cocoyl 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 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" part consisting of 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 which consists of the mixture, in particular, of N-lauroyl alanine, N-myristoyl alanine, N -capryl alanine and N-capryloyl alanine according to the proportions of fatty acid derivatives
• the above-mentioned condensation product is N-Lauroyl Alanine.
• the composition according to the invention comprises an aqueous vehicle representing 20% or more of the weight of the excipient of said composition, preferably more than 60% of the weight of the excipient and advantageously more than 75% by weight. of the excipient of said composition.
• Said condensation product is used in a salified form.
• This salified form is soluble in water and can easily be obtained using an organic amine base such as monoethylamine, diethylamine or an inorganic base such as sodium hydroxide or hydroxide of potassium.
• the latter are stable and do not precipitate when placed under usual stability conditions.
• the composition according to the invention does not comprise irritating agents, such as surfactants and organic solvents or cosolvents, which represents a significant advantage insofar as the skin of the dog to be treated is , in good standing general, particularly sensitive and already has inflammations and / or irritations.
• irritating agents such as surfactants and organic solvents or cosolvents
• the amino acid of general formula (I) is 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 a stability study demonstrated that the cocoyl alanine salt pharmaceutical composition of Example 1 was able to administer a drug topically.
• cutaneous applications in particular for cutaneous applications aimed at treating canine atopic dermatitis (DAC).
• DAC canine atopic dermatitis
• compositions according to Example 1 were prepared using a different amino acid: valine.
• compositions of Example 1 were therefore prepared using cocoyl valine in the form of sodium salt.
• the compositions obtained revealed significant instability (see Example 3 infra), rendering their use as a medicament, and in particular as a veterinary medicinal product, unsuitable.
• the process for obtaining the composition according to the invention comprises the following steps: at. Introduction of a volume of water representing between 50% and 90%, and preferably close to 75%, of the total weight of the water of the composition obtained in fine in a container equipped with a stirrer;
• 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,
• the therapeutic agent is added in an amount of between 1% and 10% the final weight of the product, preferably in an amount between 4% and 8% of the final weight of the product, preferably in an amount equivalent to about 5% of the final weight of the product.
• a solution of N-Cocoyl Alaninate is prepared in a volume of water representing 90% of the total amount of water until complete solubilization. The pH of this solution is then adjusted to a pH of about 7.8 while the heating is stopped. Once the solution is clear, ciclosporin A is added and the final volume adjustment is done with water. A clear and colorless final solution is thus obtained with a pH in the region of 7.8.
• Example 2 stability of the composition 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.
• Example No. 1 The protocol used was to place the samples obtained in Example No. 1 under the conditions of temperature and residual humidity recommended by the European Pharmacopoeia (25 ° C / 60% Residual Moisture) for a period of 12 months.
• the results presented above show that no change in the appearance of the product and no appearance of precipitate occurs during a period of 12 months following the manufacture of the product on samples placed under the conditions indicated above.
• the product can therefore be used as a medicine and distributed in a suitable packaging such as a bottle provided with a dosing pump to ensure reproducible delivery of the dose to be administered.
• the final pH of the composition defined above is close to 7.
• the formed composition is translucent immediately after manufacture but is not stable over time.
• 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 veterinary medicinal product.
• Example 4 efficacy study in dogs with atopic dermatitis
• the present invention has been used in the context of a treatment trial for atopic dermatitis in dogs.
• the product 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.
• 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.
• 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 prolonged contact with the skin, pH-stabilizing agents such as inorganic or organic acid salts and their conjugate bases, agents
• compositions 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.
• 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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• Proteomics, Peptides & Aminoacids (AREA)
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• 2011
  • 2011-02-24 FR FR1100579A patent/FR2971941B1/fr not_active Expired - Fee Related
• 2012
  • 2012-02-24 EP EP12711937.8A patent/EP2678024A1/de not_active Withdrawn
  • 2012-02-24 WO PCT/FR2012/050392 patent/WO2012114051A1/fr not_active Ceased

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