Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• • 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
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
• • 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
  • A61K47/30—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
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7015—Drug-containing film-forming compositions, e.g. spray-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
• • 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
• • 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
  • A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
• • 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
  • A61P31/10—Antimycotics

Definitions

• the present invention relates to the treatment of hyperkeratosis of pathological nails.
• Psoriasis is a chronic disease which causes significant suffering and morbidity.
• the nail is affected in 10 to 50% of the cases (Scher, 1985; van Laborde and Scher, 2000), and it is estimated that 80 to 90% of psoriatic patients have nails affected at a moment of their life (De Berker, 2000).
• Ungual psoriasis in the absence of skin disease accounts for 1 to 5% of the patients (van Laborde and Scher, 2000).
• Ungual psoriasis is painful and invalidating. More than 50% of the patients suffer from nail changes due to ungual psoriasis, about 60% estimate that ungual psoriasis limits their daily activities and 93% consider ungual psoriasis as a cosmetic handicap (De Jong et al, 1996).
• Fingernails are more frequently affected than toenails.
• Treatment of ungual psoriasis is focused on improving functional and psychosocial aspects of the disease since no curative treatment exists today. In spite of recent advances in the treatment of skin psoriasis, the treatment options for ungual psoriasis are much more limited. Depending on the disease, a distinction is made between topic, systemic and intralesional injection cortico therapies, or even PUVA therapy. Systemic therapy has the drawbacks of systemic secondary effects and drug interactions (Murdan, 2002). Intralesional injections of corticosteroids, have shown their effectiveness in certain cases of ungual matrix psoriasis but are extremely painful and have local secondary effects. Topical therapy is the primary therapy for skin psoriasis.
• An onychomycosis is defined as a fungic infection of the ungual system, i.e. of the matrix, the bed or the plate of the nail caused by dermatophytes (of the genus Trichophyton, Epidermophyton or Microsporuni), yeasts ⁇ Candida or Malassezia) or fungi (Fusarium). At the fingers, these are most often yeasts (Candida). Onychomycosis is the most frequent of ungual pathologies. It concerns 6 to
• Ungual hyperkeratosis is one of the symptoms of ungual psoriasis and of onychomycoses. This is an excessive proliferation of the bed of the nail which may lead to onycholysis. It results from the deposition of cells under the plate of the nail which have not been eliminated by desquamation. As this is a symptom which only affects the bed of the nail, it may be treated with a topical product such as varnish. Hyperkeratosis may be painful, may reduce the penetration of topical drugs and is not aesthetic. As compared with creams and ointments, curative nail varnishes are relatively new formulations, known as transungual release devices (Murdan, 2002).
• the varnish forms a film which adheres to the plate of the nail and does not flake off during daily activities.
• the film acts as a drug reservoir from where the drug is released, penetrating and acting in the nail during the whole duration of the application. Further, the formation of a film on the plate of the nail reduces the water loss of the surface of the nail, resulting in hyperhydration of the upper layers of the nail, which may also contribute to diffusion of the drug.
• Urea has been used for long time in dermatology for its kerato lytic properties.
• a nail varnish comprising a high proportion of urea intended for treating ungual hyperkeratosis providing the patient with improved comfort by reducing the thickness of the plate of the nail and by improving the aesthetic aspect of the nail as well as better compliance with the treatment, considering its ease of application.
• the inventors have developed a nail varnish, the composition of which provides urea amounts of 15% and transparence in the flask and after application.
• the object of the present invention is thus a film-forming solution comprising:
• the film-forming solution according to the invention comprises 13-17% of urea. More preferably, the film- forming solution according to the invention comprises 17% of urea.
• the film-forming solution according to the invention comprises 8 to 12% of a film-forming polymer. More preferably, the film-forming solution according to the invention comprises 10% of a film- forming polymer. Preferentially, the film-forming solution according to the invention comprises 45 to 50% of a polar solvent. More preferably, the film- forming solution according to the invention comprises 48 to 49% of a polar solvent.
• the film-forming solution according to the invention comprises 1 to 5% of a co-solvent. More preferably, the film- forming solution according to the invention comprises 4 to 5% of a co-solvent.
• the film-forming solution according to the invention comprises 0.5 to 1% of a plasticizer. More preferably, the film- forming solution according to the invention comprises 0.6 to 0.7% of a plasticizer.
• the film- forming polymer of the film- forming solution according to the invention is a Eudragit.
