Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—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
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • 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

Definitions

• the present invention relates to a composition, notably to a carrier composition for topical application of a wide range of pharmacologically active substances.
• the skin is the largest organ of the body, and it has become of interest as a route of presenting drugs for the treatment of disease states other than those of the skin.
• a number of benefits may be claimed for the transdermal route over oral or parenteral routes for the application of medicaments. For example, the variability of the so-called first pass effect following oral administration of many drugs is avoided.
• the transdermal route is non-invasive as compared to parenteral presentations.
• the transdermal route suffers from a number of disadvantages. For example, it requires the use of a carrier for the medicament which can pass through the skin, since the stratum corneum presents a profound barrier to the passage of a wide range of materials, offering great resistance to most medicaments.
• the transdermal route has usually been considered suitable only for relatively potent (low dose) medicaments. Furthermore, great care needs to be exercised to ensure that components in the carrier composition do not cause skin irritation or damage.
• composition of the invention makes it possible to apply medicaments by the transdermal route which had hitherto been considered unsuitable for use in such an application route.
• the present invention provides a composition suitable for the topical application of a medicament, which composition comprises a dermatologically acceptable carrier medium, characterised in that the carrier medium comprises as essential components at least three ingredients selected from the group consisting of: a. a physiologically acceptable polyalkylene-ether-glycol, notably one of the empirical formula HO-(C n H 2n O) ln -OH, where n has an average value of from 2 to 6 and m has an average value of from 2 to 30 or more, in which the alkylene groups can be straight or branched chain, saturated or unsaturated, and in which the hydroxyl groups can be primary, secondary and/or tertiary, and/or a physiologically acceptable alkylene-glycol, notably one of the empirical formula HO-(C H 2 ) -OH, where E has a value of from 2 to 6 and g has an average value of from 1 to 30, in which the alkylene groups can be straight or branched, saturated or unsaturated, and the hydroxy
• a physiologically acceptable C 8 -C 14 aliphatic monohydric alcohol notably a C 9 . 12 alcohol, for example lauryl or dodecyl alcohol, which latter may be derived from propylene tetramer
• a physiologically acceptable plant extract having anti- fungal and/or anti-bacterial properties at physiologically acceptable dosage levels, for example an essential oil, notably one containing a terpenoid compound, preferably an oxygen- containing terpene or mixture of such terpenes, for example as is present in tea tree oil and other essential oils derived from vegetable matter
• a physiologically acceptable material having skin moisturising properties.
• the ingredients of the composition of the invention interact synergistically to achieve a greater than expected transdermal effect and that this effect is achieved when three of the specified ingredients are present in the composition.
• the composition contains all four of the essential ingredients, optionally in admixture with other ingredients typically present in topical preparations; and preferably also contains a medicament which is to be administered transdermally.
• the medicament is present in from 0.1 to 10%, the ether glycol and/or glycol ingredient a is present in a total amount of from 0.25 to 30%, the essential oil ingredient c.
• the alcohol ingredient b is present in from 0.5 to 10%
• the skin moisturiser ingredient d is present in from 0.1 to 5%, all percentages being by weight of the active ingredient based on the total composition, the remainder of the composition typically being water or a water based gel or matrix having the medicament and essential ingredients uniformly distributed throughout.
• compositions of the invention exhibit both transdermal and intradermal properties and thus find use in the topical application of compositions where minor systemic properties are required and in the transdermal application of active compositions which are to be active systemically.
• the composition thus finds use in the application of salves and other medicaments to the skin to treat physical and other damage to the skin, for example open wounds or cuts, abrasions, ulcers or burns. Since many of the essential oils which can be used as ingredient c exhibit preservative as well as anti ⁇ bacterial properties, compositions containing such essential oils may be self preserving and assist the prevention of infection in open wounds or abrasions due to these properties of the essential oil ingredient.
• compositions find especial application in the transport of a wide range of medicaments through intact stratum corneum.
• the medicament may be selected from one or more of: anaesthetics, analgesics, anti-inflammatory agents, anti- cancer agents, cardiovascular agents, anti-fungal, anti- bacterial, anti-viral, anti-proliferative, anti-emetic drugs and hormones.
• suitable medicaments include benzocaine, lidocaine, tetracaine as local anaesthetics; ibuprofen, ketoprofen, indomethacin, diclofenac, piroxicam as anti-inflammatory agents or mild analgesics; fentanyl, buprenorphine and morphine as strong opiate analgesics; clotrimazole, miconazole, ketoconazole, amphotericin and griseofulvin as anti-fungal agents; nifedipine, nicardipine, timolol and atenolol as cardiovascular agents; methotrexate (and its analogues) or 5-fluorouracil as anti-proliferatives or cytotoxics; allantoin as an enhancer of skin repair regrowth; benzoyl peroxide or anti-biotics of the tetracycline, penicillin or cephalosporin type; anti-emetics such as metaclo
• the present invention provides a method for the topical treatment of the skin of a mammal and/or for the application of a medicament transdermally to a mammal, characterised in that it comprises applying a biologically effective amount of a composition of the invention to the skin.
