WO2016061328A1 - Topical composition - Google Patents

Topical composition Download PDF

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Publication number
WO2016061328A1
WO2016061328A1 PCT/US2015/055705 US2015055705W WO2016061328A1 WO 2016061328 A1 WO2016061328 A1 WO 2016061328A1 US 2015055705 W US2015055705 W US 2015055705W WO 2016061328 A1 WO2016061328 A1 WO 2016061328A1
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WO
WIPO (PCT)
Prior art keywords
chronic
itch
pregabalin
pruritus
composition
Prior art date
Application number
PCT/US2015/055705
Other languages
French (fr)
Inventor
Mayako KATAKUSE
Hiroko Kido
Yohei MUKOYAMA
Martin Steinhoff
Original Assignee
Maruho Co., Ltd.
The Regents Of The University Of California
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Maruho Co., Ltd., The Regents Of The University Of California filed Critical Maruho Co., Ltd.
Publication of WO2016061328A1 publication Critical patent/WO2016061328A1/en

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    • 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
    • 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
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61P17/04—Antipruritics

Definitions

  • the present invention relates to a topical composition containing pregabalin and/or gabapentin. More specifically, the present invention relates to a topical composition for improving itching by being applied to the skin or mucous membrane having chronic itch.
  • a topical dosage form (salve such as ointment and cream) containing gluco-corticosteroid or tacrolimus is known.
  • a gluco-corticosteroid preparation long-term side effects such that the skin becomes thinner and turns red by long-term use are known, and thus limit their usage, despite its indication only in inflammatory itchy diseases.
  • a tacrolimus preparation it is known that there are many patients who complain about adverse symptoms (burning sensation, etc.) at the start of application, and its usage is limited to a few, T-cell-mediated diseases .
  • a topical composition containing gluco-corticosteroid or tacrolimus suppresses inflammation of the skin, thereby improving skin symptom in inflammatory pruritic diseases, but not non-inflammatory chronic pruritus (e.g. post- zoster itch, dry skin itch, itch of the elderly, tumor-associated itch, to name a few) .
  • non-inflammatory chronic pruritus e.g. post- zoster itch, dry skin itch, itch of the elderly, tumor-associated itch, to name a few
  • H1R histamine-1 receptor
  • Non-Patent Literature 1 Journal of Clinical Pharmacy and Therapeutics, 2013; 38; p.16-18
  • Non-Patent Literature 2 Nephron Clinical Practice, 2012; 122; p .75-79
  • pregabalin and gabapentin on itchiness accompanied with chronic renal injury.
  • pregabalin and gabapentin that cross the blood-brain barrier
  • the risk of inducing systemic side effects Particularly, when itching is chronic, often high dosages and long-term treatments that may cause a severe side effect on patients with a significant burden for patient's health are necessary.
  • the action site of pregabalin and gabapentin is considered to be the spinal cord as well as the brain.
  • an object of the present invention is to provide a topical composition that can exhibit a sufficient drug efficacy by topical application on the skin or mucous membrane to suppress itch, and can alleviate or treat chronic pruritus.
  • the present inventors have studied to solve the above problems, and consequently found that a composition containing pregabalin and/or gabapentin as an active pharmaceutical ingredient (API) and using a base containing water exhibits an excellent antipruritic effect on chronic pruritus by topical application, thereby completing the present invention.
  • API active pharmaceutical ingredient
  • the present invention relates to a topical composition for alleviating or treating chronic pruritus, comprising pregabalin and/or gabapentin in a base containing water.
  • the base refers to one in which the API (pregabalin/gabapentin) is removed from the composition of the present invention.
  • pregabalin and/or gabapentin preferably exists in the form dissolved in water.
  • composition contains
  • % by weight refers to a ratio of the weight of each component based on the total weight of the composition.
  • composition of the present invention can exhibit sufficient drug efficacy even when the active ingredient is only pregabalin and/or gabapentin.
  • composition of the present invention includes a composition substantially containing no oily ingredient as a solvent of pregabalin and/or gabapentin.
  • the preferred dosage form of the composition of the present invention includes a solved lotion, a suspensive lotion, an emulsive lotion, a spray, a gel, a water-in-oil type cream, or an oil-in-water type cream.
  • Particularly preferred dosage form includes a solved lotion, a spray or a gel containing water in an amount of 70% by weight or more.
  • composition of the present invention is particularly preferred to alleviate or treat chronic pruritus accompanied with a disease selected from the group consisting of atopic dermatitis, allergic or irritant contact dermatitis, psoriasis, pityriasis rubra pilaris, polymorphic light eruption and other chronic photodermatoses associated with itch, stasis dermatitis, chronic non-histamine related urticaria, antihistamine-unresponsive mastocytosis, lichen simplex chronicus, seborrhoeic dermatitis, xeroderma, chronic prurigo, prurigo pigmentosa, bullous pemphigoid-associated chronic itch, Dermatitis herpetiformis, lichen planus, chronic scabies , chronic post-arthropod itch (Id reaction), pregnancy-induced chronic itch (e.g.
  • a disease selected from the group consisting of atopic dermatitis, allergic or irritant contact dermatitis, p
  • PUPPP eosinophilic pustular folliculitis
  • drug hypersensitivity reactions cutaneous T cell lymphoma and other lymphomas or leukemias associated with chronic itch
  • neuropathic pruritus brachioradial pruritus, postherpetic itch, notalgia paresthetica and other small fiber neuropathies
  • chronic pruritus of the elderly or dry skin itch local, generalized
  • pruritus at the scar portion after burn post-burn itch
  • genetic or vened chronic itches e.g.
  • Netherton syndrome Darier's disease (Morbus Darier) , Hailey-Hailey disease, inflammatory linear verrucous epidermal nevus (ILVEN), familial primary cutaneous amyloidosis, olmsted syndrome) , aquagenic pruritus, fiberglass dermatitis, mucous chronic itch such as anogenital itch.
  • the present invention relates to a method for alleviating or treating pruritus by applying the composition on a lesion having chronic pruritus.
  • composition according to the present invention is topically applied to a lesion having itching, whereby pregabalin and/or gabapentin can exhibit an antipruritic effect at an application position and improve itching.
  • pregabalin and/or gabapentin can exhibit an antipruritic effect at an application position and improve itching.
  • the amount of pregabalin and/or gabapentin transferred into the blood is very small, thus no effect on the central nervous system is caused.
  • the composition according to the present invention exhibits an effect on chronic itching that is difficult to treat and has few options of a therapeutic agent.
  • Fig. 1 is graphs showing the number of scratching bouts after applying a 2% aqueous pregabalin solution or vehicle to a chronic pruritus model mouse, in which (A) shows the number of scratching bouts per every 0.5 hour after application, and (B) is a graph showing the number of scratching bouts between 0.5 and 4 hours after application;
  • Fig. 2 is a graph showing the number of scratching bouts between 1 and 2 hours after applying an aqueous pregabalin solution or vehicle to a chronic pruritus model mouse;
  • Fig. 3 is a graph showing the number of scratching bouts counted in the period of 0 to 1 hour and 4 to 6 hours after challenge, when applying a 10% aqueous gabapentin solution or vehicle to a chronic pruritus model mouse at 1 hour before and 3 hours after challenge (application of an oxazolone acetone solution) ;
  • Fig. 4 is a graph showing the change of pregabalin concentration in blood plasma after percutaneously administering or orally administering pregabalin.
  • composition of the present invention comprises pregabalin and/or gabapentin as an API in a base containing water.
  • pregabalin and/or gabapentin as an API in a base containing water.
  • the structures of pregabalin and gabapentin are shown as follows;
  • pregabalin and “gabapentin” herein are intended to include not only “pregabalin” and “gabapentin” represented by the above structural formulas or ionic forms thereof but also pharmaceutically acceptable salts, complexes and solvates thereof, however they are not intended to include prodrugs thereof (the prodrug means a compound in which a functional group of pregabalin or gabapentin is substituted by another functional group or a compound in which a carbon-bonded hydrogen of pregabalin or gabapentin is substituted by any functional group) .
  • pregabalin itself herein refers to pregabalin represented by the above structural formula or ionic forms thereof (especially zwitterionic form) and the term “gabapentin itself” herein refers to gabapentin represented by the above structural formula or ionic forms thereof (especially zwitterionic form) .
  • the Salts include, without limitation, acid addition salts and base addition salts, including hemisalts.
  • Pharmaceutically acceptable acid addition salts may include nontoxic salts derived from inorganic acids (such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like) , as well nontoxic salts derived from organic acids (such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like) .
  • Potentially useful salts include acetate, aspartate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, besylate, bicarbonate, carbonate, bisulfate, sulfate, pyrosulfate, bisulfite, sulfite, borate, camsylate, caprylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride, chloride, hydrobromide, bromide, hydroiodide, iodide, isethionate, isobutyrate, lactate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,
  • Pharmaceutically acceptable base salts may include nontoxic salts derived from bases, including metal cations, such as an alkali or alkaline earth metal cation, as well as amines.
  • metal cations such as an alkali or alkaline earth metal cation, as well as amines.
  • examples of potentially useful salts include, without limitation, aluminum, arginine,
  • solvates examples include hydrates and ethanolates.
  • composition of the present invention may contain both of pregabalin and gabapentin or contain either one of them, a more preferred composition contains either one of them, and a particularly preferred composition contains pregabalin.
  • composition of the present invention contains the said pregabalin itself or gabapentin itself.
  • the composition of the present invention exhibits an excellent effect even when it does not contain other APIs.
  • a particularly preferred example of the composition of the present invention includes a composition containing only pregabalin or gabapentin as the API.
  • the "API" herein refers to an ingredient being useful for the treatment of the symptom to be treated by the composition of the present invention (i.e., chronic pruritus) , but does not refer to an ingredient which is added for unrelated purposes of treatment of the symptom.
