WO2014168228A1 - Composition pour usage topique - Google Patents

Composition pour usage topique Download PDF

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Publication number
WO2014168228A1
WO2014168228A1 PCT/JP2014/060453 JP2014060453W WO2014168228A1 WO 2014168228 A1 WO2014168228 A1 WO 2014168228A1 JP 2014060453 W JP2014060453 W JP 2014060453W WO 2014168228 A1 WO2014168228 A1 WO 2014168228A1
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WIPO (PCT)
Prior art keywords
pregabalin
composition
water
composition according
pain
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PCT/JP2014/060453
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English (en)
Japanese (ja)
Inventor
木戸　裕子
磨耶子 交久瀬
栄次郎 堀沢
史紀 鳴海
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マルホ株式会社
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Publication of WO2014168228A1 publication Critical patent/WO2014168228A1/fr

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    • 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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a topical composition containing pregabalin. More specifically, the present invention relates to a topical composition for improving symptoms at an application site by applying to the skin.
  • Oral drugs of pregabalin or gabapentin which are calcium channel ⁇ 2 ⁇ ligands, are widely used worldwide as first-line drugs for neuropathic pain. Orally ingested pregabalin and gabapentin reduce Ca 2+ influx at the synaptic end through binding to the ⁇ 2 ⁇ subunit present in the pre-neural synapse, thereby suppressing excessive release of excitatory transmitters. It is thought to exert analgesic action.
  • the site of action of pregabalin and gabapentin has been considered to be the center of the spinal cord and brain where the synaptic gap exists. Therefore, the pregabalin preparation and the gabapentin preparation currently on the market are only preparations for systemic administration (oral drugs).
  • Non-Patent Document 1 is a document disclosing a transdermal absorption patch as a transdermal drug delivery system (TDDS) of pregabalin.
  • TDDS transdermal drug delivery system
  • Non-Patent Document 1 discloses a patch for controlling the release of pregabalin over a long period of time in order to minimize the frequency of drug administration.
  • the patch of Non-Patent Document 1 is a systemic circulation type transdermal absorption preparation.
  • Patent Document 1 is a document disclosing a topical composition and a therapeutic method containing a prodrug of gabapentin or pregabalin.
  • Patent Document 1 teaches the use of prodrugs because gabapentin and pregabalin have limited percutaneous absorption following topical administration due to their physicochemical properties and the passive nature of gabapentin. For reasons such as limited permeability.
  • treatment of neuropathic pain using an ointment containing a prodrug of gabapentin is disclosed.
  • Non-Patent Document 2 is a document disclosing the topical administration of pregabalin for the treatment of neuropathic orofacial pain.
  • Non-Patent Document 2 discloses a composition for skin using PLO (Pluronic® Lecithin® Organogel) and anhydrous gel as a base, and further, topical application of a composition containing 10% pregabalin can reduce pain. It is disclosed that it is the most effective.
  • Patent Document 2 discloses a topical composition for treating peripheral neuropathy comprising at least one NMDA (N-methyl-D-aspartate) antagonist and an anticonvulsant.
  • NMDA N-methyl-D-aspartate
  • Patent Document 2 15-30% by weight of ketamine hydrochloride as the NMDA antagonist, 6% by weight of gabapentin as the anticonvulsant, 7.25-22% by weight of water, and Lipoderm (registered trademark) base
  • Lipoderm® base accounts for more than about 50% of the topical composition, and about 70% of the composition is Lipoderm® base. It is disclosed that it is preferable.
  • Non-Patent Document 3 has been considered gabapentin solubilization in H II intermediate layer (mesophase) in the intermediate layer is disclosed to permit a sustained release of gabapentin.
  • Patent Document 1 uses gabapentin prodrug
  • Patent Document 2 uses NMDA antagonist and gabapentin in combination
  • Non-Patent Document 2 uses a large amount (10%) in a base composed of PLO and anhydrous gel.