• the invention is applicable to a wide range of medicaments as described above.
• the invention may also be applied to precursors of the active medicaments, for example an acetate or acyl derivative, an alkali metal salt or an amine salt or complex thereof.
• medicament will be used herein to denote in general terms a active ingredient of a medicament, its analogues and precursors thereof, whether alone or in admixture with one another.
• composition of the invention finds widespread use in the treatment of a wide range of conditions for which the medicaments, have been indicated, eg. in the application of methotrexate in the treatment of proliferative skin disorders including: psoriasis; primarymalignant disease, for example squamous cell carcinoma, basal cell carcinoma, malignant melanoma, Kaposis sarcoma etc.; and secondary deposits in the skin and neoplasms due to or associated with warts, herpes simplex, human papilloma virus etc..
• the skin penetration properties of medicaments contained in carrier compositions containing at least three, and preferably all four, of the specified essential ingredients are generally superior to the rates obtained with formulations which use other ingredients, for example Azone, as a penetration assistant,-or formulations which do not contain at least three of the specified essential ingredients.
• the invention thus offers the ability to apply medicaments transdermally in effective amounts and also to use lower concentrations, for example from 0.1 to 2%, of the medicament, which is of advantage where large areas of the skin are to be treated.
• higher proportions for example from 5 to 10% by weight, may be used if desired and acceptable.
• the carrier composition may contain customary ingredients used in such compositions. However, we have found that the carrier composition must contain at least three of the specified ingredients in order to obtain the enhanced penetration of the medicament through the skin.
• the order of preference for the specified ingredients to be present is:
• the alkylene glycol or polyalkylene ether glycol ingredient a typically have a molecular weight in the range 100 to 600,000, but are preferably those having a molecular weight in the range 200 to 6000.
• ether glycols and glycols provide the carrier with occlusive properties as well as providing solvent and transdermal properties. Their inclusion in the carrier composition is especially preferred when the medicament is to be applied over a prolonged period where drying out of the skin could occur.
• the ehter glycols and glycols also assist formation of a matrix within which the other components of the composition are dispersed to provide a stable viscous gel consistency to the composition. Where the ehter glycol or glycol has a short chain, for example 2 to 5 carbon atoms, the ether glycol or glycol may also serve as a solvent or co- solvent for other components of the composition.
• the polyalkylene ether glycols and/or alkylene glycols are typically present in a total amount up to about 30% by weight of the total composition, preferably l to 25%, and mixtures of glycols and ether glycols may be used.
• the long chain alcohol ingredient b is preferably a straight chain aliphatic alcohol containing from 9 to 12 carbon atoms, or the analogous branched chain alcohols obtained by condensation of propylene.
• the alcohol serves as a lubrifacient to aid direct application of the composition to the skin and also assists transdermal penetration of the medicament.
• the presence of the long chain alcohol is therefore preferred when the composition would otherwise be excessively viscous and is particularly desirable when the polyalkylene ether glycol or alkylene glycol is also present.
• the long chain alcohol ingredient b is present in an amount of up to about 30%, for example from 1 to 25%, preferably 1 to 10%, of the total composition.
• the plant extract ingredient c. can be selected from a wide range of such material which exhibit anti-fungal and/or anti ⁇ bacterial properties.
• the plant extract also exhibits preservative properties at dosage rates of the ingredient which are physiologically acceptable. That is, the plant extract exhibits physiologically useful effects at a dosage rate similar to the rate at which the other ingredients are applied to the skin in the composition.
• the amount of the plant extract required to achieve useful effects does not imbalance the overall composition.
• the plant extract is an essential oil as defined at page 670 of Martindale, The Extra Pharmacopoeia, 28th edition.
• essential oils include those derived from the foliage of plants and trees and are typified as containing terpenoid compounds. These may be hydrocarbon terpenes or oxygen containing compounds, for example terpene alcohols, ketones or oxides.
• Specific preferred terpene compounds include a-pinene, a-terpinene, limonene, 1,8-cineol, gamma-terpinene, p-cymene, l-terpinen-4-ol, aromadendrene , a-terpineol, and mixtures thereof.
• the terpene compounds for present use may be synthetic or naturally occurring, as when a eucalyptus type tree oil is used, notably the oil from Melaleuca alternifolia tree, known as Tea Tree Oil.