  • a moisturizing ingredient does not fall within the definition of the active ingredient of the present invention, even if it has drug efficacy for improving dry condition of skin. Therefore, the composition of the present invention containing pregabalin and/or gabapentin together with a moisturizing ingredient falls within the definition of the composition containing only pregabalin and/or gabapentin as the active ingredient.
  • the content of pregabalin in the composition of the present invention is preferably 0.02 to 5% by weight, more preferably 0.2 to 3% by weight, particularly preferably 0.5 to 2.5% by weight, furthermore preferably 1 to 2% by weight.
  • the content of gabapentin is preferably 0.05 to 20% by weight, more preferably 1 to 15% by weight, particularly preferably 3 to 12.5% by weight, further preferably 5 to 10% by weight.
  • a particularly preferred example of the composition of the present invention includes a composition containing pregabalin in an amount of 3% by weight or less (particularly 2% by weight or less) .
  • pregabalin and/or gabapentin in the composition of the present invention exists in the formulation dissolved in water.
  • the preferred dosage form of the composition of the present invention includes a solved lotion, a suspensive lotion, an emulsive lotion, a spray, a gel, a water-in-oil type cream or an oil-in-water type cream.
  • a particularly preferred dosage form is a solved lotion, a spray, or a gel.
  • the solved lotion, the suspensive lotion or the gel is a topical dosage form exhibiting a liquid form or a gel form in which pregabalin and/or gabapentin is dissolved or suspended in an aqueous solvent (including water) .
  • the emulsive lotion, the water-in-oil type (w/o type) cream or the oil-in-water type (o/w type) cream is a topical dosage form exhibiting a liquid formulation or a creamy formulation which is obtained by emulsifying aqueous ingredients (including water) and oily ingredients with a surfactant and in which pregabalin and/or gabapentin exists in the formulation dissolved in the aqueous ingredients.
  • the aqueous solvent may consist of only water or a mixture of water and a water-soluble solvent.
  • the water-soluble solvent include one or more solvents selected from the group consisting of polyhydric alcohols such as 1,3-butylene glycol, glycerin, propylene glycol and dipropylene glycol, lower monohydric alcohols such as ethanol and isopropyl alcohol and polar oils.
  • a preferred water-soluble solvent is a polyhydric alcohol, and especially 1, 3-bulylene glycol is preferred.
  • the content of the water-soluble solvent in the composition is preferably 2 to 30% by weight, more preferably 3 to 20% by weight, particularly preferably 4 to 15% by weight, furthermore preferably 5 to 10% by weight.
  • the dosage form of the composition of the present invention is the water-in-oil type cream
  • pregabalin and/or gabapentin is present in dissolved state in a water phase of a base (an emulsion base having an inner phase being the water phase and an outer phase being an oil phase) .
  • the dosage form of the composition of the present invention is the emulsive lotion or the oil-in-water type cream
  • pregabalin and/or gabapentin is present in dissolved state in a water phase of a base (an emulsion base having an inner phase being an oil phase and an outer phase being the water phase) .
  • the water phase may contain a water-soluble ingredient together with water.
  • a water-soluble ingredient just like the said water-soluble solvent, one or more selected from the group consisting of polyhydric alcohols such as 1,3-butylene glycol, lower monohydric alcohols such as ethanol, polar oils and so on could be used.
  • oily ingredient which constitutes the oil phase examples include one or more selected from the group consisting of hydrocarbons, fats and oils, waxes, fatty acids, higher alcohols and esters.
  • surfactant for emulsifying the water phase and the oil phase and stabilizing the same, one or more selected from the group consisting of cationic surfactants, anionic surfactants, amphoteric surfactants and nonionic surfactants can be used.
  • the dosage form of the composition of the present invention is the spray, it can be prepared by filling the said lotion (liquid) into a spray container.
  • a particularly preferred spray is a spray obtained by filling the solved lotion into the spray container [0027]
  • the content of water (purified water is preferred) in the composition of the present invention is preferably 7% by weight or more, more preferably 50% by weight or more, particularly preferably 70% by weight or more, further preferably 80% by weight or more.
  • composition of the present invention include a solved lotion, a spray or a gel containing 70% by weight or more (more preferably 80% by weight or more, particularly preferably 85% by weight or more) of the water.
  • compositions include a solved lotion, a spray or a gel containing an aqueous solvent (water and the water-soluble solvent) in the total amount of 90% by weight or more (more preferably 95% by weight or more) .
  • a preferred example of the composition of the present invention includes a composition which substantially contains no oily ingredient having a solubility in water of 0.1% by weight or less at 20°C as a solvent for pregabaline and/or gabapentin.
  • a more preferable composition is a composition which substantially contains no oily ingredient having a solubility in water of 1% by weight or less at 20°C as a solvent for pregabalin and/or gabapentin.
  • the "solvent for pregabalin and/or gabapentin” herein refers to a component which can contain therein pregabalin and/or gabapentin in dissolved state.
  • substantially contain no means that its content in the composition is 3% by weight or less, preferably 2% by weight or less, more preferably 1% by weight or less.
  • composition of the present invention includes a composition containing no oily ingredient as the solvent for pregabalin and/or gabapentin.
  • Amore preferred example includes a composition substantially containing no oily ingredient therein, and a particularly preferred example includes a composition containing no oily ingredient therein.
  • the composition of the present invention may contain a thickener.
  • the content of the thickener in the composition is preferably 0.01 to 10% by weight.
  • the more preferable content of the thickener is 0.2 to 2% by weight.
  • Examples of the preferable thickener include carboxyvinyl polymer and water-soluble cellulose derivatives such as
  • hydroxyethyl cellulose hydroxypropyl cellulose, hydroxypropyl methyl cellulose and hydrophobized hydroxypropyl methyl cellulose. These may be used singly or in combination.
  • a particularly preferred thickener is carboxyvinyl polymer.
  • composition of the present invention preferably has a pH value ranging from 3 to 10.
  • a more preferable pH value is between 4 and 8, and particularly preferable pH value is between 5 and 7.
  • the pH value is less than 3 or more than 10, there is fear for the safety as a topical dosage form.
  • lactic acid, citric acid, phosphoric acid and so on can be used for adjusting to a low pH region
  • an alkali metal and alkaline-earth metal hydroxide, sodium lactate, sodium citrate, L-arginine, diisopropanolamine and son on can be used for adjusting to a high pH region.
  • a particularly preferred pH modifier is sodium hydroxide or potassium hydroxide.
  • composition of the present invention can contain a preservative (antiseptic agent) and a stabilizing excipient (viscosity stabilizer), besides the aforementioned ingredients. Also, the composition can contain any other additive which is generally used for a topical composition for skin.
  • Examples of the preservative include methyl
  • the preservative may be used singly or in combination.
  • the content of the preservative in the composition is preferably within the range of 0.01 to 2% by weight, and more preferably within the range of 0.1 to 1.0% by weight. When it is more than 2% by weight, there is fear for the safety of a drug formulation.
  • viscosity stabilizer examples include sodium edetate hydrate, tetrasodium edetate hydrate, tetrasodium edetate tetrahydrate, sodium metaphosphate and so on.
  • the content of the viscosity stabilizer in the composition is preferably within the range of 0.005 to 1% by weight, and more preferably within the range of 0.01 to 0.5% by weight. When it is more than 1% by weight, there is fear for the safety of a drug formulation.
  • a particularly preferred viscosity stabilizer is sodium edetate hydrate.
  • the composition of the present invention can exhibit sufficient drug effect even when it contains no lower monohydric alcohol (monohydric alcohol with 1 to 3 carbon atoms) such as ethanol Since the lower monohydric alcohol such as ethanol is high volatile and there is concern about affecting skin when it is added to a topical dosage form, it is preferable that the composition of the present invention does not contain the lower monohydric alcohol.
  • composition of the present invention can exhibit sufficient drug effect even when it contains no substance exhibiting a percutaneous absorption promoting action such as
  • the composition of the present invention can alleviate or treat itching by being applied to a region (such as a skin and a mucous membrane) having chronic itching.
  • the composition of the present invention is particularity suitable for alleviating or treating chronic pruritus of skin. Contrary to a topical dosage form containing steroid or tacrolimus which alleviates itching by suppressing inflammation, the composition of the present invention can alleviate itching despite a lack of inflammation-suppressive effect. Therefore, the composition of the present invention has efficacy for cutaneous pruritus which is characterized by intense itching of skin despite a lack of primary skin rash on the surface of the skin.
  • the dermal pruritus arises from a variety of causes, and there are cases resulting from visceral diseases such as chronic renal failure, liver disease and diabetes or cases resulting from skin dryness caused by aging or environment (such as low-humidity or cold) .
  • visceral diseases such as chronic renal failure, liver disease and diabetes
  • cases resulting from skin dryness caused by aging or environment such as low-humidity or cold.
  • the cutaneous pruritus is characterized by the development of itching despite a lack of lesion that causes the itching of skin, there are cases that scratches and eczemas on skin are caused by scratching the skin because of the itching.
  • disorder accompanied with chronic itching include atopic dermatitis, contact dermatitis, seborrhoeic dermatitis, psoriasis, lichen planus and so on (full list, see paragraph [0014]), which are characterized in that a skin inflammation such as eczema develops, thereby causing itching .
  • the composition of the present invention also has efficacy for itching due to abnormality (such as inflammation) on the surface of skin.
  • composition of the present invention also has an efficacy for the abovementioned chronic itching.
  • the amount and the frequency of administration of the composition of the present invention onto a lesion site may be appropriately regulated in accordance with the severity of itchiness, the concentration of pregabalin and/or gabapentin in the composition, the patient's age and body weight and so on.
  • the daily dosage thereof (the amount of pregabalin itself and/or gabapentin itself) is about 5 to 15 mg.
  • the oral preparation of pregabalin which are currently available in Japan is administered to an adult in a drug dose of 150-300 mg (up to 600mg) per day and the oral preparation of gabapentin which are currently available in Japan is administered to an adult in a drug dose of 600-1800 mg (up to 2400mg) per day. Therefore, according to the present invention, it is possible to improve the symptom at a much lower dose than the oral preparation.