  • Non-patent document 3 actually discloses the sustained release of gabapentin, respectively.
  • a drug having a central action such as gabapentin or pregabalin is preferably administered in a small amount even when administered transdermally. Therefore, there is still a demand for the development of a calcium channel ⁇ 2 ⁇ ligand-containing composition capable of rapidly exerting sufficient efficacy with local administration of a small amount of drug.
  • an object of the present invention is to provide a calcium channel ⁇ 2 ⁇ ligand-containing composition that has a sufficient medicinal effect by locally administering a small amount to the skin, has a rapid onset of medicinal effect, and has few side effects. To do.
  • the present inventors have repeatedly studied on a skin composition containing a calcium channel ⁇ 2 ⁇ ligand, and as a result, by using a base containing water as the base of the composition.
  • the inventors have found that even if the pregabalin content is small (3 wt% or less), excellent medicinal effects can be obtained quickly.
  • using the above-mentioned base containing water using pregabalin as an active ingredient provides higher efficacy than using the same amount of gabapentin, and gabapentin has a concentration of about 1% by weight.
  • the efficacy of pregabalin increases in a concentration-dependent manner even when the concentration exceeds 1% by weight, and the present invention has been completed.
  • the present invention is a composition for topical application to the skin, wherein pregabalin is contained in a base containing water, and the pregabalin content is 0.2 to 3% by weight relative to the total amount of the composition. It is characterized by being.
  • the base means a composition obtained by removing the active ingredient (pregabalin) from the composition according to the present invention.
  • composition according to the present invention can exhibit excellent medicinal effects even if the pregabalin content is small (0.2 to 3% by weight).
  • “% by weight” means the ratio of the weight of each component to the total weight of the composition.
  • the composition which concerns on this invention can exhibit sufficient medicinal effect, even if an active ingredient is only pregabalin.
  • composition according to the present invention a composition substantially free from oily components as a pregabalin solubilizer can be mentioned.
  • pregabalin is preferably present in a form dissolved in water.
  • compositions according to the present invention include solution lotions, emulsion lotions, sprays, gels, water-in-oil creams, and oil-in-water creams.
  • Particularly preferred dosage forms include solution lotions, sprays or gels containing 70% by weight or more of water.
  • composition according to the present invention can be used as an analgesic external preparation that is applied to an affected skin area in which neuropathic pain occurs and reduces pain.
  • neuropathic pain include postherpetic neuralgia, diabetic neuralgia, acute herpes zoster pain, myofibrogia, complex regional pain syndrome (CRPS), chemotherapy-induced neuropathy, trigeminal neuralgia or chronic joint pain It is done.
  • CRPS complex regional pain syndrome
  • composition according to the present invention can be applied to the symptomatic skin locally so that pregabalin exerts a medicinal effect at the application site and can improve the symptoms. Moreover, since sufficient medicinal effects can be obtained even if the pregabalin content is low, the amount of pregabalin that migrates into the blood can be suppressed very slightly. Therefore, unlike the oral preparation, there are no central nervous system side effects. In addition, since the medicinal effects appear about 1 hour after application to the skin, the symptoms can be quickly improved.
  • FIG. 1 is a graph showing the analgesic effect of pregabalin administration, where a) shows the result of oral administration, and b) shows the result of transdermal administration.
  • FIG. 2 is a graph showing the analgesic effect of gabapentin administration, where a) shows the result of oral administration, and b) shows the result of transdermal administration.
  • FIG. 3 is a graph showing the analgesic effect of transdermal administration of pregabalin or gabapentin.
  • FIG. 4 is a graph showing the analgesic effect of transdermal administration of pregabalin.
  • FIG. 5 is a graph showing the expression of central side effects due to pregabalin administration, where a) shows the result of oral administration, and b) shows the result of transdermal administration.
  • FIG. 6 is a graph showing changes in plasma concentration after oral administration or transdermal administration of pregabalin.