• the plant extract ingredient c. may thus be used as the naturally occurring mixture of materials containing the active ingredient, or may be used in the form of an isolated and refined extract containing a raised proportion of the active ingredient or as an individual synthetically prepared single compound or mixture of isomers.
• the plant extract ingredient c is typically present in up to 15%, for example from 0.1 to 10%, preferably 0.5 to 5%, notably from 0.5 to 2.5%, by weight ⁇ f active ingredient based on the total composition and serves primarily as a penetration assistant in the composition. It is therefore preferred that such a plant extract be .present as one of the specified ingredients in any composition according to the invention.
• the skin moisturising agent for use as ingredient d is a compound or mixture of compounds which maintains or increases the hydration of the stratum corneum of the skin.
• a number of materials are known to possess this property and specific examples include: urea; lactic, ascorbic or glycollic acids and salts thereof; cholesterol; liposomes and niosomes; pyrrolidone carboxylic acid and salts thereof; gamma-linoleic acid and its salts; mono- and poly-aminosaccharides; chitins and chemically modified chitins which contain ether and extra alkyl groups; and hyaluronic acid. Mixtures of such skin moisturising agents may be used if desired.
• the skin moisturising agent ingredient d is present in an amount of up to about 10%, for example from 0.1 to 5%, preferably from 0.1 to 2% by weight of the total composition.
• the composition may contain other ingredients normally present in topically applied compositions. Typically these will provide up to 50%, for example from 0.1 to 35% by weight of the total composition.
• Such other ingredients include for example solvents or co-solvents, such as water, low molecular weight alcohols, eg. ethyl or propyl alcohols or glycols; and penetration enhancers, such as long chain acids, esters, glycols or saccharide derivatives.
• solvents or co-solvents such as water, low molecular weight alcohols, eg. ethyl or propyl alcohols or glycols
• penetration enhancers such as long chain acids, esters, glycols or saccharide derivatives.
• the presence of long chain fatty acids and derivatives, notably esters, thereof is especially preferred since they aid formation of stable gels when all four of the specified ingredients are present.
• Particularly preferred fatty acids and esters thereof for present use are those of the empirical formula Alk-OOCAcid where Alk denotes a straight or branched alkyl group containing from 2 to 18 carbon atoms and Acid denotes a saturated or unsaturated straight or branched chain alkyl group which may carry one or more Alk-OOC- substituents.
• Typical of such fatty acid esters are c. to C 18 alkyl esters of octanoic acid or octanoic acid itself.
• ingredients which may also be present include, for example, a pH controlling agent such as sodium, potassium, ammonium or an alkaline-earth metal hydroxide, or an organic base of the primary, secondary or tertiary amine type, to give a final pH in the range 4.5 - 9.0 and more preferably 7.0 - 8.5.
• a pH controlling agent such as sodium, potassium, ammonium or an alkaline-earth metal hydroxide, or an organic base of the primary, secondary or tertiary amine type, to give a final pH in the range 4.5 - 9.0 and more preferably 7.0 - 8.5.
• the ingredients c. are often obtained from natural materials and will therefore differ in composition and be a mixture of the desired ingredient with other materials. Such mixtures may be used without the need to isolate the specified ingredient and the percentages given above are in terms of the desired component of such mixtures, Where the mixture contains large amounts of physiologically acceptable other components, these may themselves provide beneficial other properties, for example fragrance to the composition, and it may be necessary to use larger amounts of the mixture to achieve the desired proportion of the desired essential oil component than the percentages given above. The percentages should therefore be treated as guides to the desired amounts and the optimal amounts can be readily determined by simple tests.
• compositions of the invention can be prepared using a wide range -of techniques, for example by admixing and stirring together the desired amounts of the various ingredients to form a cream, paste or gel.
• the ingredients can be pre- dissolved or suspended in one or more of the other ingredients, for example in a propylene glycol solvent, to aid formation of a stable gel or emulsion.
• the pH of the composition can be adjusted by the addition of a suitable pH regulator after the other ingredients have been incorporated.
• compositions of the invention are applied to the affected areas of the skin of a mammal, notably a human being, to treat the wound, psoriasis or other skin damage or disorder by applying the composition as a coating over the affected area or can be applied to any desired area where the medicament is to be absorbed into the body for a systemic effect elsewhere in the body, for example in the treatment of hypertension etc.
• This can be achieved by applying the composition directly in the required amount as a cream, paste or gel to the skin, for example by wiping a gel stick type presentation of the composition which exposes a desired length of stick across the desired area of the skin until the exposed portion of the stick has been applied to the skin.
• the composition can be put up in a pressurised dispenser formulation and applied as a spray, foam, mousse or gel via a metered dose valve, which dose can then be spread over and/or massaged into the skin.