  • compositions in which these compounds are arbitrarily combined and further include compositions in which the respective concentration ranges described about the essential components and the optional components are arbitrarily combined.
  • the respective numerical ranges of the concentrations, the pH values, and the like that are described in the preceding paragraphs may be arbitrarily combined.
  • the respective upper limit values of the numerical ranges or the respective lower limits thereof may be arbitrarily combined.
  • pregabalin or gabapentin was unsuitable for percutaneous administration because it need to be dissolved in an oily solvent in order to increase the absorption thereof when administered percutaneously .
  • subsequent studies showed that a composition in which pregabalin or gabapentin is dissolved in water exhibits dug efficacy when administered precutaneously .
  • Biostir AD atopic dermatitis causing ointment including mite allergens derived from Dermatophagoides farinae
  • the ointment (Biostir AD) was applied to the back of the neck of PAR20E mouse twice a week for 6 weeks.
  • the scratching behavior of each mouse was monitored for an hour at the same time each day of 4, 5 and 6 days after the last application of the ointment and the individual, for which the scratching bouts were observed at least 100 per hour, was selected as the chronic itch model.
  • Biostir AD was applied to the model once a week in order to keep the inflammation.
  • mice Ten (10) mice were divided into 2 groups (5 mice per group), and vehicle (0.1% aqueous Tween 20 solution) was applied to one group (group A) as a control, and a 2% aqueous pregabalin solution prepared by adding pregabalin to the vehicle was applied to other group (group B) , and the number of scratching bouts was counted.
  • the 2% aqueous pregabalin solution was applied to the group A, and the vehicle was applied to the group B, and the number of scratching bouts was counted.
  • Fig. 1 (B) The number of scratching at 0.5 to 4 hours after application of the test substance is shown in Fig. 1 (B) .
  • the mean number of scratching bouts at 0.5 to 4 hours exceeded 600 times (633 times) in the vehicle group, whereas the mean number fell below 200 times (184 times) in the 2 % agueous pregabalin solution group.
  • the composition of the present invention shows a significant antipruritic effect in an atopic dermatitis model (chronic itch model) .
  • a significant healing effect on dermatitis by 2% pregabalin application could not be confirmed.
  • a steroid product is applied to an atopic dermatitis model, dermatitis is significantly improved, and the number of scratching bouts accordingly decreases.
  • a pregabalin-containing composition alleviates only pruritus regardless of the treatment of inflammation, different from a steroid product . Therefore, it is considered that the composition of the present invention is effective also for pruritus not accompanied by inflammation, different from a steroid product.
  • NC/Nga TndCrlj Mouse purchased from Charles River Laboratories Japan, Inc .
  • Biostir AD atopic dermatitis causing ointment including mite allergens derived from Dermatophagoides farinae
  • NC/Nga mouse The back part and auricular part of NC/Nga mouse was sheared with a hair clipper and an electric shaver, then a depilatory (trade name: epilat, manufactured by Kracie Holdings, Ltd.) was applied in an appropriate amount, and hair was removed.
  • a depilatory trade name: epilat, manufactured by Kracie Holdings, Ltd.
  • Biostir AD 100 mg was uniformly applied to the back of the neck.
  • the second or layer challenge treatment was performed twice a week for 3 weeks, and an atopic dermatitis mouse was prepared by a total of 6 times of treatment. After a lapse of 3 weeks, the mouse had an inflammation on the skin, and continued scratching behavior even when Biostir AD was not applied.
  • Control vehicle or an aqueous pregabalin solution (0.2%, 2%) was percutaneously administered to the atopic dermatitis model once a day, for consecutive 3 days.
  • the application amount was set to 50 ⁇ / ⁇ 36.
  • the vehicle was a 0.1% aqueous Tween 80 solution, and the aqueous pregabalin solution was prepared by adding pregabalin to the vehicle.
  • mice After applying control (vehicle) or an aqueous pregabalin solution to mice, all the individuals were recorded for 4 hours, and the number of scratching bouts was visually counted using the recorded data.
  • the mean number of scratching bouts per an hour at 1 to 4 hours after application, on Day 1, Day 2 and Day 3 of application is shown in Table 3. It can be seen from Table 3 that, in the vehicle and pregabalin (0.2%) applied groups, a tendency that the number of scratching bouts increased or decreased was not found, and scratching behavior was constantly found, throughout the observation time at 1 to 4 hours after application. On the other hand, in the pregabalin (2%) applied group, a tendency to suppress the number of scratching bouts at 1 to 4 hours after application was found, and a significant decrease in the number of scratching bouts was found at a significance level of 1% on Day 3 of application, as compared to the decrease in the vehicle group.
  • the suppression of itchiness by pregabalin application is considered to be independent of the suppression of inflammation.
  • Oxazolone 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one ; produced by Wako Pure Chemical Industries, Ltd.
  • the back of the neck of the mouse was sheared with an electrical hair clipper and a safety razor, then 10 ⁇ L/site of 0.5% (w/v) oxazolone acetone solution was applied to the sheared part (percutaneous sensitization) .
  • challenge day 0 From the Seventh day (referred to as challenge day 0) after the percutaneous sensitization, 10 of 0.5% (w/v) oxazolone acetone solution was applied to the same area at 2- or 3-day intervals (challenge days 0, 2, 4, 7, 9, 11, 14, and 16) .
  • challenge day 16 On challenge day 16 (after the last oxazolone application), the scratching behavior of the mouse was monitored in the following way.
  • control vehicle or a 10% aqueous gabapentin solution was percutaneously administered to the mouse.
  • vehicle was a 0.1% aqueous Tween 80 solution, and the 10% aqueous gabapentin solution was prepared by adding gabapentin to the vehicle.
  • the amount of percutaneous administration was set to each 60 ⁇ , (60 ⁇ , x twice, total of 120 ⁇ -L) .
  • the scratching behavior was recorded for 1 hour immediately after challenge (0 to 1 hour after challenge) and for 2 hours from 4 hours after challenge (4 to 6 hours after challenge) , and the number of scratching bouts was visually counted using the recorded data.
  • the results are shown in Table 5 and Fig. 3.
  • Test group between 0 and 1 hour between 4 and 6 hours
  • Test substances are shown in Table 6.
  • Pregabalin (PGB) for oral administration was dissolved in injection water, and pregabalin for percutaneous administration was dissolved in a 0.1
  • Tween 80 solution so as to have the following concentration.
  • test substance was orally administered (25 mL/kg) or percutaneously administered (50 ⁇ ,) to the back of the neck of the mouse.
  • percutaneous administration hair in the back of the neck of the mouse was removed using an electric hair clipper and an electric shaver, then the stratum corneum was exfoliated 10 times with a mending tape while rotating the peeling direction by 90 degrees.
  • the mouse was transferred to a rota-rod at a rate of 15 rpm or 20 rpm, and the residence time was measured (measured for up to 60 seconds) .
  • Test substances are shown in Table 9.
  • Pregabalin (PGB) for oral administration was dissolved in injection water, and pregabalin for percutaneous administration was dissolved in a 0.1 % agueous Tween 80 solution, so as to have the following concentration.
  • Table 9 Pregabalin (PGB) for oral administration was dissolved in injection water, and pregabalin for percutaneous administration was dissolved in a 0.1 % agueous Tween 80 solution, so as to have the following concentration.
  • a test substance was orally administered (12 mL/kg) or percutaneously administered (50 ⁇ ,) to the back of the neck of the mouse.
  • percutaneous administration hair in the back of the neck of the mouse was removed using an electric hair clipper and an electric shaver, then the stratum corneum was exfoliated 10 times with a mending tape while rotating the peeling direction by 90 degrees.
  • the mouse was retained in the back position under isoflurane anesthesia after 5, 15, 30, 60, 120 and 240 minutes, and blood sampling from the abdomen aorta was performed with a syringe treated with heparin sodium.
  • the blood was immediately ice-cooled, and centrifuged (about 1850 x g, 4°C, 15 min) to collect blood plasma, and unchanged pregabalin was quantified by a liquid chromatography tandem mass spectrometry (LC/MS/MS) .
  • LC/MS/MS liquid chromatography tandem mass spectrometry
  • the concentration of pregabalin in blood plasma was high, in the 300 mg/kg oral administration group in which the expression of central nervous system side effects was observed in Example 4, and the highest concentration reached nearly 300 ⁇ g/mL.
  • the concentrations of pregabalin in blood plasma in the 30 mg/kg oral administration group, 0.2% percutaneous administration group and 2% percutaneous administration group in which the expression of central nervous system side effects was hardly or not observed at all were significantly low.
  • the highest concentration in blood plasma in the 30 mg/kg oral administration group was about 25 ⁇ g/mL, whereas it was about 15 ⁇ g/mL (2% percutaneous administration group) or about 2 ⁇ g/mL (0.2% percutaneous administration group) in the percutaneous administration groups. Therefore, it was supported that, in the percutaneous administration of pregabalin, the amount of pregabalin transferred to blood plasma is very small, and a central nervous system side effect is not caused.
  • PGB pregabalin
  • DPH diphenhydramine
  • MC methylcellulose
  • test substance is orally administered (5 mL/kg) or percutaneously administered (50 ⁇ ,) to the back part of the mouse.
  • percutaneous administration hair in the back part of the mouse was removed using an electric hair clipper and an electric shaver under isoflurane anesthesia, and then application was performed.
  • 50 ⁇ , of an itch-inducing agent 25 nmol histamine solution: the solvent was a phosphate buffered physiological saline
  • itch-inducing agent 25 nmol histamine solution: the solvent was a phosphate buffered physiological saline
  • compositions in Table 13 were prepared by the following procedures .
