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WO2019002362A1 - Compositions topiques de cyclosporine a - Google Patents

Compositions topiques de cyclosporine a Download PDF

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Publication number
WO2019002362A1
WO2019002362A1 PCT/EP2018/067237 EP2018067237W WO2019002362A1 WO 2019002362 A1 WO2019002362 A1 WO 2019002362A1 EP 2018067237 W EP2018067237 W EP 2018067237W WO 2019002362 A1 WO2019002362 A1 WO 2019002362A1
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WIPO (PCT)
Prior art keywords
ethanol
triacetin
ethoxyethoxy
pvm
copolymer
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PCT/EP2018/067237
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English (en)
Inventor
Maria Isabel BERGES FRAILE
Nuria LLUCH LAFUENTE
Benjamín SANTOS LOBO
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Spherium Biomed, S.L.
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Publication of WO2019002362A1 publication Critical patent/WO2019002362A1/fr

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    • 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
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61P17/06—Antipsoriatics

Definitions

  • the invention relates to pharmaceutical compositions of cyclosporine A for topical application, to a process for the production of said compositions and to their use in medicine, particularly in the prevention and/or treatment of psoriasis or atopic dermatitis.
  • Cyclosporine A was discovered in 1972 while searching for novel antifungal agents. It is a cyclic polypeptide consisting of 11 amino acids and is produced as a metabolite by the fungus species Beauveria nivea. Although cyclosporine A was initially noted to have only a narrow antifungal spectrum, it was subsequently found to be a potent immunosuppressive drug in 1976.
  • Cyclosporine A was the first immunosuppressive drug found to act selectively on T cells.
  • the helper T cell is the main target, but the T suppressor cell may also be affected.
  • Cyclosporine A forms a complex with cyclophilin, an intracellular immunophilin, and inhibits the activity of calcineurin phosphatase, a calcium/calmodulin-dependent serine-threonine phosphatase. As a result, calcineurin phosphatase is unable to phosphorylate nuclear factor of activated T cells (NFAT), a transcription factor.
  • NFAT nuclear factor of activated T cells
  • NFAT requires phosphorylation before transportation to the nucleus for transcription of genes encoding interleukin-2 (IL-2), a cytokine that is necessary for full activation of the T-cell pathway, interferon-gamma, and granulocyte-macrophage colony-stimulating factor (GM-CSF).
  • IL-2 interleukin-2
  • GM-CSF granulocyte-macrophage colony-stimulating factor
  • Cyclosporine A also inhibits keratinocyte hyperproliferation, inhibits the release of histamine from mast cells, and downregulates the expression of cellular adhesion molecules on dermal capillary endothelium [Amor et al, J. Am. Acad. Dermatol, 2010, 63, 925-946].
  • cyclosporine A was found to be successful in preventing rejection in renal transplant patients who received mismatched cadaver kidneys.
  • cyclosporine A improved psoriasis.
  • cyclosporine A was approved by the FDA for the treatment of this disease in 1997. More recent reports, have disclosed that cyclosporine A is useful for the treatment of a variety of dermato logical diseases.
  • Cyclosporine A has also been used in veterinary dermatology; in particular, it has been reported [Kovalik et al, The Veterinary Journal, 2012, 193, 317- 325] to be useful for the treatment of atopic dermatitis, sebaceous adenitis, pemphigus foliaceus and erythematosus, vesicular cutaneous lupus erythematosus, and cutaneous reactive histiocytosis, in cats and dogs. Further dermatologic indications of cyclosporine A in veterinary have been reported by Palmeiro [Vet. Clin.
  • Cyclosporine A can also be used for the treatment of vitiligo due to its immunosuppressant activity, in particular due to its activity as calcineurin inhibitor, a class of drugs which have shown promising results in repigmentation of affected areas in patients with vitiligo [Caridi et al, Topical Calcineurin Inhibitors in the Treatment of Vitiligo in Bitiligo - Management and Therapy, Dr. Kelly KyunHwa Park Ed., 2001]. Cyclosporine A exhibits very poor solubility in water, and, as a consequence, suspension and emulsion forms were been developed for oral administration and for injection, such as Sandimmune ® and Neoral ® (Novartis Pharmaceuticals). However, systemic therapies, such as oral and intravenous administrations, have the drawback of producing significant side effects.
  • topical cyclosporine A formulations suitable for topical administration of cyclosporine A in particular to permit site specific delivery to the skin.
  • the key challenges for topical delivery of this drug are its poor water solubility, high molecular weight and limited cutaneous permeation.
  • Ophthalmic emulsions containing cyclosporine A, glycerin, castor oil, polysorbate 80, carbomer copolymer A, and water have been disclosed [US 8,642,556 B2; US 8,629,111 B2; US 8,618,064 B2; US 8,633,162 B2; US 8,648,048 B2; and US 8,685,930 B2], one of them being marketed under the trademark Restasis ® .
  • the concentration of cyclosporine A in these emulsions is not greater than 0.1% by weight.
  • Topical compositions comprising higher concentrations of cyclosporine A, from 0.1 to 10%) by weight, can be formulated by using a polyalkyl ester of polycarboxylic acid, such as adipic, pimelic, azelaic, sebacic and phthalic dialkyl esters, as disclosed in US 5,891,846.
  • a polyalkyl ester of polycarboxylic acid such as adipic, pimelic, azelaic, sebacic and phthalic dialkyl esters
  • compositions comprising cyclosporine A, in particular that allow the local delivery of cyclosporine A to skin compartment, capable of containing high concentrations of cyclosporine A, having high stability. It is also desirable that the preparation of these compositions avoid the use of toxic organic solvents or complex techniques.
  • compositions comprising a volatile alcohol, 2-(2-ethoxyethoxy)ethanol, a non- volatile organic solvent and a surfactant or mixture of surfactants having an HLB value from 10 to 18 and optionally a half C 1-4 - alkylester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, triacetin, water and/or a medium chain triglyceride, are capable of containing high concentrations of cyclosporine A. These compositions are stable and suitable for topical application.
  • compositions of the invention have one or several advantages over other formulations of the prior art such as improved drug solubilization, skin bioadhesive properties, physical and chemical stability, percutaneous absorption, spontaneous formation, ease of manufacturing and scale-up and/or suitability for preparing formulations suitable for spraying.
