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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
• • 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
  • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
  • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
• • 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
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
• • 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
  • 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
  • A61K9/08—Solutions
• • 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
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics

Definitions

• This invention relates to new pharmaceutical compositions that are useful in topical application for the treatment of fungal nail infections, in particular onychomycosis.
• Nail fungus is also a very difficult condition to treat. Treatment times are often long; it can take a year or more for an infected nail to come away and a healthy new nail to grow out. Such longevity of treatment is known to cause poor compliance, meaning that the majority of patients are poorly treated or, in essence, untreated.
• Emtrix® or Nalox®. It is indicated primarily in the treatment of nail discoloration and damage caused by fungal nail infection or psoriasis.
• Emtrix ® ingredients are all GRAS (General Regarded as Safe by FDA) listed compounds and are fully biodegradable. The product is free from preservatives and fragrances. It is applied as a solution directly to the damaged nail.
• urea hydrogen peroxide or carbamide peroxide
• a skin composition comprising urea is stabilised by the addition of a nucleotide in combination with an ester from a lower fatty acid and glycerol.
• a pharmaceutical composition suitable for topical application to the nails and/or skin which comprises:
• the urea-based component may comprise urea itself, and/or may comprise urea peroxide, also known as urea hydrogen peroxide (UHP), percarbamide or carbamide peroxide, which is an adduct of hydrogen peroxide and urea, and is used mainly as a disinfecting or bleaching agent in cosmetics and pharmaceuticals.
• UHP urea hydrogen peroxide
• percarbamide or carbamide peroxide which is an adduct of hydrogen peroxide and urea
• the diol component comprises at least one diol.
• the diol component are ethylene glycol, propylene glycol, butanediol, pentanediol (for example 1 ,5-pentanediol), hexanediol, and mixtures thereof.
• the diol component may be a mixture of diols such as a mixture of propylene glycol and another diol, such as 1 ,5- pentanediol.
• a preferred diol is propylene glycol.
• Organic acidic components that may be employed enable the provision (at the site of application of compositions of the invention) of a pH of between about 2.0 (e.g. about 3.5) and about 6.5.
• the term includes substances that are safe for use in mammals, such as weak acids.
• Typical pKas of weak acids are in the range of between about -1.5 (e.g. about -1.74, such as about 1.00, e.g. 2.00 and about 16 (e.g. about 15.74) (e.g. see Vollhardt, Organic Chemistry (1987)).
• a preferred range is between about 1 and about 10.
• the organic acid component may thus comprise a C - 0 carboxylic acid, which may be provided pure/neat and/or in (e.g. aqueous) solution.
• C -10 carboxylic acid include saturated and/or unsaturated, straight and/or branched aliphatic mono-, di- and polycarboxylic acids having 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, alkylaryl or aromatic dicarboxylic acids, oxy and hydroxyl carboxylic acids (e.g. alpha-hydroxy acids) having 1 , 2, 3, 4, 5, 6, 7 or 8 carbon atoms.
• suitable organic acid components include one or more of formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, capryic acid, capric acid, sorbic acid, oxalic acid, hydroxybutyric acid, hydroxypropionic acid (e.g. 2-hydroxypropionic acid, hereinafter lactic acid), glycolic acid, citric acid, malic acid, tartaric acid, malonic acid, fumaric acid, succinic acid, glutaric acid, apidic acid, pimelic acid, oxalacetic acid, phthalic acid, tartronic acid and pyruvic acid.
• Preferred organic acids include hydroxy acids, such as hydroxybutyric acid, hydroxypropionic acids (e.g.
• lactic acid lactic acid
• glycolic acid citric acid
• malic acid More preferred organic acids include lactic acid.
• Lactic acid may be provided in e.g. a 90% aqueous solution.
• Urea-based components, diol components and/or organic acid components may be employed in pharmacologically effective amounts, which refers to amounts of such components that are capable, in combination, of conferring a desired therapeutic effect on a treated patient, whether administered alone or in combination with another ingredient. Such an effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of a positive effect).
• compositions of the invention may be determined by the skilled person, in relation to what will be most suitable for an individual patient. Although this may vary with the type and severity of the condition that is to be treated, and the response of the particular patient to be treated, typical total amounts that may be employed in a composition of the invention of:
• urea-based components are in the range of about 1 % to about 35%, such as about 3% (e.g. about 5%) to about 30%, for example about 8% (e.g. about 10%) to about 25%; and
• diol components are in the range of about 40% to about 80%, such as about 45% to about 75%, for example about 50% to about 70%; and (iii) organic acid components are in the range of about 1% (e.g. about 2%) to about 20%, preferably from about 3% (e.g. about 4%) to about 15%, and more preferably from about 5% (e.g. about 8%) to about 12%,
• Suitable concentration ratios of the organic acid component and the diol component from about 1 :20 to about 1 :1 , preferably from about 1 :15 to about 1 :2 and more preferably from about 1 : 12 to about 1 :4, by weight based on the total weight of the composition.
• the total combined concentration of the diol component and the organic acid component in the formulation are preferably in the range of about 50% to about 90%, such as about 55% to about 85%, for example about 60% to about 80%.
• compositions of the invention optionally comprise a volatile organic solvent.
• volatile organic solvent may be chosen so that it evaporates within about 5 minutes, more preferably within about 3 minutes after application in room temperature.