  • pregabalin or gabapentin
  • 1,3-butylene glycol, methyl parahydroxybenzoate, a sodium edetate hydrate, purified water and carboxyvinyl polymer aqueous solution
  • Pregabalin or gabapentin
  • sodium hydroxide aqueous solution
  • pregabalin or gabapentin
  • an aqueous base a base mainly consisting of a mixture of water and 1, 3-butylene glycol
  • the composition according to the present invention exhibits an antipruritic effect on chronic itching, and has a low expression risk of central nervous system side effects, thus is useful as a therapeutic agent for a patient suffered from chronic pruritus.
  • the composition according to the present invention can suppress not only itchiness accompanied with inflammation but also itchiness not accompanied with inflammation, and thus an antipruritic effect is expected also on dermal pruritus that cannot be treated by steroid or tacrolimus.

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Abstract

The invention provides a composition that can alleviate or treat chronic pruritus (itch) by being applied to a lesion and a method for alleviating or treating chronic pruritus with the composition. The composition of the present invention comprises pregabalin and/or gabapentin in a base containing water. Pregabalin and/or gabapentin preferably exists in the form dissolved in water. Also, the method of the present invention can alleviate or treat pruritus by applying the composition to a lesion having chronic pruritus.

Description

DESCRIPTION
TITLE OF THE INVENTION: TOPICAL COMPOSITION
TECHNICAL FIELD
[0001]
The present invention relates to a topical composition containing pregabalin and/or gabapentin. More specifically, the present invention relates to a topical composition for improving itching by being applied to the skin or mucous membrane having chronic itch.
BACKGROUND ART
[0002]
Itchiness (pruritus) is an unpleasant feeling leading to the desire to scratch a region having itching, thus chronicity of itching worsens the quality of life (QOL) of patients. In addition, scratching behavior itself serves as a stimulus to cause further itching (positive feedback) . Thus, there is an important need to suppress itching and scratching behavior in patients with chronic itch. Of note, itch is the most frequent symptom in dermatology and a major problem for patient' s wellness. Despite that fact, only a few therapeutic agents for chronic pruritus exist (e.g. antihistamines, kappa opioid agonists) . Importantly, these treatments are effective only in a minority of all causes of chronic itch, often bear the risk of severe side effects such as myelosuppression, liver or kidney damage, depression, suicidal emotions, dizziness, just to name a few. Thus, the therapeutic options to treat chronic itch are very limited.
[0003]
For example, as a therapeutic agent exhibiting excellent effect on atopic dermatitis accompanied with chronic itching, a topical dosage form (salve such as ointment and cream) containing gluco-corticosteroid or tacrolimus is known. However, as for a gluco-corticosteroid preparation, long-term side effects such that the skin becomes thinner and turns red by long-term use are known, and thus limit their usage, despite its indication only in inflammatory itchy diseases. Furthermore, as for a tacrolimus preparation, it is known that there are many patients who complain about adverse symptoms (burning sensation, etc.) at the start of application, and its usage is limited to a few, T-cell-mediated diseases .
Thus, a topical composition containing gluco-corticosteroid or tacrolimus (pimecrolimus ) suppresses inflammation of the skin, thereby improving skin symptom in inflammatory pruritic diseases, but not non-inflammatory chronic pruritus (e.g. post- zoster itch, dry skin itch, itch of the elderly, tumor-associated itch, to name a few) . Hence, there is a problem that no effect is exhibited when there is no lesion that causes itching, even when having itching on the skin. Also, even when inflammation is suppressed, itching sometimes continues, thus it remains a clinical problem, even after the inflammation has disappeared.
[0004]
As an oral drug that suppresses itching, an antihistaminic preparation is best known. Its effectiveness, however, is limited to diseases in which the histamine-1 receptor (H1R) is involved, which are mainly the cases in urticaria and mastocytosis, but more than a dozen other origins of chronic itch are unrelated to the histamine-dependent itch pathway and thus do not respond to antihistamines .
When itching covers the wide area of the whole body, oral applications of gluco-corticosteroids , cyclosporins or other immunosuppressants are sometimes used. Unfortunately, all are associated with frequent and moderate to severe side effects, and are thus rarely or only shortly used.
Recently, successful treatments of various chronic pruritic diseases using oral (per os) pregabalin or gabapentin have been reported. For example, Non-Patent Literature 1 (Journal of Clinical Pharmacy and Therapeutics, 2013; 38; p.16-18) reports an effect of pregabalin on itching due to prurigo nodularis, and Non-Patent Literature 2 (Nephron Clinical Practice, 2012; 122; p .75-79) reports an effect of pregabalin and gabapentin on itchiness accompanied with chronic renal injury. [0005]
However, systemically-administered medicines, especially medicines such as pregabalin and gabapentin that cross the blood-brain barrier, bear the risk of inducing systemic side effects Particularly, when itching is chronic, often high dosages and long-term treatments that may cause a severe side effect on patients with a significant burden for patient's health are necessary. Particularly, the action site of pregabalin and gabapentin is considered to be the spinal cord as well as the brain. Because of its effect on nerve synaptic signaling, there still remains a major concern that the effects on the central nervous system will lead to significant side effect undesired by patients such as dizziness, drowsiness, sleepiness, headache, emesis, suicidal thoughts or worsening of depression or psycho-affective behavior.
SUMMARY OF THE INVENTION
PROBLEMS TO BE SOLVED BY THE INVENTION
[0006]
Therefore, an object of the present invention is to provide a topical composition that can exhibit a sufficient drug efficacy by topical application on the skin or mucous membrane to suppress itch, and can alleviate or treat chronic pruritus.
MEANS FOR SOLVING THE PROBLEMS [0007]
The present inventors have studied to solve the above problems, and consequently found that a composition containing pregabalin and/or gabapentin as an active pharmaceutical ingredient (API) and using a base containing water exhibits an excellent antipruritic effect on chronic pruritus by topical application, thereby completing the present invention.
[0008]
More specifically, the present invention relates to a topical composition for alleviating or treating chronic pruritus, comprising pregabalin and/or gabapentin in a base containing water. Here, in the composition of the present invention, the base refers to one in which the API (pregabalin/gabapentin) is removed from the composition of the present invention.
[0009]
In the composition, pregabalin and/or gabapentin preferably exists in the form dissolved in water.
[0010]
In addition, it is preferred that the composition contains
0.02 to 5% by weight of pregabalin or 0.05 to 20% by weight of gabapentin. The "% by weight" herein refers to a ratio of the weight of each component based on the total weight of the composition.
[0011] Also, the composition of the present invention can exhibit sufficient drug efficacy even when the active ingredient is only pregabalin and/or gabapentin.
[0012]
A preferred example of the composition of the present invention includes a composition substantially containing no oily ingredient as a solvent of pregabalin and/or gabapentin.
[0013]
The preferred dosage form of the composition of the present invention includes a solved lotion, a suspensive lotion, an emulsive lotion, a spray, a gel, a water-in-oil type cream, or an oil-in-water type cream. Particularly preferred dosage form includes a solved lotion, a spray or a gel containing water in an amount of 70% by weight or more.
[0014]
The composition of the present invention is particularly preferred to alleviate or treat chronic pruritus accompanied with a disease selected from the group consisting of atopic dermatitis, allergic or irritant contact dermatitis, psoriasis, pityriasis rubra pilaris, polymorphic light eruption and other chronic photodermatoses associated with itch, stasis dermatitis, chronic non-histamine related urticaria, antihistamine-unresponsive mastocytosis, lichen simplex chronicus, seborrhoeic dermatitis, xeroderma, chronic prurigo, prurigo pigmentosa, bullous pemphigoid-associated chronic itch, Dermatitis herpetiformis, lichen planus, chronic scabies , chronic post-arthropod itch (Id reaction), pregnancy-induced chronic itch (e.g. PUPPP) , eosinophilic pustular folliculitis, drug hypersensitivity reactions, cutaneous T cell lymphoma and other lymphomas or leukemias associated with chronic itch, neuropathic pruritus (brachioradial pruritus, postherpetic itch, notalgia paresthetica and other small fiber neuropathies) , chronic pruritus of the elderly or dry skin itch (local, generalized) , and pruritus at the scar portion after burn (post-burn itch) , genetic or nevoid chronic itches (e.g. Netherton syndrome, Darier's disease (Morbus Darier) , Hailey-Hailey disease, inflammatory linear verrucous epidermal nevus (ILVEN), familial primary cutaneous amyloidosis, olmsted syndrome) , aquagenic pruritus, fiberglass dermatitis, mucous chronic itch such as anogenital itch.
[0015]
Also, the present invention relates to a method for alleviating or treating pruritus by applying the composition on a lesion having chronic pruritus.
EFFECT OF THE INVENTION
[0016]
The composition according to the present invention is topically applied to a lesion having itching, whereby pregabalin and/or gabapentin can exhibit an antipruritic effect at an application position and improve itching. In addition, different from an oral administration preparation, the amount of pregabalin and/or gabapentin transferred into the blood is very small, thus no effect on the central nervous system is caused. Also, the composition according to the present invention exhibits an effect on chronic itching that is difficult to treat and has few options of a therapeutic agent. BRIEF DESCRIPTION OF THE DRAWINGS
[0017]
Fig. 1 is graphs showing the number of scratching bouts after applying a 2% aqueous pregabalin solution or vehicle to a chronic pruritus model mouse, in which (A) shows the number of scratching bouts per every 0.5 hour after application, and (B) is a graph showing the number of scratching bouts between 0.5 and 4 hours after application;
Fig. 2 is a graph showing the number of scratching bouts between 1 and 2 hours after applying an aqueous pregabalin solution or vehicle to a chronic pruritus model mouse;
Fig. 3 is a graph showing the number of scratching bouts counted in the period of 0 to 1 hour and 4 to 6 hours after challenge, when applying a 10% aqueous gabapentin solution or vehicle to a chronic pruritus model mouse at 1 hour before and 3 hours after challenge (application of an oxazolone acetone solution) ; and
Fig. 4 is a graph showing the change of pregabalin concentration in blood plasma after percutaneously administering or orally administering pregabalin.