  • Said compositions are capable of solving all or some of the drawbacks related to other compositions of cyclosporine A, for example, low long-term stability, low encapsulation efficacy, poor drug solubilization, low percutaneous absorption, systemic absorption, high cost and complex production process which requires the use of toxic organic solvents or complex techniques.
  • compositions of the invention have high stability under accelerated storage conditions both in terms of physical stability of the composition and chemical stability (in particular avoiding degradation of cyclosporine A) and are effective in the treatment of dermatological conditions.
  • compositions comprising:
  • composition comprises the half Ci-4-alkylester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, it does not comprise an oil selected from the group consisting of oleic acid, ethyl oleate, medium chain triglyceride and isopropyl myristate.
  • PVM/MA poly(methyl vinyl ether-co-maleic anhydride)
  • the invention relates to a process for producing a topical pharmaceutical composition as defined in the first aspect comprising the half Ci-4-alkyl ester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, the process comprising:
  • step (iii) adding the solution obtained in step (ii) to the product of step (i) under stirring,
  • step (iv) adding 2-(2-ethoxyethoxy)ethanol and the surfactant or surfactant mixture having an HLB value from 10 to 18to the mixture obtained in step (iii) and stirring until a homogeneous solution is obtained, and
  • step (v) optionally adding water to the mixture obtained in step (iv) and stirring until a homogeneous solution is obtained.
  • the invention relates to a process for producing a topical pharmaceutical composition as defined in the first aspect which does not comprise the half Ci-4-alkyl ester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, the process comprising:
  • step (ii) adding the volatile alcohol and the non- volatile organic solvent other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin, 2-(2-ethoxyethoxy)ethanol, the surfactant or surfactant mixture having an HLB value from 10 to 18 and optionally triacetin to the product obtained in step (i) and stirring until a homogeneous solution is obtained, and
  • the invention relates to a topical pharmaceutical composition as defined in the first aspect for use as a medicament, in particular a medicament for human or veterinary use.
  • the invention relates to a topical pharmaceutical composition as defined in the first aspect for use in the prevention and/or treatment of a disease selected from the group consisting of psoriasis, atopic dermatitis, allergic dermatitis, pyoderma gangrenosum, refractory chronic idiopathic urticaria, dyshidrotic eczema, Behcet disease, pityriasis rubra pilaris, dermatomyositis, pemphigus vulgaris, benign familiar pemphigus, pemphigus foliaceus and erythematosus, epidermolysis bullosa acquisita, photodermatoses, lichen planus, prurigonodularis, alopecia areata, eosinophilic pustular folliculitis, granulomatous folliculitis and furunculosis, mular folliculitis, hidradenitis s
  • a disease
  • the invention relates to the use of a topical pharmaceutical composition as defined in the first aspect for the manufacture of a medicament for the prevention and/or treatment of a disease selected from the group consisting of psoriasis, atopic dermatitis, allergic dermatitis, pyoderma gangrenosum, refractory chronic idiopathic urticaria, dyshidrotic eczema, Behcet disease, pityriasis rubra pilaris, dermatomyositis, pemphigus vulgaris, benign familiar pemphigus, pemphigus foliaceus and erythematosus, epidermolysis bullosa acquisita, photodermatoses, lichen planus, prurigo nodularis, alopecia areata, eosinophilic pustular folliculitis, granulomatous folliculitis and furunculosis, mular folliculitis,
  • the invention relates to a method of prevention and/or treatment of a subject suffering from a disease selected from the group consisting of psoriasis, atopic dermatitis, allergic dermatitis, pyoderma gangrenosum, refractory chronic idiopathic urticaria, dyshidrotic eczema, Behcet disease, pityriasis rubra pilaris, dermatomyositis, pemphigus vulgaris, benign familiar pemphigus, pemphigus foliaceus and erythematosus, epidermolysis bullosa acquisita, photodermatoses, lichen planus, prurigo nodularis, alopecia areata, eosinophilic pustular folliculitis, granulomatous folliculitis and furunculosis, mular folliculitis, hidradenitis suppurativa, s
  • a disease
  • the invention relates to a topical pharmaceutical composition
  • a topical pharmaceutical composition comprising:
  • composition comprises the half Ci-4-alkylester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, it does not comprise an oil selected from the group consisting of oleic acid, ethyl oleate, medium chain triglyceride and isopropyl myristate.
  • PVM/MA poly(methyl vinyl ether-co-maleic anhydride)
  • compositions of the invention are suitable for topical application.
  • “topical” is used herein to designate application in the exterior of the body such as, without limitation, the skin, scalp and nails; and also the application to mucosae such as, without limitation, buccal, nasal or rectal mucosae.
  • compositions of the invention are pharmaceutically acceptable to the patient (such as a mammal) from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view, due to the identity of the components forming the composition.
  • w/w in the context of the present invention, relates to the weight of each component relative to the total weight of the composition, unless otherwise stated.
  • Component (a) in the pharmaceutical compositions of the present invention is cyclosporine A.
  • cyclosporine A refers to a cyclic undecapeptide compound with chemical name (3S,6S,9S, 12iU5S, 18S,21S,24S,30S,33S)-30-ethyl-33- [( 1R,2R,4E)- 1 -hydroxy-2-methyl-4-hexen- 1 -yl]-6,9, 18,24-tetraisobutyl-3 ,21 - diisopropyl-1 ,4,7, 10, 12, 15, 19,25, 28-nonamethyl- 1 ,4,7, 10, 13, 16, 19,22,25,28,31- undecaazacyclotritriacontane-2, 5, 8, 1 1 ,14, 17,20,23,26,29, 32-undecone or cyclo[[(E)- (25',3i?,4i?)-3-hydroxy-4-methyl-2-(methylamino)-6-octenoyl]-L-2-aminobutyryl
  • Cyclosporine A is a calcineurin phosphatase inhibitor, having potent immunosuppressive activity.
  • compositions of the invention comprise from 0.1% w/w to 10% w/w by weight of cyclosporine A relative to the total weight of the composition, preferably from 0.1%) w/w to 7% w/w, more preferably from 0.1 % w/w to 5% w/w, still more preferably from 1% w/w to 7% w/w, still more preferably from 1% w/w to 5% w/w, even more preferably from 3% w/w to 5% w/w, even more preferably about 5% w/w.
  • the term "about” refers to the indicated value ⁇ 5% of said value, preferably to the indicated value ⁇ 1% of said value.
  • Component (f) in the pharmaceutical composition of the present invention is a half Ci-4-alkyl ester of a poly (methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer.