• the film- forming polymer of the film-forming solution according to the invention is a Eudragit E, RL, RS, L or S. More preferably, the film- forming polymer of the film- forming solution according to the invention is Eudragit ElOO, Eudragit RL/RS, Eudragit LlOO, Eudragit SlOO and Eudragit L100-55.
• Eudragit ElOO is a copolymer of methyl methacrylate and of butyl methacrylate.
• Eudragit RL/RS is a copolymer of trimethyl ammonioethyl methacrylate chloride.
• Eudragit L are copolymers of methacrylic acid and of ethyl acrylates.
• Eudragit S are copolymers of methacrylic acid and of methacrylates.
• the polar solvent of the film-forming solution according to the invention is ethyl alcohol, preferably 96% ethyl alcohol.
• the co-solvent of the film-forming solution according to the invention is selected from the list consisting of propylene glycol, glycerin, sorbitol, ethoxyglycol, ethyl acetate, isopropanol, butyl alcohol, and polyethylene glycol 200, for example from the list consisting of propylene glycol, glycerin, sorbitol and polyethylene glycol 200.
• these co-solvents have sufficient volatility in order to achieve rapid drying of the varnish while improving the solubility of the urea in the presence of the film- forming polymer.
• the co-solvent of the film- forming solution according to the invention is propylene glycol which has proved to be the best co-solvent for solubilizing urea in the presence of the film- forming polymer.
• the plasticizer or the second co-solvent of the film-forming solution according to the invention is selected from the list consisting of diethyl phthalate, triethyl citrate, triacetine, dibutyl sebacate, diethyl sebacate, dibutyl phthalate, acetyltriethyl citrate, and polyethylene glycols. Indeed, with these plasticizers and co-solvents it is possible to obtain the sought transparency.
• the plasticizer or the second co-solvent of the film-forming solution according to the invention is selected from the group consisting of diethyl phthalate, triethyl citrate, dibutyl sebacate, diethyl sebacate, dibutyl phthalate, acetyltriethyl citrate, and polyethylene glycols.
• Diethyl phthalate further has an interesting potential as a bitterness agent which may be prove to be useful in a nail varnish for nail-biting patients.
• the mentioned plasticizers are used as an additional co-solvent, for example the solution according to the invention comprises from 0.01 to 5%, for example from 0.01% to 1%, for example from 0.5 to 5%, for example from 0.5 to 1% of said agents in addition to the co-solvents mentioned earlier.
• the film- forming solution comprises 10 to 20% of urea, 45 to 65% of a polar solvent, 5 to 15% of a co-solvent, 5 to 15% of a film- forming agent, 0.5 to 5%, for example 0.5 to 1% of a second so-solvent and water up to 100%.
• the film- forming solution comprises 10 to 20% of urea, 45 to 65% of 96% ethyl alcohol, 5 to 15% of propylene glycol, 5 to 15% of Eudragit ElOO, 0.5 to 5% for example 0.5 to 1% of diethyl phthalate and water up to 100%.
• a preferred film-forming solution of the invention comprises: 15 % of urea, - 48.69 % of 96% ethyl alcohol,
• the film-forming solution according to the invention is used for treating nails having hyperkeratosis.
• This hyperkeratosis may be related to another pathology, for example a hyperkeratosis related to lupus. .
• Another object of the invention is a film-forming solution according to the invention for a use intended to remove abnormal ungual keratinous material, in particular abnormal ungual keratinous material resulting from psoriasis or onychomycosis.
• Another object of the invention is the use of a film- forming solution according to the invention for making a drug intended for removing abnormal ungual keratinous material.
• this abnormal ungual keratinous material results from onychomycosis or psoriasis.
• Example 1 Formulation according to the invention Formula SR2852
• Example 3 Method for preparing a formulation according to the invention
• the operating procedure for making the formula or Example 1 for a batch of 500 g is the following:
• Example 4 Effectiveness and tolerance of the medical device with 15% urea nail varnish in the treatment of hyperkeratosis of psoriatic nails of the hand: an exploratory study.
• the thickness of the treated nail is measured in millimeters with a vernier caliper. At each visit, the measurement is made at the same nail area (defined as the initial condition), where the thickness is the largest at the moment of the inclusion.
• the investigator determines a global dynamic score (dynamic Investigator Physician Global Assessment) which assesses global improvement after 1.5, 3 and 6 months as compared with the initial condition. At each visit, a global clinical assessment is carried out by comparison with photographs taken at the inclusion.
• a global dynamic score dynamic Investigator Physician Global Assessment
• the investigator determines a global statistic score (static Investigator Physician Global Assessment, sIPGA) at each visit (inclusion, after 1.5, 3 and 6 months) without any comparison with the initial condition.
• the severity of psoriasis i.e. the ungual surface having psoriatic lesions, is assessed according to the scale detailed below.
• the affected nails are not assessed separately, but a global score is assigned for the whole of the affected nails.

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• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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• 2008
  • 2008-10-21 FR FR0857146A patent/FR2937250B1/fr active Active
• 2009
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