MODE FOR CARRYING OUT THE INVENTION
[0018]
The composition of the present invention comprises pregabalin and/or gabapentin as an API in a base containing water. The structures of pregabalin and gabapentin are shown as follows;
Figure imgf000011_0001
(1) Pregabalin (2) Gabapentin
The terms "pregabalin" and "gabapentin" herein are intended to include not only "pregabalin" and "gabapentin" represented by the above structural formulas or ionic forms thereof but also pharmaceutically acceptable salts, complexes and solvates thereof, however they are not intended to include prodrugs thereof (the prodrug means a compound in which a functional group of pregabalin or gabapentin is substituted by another functional group or a compound in which a carbon-bonded hydrogen of pregabalin or gabapentin is substituted by any functional group) . Also, the term "pregabalin itself" herein refers to pregabalin represented by the above structural formula or ionic forms thereof (especially zwitterionic form) and the term "gabapentin itself" herein refers to gabapentin represented by the above structural formula or ionic forms thereof (especially zwitterionic form) .
[0019]
The Salts include, without limitation, acid addition salts and base addition salts, including hemisalts. Pharmaceutically acceptable acid addition salts may include nontoxic salts derived from inorganic acids (such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like) , as well nontoxic salts derived from organic acids (such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like) . Potentially useful salts include acetate, aspartate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, besylate, bicarbonate, carbonate, bisulfate, sulfate, pyrosulfate, bisulfite, sulfite, borate, camsylate, caprylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride, chloride, hydrobromide, bromide, hydroiodide, iodide, isethionate, isobutyrate, lactate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, phthalate, propionate, saccharate, sebacate, stearate, suberate, succinate, tartrate, tosylate, trifluoroacetate, and the like. Pharmaceutically acceptable base salts may include nontoxic salts derived from bases, including metal cations, such as an alkali or alkaline earth metal cation, as well as amines. Examples of potentially useful salts include, without limitation, aluminum, arginine,
N, ' -dibenzylethylenediamine, calcium, chloroprocaine, choline, diethanolamine, diethylamine, dicyclohexylamine, ethylenediamine, glycine, lysine, magnesium, N-methylglucamine, olamine, potassium, procaine, sodium, tromethamine, zinc, and the like.
Examples of solvates include hydrates and ethanolates.
[0020]
While the composition of the present invention may contain both of pregabalin and gabapentin or contain either one of them, a more preferred composition contains either one of them, and a particularly preferred composition contains pregabalin.
Also, it is preferable that the composition of the present invention contains the said pregabalin itself or gabapentin itself.
[0021] The composition of the present invention exhibits an excellent effect even when it does not contain other APIs. A particularly preferred example of the composition of the present invention includes a composition containing only pregabalin or gabapentin as the API. The "API" herein refers to an ingredient being useful for the treatment of the symptom to be treated by the composition of the present invention (i.e., chronic pruritus) , but does not refer to an ingredient which is added for unrelated purposes of treatment of the symptom. For example, a moisturizing ingredient does not fall within the definition of the active ingredient of the present invention, even if it has drug efficacy for improving dry condition of skin. Therefore, the composition of the present invention containing pregabalin and/or gabapentin together with a moisturizing ingredient falls within the definition of the composition containing only pregabalin and/or gabapentin as the active ingredient.
[0022]
The content of pregabalin in the composition of the present invention is preferably 0.02 to 5% by weight, more preferably 0.2 to 3% by weight, particularly preferably 0.5 to 2.5% by weight, furthermore preferably 1 to 2% by weight. The content of gabapentin is preferably 0.05 to 20% by weight, more preferably 1 to 15% by weight, particularly preferably 3 to 12.5% by weight, further preferably 5 to 10% by weight. When the composition of the present invention is applied to the skin, pregabalin and/or gabapentin is little observed in the blood plasma, and there is little risk of central nervous system side effects which are caused by oral administration. A particularly preferred example of the composition of the present invention includes a composition containing pregabalin in an amount of 3% by weight or less (particularly 2% by weight or less) .
[0023]
It is preferred that pregabalin and/or gabapentin in the composition of the present invention exists in the formulation dissolved in water. The preferred dosage form of the composition of the present invention includes a solved lotion, a suspensive lotion, an emulsive lotion, a spray, a gel, a water-in-oil type cream or an oil-in-water type cream. A particularly preferred dosage form is a solved lotion, a spray, or a gel.
The solved lotion, the suspensive lotion or the gel is a topical dosage form exhibiting a liquid form or a gel form in which pregabalin and/or gabapentin is dissolved or suspended in an aqueous solvent (including water) . The emulsive lotion, the water-in-oil type (w/o type) cream or the oil-in-water type (o/w type) cream is a topical dosage form exhibiting a liquid formulation or a creamy formulation which is obtained by emulsifying aqueous ingredients (including water) and oily ingredients with a surfactant and in which pregabalin and/or gabapentin exists in the formulation dissolved in the aqueous ingredients.
[0024]
When the dosage form of the composition of the present invention is the lotion or the gel, the aqueous solvent may consist of only water or a mixture of water and a water-soluble solvent. Examples of the water-soluble solvent include one or more solvents selected from the group consisting of polyhydric alcohols such as 1,3-butylene glycol, glycerin, propylene glycol and dipropylene glycol, lower monohydric alcohols such as ethanol and isopropyl alcohol and polar oils. A preferred water-soluble solvent is a polyhydric alcohol, and especially 1, 3-bulylene glycol is preferred. The content of the water-soluble solvent in the composition is preferably 2 to 30% by weight, more preferably 3 to 20% by weight, particularly preferably 4 to 15% by weight, furthermore preferably 5 to 10% by weight.
[0025]
When the dosage form of the composition of the present invention is the water-in-oil type cream, pregabalin and/or gabapentin is present in dissolved state in a water phase of a base (an emulsion base having an inner phase being the water phase and an outer phase being an oil phase) .
When the dosage form of the composition of the present invention is the emulsive lotion or the oil-in-water type cream, pregabalin and/or gabapentin is present in dissolved state in a water phase of a base (an emulsion base having an inner phase being an oil phase and an outer phase being the water phase) .
The water phase may contain a water-soluble ingredient together with water. As the water-soluble ingredient, just like the said water-soluble solvent, one or more selected from the group consisting of polyhydric alcohols such as 1,3-butylene glycol, lower monohydric alcohols such as ethanol, polar oils and so on could be used.
Examples of the oily ingredient which constitutes the oil phase include one or more selected from the group consisting of hydrocarbons, fats and oils, waxes, fatty acids, higher alcohols and esters.
Also, as the surfactant (emulsifying agent) for emulsifying the water phase and the oil phase and stabilizing the same, one or more selected from the group consisting of cationic surfactants, anionic surfactants, amphoteric surfactants and nonionic surfactants can be used.
[0026]
When the dosage form of the composition of the present invention is the spray, it can be prepared by filling the said lotion (liquid) into a spray container. A particularly preferred spray is a spray obtained by filling the solved lotion into the spray container [0027]
The content of water (purified water is preferred) in the composition of the present invention is preferably 7% by weight or more, more preferably 50% by weight or more, particularly preferably 70% by weight or more, further preferably 80% by weight or more.
Preferred examples of the composition of the present invention include a solved lotion, a spray or a gel containing 70% by weight or more (more preferably 80% by weight or more, particularly preferably 85% by weight or more) of the water.
Particularly preferred examples of the composition include a solved lotion, a spray or a gel containing an aqueous solvent (water and the water-soluble solvent) in the total amount of 90% by weight or more (more preferably 95% by weight or more) .
[0028]
A preferred example of the composition of the present invention includes a composition which substantially contains no oily ingredient having a solubility in water of 0.1% by weight or less at 20°C as a solvent for pregabaline and/or gabapentin. A more preferable composition is a composition which substantially contains no oily ingredient having a solubility in water of 1% by weight or less at 20°C as a solvent for pregabalin and/or gabapentin. The "solvent for pregabalin and/or gabapentin" herein refers to a component which can contain therein pregabalin and/or gabapentin in dissolved state. Also, "substantially contain no" means that its content in the composition is 3% by weight or less, preferably 2% by weight or less, more preferably 1% by weight or less.
A preferred example of the composition of the present invention includes a composition containing no oily ingredient as the solvent for pregabalin and/or gabapentin.
Amore preferred example includes a composition substantially containing no oily ingredient therein, and a particularly preferred example includes a composition containing no oily ingredient therein.
[0029]
The composition of the present invention may contain a thickener. The content of the thickener in the composition is preferably 0.01 to 10% by weight. The more preferable content of the thickener is 0.2 to 2% by weight.
Examples of the preferable thickener include carboxyvinyl polymer and water-soluble cellulose derivatives such as
hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and hydrophobized hydroxypropyl methyl cellulose. These may be used singly or in combination. A particularly preferred thickener is carboxyvinyl polymer.
[0030]
The composition of the present invention preferably has a pH value ranging from 3 to 10. A more preferable pH value is between 4 and 8, and particularly preferable pH value is between 5 and 7. When the pH value is less than 3 or more than 10, there is fear for the safety as a topical dosage form.
[0031]
As a pH modifier for adjusting the pH value of the composition within the aforementioned range, lactic acid, citric acid, phosphoric acid and so on can be used for adjusting to a low pH region, and an alkali metal and alkaline-earth metal hydroxide, sodium lactate, sodium citrate, L-arginine, diisopropanolamine and son on can be used for adjusting to a high pH region. A particularly preferred pH modifier is sodium hydroxide or potassium hydroxide.
[0032]
The composition of the present invention can contain a preservative (antiseptic agent) and a stabilizing excipient (viscosity stabilizer), besides the aforementioned ingredients. Also, the composition can contain any other additive which is generally used for a topical composition for skin.