  • This component may be present or absent. When present, it provides adhesive properties to the product, therefore enhancing its adhesion to the skin.
  • the composition of the invention does not comprise an oil selected from the group consisting of oleic acid, ethyl oleate, medium chain triglyceride and isopropyl myristate.
  • Ci-4-alkyl refers to a linear or branched saturated monovalent hydrocarbon chain containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.
  • half C 1 - 4 -alkyl ester of a poly (methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer” or “half C 1 - 4 -alkyl ester of a PVM/MA copolymer” are used interchangeably here and refer to water-insoluble copolymers that are water- soluble when neutralized by bases in aqueous solution and having a structure of formula
  • R is a Ci-4-alkyl, i.e. PVM/MA copolymer ester in which only one of the two carboxyl groups is esterified.
  • PVM/MA copolymer ester in which only one of the two carboxyl groups is esterified.
  • These half esters include the half ester form of PVM/MA with different alkyl chain lengths (such as monoethyl ester, wherein R is ethyl; monobutyl ester, wherein R is butyl; and isopropyl ester, wherein R is isopropyl).
  • Said copolymers are commercialized by International Specialty Products (ISP) under trademark Gantrez® ES and include Gantrez® ES 225 (monoethyl ester), Gantrez® ES 425 (monobutyl ester) and Gantrez® ES335I (isopropyl ester) and are supplied as alcoholic solutions, for example, in ethanolic solutions [50% (w/v)].
  • ISP International Specialty Products
  • the half Ci-4-alkylalkyl ester of a PVM/MA copolymer is selected from the group consisting of ethyl ester of a PVM/MA copolymer, isopropyl ester of a PVM/MA copolymer and n-butyl ester of a PVM/MA copolymer; more preferably n-butyl ester of a PVM/MA copolymer.
  • composition of the invention comprises from
  • a half Ci-4-alkyl alkyl ester of a PVM/MA copolymer preferably from 0.01 to 1% w/w, more preferably from 0.05 to 0.2% w/w.
  • the half Ci-4-alkylalkyl ester of a PVM/MA copolymer is present in the compositions of the invention, it is dissolved in a volatile alcohol, in a non-volatile organic solvent other than 2-(2-ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin, or in a mixture of one or several volatile alcohol and one or several non- volatile organic solvent other than 2-(2-ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin, i.e. in components (b) and (c) of the composition of the invention.
  • non-volatile organic solvent refers to an organic liquid that does not evaporate easily or evaporates very slowly at room temperature, i.e. that has vapor pressure lower than 1 kPa at 25 °C and boiling point higher than 1 10 °C at standard atmospheric pressure (101.325 kPa), but which does not include 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin.
  • 2-(2-ethoxyethoxy)ethanol, some surfactants having an HLB value from 10 to 18 and triacetin are not considered within the scope of non-volatile organic solvent in the compositions of the present invention and, therefore, they are explicitly excluded from this category (component (b)).
  • non- volatile organic solvents other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin that can be used in the present invention include, without limitation, propylene glycol and polyethylene glycol.
  • the non- volatile organic solvent other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin, i.e. component (b), is propylene glycol.
  • non-volatile organic solvent other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin also encompasses a mixture of one or more non-volatile organic solvents as herein defined, such as a mixture of one, two or three non-volatile organic solvents as herein defined, preferably only one non- volatile organic solvent other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin.
  • the composition of the invention comprises from 5% w/w to 20% w/w of a non-volatile organic solvent other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin; preferably from 7% w/w to 17% w/w when the composition does not comprise the half Ci-4-alkylalkyl ester of a PVM/MA copolymer, or alternatively from 10% w/w to 20% w/w when the composition contains the half Ci-4-alkylalkyl ester of a PVM/MA copolymer; more preferably from 10%> w/w to 15%> w/w when the composition does not comprise the half Ci-4-alkylalkyl ester of a PVM/MA copolymer or alternatively from 13% w/w to 18% w/w when the composition contains the half Ci-4-alkylalkyl ester of a PVM/MA copolymer.
  • non- volatile organic solvent other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin is propylene glycol.
  • propylene glycol refers to propane- 1 ,2-diol.
  • the composition of the invention comprises from 5% w/w to 20%) w/w of is propylene glycol; preferably from 7%> w/w to 17%> w/w of propylene glycol when the composition does not comprise the half Ci-4-alkylalkyl ester of a PVM/MA copolymer, or alternatively from 10% w/w to 20% w/w of propylene glycol when the composition contains the half Ci-4-alkylalkyl ester of a PVM/MA copolymer; more preferably from 10% w/w to 15% w/w of propylene glycol when the composition does not comprise the half Ci-4-alkylalkyl ester of a PVM/MA copolymer or alternatively from 13% w/w to 18% w/w of propylene glycol when the composition contains the half Ci-4-alkylalkyl ester of a PVM/MA copolymer.
  • Component (c) in the pharmaceutical compositions of the present invention is a volatile alcohol.
  • the term “alcohol” refers to a linear or branched saturated monovalent hydrocarbon chain containing the indicated number of carbon atoms, typically from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms, said hydrocarbon chain being linked to an OH group. Examples of volatile alcohols are methanol, ethanol, isopropanol, isobutanol, etc.
  • the composition of the invention comprises from 5% w/w to 20%) w/w of a volatile alcohol; preferably from 5% w/w to 15% w/w of a volatile alcohol when the composition does not comprise the half C 1 - 4 -alkylalkyl ester of a PVM/MA copolymer or alternatively from 7% w/w to 17% w/w of a volatile alcohol when the composition contains the half C 1 - 4 -alkylalkyl ester of a PVM/MA copolymer; more preferably from 7% w/w to 1 1% w/w of a volatile alcohol when the composition does not comprise the half C 1 - 4 -alkylalkyl ester of a PVM/MA copolymer or alternatively from 10% w/w to 14% w/w of a volatile alcohol when the composition contains the half C 1 - 4 -alkylalkyl ester of a PVM/MA copolymer.
  • the volatile alcohol is ethanol.