  • FIG. 7 is a graph showing the analgesic effect of the comparative composition and the composition according to the present invention, in which a) shows the change in pain threshold over time, and b) shows the maximum pain threshold.
  • the composition according to the present invention contains pregabalin as an active ingredient in a base containing water.
  • pregabalin is used to mean not only “pregabalin” represented by the above structural formula or ionic form thereof, but also pharmaceutically acceptable salts, complexes, and solvates thereof. However, it does not include a prodrug (a compound in which the functional group of pregabalin is replaced with another functional group or a compound in which the carbon-bonded hydrogen of pregabalin is replaced with any functional group).
  • pregabalin itself means pregabalin represented by the above structural formula or its ionic form (particularly, zwitterionic form).
  • Such salts include, but are not limited to, acid addition and base addition salts, including hemisalts.
  • Pharmaceutically acceptable acid addition salts include non-toxic substances obtained from inorganic acids (for example, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc.) Salts, and non-toxic salts obtained from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. obtain.
  • Potentially useful salts include acetate, aspartate, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, besylate, bicarbonate, carbonate, bisulfate, Sulfate, pyrosulfate, bisulfite, sulfite, borate, cansylate, caprylate, citrate, edicylate, esylate, formate, fumarate, glucoceptate, gluconate, Glucuronate, hexafluorophosphate, hibenzate, hydrochloride, chloride, hydrobromide, bromide, hydroiodide, iodide, isethionate, isobutyrate, lactate, malic acid Salt, maleate, malonate, mandelate, mesylate, methyl sulfate, naphthylate, 2-naphthylate, nicotinate, nitrate, orotate, oxalate, palmitate,
  • Pharmaceutically acceptable base salts can include non-toxic salts obtained from bases including metal cations, such as alkali metal or alkaline earth metal cations, and amines.
  • metal cations such as alkali metal or alkaline earth metal cations, and amines.
  • potentially useful salts include aluminum, arginine, N, N′-dibenzylethylenediamine, calcium, chloroprocaine, choline, diethanolamine, diethylamine, dicyclohexylamine, ethylenediamine, glycine, lysine, magnesium, N-methylglu
  • examples include, but are not limited to, camin, olamine, potassium, procaine, sodium, tromethamine, zinc and the like.
  • the solvate include hydrate and ethanolate.
  • the composition according to the present invention preferably contains the pregabalin itself.
  • the composition according to the present invention exhibits excellent effects even if it does not contain other active ingredients (such as NMDA antagonists) like the composition of Patent Document 2.
  • a preferred example of the composition according to the present invention includes a composition containing no NMDA antagonist.
  • a particularly preferred example of the composition according to the present invention is a composition containing only pregabalin as an active ingredient.
  • the active ingredient means an ingredient useful for treatment of a disease which is a treatment target of the composition according to the present invention, and does not mean an ingredient added for the purpose unrelated to the treatment of the disease. .
  • the moisturizing ingredient is included in the active ingredient contemplated by the present invention even if it has the medicinal effect of improving the dryness of the skin. I can't. Therefore, the composition according to the present invention containing pregabalin and a moisturizing component also corresponds to a composition containing only pregabalin as an active ingredient.
  • the content of pregabalin is preferably 0.2 to 3% by weight, more preferably 0.3 to 3% by weight, particularly preferably 0.5 to 2.5% by weight, and further preferably 1 to 2% by weight.
  • a composition containing 10% pregabalin is considered to be the most effective.
  • 6% by weight of gabapentin is used together with 15% by weight or more of NMDA antagonist.
  • the composition according to the present invention exhibits a pain improving effect comparable to that of an orally-administered preparation even when the active ingredient is at a low concentration (0.2 to 3.0% by weight), as shown in Examples described later. Can do.