[0033]
Examples of the preservative include methyl
parahydroxybenzoate, ethyl parahydroxybenzoate, propyl
parahydroxybenzoate, sodium benzoate, phenoxyethanol and so on. The preservative may be used singly or in combination. The content of the preservative in the composition is preferably within the range of 0.01 to 2% by weight, and more preferably within the range of 0.1 to 1.0% by weight. When it is more than 2% by weight, there is fear for the safety of a drug formulation.
[0034]
Examples of the stabilizing excipient (viscosity stabilizer) include sodium edetate hydrate, tetrasodium edetate hydrate, tetrasodium edetate tetrahydrate, sodium metaphosphate and so on. The content of the viscosity stabilizer in the composition is preferably within the range of 0.005 to 1% by weight, and more preferably within the range of 0.01 to 0.5% by weight. When it is more than 1% by weight, there is fear for the safety of a drug formulation. A particularly preferred viscosity stabilizer is sodium edetate hydrate.
[0035]
The composition of the present invention can exhibit sufficient drug effect even when it contains no lower monohydric alcohol (monohydric alcohol with 1 to 3 carbon atoms) such as ethanol Since the lower monohydric alcohol such as ethanol is high volatile and there is concern about affecting skin when it is added to a topical dosage form, it is preferable that the composition of the present invention does not contain the lower monohydric alcohol.
Also, the composition of the present invention can exhibit sufficient drug effect even when it contains no substance exhibiting a percutaneous absorption promoting action such as
dimethylsulfoxide (DMSO) . [0036]
The composition of the present invention can alleviate or treat itching by being applied to a region (such as a skin and a mucous membrane) having chronic itching. The composition of the present invention is particularity suitable for alleviating or treating chronic pruritus of skin. Contrary to a topical dosage form containing steroid or tacrolimus which alleviates itching by suppressing inflammation, the composition of the present invention can alleviate itching despite a lack of inflammation-suppressive effect. Therefore, the composition of the present invention has efficacy for cutaneous pruritus which is characterized by intense itching of skin despite a lack of primary skin rash on the surface of the skin. The dermal pruritus arises from a variety of causes, and there are cases resulting from visceral diseases such as chronic renal failure, liver disease and diabetes or cases resulting from skin dryness caused by aging or environment (such as low-humidity or cold) . Although the cutaneous pruritus is characterized by the development of itching despite a lack of lesion that causes the itching of skin, there are cases that scratches and eczemas on skin are caused by scratching the skin because of the itching.
Other examples of disorder accompanied with chronic itching include atopic dermatitis, contact dermatitis, seborrhoeic dermatitis, psoriasis, lichen planus and so on (full list, see paragraph [0014]), which are characterized in that a skin inflammation such as eczema develops, thereby causing itching . The composition of the present invention also has efficacy for itching due to abnormality (such as inflammation) on the surface of skin.
It is known that the number of therapeutic agents having efficacy for chronic itching is small and the option of the therapeutic agent is very limited, however, the composition of the present invention also has an efficacy for the abovementioned chronic itching.
[0037]
The amount and the frequency of administration of the composition of the present invention onto a lesion site may be appropriately regulated in accordance with the severity of itchiness, the concentration of pregabalin and/or gabapentin in the composition, the patient's age and body weight and so on.
Generally, it can be applied to the lesion site ( skin or mucosa membrane) from once a day to three times a day and the daily dosage thereof (the amount of pregabalin itself and/or gabapentin itself) is about 5 to 15 mg. The oral preparation of pregabalin which are currently available in Japan is administered to an adult in a drug dose of 150-300 mg (up to 600mg) per day and the oral preparation of gabapentin which are currently available in Japan is administered to an adult in a drug dose of 600-1800 mg (up to 2400mg) per day. Therefore, according to the present invention, it is possible to improve the symptom at a much lower dose than the oral preparation. [0038]
Names of the preferred compounds of the optional components used in the composition of the present invention are described in the preceding paragraphs. Examples of the composition of the present invention include compositions in which these compounds are arbitrarily combined, and further include compositions in which the respective concentration ranges described about the essential components and the optional components are arbitrarily combined. The respective numerical ranges of the concentrations, the pH values, and the like that are described in the preceding paragraphs may be arbitrarily combined. When plural numerical ranges are described, the respective upper limit values of the numerical ranges or the respective lower limits thereof may be arbitrarily combined.
[0039]
In the following, the present invention will be described more specifically by Examples, however, the present invention is not limited by these examples. Percentages expressed in Examples refer to weight percentages unless otherwise specified. Pregabalin and Gabapentin used in Examples are "pregabalin itself" and "gabapentin itself" represented by the above structural formula.
EXAMPLES
[0040]
[Examination of base] Solubility of pregabalin in each of solubilizers was tested. The result is shown in Table 1. As seen from Table 1, pregabalin was little dissolved in each solubilizer regardless of whether it was an oily solvent or an aqueous solvent. Upon examining solubility in water, the saturated solubility in water was about 3%. As well as pregabalin, Gabapentin was little dissolved in each solubilizer shown in Table 1.
[0041]
Table 1. Saturated solubility of pregabalin in each solubilizer
Figure imgf000025_0001
[0042]
It was expected that pregabalin or gabapentin was unsuitable for percutaneous administration because it need to be dissolved in an oily solvent in order to increase the absorption thereof when administered percutaneously . However, contrary to the expectation, subsequent studies showed that a composition in which pregabalin or gabapentin is dissolved in water exhibits dug efficacy when administered precutaneously .
Therefore, efficacy and safety when a composition comprising pregabalin and/or gabapentin in a base containing water is applied topically to a skin were studied.
[0043]
[Example 1] Effect of Pregabalin Percutaneous Administration in Mite Extract Ointment-Induced Pruritus Model (PAR20E mouse) (Suppression of Scratching Behavior)
<Mouse and Material Used in This Experiment>
PAR20E Mouse (provided by Dr. Shaun Coughlin at University of California at San Francisco [UCSF] )
Biostir AD (atopic dermatitis causing ointment including mite allergens derived from Dermatophagoides farinae)
Pregabalin
[0044]
<Creation of Atopic Dermatitis Model (Chronic Itch Model) >
The ointment (Biostir AD) was applied to the back of the neck of PAR20E mouse twice a week for 6 weeks. The scratching behavior of each mouse was monitored for an hour at the same time each day of 4, 5 and 6 days after the last application of the ointment and the individual, for which the scratching bouts were observed at least 100 per hour, was selected as the chronic itch model. After the said application of Biostir AD twice a week for 6 weeks, Biostir AD was applied to the model once a week in order to keep the inflammation.
[0045]
<Application of Test Substance and Counts of Number of Scratching Bouts>
Ten (10) mice were divided into 2 groups (5 mice per group), and vehicle (0.1% aqueous Tween 20 solution) was applied to one group (group A) as a control, and a 2% aqueous pregabalin solution prepared by adding pregabalin to the vehicle was applied to other group (group B) , and the number of scratching bouts was counted.
Next, to eliminate the influence of an individual difference, after one week, the 2% aqueous pregabalin solution was applied to the group A, and the vehicle was applied to the group B, and the number of scratching bouts was counted.
After applying the vehicle or 2% aqueous pregabalin solution, all the individuals were recorded for 4 hours, and the number of scratching bouts was visually counted using the recorded data.
The mean number and standard deviation of the number of scratching bouts every 30 minutes from the start of application are shown in Table 2 and Fig. 1 (A) .
[0046] Table 2. Number of scratching bouts 6=10)
Figure imgf000028_0001
[0047]
As shown in Table 2 and Fig. 1 (A) , it was found that the number of scratching bouts at 0 to 0.5 hour after application tends to be largest in both groups, throughout the entire observation time. The cause of this tendency is considered that the behavior intended to wipe off the adhered foreign matter (test substance) of the mouse to which the test substance was applied appeared as the scratching behavior at 0 to 0.5 hour after application. After 0.5 hour after application, the number of scratching bouts remarkably decreases as compared to the number at 0 to 0.5 hour after application in both groups. In the pregabalin (2%) applied group, after 0.5 hour after application, a significant decrease in the number of scratching bouts was found as compared to the decrease in the vehicle group.
[0048]
The number of scratching at 0.5 to 4 hours after application of the test substance is shown in Fig. 1 (B) . As can be seen from Fig. 1 (B) , the mean number of scratching bouts at 0.5 to 4 hours exceeded 600 times (633 times) in the vehicle group, whereas the mean number fell below 200 times (184 times) in the 2 % agueous pregabalin solution group.
[0049]
Based on the present example, it could be confirmed that the composition of the present invention shows a significant antipruritic effect in an atopic dermatitis model (chronic itch model) . Also, while the mouse used in the present test had dermatitis, a significant healing effect on dermatitis by 2% pregabalin application could not be confirmed. When a steroid product is applied to an atopic dermatitis model, dermatitis is significantly improved, and the number of scratching bouts accordingly decreases. Thus, it is considered that a pregabalin-containing composition alleviates only pruritus regardless of the treatment of inflammation, different from a steroid product . Therefore, it is considered that the composition of the present invention is effective also for pruritus not accompanied by inflammation, different from a steroid product.
[0050]
[Example 2] Effect of Pregabalin Percutaneous Administration in Mite Extract Ointment-induced Pruritus Model (NC/Nga Mouse) (Suppression of Scratching Behavior)
<Mouse and Material Used in This Experiment> NC/Nga TndCrlj Mouse (purchased from Charles River Laboratories Japan, Inc . )
Biostir AD (atopic dermatitis causing ointment including mite allergens derived from Dermatophagoides farinae)
Pregabalin
[0051]
<Creation of Atopic Dermatitis Model (Chronic Itch Model) >
I. Initial Sensitization
The back part and auricular part of NC/Nga mouse was sheared with a hair clipper and an electric shaver, then a depilatory (trade name: epilat, manufactured by Kracie Holdings, Ltd.) was applied in an appropriate amount, and hair was removed.