  • the composition of the invention comprises from 5% w/w to 20%) w/w of ethanol; preferably from 5% w/w to 15% w/w of ethanol when the composition does not comprise the half C 1 - 4 -alkylalkyl ester of a PVM/MA copolymer or alternatively from 7% w/w to 17% w/w of ethanol when the composition contains the half Ci-4-alkylalkyl ester of a PVM/MA copolymer; more preferably from 7% w/w to 1 1% w/w of ethanol when the composition does not comprise the half C 1 - 4 -alkylalkyl ester of a PVM/MA copolymer or alternatively from 10% w/w to 14% w/w of ethanol when the composition contains the half C 1 - 4 -alkylalkyl ester of a PVM/MA copolymer
  • Component (d) in the pharmaceutical compositions of the present invention is 2- (2-e
  • 2-(2-Ethoxyethoxy)ethanol is commercialized under the name transcutol.
  • the composition of the invention comprises from 15% w/w to 35% w/w of 2-(2-ethoxyethoxy)ethanol; preferably from 18% w/w to 28% w/w of 2-(2-ethoxyethoxy)ethanol when the composition does not comprise the half Ci- 4-alkylalkyl ester of a PVM/MA copolymer or alternatively from 25% w/w to 35% w/w of 2-(2-ethoxyethoxy)ethanol when the composition contains the half Ci-4-alkylalkyl ester of a PVM/MA copolymer; more preferably from 20% w/w to 25% w/w of 2-(2- ethoxyethoxy)ethanol when the composition does not comprise the half Ci-4-alkylalkyl ester of a PVM/MA copolymer or alternatively from 25% w/w to 32% w/w of 2-(2- ethoxyethoxy)ethanol when the composition contains the half Ci-4-alkylalkyl este
  • Component (g) in the pharmaceutical compositions of the present invention is a medium chain triglyceride. This component may be present or absent. When present, the composition of the invention does not comprise a half Ci-4-alkylalkyl ester of a PVM/MA copolymer.
  • medium-chain triglyceride refers to triglycerides triesters of glycerol and 6-12 carbon fatty acid.
  • the fatty acids found in medium-chain triglycerides are called medium-chain fatty acids.
  • medium-chain triglycerides are composed of a glycerol backbone and three fatty acids. In the case of medium-chain triglycerides, 2 or 3 of the fatty acid chains attached to glycerol are medium-chain in length.
  • the three fatty acids of the MCT can be the same or different, preferably there are two different fatty acids.
  • medium fatty acids examples include caproic or hexanoic acid (C6:0), caprylic or octanoic acid (C8:0), capric or decanoic acid (C10:0) and lauric or dodecanoic acid (C12:0).
  • composition of the invention comprises from 15% w/w to 25% w/w of a MCT, preferably from 19% w/w to 23% w/w of a MCT.
  • the medium chain triglyceride is caprylic/capric acid triglyceride.
  • the composition of the invention comprises from 15% w/w to 25% w/w of caprylic/capric acid triglyceride, preferably from 19%> w/w to 23%o w/w of caprylic/capric acid triglyceride.
  • Component (e) in the pharmaceutical compositions of the present invention is a surfactant or surfactant mixture having an HLB value from 10 to 18.
  • surfactant refers to a compound that lowers the surface tension or interfacial tension between two liquids or between a liquid and a solid. Surfactants may act as detergents, wetting agents, emulsifiers, foaming agents and dispersants.
  • HLB refers to the hydrophilic- lipophilic balance and is a measure of the degree to which a surfactant is hydrophilic or lipophilic.
  • the HLB values of surfactants are widely reported in the literature [see for example Griffin, Journal of the Society of Cosmetic Chemists, 1949, 1, 31 1-326; Raymond C Rowe, Poul, J. Sheskey, Marian E Quinn (Eds). Handbook of pharmaceutical excipients. Published by the Pharmaceutical Press and the American Pharmacists Association. Sixth edition, 2009].
  • the total HLB t value of the mixture of said two or more nonionic surfactants is calculated as the weight average of the HLB values of the two or more nonionic surfactants (see following equation (1)).
  • HLB t ( ⁇ Wi -HLB t ) / ( ⁇ Wi) Equation (1)
  • Wi and HLBi indicate the weight and the HLB value of the i-th nonionic surfactant, respectively
  • Surfactants having an HLB value from 10 to 18 that can be used in the present invention are, among others, polysorbates and poloxamers.
  • Polysorbates refer to esters of sorbitan with fatty acids such as lauric acid, palmitic acid, stearic acid and oleic acid. The number following the polysorbate part is related to the type of fatty acid associated with the polyoxyethylene sorbitan part of the molecule. Monolaurate is indicated by 20, monopalmitate is indicated by 40, monostearate by 60 and monooleate by 80.
  • Non-limiting examples of polysorbates having an HLB value from 10 to 18 that can be used in the present invention arepolysorbate-20, polysorbate-21 , polysorbate-40, polysorbate-60, polysorbate-65, polysorbate-80 and polysorbate-81. Poloxamers refer to polyoxyethylene-polyoxypropylene copolymers.
  • Non- limiting examples of poloxamers having an HLB value from 10 to 18 that can be used in the present invention are poloxamer 184 and poloxamer 185.
  • the particular poloxamers are followed by a number, the first two digits of which, when multiplied by 100, correspond to the approximate average molecular weight of the polyoxypropylene portion of the copolymer, and the third digit, when multiplied by 10, corresponds to the percentage by weight of the polyoxyethylene portion.
  • the composition of the invention comprises from 8% w/w to 20% w/w of a surfactant or surfactant mixture having an HLB value from 10 to 18; preferably from 8% w/w to 18% w/w of a surfactant or surfactant mixture having an HLB value from 10 to 18 when the composition does not comprise the half Ci- 4 - alkylalkyl ester of a PVM/MA copolymer or alternatively from 10% w/w to 20% w/w of a surfactant or surfactant mixture having an HLB value from 10 to 18 when the composition contains the half Ci- 4 -alkylalkyl ester of a PVM/MA copolymer; more preferably from 10% w/w to 15% w/w of a surfactant or surfactant mixture having an HLB value from 10 to 18 when the composition does not comprise the half Ci- 4 - alkylalkyl ester of a PVM/MA copolymer or alternatively from 15% w/w
  • the surfactant is polysorbate 80.
  • polysorbate 80 also known as Tween 80, refers to a nonionic surfactant and emulsifier often used in foods and cosmetics.