  • composition according to the present invention when the composition according to the present invention is applied to the skin, almost no pregabalin is observed in the plasma, and there is almost no risk of central nervous system side effects that cause problems during oral administration.
  • a particularly preferred example of the composition according to the present invention is a composition having a pregabalin content of 2% by weight or less.
  • pregabalin is preferably present in a form dissolved in water.
  • Preferable dosage forms of the composition according to the present invention include solution lotions, emulsion lotions, sprays, gels, water-in-oil creams, and oil-in-water creams. Particularly preferred dosage forms are solution lotions, sprays or gels.
  • the solution lotion or gel is a liquid or gel external preparation in which pregabalin is dissolved in an aqueous solvent (including water).
  • Emulsion lotions, water-in-oil (W / O) creams or oil-in-water (O / W) creams are prepared by emulsifying aqueous components (including water) and oily components with surfactants. It is a liquid or creamy external preparation, and pregabalin is present in a form dissolved in an aqueous component.
  • the aqueous solvent may be water alone or a mixture of water and a water-soluble solvent.
  • water-soluble solvents are 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, polar oils, and the like.
  • a preferred water-soluble solvent is a polyhydric alcohol, particularly preferably 1,3-butylene glycol.
  • 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, More preferably, it is 10% by weight.
  • the dosage form of the composition according to the present invention is a water-in-oil cream
  • pregabalin is dissolved in the aqueous phase in the base (emulsion base in which the internal phase is the aqueous phase and the external phase is the oil phase). It is included in the form.
  • pregabalin is water in a base (emulsion base in which the internal phase is an oil phase and the external phase is an aqueous phase). Contained in dissolved form in the phase.
  • the aqueous phase may contain a water-soluble component in addition to water.
  • the water-soluble component is 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, etc. Can be used.
  • the oily component constituting the oil phase include one or more selected from the group consisting of hydrocarbons, fats and oils, waxes, fatty acids, higher alcohols, and esters.
  • a surfactant emulsifier
  • cationic surfactants cationic surfactants
  • anionic surfactants anionic surfactants
  • amphoteric surfactants amphoteric surfactants
  • nonionic surfactants One or more selected from the group consisting of can be used.
  • the dosage form of the composition according to the present invention is a spray
  • it can be prepared by filling the above-mentioned lotion (liquid) in a spraying container.
  • a particularly preferred spray is a spray prepared by filling a solution container with a solution lotion.
  • the content of water is preferably 7% by weight or more, more preferably 50% by weight or more, particularly preferably 70% by weight or more, and further preferably 80% by weight or more.
  • Preferable examples of the composition according to the present invention include solution lotions, sprays or gels containing 70% by weight or more (more preferably 80% by weight or more, particularly preferably 85% by weight or more) of water.
  • particularly preferred compositions include solution lotions, sprays or gels containing a total of 90% by weight (more preferably 95% by weight or more) of an aqueous solvent (water and water-soluble solvent).
  • a preferred example of the composition according to the present invention is a composition that does not substantially contain an oily component having a water solubility of 0.1% by weight or less at 20 ° C. as a pregabalin solubilizer.
  • a more preferable composition is a composition which does not substantially contain an oily component having a solubility in water of 1% by weight or less at 20 ° C. as a pregabalin solubilizer.
  • the pregabalin solubilizer means a component containing pregabalin dissolved therein.
  • substantially free means that the content in the composition is 3% by weight or less, preferably 2% by weight or less, more preferably 1% by weight or less.
  • composition according to the present invention a composition containing no oily component as a pregabalin solubilizer can be mentioned. Further, as a more preferred example, a composition that does not substantially contain the oil component in the composition is mentioned, and as a particularly preferred example, a composition that does not contain the oil component in the composition.
  • the composition according to the present invention may contain a thickener.
  • the content of the thickener in the composition is preferably 0.01 to 10% by weight.
  • a more preferable content of the thickener is 0.2 to 2% by weight.