After wiping off the depilatory, 100 mg of the ointment (Biostir AD) was uniformly applied to the back part and auricular part of the mouse.
II. Second or Later Challenge
After removing hair of the mouse with a shaver as necessary,
150 μΐ of a 4% aqueous SDS solution was added dropwise and uniformly applied to the back of the neck.
Thereafter, the mouse was naturally dried for 2 or 3 hours,
100 mg of Biostir AD was uniformly applied to the back of the neck. The second or layer challenge treatment was performed twice a week for 3 weeks, and an atopic dermatitis mouse was prepared by a total of 6 times of treatment. After a lapse of 3 weeks, the mouse had an inflammation on the skin, and continued scratching behavior even when Biostir AD was not applied.
[0052]
Control (vehicle) or an aqueous pregabalin solution (0.2%, 2%) was percutaneously administered to the atopic dermatitis model once a day, for consecutive 3 days. The application amount was set to 50 μΙ/ιηου36. Here, the vehicle was a 0.1% aqueous Tween 80 solution, and the aqueous pregabalin solution was prepared by adding pregabalin to the vehicle.
[0053]
<Counts of Number of Scratching Bouts>
After applying control (vehicle) or an aqueous pregabalin solution to mice, all the individuals were recorded for 4 hours, and the number of scratching bouts was visually counted using the recorded data.
Here, it was found that the number of scratching bouts at 0 to 1 hour after application tends to be largest in each group, throughout the entire observation time. The cause of this tendency is considered that behavior intended to wipe off the adhered foreign matter (test substance) of the mouse to which the test substance was applied appeared as the scratching behavior at 0 to 1 hour after application .
The mean number of scratching bouts per an hour at 1 to 4 hours after application, on Day 1, Day 2 and Day 3 of application is shown in Table 3. It can be seen from Table 3 that, in the vehicle and pregabalin (0.2%) applied groups, a tendency that the number of scratching bouts increased or decreased was not found, and scratching behavior was constantly found, throughout the observation time at 1 to 4 hours after application. On the other hand, in the pregabalin (2%) applied group, a tendency to suppress the number of scratching bouts at 1 to 4 hours after application was found, and a significant decrease in the number of scratching bouts was found at a significance level of 1% on Day 3 of application, as compared to the decrease in the vehicle group.
[0054]
Table 3. Number of scratching bouts between 1 and 4 hr after application (n=8)
Figure imgf000032_0001
a) Mean mumber of scrathing bouts between 1 and 4 hr after application ffiean+S.E.)
[0055]
In addition, at 1 to 2 hours after application, the difference in the number of scratching bouts was further remarkable. The numbers of scratching counted at 1 to 2 hours after application are shown in Table 4 and Fig. 2. Table 4. Number of scratching bouts between 1 and 2 hr after application (n=8)
Mean number of scratching bouts (times/h)a>
Test group
Day 1 Day 2 Day 3
Vehicle 178140 184+44 179+30
i 0.2% Pregabalin 97124 166+42 106+22
2% Pregabalin 62 +15 60+13 65+ 10
a) Mean mumber of scrathing bouts between 1 and 2 hr after application ffiean+S.E.)
[0056]
As can be seen from Table 4 and Fig. 2, in the 2% pregabalin applied group, the number of scratching bouts counted at 1 to 2 hours after application remarkably decreased as compared to the number in the vehicle applied group, and a significant decrease in the number of scratching bouts was found at a significance level of 1% on Day 1 and Day 3 of application. Furthermore, a significant decrease in the number of scratching bouts was found at a significance level of 5% on Day 2 of application.
In addition, in the 0.2% pregabalin applied group, a significant decrease in the number of scratching bouts was found at a significance level of 5% on Day 1 and Day 3 of application, as compared to the decrease in the vehicle applied group.
From the above results, it was confirmed that an antipruritic effect by percutaneous administration of an aqueous pregabalin solution was concentration dependent, and a scratching behavior-suppressing action was found in an early stage after application .
[0057]
Here, in the present example, since a healing effect on dermatitis of mouse model by pregabalin application was not confirmed, also from the result of the present example, the suppression of itchiness by pregabalin application is considered to be independent of the suppression of inflammation.
[0058]
[Example 3] Effect of Gabapentin Percutaneous Administration in Oxazolone-Induced Pruritus Model (BALB/c Mouse) (Suppression of Scratching Behavior)
<Mouse and Material Used in This Experiment>
BALB/cAnNCrlCrlj mouse (purchased from Charles River Laboratories Japan, Inc.)
Gabapentin
Oxazolone ( 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one ; produced by Wako Pure Chemical Industries, Ltd.)
[0059]
<Creation of Oxazolone-Induced Recurrent Pruritus Model (Chronic Itch Model) >
I. Sensitization
The back of the neck of the mouse was sheared with an electrical hair clipper and a safety razor, then 10 μL/site of 0.5% (w/v) oxazolone acetone solution was applied to the sheared part (percutaneous sensitization) .
I I . Challenge
From the Seventh day (referred to as challenge day 0) after the percutaneous sensitization, 10
Figure imgf000035_0001
of 0.5% (w/v) oxazolone acetone solution was applied to the same area at 2- or 3-day intervals (challenge days 0, 2, 4, 7, 9, 11, 14, and 16) . On challenge day 16 (after the last oxazolone application), the scratching behavior of the mouse was monitored in the following way.
[0060]
<Application of Test Substance>
At 1 hour before and 3 hours after the last application of oxazolone acetone solutin on challenge day 16, control (vehicle) or a 10% aqueous gabapentin solution was percutaneously administered to the mouse. The vehicle was a 0.1% aqueous Tween 80 solution, and the 10% aqueous gabapentin solution was prepared by adding gabapentin to the vehicle. The amount of percutaneous administration was set to each 60 μΐ, (60 μΐ, x twice, total of 120 μ-L) .
[0061]
<Counts of Number of Scratching Bouts>
The scratching behavior was recorded for 1 hour immediately after challenge (0 to 1 hour after challenge) and for 2 hours from 4 hours after challenge (4 to 6 hours after challenge) , and the number of scratching bouts was visually counted using the recorded data. The results are shown in Table 5 and Fig. 3.
[0062]
Table 5. Number of scratching bouts (n=5)
Number of scratching bouts
Test group between 0 and 1 hour between 4 and 6 hours
after challenge after challenge
Vehicle 225±38 132±77
10% Gabapentin 105±29 25±8
i(iean±S . E . )
[0063]
As shown in Table 5 and Fig. 3, a significant decrease in the number of scratching bouts at 0 to 1 hour after challenge was shown by percutaneous administration of the aqueous gabapentin solution, as compared to the vehicle group.
Here, while the model mouse used in the present test also had dermatitis, a healing effect on inflammation by gabapentin application was not confirmed. Therefore, as well as pregabalin, the suppression of itchiness by gabapentin application is also considered to be independent of the suppression of inflammation.
[0064]
[Example 4] Evaluation of Central Nervous System Side Effect of
Pregabaline Percutaneous Administration (Coordinated
Movement-Suppressing Action)
<Mouse Used in This experiment> C57BL/ 6NCrlCrlj Mouse (purchased from Charles River Laboratories Japan, Inc . )
<Test Substance>
Test substances are shown in Table 6. Pregabalin (PGB) for oral administration was dissolved in injection water, and pregabalin for percutaneous administration was dissolved in a 0.1
Tween 80 solution, so as to have the following concentration.
Figure imgf000037_0001
[0065]
<Test Method> A test substance was orally administered (25 mL/kg) or percutaneously administered (50 μΐ,) to the back of the neck of the mouse. In the percutaneous administration, hair in the back of the neck of the mouse was removed using an electric hair clipper and an electric shaver, then the stratum corneum was exfoliated 10 times with a mending tape while rotating the peeling direction by 90 degrees. After 30, 60, 90 and 120 minutes after administering the test substance, the mouse was transferred to a rota-rod at a rate of 15 rpm or 20 rpm, and the residence time was measured (measured for up to 60 seconds) . The severer the central nervous system side effects (coordinated movement-suppressing action) by pregabalin, the shorter the residence time. A breeding for acclimating mice to a rota-rod apparatus was performed in advance, and an individual mouse that does not fall from the rota-rod for 60 seconds or more was selected and used for a test. The result of 15 rpm rota-rod is shown in Table 7, and the result of 20 rpm rota-rod is shown in Table 8.
[0066]
Table 7. Residence time (15rpm Rota-rod, n=5)
Figure imgf000039_0001
i(iean+SD)
[0067]
As can be seen from Table 7 and Table 8, in the case of percutaneously administering pregabalin, at a rotation rate of 15 rpm, a declining tendency of the residence time was seen in a 300 mg/kg administration group, and the residence time significantly decreased in a 1000 mg/kg administration group. Furthermore, at a rotation rate of 20 rpm, a significant decrease in the residence time was observed not only in the 1000 mg/kg administration group but also in the 300 mg/kg administration group, and coordinated movement-suppressing action by oral administration of pregabalin was confirmed.
On the other hand, in the pregabalin percutaneous administration group, a declining tendency of coordinated movement ability was not observed at rotation rates of both 15 and 20 rpm.