  • the synthetic compound is a viscous, water-soluble yellow liquid derived from polyethoxylated sorbitan and oleic acid. Its full chemical name is polyoxyethylene (20) sorbitan monooleate or (x)-sorbitan mono- 9-octadecenoate poly(oxy-l ,2-ethanediyl). Its chemical formula is:
  • the composition of the invention comprises from 8% w/w to 20% w/w of polysorbate 80; preferably from 8% w/w to 18% w/w of polysorbate 80 when the composition does not comprise the half Ci-4-alkylalkyl ester of a PVM/MA copolymer or alternatively from 10% w/w to 20% w/w of polysorbate 80 when the composition contains the half Ci-4-alkylalkyl ester of a PVM/MA copolymer; more preferably from 10% w/w to 15% w/w of polysorbate 80 when the composition does not comprise the half Ci-4-alkylalkyl ester of a PVM/MA copolymer or alternatively from 15% w/w to 20% w/w of polysorbate 80 when the composition contains the half Ci-4-alkylalkyl ester of a PVM/MA copolymer.
  • Component (h) i.e. water, is optionally present in the pharmaceutical compositions of the present invention.
  • water is present in the compositions of the invention.
  • the composition of the invention is water-free.
  • water-free when characterizing the composition of the invention refers compositions substantially free from water.
  • the water-free composition of the invention may contain non-significant quantities of water coming from the rest of the components of the formulation.
  • the water-free composition of the invention does not comprise more than 2% w/w of water.
  • the water-free composition of the invention may comprise between 0% w/w and 2% w/w of water.
  • the compositions of the invention are substantially free from water, i.e. do not comprise more than 2% w/w of water.
  • the water-free compositions of the invention have particularly advantageous organoleptic properties and extensibility on the skin.
  • the compositions of the invention are water-free.
  • Component (i) is optionally present in the pharmaceutical compositions of the present invention and is triacetin.
  • the compositions of the invention comprise triacetin.
  • triacetin is the triglyceride 1 ,2,3-triacetoxypropane and is also known as glycerin triacetate or l ,3-diacetyloxypropan-2-yl-acetate and its chemical formula is the following:
  • triacetin is present in the composition of the invention.
  • the composition of the invention comprises from 10% w/w to 25% w/w of triacetin; preferably from 10% w/w to 20% w/w of triacetin when the composition does not comprise the half Ci-4-alkylalkyl ester of a PVM/MA copolymer or alternatively from 15% w/w to 25% w/w of triacetin when the composition contains the half Ci-4-alkylalkyl ester of a PVM/MA copolymer; more preferably from 15% w/w to 19% w/w of triacetin when the composition does not comprise the half C 1 -4- alkylalkyl ester of a PVM/MA copolymer or alternatively from 20% w/w to 23% w/w of triacetin when the composition contains the half Ci-4-alkylalkyl ester of a PVM/MA copolymer.
  • compositions of the invention comprise either component (f) (i.e. the half Ci-4-alkyl ester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer) or component (g) (i.e. the medium chain triglyceride).
  • component (f) i.e. the half Ci-4-alkyl ester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer
  • component (g) i.e. the medium chain triglyceride
  • composition of the present invention comprises:
  • composition optionally from 10%> w/w to 25% w/w of triacetin, wherein w/w is the weight of each component relative to the total weight of the composition, and with the proviso that, when the composition comprises the half C1-4- alkylester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, it does not comprise an oil selected from the group consisting of oleic acid, ethyl oleate, medicum chain triglyceride and isopropyl myristate.
  • PVM/MA poly(methyl vinyl ether-co-maleic anhydride)
  • composition of the invention is as described in the paragraph above but being water- free and comprising triacetin.
  • composition of the present invention comprises:
  • w/w is the weight of each component relative to the total weight of the composition, and with the proviso that, when the composition comprises the half C1-4- alkylester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, it does not comprise an oil selected from the group consisting of oleic acid, ethyl oleate, medicum chain triglyceride and isopropyl myristate.
  • PVM/MA poly(methyl vinyl ether-co-maleic anhydride)
  • composition of the invention is as described in the paragraph above but being water- free and comprising triacetin.
  • composition of the present invention comprises:
  • w/w is the weight of each component relative to the total weight of the composition, and with the proviso that, when the composition comprises the half C1-4- alkylester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, it does not comprise an oil selected from the group consisting of oleic acid, ethyl oleate, medicum chain triglyceride and isopropyl myristate.
  • PVM/MA poly(methyl vinyl ether-co-maleic anhydride)
  • composition of the invention is as described in the paragraph above but being water- free and comprising triacetin.
  • the composition of the present invention comprises: (a) from 1% w/w to 7% w/w of cyclosporine A,
  • composition of the invention is water-free.
  • composition of the present invention comprises: (a) from 1% w/w to 5% w/w of cyclosporine A,
  • w/w is the weight of each component relative to the total weight of the composition, and wherein the composition does not comprise a half Ci-4-alkylester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer.
  • PVM/MA poly(methyl vinyl ether-co-maleic anhydride)
  • composition of the invention described in the paragraph above is water-free.
  • composition of the present invention comprises: (a) from 1% w/w to 7% w/w of cyclosporine A,
  • w/w is the weight of each component relative to the total weight of the composition, and wherein the composition does not comprise a half Ci-4-alkylester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer.
  • PVM/MA poly(methyl vinyl ether-co-maleic anhydride)
  • composition of the invention described in the paragraph above is water-free.
  • composition of the present invention comprises:
  • w/w is the weight of each component relative to the total weight of the composition, and wherein the composition does not comprise a half Ci-4-alkylester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer.
  • PVM/MA poly(methyl vinyl ether-co-maleic anhydride)
  • composition of the invention described in the paragraph above is water-free.
  • composition of the present invention comprises:
  • w/w is the weight of each component relative to the total weight of the composition, and wherein the composition does not comprise an oil selected from the group consisting of oleic acid, ethyl oleate, medium chain triglyceride and isopropyl myristate.
  • composition of the invention described in the paragraph above is water-free.
  • composition of the present invention comprises:
  • w/w is the weight of each component relative to the total weight of the composition, and wherein the composition does not comprise an oil selected from the group consisting of oleic acid, ethyl oleate, medium chain triglyceride and isopropyl myristate.
  • composition of the invention described in the paragraph above is water-free.
  • composition of the present invention comprises: (a) from 1% w/w to 7% w/w of cyclosporine A,
  • composition of the invention is water-free.
  • composition of the present invention comprises: (a) from 1% w/w to 5% w/w of cyclosporine A,
  • w/w is the weight of each component relative to the total weight of the composition, and wherein the composition does not comprise an oil selected from the group consisting of oleic acid, ethyl oleate, medium chain triglyceride and isopropyl myristate.