• a volatile organic solvent with a vapor pressure of at least 2 kPa at 20°C may be used, for example polar solvents such as esters, alcohols, ketones and saturated hydrocarbons with a high vapor pressure (greater than about 2 kPa at 20 °C).
• suitable volatile organic solvents include methyl acetate, isopropanol (isopropyl alcohol), ethanol, acetone, methyl ethyl ketone and methyl isobutyl ketone, particularly ethyl acetate and/or butyl acetate.
• compositions of the invention may be stored under normal storage conditions, with an insignificant degree of chemical degradation or decomposition.
• normal storage conditions include temperatures of between minus 80 and plus 50°C (preferably between 0 and 40°C and more preferably ambient temperature, such as between 15 and 30°C), pressures of between 0.1 and 2 bars (preferably atmospheric pressure), relative humidities of between 5 and 95% (preferably 10 to 60%), and/or exposure to 460 lux of UV/visible light, for prolonged periods (i.e. greater than or equal to six months).
• compositions of the invention optionally comprise an antifungal drug compound, such as one of the type mentioned hereinbefore.
• compositions of the invention may include compounds that improve texture during administration and on the nail during treatment. This results in an increased viscosity at administration which facilitates dosing. It also allows the product to stay at the surface of the nail to perform its effect.
• the composition comprises a polymer having suitable viscosity-increasing properties (hereinafter referred to as a "viscosity-increasing agent").
• a viscosity-increasing agent includes cellulose derivatives such as ethyl cellulose, cellulose acetate butyrate and polymethacrylates such as Eudragit. Suitable concentrations of such viscosity-increasing agents may be determined by a person skilled in the art.
• a preferred embodiment of the invention comprises about 50% to about 70% of a diol component, such a propylene glycol, about 5 (e.g. about 7%) to about 15% (e.g. about 12%) of an organic acid component, such as lactic acid, about 8% (e.g. about 15%) to about 25% of a urea-based component, such as urea and/or carbamide peroxide, about 5% to about 10% (e.g. about 7.5%) of a triol component, such as glycerol, and, optionally, about 2% to about 5% of aqueous base, such as 10 M sodium hydroxide.
• a diol component such as propylene glycol
• an organic acid component such as lactic acid
• about 8% (e.g. about 15%) to about 25% of a urea-based component such as urea and/or carbamide peroxide
• a triol component such as glycerol
• aqueous base such as 10 M sodium hydroxide.
• compositions of the invention may thus be incorporated into various kinds of pharmaceutical preparations intended for topical administration using standard techniques (see, for example, Lachman et al, "The Theory and Practice of Industrial Pharmacy”, Lea & Febiger, 3 rd edition (1986) and “Remington: The Science and Practice of Pharmacy” , Gennaro (ed.), Philadelphia College of Pharmacy & Sciences, 19 th edition (1995)), by combining compositions of the invention with conventional pharmaceutical additives and/or excipients used in the art for such preparations.
• compositions of the invention may be employed in the treatment of nail diseases, such as fungal infections of the nail, for example onychomycosis.
• a method for treating a nail disease which comprises administering a composition of the invention to the nail of a patient.
• compositions of the invention may be combined in treatment with one or more other antifungal nail treatments, including laser therapy, oral antifungal preparations, such as terbinafine and/or topical antifungal treatments, such as preparations comprising ciclopiroxolamine, amorolfine and the like.
• treatment of nail and/or skin diseases we include the therapeutic and/or cosmetic treatment, as well as the symptomatic, prophylactic and palliative treatment of the disease. Treatment this includes the alleviation of symptoms of fungal diseases as well as the improvement in the appearance of nails and/or skin.
• compositions of the invention are easy and inexpensive to manufacture, are easily applied topically, and may enabling rapid relief of symptoms, such as those described hereinbefore.
• Compositions of the invention may also have the advantage that they may be prepared using established pharmaceutical processing methods and employ materials that are approved for use in food, pharmaceuticals or cosmetics and/or of like regulatory status.
• compositions of the invention may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, possess a better patient acceptability than, have a better pharmaceutical profile than, and/or have other useful pharmacological, physical, or chemical properties over, pharmaceutical compositions known in the prior art, whether for use in the treatment of skin or nail diseases or otherwise.
• the invention is illustrated by way of the following examples, with reference to the attached Figure 1 , which shows a comparison of chemical stability of compositions of the invention compared to a commercial composition of the prior art. Comparative Example 1
• composition with ingredients in the following proportions was prepared in a three batch sizes (450 kg, 150 kg and 20 kg), each by dissolving urea in propylene glycol before adding lactic acid and then 10M aqueous NaOH.
• composition with ingredients in the following proportions was prepared in a batch size of 0.5 kg by dissolving urea in propylene glycol and glycerol before adding lactic acid and then 10M aqueous NaOH.
• composition with ingredients in the following proportions was prepared in a batch size of 50 g by dissolving urea hydrogen peroxide in lactic acid and glycerol before adding propylene glycol and urea. 10 NaOH was added at the end of the sample preparation when the urea was fully dissolved.
• composition with ingredients in the following proportions was prepared in a batch size of 3 kg by dissolving urea in propylene glycol and glycerol before adding lactic acid and then 10M aqueous NaOH.
• An analytical method (RP-HPLC-UV) was used for determination of urea content. The results are shown in Table 1 below and in Figure 1. All three Example 1 batches are out of specification (OOS) at 6 months. One is OOS at 3 months. However, the urea content for Example 2 is within specification for the whole of the 6 month study.
• glycerol improves the stability of urea in a product formulation stored at accelerated conditions (40°C).

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