  • Preferable thickeners include carboxyvinyl polymer and water-soluble cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and hydrophobized hydroxypropyl methylcellulose. These may be used alone or in combination.
  • carboxyvinyl polymer can be mentioned.
  • composition according to the present invention preferably has a pH value in the range of 3 to 10.
  • a more preferred pH value is 4 to 8, and a particularly preferred pH value is 5 to 7. If the pH value is less than 3 or more than 10, the safety of the preparation may be a concern.
  • Examples of the pH adjusting agent for adjusting the composition to a pH value in the above range include lactic acid, citric acid, and phosphoric acid, which are used to adjust to the low pH region, and adjust to the high pH region.
  • Examples of such materials include alkali metal and alkaline earth metal hydroxides, sodium lactate, sodium citrate, L-arginine, and diisopropanolamine.
  • Particularly preferred pH adjusting agents include sodium hydroxide and potassium hydroxide.
  • composition according to the present invention may contain a preservative (preservative) and a stabilizer (thickening aid) in addition to the above components.
  • a preservative preservative
  • a stabilizer thickening aid
  • additives commonly used in external preparations for skin can be included.
  • the preservative examples include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, sodium benzoate, phenoxyethanol and the like.
  • the preservative may be used alone or in combination.
  • the content of the preservative in the composition is preferably in the range of 0.01 to 2% by weight, and more preferably in the range of 0.1 to 1.0% by weight. If it exceeds 2% by weight, the safety of the preparation may be a concern.
  • the stabilizer examples include edetate sodium hydrate, edetate tetrasodium hydrate, edetate tetrasodium tetrahydrate, sodium metaphosphate, and the like.
  • the content of the thickening aid in the composition is preferably in the range of 0.005 to 1% by weight, more preferably in the range of 0.01 to 0.5% by weight. If it exceeds 1% by weight, the safety of the preparation may be a concern.
  • a particularly preferred thickening aid is sodium edetate hydrate.
  • the composition according to the present invention can exhibit sufficient medicinal effects even when it does not contain a lower monohydric alcohol (monohydric alcohol having 1 to 3 carbon atoms) such as ethanol. Since the lower monohydric alcohol such as ethanol has high volatility and there is a concern that the effect on the skin is concerned by adding to the external preparation, the composition according to the present invention does not contain the lower monohydric alcohol. It is preferable.
  • the composition according to the present invention can exhibit a sufficient medicinal effect even if it does not contain a substance having a transdermal absorption promoting action such as dimethyl sulfoxide (DMSO).
  • DMSO dimethyl sulfoxide
  • the composition according to the present invention is an external preparation for skin, and pain can be alleviated by applying it locally to the affected skin area where pain occurs.
  • pain examples include postherpetic neuralgia, diabetic neuralgia, acute herpes zoster pain, myofibalgia, complex regional pain syndrome (CRPS), chemotherapy-induced neuropathy, trigeminal neuralgia and Chronic joint pain is mentioned.
  • the composition according to the present invention is effective for the treatment of postherpetic neuralgia.
  • the amount and frequency of application of the composition according to the present invention to the skin may be appropriately adjusted according to the degree of pain, the concentration of pregabalin in the composition, the age and weight of the patient, and the like. Usually, it may be applied to the affected skin area with a frequency of 1 to 3 times a day, and the daily use amount (the amount of pregabalin itself) is generally about 5 to 15 mg.
  • the pregabalin oral dosage form currently sold in Japan is administered to adults at a dose of 150-300 mg (up to 600 mg) daily, so according to the present invention, the dosage is much less than the oral dosage form. Can improve symptoms.
  • composition of the present invention includes a composition obtained by arbitrarily combining these, and Also included are compositions obtained by arbitrarily combining the concentration ranges described for the essential and optional components.
  • numerical ranges such as concentrations and pH values described in the preceding paragraph can be arbitrarily combined, and when a plurality of numerical ranges are described, an upper limit value or a lower limit value of each numerical range can be arbitrarily combined. .