  • composition of the invention described in the paragraph above is water-free.
  • PVM/MA poly(methyl vinyl ether-co-maleic anhydride) copolymer
  • component (f) when present in the composition, is the half n-butyl ester of a P
  • compositions described above may also comprise other amounts of cyclosporine A, such as from 0.1 % w/w to 7% w/w by weight of cyclosporine A relative to the total weight of the composition, from 0.1% w/w to 5% w/w, from 3%) w/w to 5% w/w, or about 5% w/w, in particular when the half C 1 - 4 -alkyl ester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer (component (f)), when present in the composition, is the half n-butyl ester of a PVM/MA copolymer, the non- volatile organic solvent capable other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin (component (b)) is propylene glycol, the volatile alcohol (component (c)) is ethanol, the medium chain triglyceride (com
  • the composition of the invention does not comprise neither component (f) (i.e. the half Ci-4-alkylester of a poly(methyl vinyl ether-co- maleic anhydride) (PVM/MA) copolymer) nor component (g) (i.e. the medium chain triglyceride).
  • component (f) i.e. the half Ci-4-alkylester of a poly(methyl vinyl ether-co- maleic anhydride) (PVM/MA) copolymer
  • component (g) i.e. the medium chain triglyceride
  • the composition consists of the ingredients explicitly mentioned with respect to any of the embodiments described herein, i.e. they do not comprise ingredients other than those explicitly mentioned.
  • compositions of the invention do not require the use of preservatives. Therefore, in another embodiment, the composition does not contain additional preservatives.
  • additional preservatives is understood as substances added to pharmaceutical products to prevent decomposition by microbial growth or by undesirable chemical changes. Additional preservatives include antimicrobial additives and antioxidants.
  • compositions of the invention may contain preservatives.
  • exemplary preservatives that can be used in the compositions of the invention include, without limitation, potassium sorbate, sodium benzoate, phenoxy ethanol, sorbic acid, thimerosal, benzalkonium chloride, parabens, etc.
  • the composition does not contain oleic acid.
  • the composition does not contain additional preservatives and oleic acid.
  • compositions of the present invention are stable and allow formulating high concentrations of cyclosporine A, without the use of a polyalkyl ester of polycarboxylic acid, such as adipic, pimelic, azelaic, sebacic and phthalic dialkyl esters.
  • polyalkyl ester of polycarboxylic acid refers to the polyalkyl ester of polycarboxylic acids disclosed in US 5,891,846 (which is incorporated by reference with respect to their definition), and are defined as those which are liquid at ordinary temperature.
  • esters having a total carbon atom number of 10 to 25 are preferable and the esters having polycarboxylic acids having at least two carboxyl groups and linear or branched alcohols, in which the carboxyl group may be an aliphatic group, aromatic aliphatic group, or aromatic group having the carboxyl groups bonded aliphatically or aromatically are preferable. Partial ester compounds may also be used. These esters may be used alone or in a mixture of two kinds or more.
  • adipic dialkyl esters of a total of 12 to 22 carbon atoms pimelic dialkyl esters having a total of 13 to 23 carbon atoms, sebacic dialkyl esters having a total of 14 to 22 carbon atoms, phthalic dialkyl esters having a total of 14 to 24 carbon atoms (these alkyl groups may be straight or branched and the alkyl portion of the dialkyl may be the same or different).
  • Preferable examples are dibutyl phthalate, diethyl phthalate, diiso butyl phthalate, dibutyl sebacate, diethyl sebacate, diisopropyl azelate, diisopropyl adipate, dibutyl adipate, and diisobutyl adipate.
  • the composition of the present invention does not contain a polyalkyl ester of polycarboxylic acid.
  • the composition does not contain additional preservatives and a polyalkyl ester of polycarboxylic acid.
  • the composition of the invention may contain excipients.
  • excipient refers to an inactive substance that can be liquid, solid or semisolid, used as a medium or carrier for the active ingredients of a composition.
  • excipients are butyl hydroxytoluene (BHT), liquid paraffin or melted lipids such as wax, cotton oil, hydrogenated vegetable oil, canola oil, coconut oil, etc.
  • Thickening agents i.e. substances that increase the viscosity of the compositions, may also be added to the compositions of the invention.
  • compositions of the invention may be administered in the form of pharmaceutical compositions comprising cyclosporine A as a sole active ingredient or in combinations with other active ingredients.
  • compositions of the invention can be administered by different topical routes such as, without limitation, cutaneous, buccal, nasal or rectal route.
  • they are applied on the skin, i.e. cutaneous route, preferably by spraying. More preferably they are applied by massage.
  • the process used for the preparation of the pharmaceutical compositions of the invention depends on the presence of absence of the half Ci-4-alkyl ester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer.
  • PVM/MA poly(methyl vinyl ether-co-maleic anhydride)
  • the invention relates to a process for producing a topical pharmaceutical composition as defined in the first aspect comprising the half Ci-4-alkyl ester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, the process comprising:
  • HLB value from 10 to 18 and triacetin, and the half Ci-4-alkylester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer;
  • step (iv) adding 2-(2-ethoxyethoxy)ethanol and the surfactant or surfactant mixture having an HLB value from 10 to 18 to the mixture obtained in step (iii) and stirring until a homogeneous solution is obtained, and
  • step (v) optionally adding water to the mixture obtained in step (iv) and stirring until a homogeneous solution is obtained.
  • Step (i) comprises providing cyclosporine A, optionally in a mixture with the medium chain triglyceride and/or triacetin.
  • the medium chain triglyceride and/or triacetin is present, the cyclosporine A and medium chain triglyceride and/or triacetin mixture is stirred until complete dissolution of cyclosporine A or until an homogeneous suspension is obtained, preferably at room temperature (20-25°C). In particular the mixing is carried out for at least three hours.
  • Step (ii) comprises mixing the volatile alcohol and the non- volatile organic solvent other than 2-(2-ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin, and the half Ci-4-alkyl ester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, and stirring until the copolymer is completely dissolved, preferably at room temperature (20-25°C). In particular the mixing is carried out for at least one hour.
  • PVM/MA poly(methyl vinyl ether-co-maleic anhydride)
  • Step (iii) comprises adding the solution obtained in step (ii) to the cyclosporine
  • step (i) A product obtained in step (i) under stirring, preferably at room temperature (20-25°C).