[0068]
[Example 5] Observation of Concentration Change of Pregabalin in Blood Plasma
<Mouse used in this Experiment>
C57BL/ 6NCrlCrlj Mouse (purchased from Charles River Laboratories Japan, Inc . )
<Test Substance>
Test substances are shown in Table 9. Pregabalin (PGB) for oral administration was dissolved in injection water, and pregabalin for percutaneous administration was dissolved in a 0.1 % agueous Tween 80 solution, so as to have the following concentration. Table 9
Test substance Concentration Vehicle
30mg/kg PGB (oral
2.5mg/mL Injection water administration)
300mg/kg PGB (oral
25mg/mL Injection water administration)
0.2% PGB (percutaneous 0.1% aqueous
0.2%
administration) Tween80 solution
2% PGB (percutaneous 0.1% aqueous
2%
administration) Tween80 solution
[0069]
<Test Method>
A test substance was orally administered (12 mL/kg) or percutaneously administered (50 μΐ,) to the back of the neck of the mouse. In the percutaneous administration, hair in the back of the neck of the mouse was removed using an electric hair clipper and an electric shaver, then the stratum corneum was exfoliated 10 times with a mending tape while rotating the peeling direction by 90 degrees. After oral or percutaneous administration, the mouse was retained in the back position under isoflurane anesthesia after 5, 15, 30, 60, 120 and 240 minutes, and blood sampling from the abdomen aorta was performed with a syringe treated with heparin sodium. The blood was immediately ice-cooled, and centrifuged (about 1850 x g, 4°C, 15 min) to collect blood plasma, and unchanged pregabalin was quantified by a liquid chromatography tandem mass spectrometry (LC/MS/MS) . The result was shown in Table 10 and Fig. 4 (the scale interval of the vertical axis was altered from the middle in Fig. 4) .
[0070] iTable 10. Pregabalin concentration in plasma 6 = 3)
Time after Concentration in blood plasma i&g/mL)
: admini stration 0.2% 2% 30mg/kg 300mg/kg
(min) (percutaneous ) (percutaneous ) (oral) (oral)
5 0 58810. 169 7.490+1.736 15.48+11.40 131.3+36.4
15 1 07410. 507 12.3914.59 25.70+1.91 297.8+62.5
30 1 942+0. 350 13.80+1.21 23.72+2.97 263.9+24.1
60 1 700+0. 483 14.53+6.80 16.40+1.58 197.0+9.7
120 1 447+1. 061 5.931+2.381 8.362+1.254 84.65+12.84
240 0 369+0. 068 2.364+0.361 1.660+0.328 31.73+6.62
i(iean+SD) [0071]
As shown in Table 10 and Fig. 4, the concentration of pregabalin in blood plasma was high, in the 300 mg/kg oral administration group in which the expression of central nervous system side effects was observed in Example 4, and the highest concentration reached nearly 300 μg/mL. In comparison with the above, the concentrations of pregabalin in blood plasma in the 30 mg/kg oral administration group, 0.2% percutaneous administration group and 2% percutaneous administration group in which the expression of central nervous system side effects was hardly or not observed at all were significantly low. In addition, the highest concentration in blood plasma in the 30 mg/kg oral administration group was about 25 μg/mL, whereas it was about 15 μg/mL (2% percutaneous administration group) or about 2 μg/mL (0.2% percutaneous administration group) in the percutaneous administration groups. Therefore, it was supported that, in the percutaneous administration of pregabalin, the amount of pregabalin transferred to blood plasma is very small, and a central nervous system side effect is not caused.
[0072]
[Example 6] Examination of Effect of Pregabalin on Histamine-Induced Scratching Behavior (Acute Itchiness)
<Mouse Used in This Experiment>
ICR Mouse (purchased from Japan SLC, Inc.)
< Test Substance>
Test substances are shown in Table 11.
Figure imgf000043_0001
In Table 11, PGB represents pregabalin, DPH represents diphenhydramine and MC represents methylcellulose.
[0073]
<Test Method> A test substance is orally administered (5 mL/kg) or percutaneously administered (50 μΐ,) to the back part of the mouse. In the percutaneous administration, hair in the back part of the mouse was removed using an electric hair clipper and an electric shaver under isoflurane anesthesia, and then application was performed. At 1 hour after administration, 50 μΐ, of an itch-inducing agent (25 nmol histamine solution: the solvent was a phosphate buffered physiological saline) was intradermally administered, and the induced scratching behavior was monitored for 30 minutes. The results are shown in Table 12.
[0074]
Table 12. Numbers of scratching bouts £=3-4)
Numbers of scratching bouts
Test group
(30min)
Vehicle (oral) 55.6712.3
Vehicle (percutaneous) 82150.6
Pregabalin (percutaneous) 70.25117.2
Pregabalin (oral) 1216.4
diphenhydramine (oral) 20+10.8
i(iean±S . E . ) i
[0075]
As can be seen from Table 12, it was shown that oral administration of pregabalin significantly decreases the number of scratching bouts due to histamine-induced pruritus, and is effective to acute itching as reported in documents. Also, oral administration of diphenhydramine also significantly decreased the number of scratching bouts due to histamine-induced pruritus. On the other hand, a significant decrease in the number of scratching bouts was not observed by percutaneous administration of pregabalin, and it was shown that the percutaneous administration of pregabalin is not effective to acute itching.
[0076]
[Example 7] Preparation of Composition Containing Pregabalin or Gabapentin
Preferred examples of the composition (the dosage form is a gel) containing pregabalin (or gabapentin) are shown in Table 13. The compositions in Table 13 were prepared by the following procedures .
First, pregabalin (or gabapentin), 1,3-butylene glycol, methyl parahydroxybenzoate, a sodium edetate hydrate, purified water and carboxyvinyl polymer (aqueous solution) were weighed, put into one container, and warmed. Pregabalin (or gabapentin) was dissolved and confirmed to be a uniform solution, then sodium hydroxide (aqueous solution) was added as a pH adjuster, and the mixture was stirred, whereby pregabalin (or gabapentin) was dissolved in an aqueous base (a base mainly consisting of a mixture of water and 1, 3-butylene glycol) , and a gel in which pH was adjusted to 5.5 to 6.0 was obtained.
[0077] Table 13. Composition of each gel containing pregabalin or gabapent
Numerical values in Table represent % by weight)
Figure imgf000046_0001
INDUSTRIAL APPLICABILITY
[0078]
The composition according to the present invention exhibits an antipruritic effect on chronic itching, and has a low expression risk of central nervous system side effects, thus is useful as a therapeutic agent for a patient suffered from chronic pruritus. In addition, the composition according to the present invention can suppress not only itchiness accompanied with inflammation but also itchiness not accompanied with inflammation, and thus an antipruritic effect is expected also on dermal pruritus that cannot be treated by steroid or tacrolimus.

Claims

1. A topical composition for alleviating or treating chronic pruritus, comprising pregabalin and/or gabapentin in a base containing water.
2. The composition according to claim 1, wherein pregabalin and/or gabapentin exists in the form dissolved in water.
3. The composition according to claim 1 or 2, comprising 0.02 to 5% by weight of pregabalin or 0.05 to 20% by weight of gabapentin .
4. The composition according to any one of claims 1 to 3, wherein the active pharmaceutical ingredient contained in the composition is only pregabalin and/or gabapentin.
5. The composition according to any one of claims 1 to 4, substantially containing no oily ingredient as a solvent of pregabalin and/or gabapentin.
6. The composition according to any one of claims 1 to 5, wherein the dosage form of the composition is a solved lotion, a suspensive lotion, an emulsive lotion, a spray, a gel, a water-in-oil type cream or an oil-in-water type cream.
7. The composition according to any one of claims 1 to 6, which is a solved lotion, a spray or a gel containing water in an amount of 70% by weight or more.
8. The composition according to any one of claims 1 to 7, for alleviating or treating chronic pruritus accompanied with a disease selected from the group consisting of atopic dermatitis, allergic or irritant contact dermatitis, psoriasis, pityriasis rubra pilaris, polymorphic light eruption and other chronic photodermatoses associated with itch, stasis dermatitis, chronic non-histamine related urticaria, antihistamine-unresponsive mastocytosis, lichen simplex chronicus, seborrhoeic dermatitis, xeroderma, chronic prurigo, prurigo pigmentosa, bullous
pemphigoid-associated chronic itch, dermatitis herpetiformis, lichen planus, chronic scabies, chronic post-arthropod itch (Id reaction), pregnancy-induced chronic itch (e.g. PUPPP) ,
eosinophilic pustular folliculitis, drug hypersensitivity reactions, cutaneous T cell lymphoma and other lymphomas or leukemias associated with chronic itch, neuropathic pruritus
(brachioradial pruritus, postherpetic itch, notalgia paresthetica and other small fiber neuropathies) , chronic pruritus of the elderly or dry skin itch (local, generalized) , and pruritus at the scar portion after burn (post-burn itch) , genetic or nevoid chronic itches (e.g. Netherton syndrome, Darier's disease, Hailey-Hailey disease, ILVEN, familial primary cutaneous amyloidosis, olmsted syndrome) , aquagenic pruritus, fiberglass dermatitis, mucous chronic itch such as anogenital itch.
9. A method for alleviating or treating pruritus by applying the composition according to any one of claims 1 to 8 on a lesion having chronic pruritus.
10. A method according to claim 9, for alleviating or treating chronic pruritus accompanied with a disease selected from the group consisting of atopic dermatitis, allergic or irritant contact dermatitis, psoriasis, pityriasis rubra pilaris , polymorphic light eruption and other chronic photodermatoses associated with itch, stasis dermatitis, chronic non-histamine related urticaria, antihistamine-unresponsive mastocytosis, lichen simplex chronicus, seborrhoeic dermatitis, xeroderma, chronic prurigo, prurigo pigmentosa, bullous pemphigoid-associated chronic itch,
dermatitis herpetiformis, lichen planus, chronic scabies, chronic post-arthropod itch (Id reaction), pregnancy-induced chronic itch
(e.g. PUPPP) , eosinophilic pustular folliculitis, drug
hypersensitivity reactions, cutaneous T cell lymphoma and other lymphomas or leukemias associated with chronic itch, neuropathic pruritus (brachioradial pruritus, postherpetic itch, notalgia paresthetica and other small fiber neuropathies) , chronic pruritus of the elderly or dry skin itch (local, generalized) , and pruritus at the scar portion after burn (post-burn itch) , genetic or nevoid chronic itches (e.g. Netherton syndrome, Darier's disease, Hailey-Hailey disease, ILVEN, familial primary cutaneous amyloidosis, olmsted syndrome) , aquagenic pruritus, fiberglass dermatitis, mucous chronic itch such as anogenital itch.
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