• the composition can be applied to an adhesive plaster, pad, gauze or other backing support member or carrier which is then applied over the affected area.
• the coating of the composition on the skin or on the support member can have applied thereto a vapour barrier film, for example a plastic film or a spray on film-forming resin, for example a synthetic skin type composition, which serves to retain water and other fluids in the composition and the skin.
• a vapour barrier film for example a plastic film or a spray on film-forming resin, for example a synthetic skin type composition, which serves to retain water and other fluids in the composition and the skin.
• the polyalkylene ether glycol or alkylene glycol ingredient a is present in sufficient amounts, this may provide a gel matrix for the other components and also impart sufficient occlusive properties for the use of a vapour barrier
• the amount of the composition applied will be sufficient to apply the biologically effective amount of the active ingredient(s) therein to the affected area of the skin or to achieve the desired dosage application. This amount will vary according to the treatment required and the content of active ingredient in the composition. The optimal amount required to achieve the desired biological effect can readily be established as is known from a knowledge of these.
• a co-solution of stearic acid (8 parts by weight) and propylene glycol (8 parts by weight) was prepared at 70°C with mechanical stirring.
• a separate solution of a mixture of polyethylene glycol (ingredient a, average molecular weight 400, 6 parts by weight) in polyethylene glycol (ingredient a, average molecular weight 4000, 20 parts by weight) was prepared similarly.
• the two solutions were mixed together at 60-65°C using a mixer without entrainment of air.
• a solution of sodium hydroxide (1.12 parts), a polyaminosaccharide condensate skin moisturising agent (ingredient d, l.l parts by weight) in deionised water (25 parts by volume) was slowly added with stirring.
• the mixture was slowly cooled to 30°C with high shear mixing without entrainment of air to give a viscous white pasty mass.
• the mass was mixed with a solution of Tea Tree oil (ingredient c, 1 part by volume), dodecanol (ingredient b, 2 parts by weight) and, as a lubrifacient to aid preparation of the mixture and application of the composition to the skin, an emollient ester of polypropylene glycol and myristic acid (0.2 parts by weight) in ethanol (24 parts by volume).
• the mixture was stirred continuously for one hour to give a creamy hydrogel base and packed into a sealed container until used (Formulation II, FII).
• Formulation I FII
• Formulation III FII
• cety-1 alcohol replaces dodecanol
• Formulation IV FII
• Formulation V FII
• methyl cellulose 5 parts in place c5 polyethylene glycol ingredient
• Formulation VI FII
• Formulation VII FII, omitting the essential oil ingredient c.
• Methotrexate of BP grade was mechanically admixed in varying amounts (1% w/w, 0.5% w/w, 0.25% w/w, 0.2% w/w and 0.1% w/w) with the hydrogel bases and the resultant compositions stored in sealed, light-tight containers until used.
• compositions were applied as a coating of about 0.05 to 0.1 grams per square cm to samples of isolated human stratum corneum (obtained from mammary reduction or abdomenoplasty for several different donors) prepared as described by Skerrow & Skerrow (1985) or Kligman & Christophers (Arch.Dermatol. 8JB 702 (1974) .
• Transdermal delivery was measured in micrograms per square centimetre per hour using a stability indicating hplc assay method, sampling the stirred receptor layer over periods up to 96 hours.
• the cells made of glass
• the compositions were applied to the epidermal surface of the stratum corneum and the dermal side was bathed by a stirred phosphate buffered saline solution containing 10% ethanol.
• the system was maintained at 32°C, light was excluded and the exposed surface of the applied composition was occluded to prevent alcohol and water loss.
• Two or more cells were run for each formulation and the skin integrity was assessed visually both before and after the experiment using a hand lens. The results for these tests are set out below:
• Formulation Ila formulation II with addition of 1 part of a silicone wetting agent - dimethicone CS20.
• Formulations corresponding to Formulation II of Example 1 were prepared using a range of different medicaments. These were tested as in Example 1 and the following cumulative amounts of the medicament were transferred over the stated periods:
• heparin 1.5 to 2.2 IUs/c 2 over 72 hours
• fenclofenac 263 cg/cm 2 over 24 hours
• piroxica 109 mcg/cm 2 over 24 hours
• metoclopramide 10.5 mcg/cm 2 over 24 hours vincristine: 2.0.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
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• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
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• Life Sciences & Earth Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Inorganic Chemistry (AREA)
• Dermatology (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines Containing Plant Substances (AREA)

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• 1992
  • 1992-10-23 AU AU27830/92A patent/AU2783092A/en not_active Abandoned
  • 1992-10-23 EP EP92922113A patent/EP0609330A1/de not_active Withdrawn
  • 1992-10-23 WO PCT/GB1992/001950 patent/WO1993007901A1/en not_active Application Discontinuation
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