  • Step (iv) comprises adding 2-(2-ethoxyethoxy)ethanol and the surfactant or surfactant mixture having an HLB value from 10 to 18 to the mixture obtained in step
  • step (iii) and stirring until a homogeneous solution is obtained, preferably at room temperature (20-25°C). In particular the mixing is carried out for at least five hours. If other excipients are present in the composition of the invention, they are added at this step. At the end of step (iv), a clear solution is obtained.
  • step (v) comprises adding water to the mixture obtained in step (iv) and stirring until a homogeneous solution is obtained, preferably at room temperature (20-
  • the invention relates to a process for producing a topical pharmaceutical composition as defined in the first aspect which does not comprise the half Ci-4-alkyl ester of a poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA) copolymer, the process comprising:
  • step (ii) adding the volatile alcohol and the non- volatile organic solvent other than 2-(2- ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin, 2-(2-ethoxyethoxy)ethanol, the surfactant or surfactant mixture having an HLB value from 10 to 18 and optionally triacetin to the product obtained in step (i) and stirring until a homogeneous solution is obtained, and
  • step (iii) optionally adding water to the mixture obtained in step (ii) and stirring until a homogeneous solution is obtained.
  • Step (i) comprises providing cyclosporine A, optionally in a mixture with the medium chain triglyceride.
  • the medium chain triglyceride is present, the cyclosporine A and medium chain triglyceride mixture is stirred until complete dissolution of cyclosporine A or until an homogeneous suspension is obtained, preferably at room temperature (20-25°C). In particular the mixing is carried out for at least three hours.
  • Step (ii) comprises adding the volatile alcohol and the non- volatile organic solvent other than 2-(2-ethoxyethoxy)ethanol, surfactants having an HLB value from 10 to 18 and triacetin, 2-(2-ethoxyethoxy)ethanol, the surfactant or surfactant mixture having an HLB value from 10 to 18 and optionally triacetin to the product obtained in step (i) and stirring until a homogeneous solution is obtained. In particular the stirring is carried out for at least five hours. If other excipients are present in the composition of the invention, they are added at this step. At the end of step (ii), a clear solution is obtained.
  • step (iii) comprises adding water to the mixture obtained in step (ii) and stirring until a homogeneous solution is obtained, preferably at room temperature (20- 25°C).
  • compositions of the invention can be applied for the treatment of all diseases that can be topically treated with cyclosporine A, said diseases being disclosed in the background section of the present document.
  • the invention relates to a topical pharmaceutical composition of the invention for use as a medicament, in particular a medicament for human or veterinary use.
  • the invention relates to a topical pharmaceutical composition as defined in the first aspect for use in the prevention and/or treatment of a disease selected from the group consisting of psoriasis, atopic dermatitis, allergic dermatitis, pyoderma gangrenosum, refractory chronic idiopathic urticaria, dyshidrotic eczema, Behcet disease, pityriasis rubra pilaris, dermatomyositis, pemphigus vulgaris, benign familiar pemphigus, pemphigus foliaceus and erythematosus, epidermolysis bullosa acquisita, photodermatoses, lichen planus, prurigo nodularis, alopecia areata, eosinophilic pustular folliculitis, granulomatous folliculitis and furunculosis, mular folliculitis, hidradenitis s
  • a disease
  • the invention relates to the use of a topical pharmaceutical composition of the invention for the manufacture of a medicament for the prevention and/or treatment of a disease selected from the group consisting of psoriasis, atopic dermatitis, allergic dermatitis, pyoderma gangrenosum, refractory chronic idiopathic urticaria, dyshidrotic eczema, Behcet disease, pityriasis rubra pilaris, dermatomyositis, pemphigus vulgaris, benign familiar pemphigus, pemphigus foliaceus and erythematosus, epidermolysis bullosa acquisita, photodermatoses, lichen planus, prurigo nodularis, alopecia areata, eosinophilic pustular folliculitis, granulomatous folliculitis and furunculosis, mular folliculitis, hidradenit
  • the invention relates to a method of prevention and/or treatment of a subject suffering from a disease selected from the group consisting of psoriasis, atopic dermatitis, allergic dermatitis, pyoderma gangrenosum, refractory chronic idiopathic urticaria, dyshidrotic eczema, Behcet disease, pityriasis rubra pilaris, dermatomyositis, pemphigus vulgaris, benign familiar pemphigus, pemphigus foliaceus and erythematosus, epidermolysis bullosa acquisita, photodermatoses, lichen planus, prurigo nodularis, alopecia areata, eosinophilic pustular folliculitis, granulomatous folliculitis and furunculosis, mular folliculitis, hidradenitis suppurativa, scler
  • the disease is psoriasis.
  • the disease is atopic dermatitis.
  • the disease is allergic dermatitis.
  • the disease is psoriasis or atopic dermatitis.
  • prevention refers to the administration of the composition of the invention in an initial or early stage of a disease, or to also prevent its onset.
  • treatment is used to designate the administration of the composition of the invention to control disorder progression before or after the clinical signs had appeared.
  • control of the disorder progression it is meant to designate beneficial or desired clinical results including, but not limited to, reduction of symptoms, reduction of the length of the disorder, stabilization pathological state (specifically avoidance of further deterioration), delay in the disorder's progression, improvement of the pathological state and remission (both partial and total).
  • the composition of the invention is used to control the disorder progression once at least one of the disorder's clinical signs has appeared.
  • medicament refers to a pharmaceutical composition of the invention comprising cyclosporine A.
  • the medicament may be administered by any suitable topical route. It is prepared by conventional means with pharmaceutically acceptable excipients. Formulations for application on the skin are preferred.
  • subject refers to any animal or human that is suffering from one of the diseases disclosed above.
  • the subject is a mammal.
  • mammal refers to any mammalian species, including but not being limited to domestic and farm animals (cows, horses, pigs, sheep, goats, dogs, cats or rodents), primates, and humans.
  • the mammal is selected from a human being, a dog, a cat and a horse.
  • the mammal is suffering from a disease selected from the group consisting of psoriasis, atopic dermatitis, allergic dermatitis, pyoderma gangrenosum, refractory chronic idiopathic urticaria, dyshidrotic eczema, Behcet disease, pityriasis rubra pilaris, dermatomyositis, pemphigus vulgaris, benign familiar pemphigus, pemphigus foliaceus and erythematosus, epidermolysis bullosa acquisita, photodermatoses, lichen planus, prurigo nodularis, alopecia areata, eosinophilic pustular folliculitis, granulomatous folliculitis and furunculosis, mular folliculitis, hidradenitis suppurativa, scleroderma, vitiligo,
  • a disease selected from
  • Cyclosporine A was purchased from Concorde Biothech Ltd.
  • Gantrez ® ES poly(methyl vinyl ether-maleic acid monobutyl ester) (GES 425) was purchased from Sigma-Aldrich.
  • 2-(2-ethoxyethoxy)ethanol P ® was purchased from Fagron.
  • Triacetin and ethanol absolute were purchased from Panreac.
  • Acetonitrile HPLC grade was purchased from Merck. 2.
  • compositions were prepared:
  • * GES425 refers to the commercial Gantrez® ES (poly(methyl vinyl ether- maleic acid monobutyl ester) which is a solution of said polymer 50% w/w in ethanol.
  • compositions 1 and 3 were manufactured according to the following process:
  • Cyclosporine A was weighed and MCT was added. This solution was kept under magnetic stirring at room temperature for at least three hours. - To the previously described drug solution, the rest of the components were added in this order: ethanol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, tween 80 and triacetin. The mixture was kept under vigorous magnetic stirring at room temperature for at least five hours until a clear and homogeneous solution was obtained.
  • compositions 2 and 4 were manufactured according to the following process:
  • compositions 1-4 showed appropriate properties to be administered by spraying.
  • the cyclosporine A- loaded topical compositions 1-4 described previously were kept for one week at 40 °C and 75% RH. Then they were subjected to stress conditions, i.e. three freezing cycles of 15 hours at -20 °C followed by 2 h at 80 °C. All the formulations were stable by macroscopical examination (i.e. the formulations remained transparent).
  • compositions 1-4 described previously were kept at 25 °C and 60% RH and at 40 °C and 75% RH.
  • the compositions remained stable after 3 months by macroscopical examination (i.e. the formulations remained transparent).
  • the cyclosporine A- loaded topical compositions 1-4 described previously were kept at 25 °C and 60% RH at 40 °C and 75% RH for three months.
  • the formulations were analyzed by HPLC chromatography before and after the three month storage.
  • cyclosporine A content was measured in triplicate by weighing 100 mg of each formulation into 10 mL volumetric flasks and then filling to the mark with acetonitrile for analysis.
  • cyclosporine A content was measured in triplicate by weighing 200 mg of each formulation into 5 mL volumetric flasks and then filling to the mark with acetonitrile for analysis.
  • the relative error was calculated for each formulation as the concentration of cyclosporine A before storage with respect to the concentration after the period of storage and expressed as %. Formulations having a relative error of less than 5% were considered as chemically stable. Formulations having a relative error of 5% or more were considered as chemically unstable.
  • compositions 1-4 remained stable after 3 months of storage. 5. Biological activity studies
  • compositions 1 and 2 described previously, applied topically, were assessed on the inflammation reaction produced by the induction of an allergic contact dermatitis on farm pigs' skin (a validated model of allergic dermatitis).
  • As reference formulation a 0.1% tacrolimus commercially available formulation (Protopic 0.1%) was used.
  • the treatments were applied topically to circular areas approximately 2 cm in diameter (3.14 cm 2 surface), on the back of the animals.
  • the amount of the test formulation to be applied for each treatment was 30 ⁇ on each application site.
  • the sensitization started on what was considered day 1 of the study by means of topical administration of 100 of 10% difluoronitrobenzene (DNFB, Sigma Aldrich) on the ears (medial aspects) and groins of the animals.
  • DNFB difluoronitrobenzene
  • 100 of DNFB was administered at a concentration of 2% on the ears of each animal, avoiding the application site of day 1.
  • the application of DNFB on days 1 and 4 was performed by spreading the formulation on the cited areas. Four days before the challenge test, the animals were shaved to assure the correct application of the treatments.
  • the challenge was induced by means of the topical application of 20 of 1% DNFB on six application sites (2 cm in diameter) on each side of the back of the animals (12 application sites in total).
  • the application sites were located in a dorsal position, avoiding the flexor area of the neck of the animals.
  • the first application sites, with respect to a craniocaudal position, were reserved for the control (no treatment).
  • the rest of treatments were applied after the control treatment position. Both the reference formulation treatment and the treatments corresponding to the test compositions were applied randomly in the application sites of all the animals.
  • the three animals of the study were treated with the reference formulation and compositions 1 and 2.
  • the assigned treatments were applied on the aforementioned sensitized areas 0.5 and 6 hours after the induction of the challenge. The application were applied and then massaged until they were absorbed. Before the application of the treatments at 6 h, the remainder of the test formulations was removed with gauze moistened with physiological saline. Each treatment was administered on two of the application sites on each animal (one application on each side of the back of the animal). No treatment was applied to the control sites. Twenty- four hours after the induction of the challenge, the remainder of the test formulations was removed with a gauze moistened with physiological saline and approximately four minutes later, the areas of the skin where the treatments were applied were evaluated.
  • the intensity and extension of the erythema and the consistency of the lesions was assessed on a scale of 0-4 according to the following criteria:
  • the means of the scores obtained were calculated for the different parameters to be evaluated, both per animal and per treatment group.
  • the mean, standard error (SE), and the standard error of the mean (SEM) were calculated for each treatment group.
  • the percentage of inhibition for each criteria was calculated for each treatment group using the following formula:
  • compositions 1 and 2 described previously and the reference treatment with Protopic 0.1%) with respect to the control treatment are gathered in the table below:
  • compositions 1 and 2 showed good inhibitory response against the reaction induced by the application of DNFB.

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Abstract

La présente invention concerne des compositions pharmaceutiques topiques de cyclosporine A comprenant au moins un alcool volatil, du 2-(2-éthoxyéthoxy)éthanol, un tensioactif ou un mélange tensioactif ayant une valeur HLB de 10 à 18, et un solvant organique non volatil autre que le 2-(2-éthoxyéthoxy)éthanol, les tensioactifs ayant une valeur HLB de 10 à 18 et de la triacétine. L'invention concerne également un procédé de préparation desdites compositions et leur utilisation dans la prévention et/ou le traitement de plusieurs maladies, en particulier le psoriasis et la dermatite atopique.
PCT/EP2018/067237 2017-06-28 2018-06-27 Compositions topiques de cyclosporine a WO2019002362A1 (fr)

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