  • % means “% by weight” unless otherwise specified.
  • the pregabalin used in the examples is pregabalin itself represented by the structure of [Chemical Formula 1].
  • Pregabalin was expected to be unsuitable for transdermal administration because it must be dissolved in an oily solvent in order to improve absorption in transdermal administration, but in subsequent studies, pregabalin was dissolved in water contrary to the above prediction. It has been found that the resulting composition exerts an analgesic effect upon transdermal administration. Based on this, studies were conducted on the efficacy and safety when a pregabalin-containing composition was locally administered to the skin in a base containing water.
  • Example 1 Preparation of a composition containing pregabalin A composition having a composition shown in Table 2 below (the dosage form was a gel) was prepared. First, pregabalin, 1,3-butylene glycol, methyl paraoxybenzoate, sodium edetate hydrate, purified water, and carboxyvinyl polymer (aqueous solution) were weighed and placed in one container and heated. After confirming that pregabalin was dissolved and became a homogeneous solution, sodium hydroxide (aqueous solution) was added as a pH adjuster and stirred, so that pregabalin was dissolved in an aqueous base (water and 1,3-butylene glycol). The mixture was dissolved in a main base) to obtain a gel having a pH adjusted to 5.5 to 6.0.
  • aqueous base water and 1,3-butylene glycol
  • Example 2 Comparison of analgesic effect between oral administration and transdermal administration of pregabalin In postherpetic neuralgia (PHN), a sensory abnormality called allodynia that recognizes even a minute stimulus that does not usually cause pain as pain. Often shown.
  • Rat spinal nerve ligation model is known as an animal model of allodynia. Using this animal model, the analgesic effect was compared between oral administration and predermal administration of pregabalin.
  • a spinal nerve partial ligation (SNL) model was prepared by completely ligating the spinal nerves (left side of L5 and L6 nerves) of SD rats. Individuals with reduced pain thresholds were selected 7 or 8 days after surgery, pregabalin was orally or transdermally administered, and then the pain threshold due to mechanical stimulation in the left footpad (model foot) was evaluated. Each test was performed using 5 rats (body weight approximately 200-250 g).
  • pregabalin was administered to rats at 3 mg, 10 mg, or 30 mg per kg body weight, and for the transdermal administration group, the 0.1%, 0.3%, and 1% preparations prepared in Example 1 were given in an amount of 100 ⁇ L / site ( The amount of pregabalin applied was about 0.1 mg, 0.3 mg, and 1 mg, respectively, on the left footpad of the rat.
  • purified water was used as a control. Pain threshold was measured at 30, 60, 90, 120 and 240 minutes after administration using a Dynamic Plantar Aesthesiometer (37400, Ugobasil). Table 3 and FIG. 1 show values obtained by averaging the maximum pain threshold values of each individual (maximum pain threshold values).
  • Table 4 shows the average pain threshold value at each measurement time.
  • the value “0” after administration means the measured value immediately before administration.
  • SE in each table is an abbreviation for standard error.
  • Sun Ho Kim and Jin Mo Chung An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat.Pain, 50 (1992) 355-363.
  • pregabalin at 10 mg / kg or 30 mg / kg increased the maximum pain threshold as compared with control, confirming the analgesic effect of pregabalin.
  • 10% / kg oral administration of pregabalin per rat is achieved by application of 0.3% or 1% pregabalin preparation (applying pregabalin of about 0.3 mg or 1 mg per rat).
  • transdermal administration of a 1% formulation of gabapentin (approx. 1 mg of gabapentin per rat) was administered orally at 30 mg / kg of gabapentin (gabapentin per rat). It has been found that the oral dose of is more than about 6 to 7.5 mg). However, in the case of transdermal administration, there was no change in the maximum pain threshold as the concentration of gabapentin increased from 1% to 3% and 10%. From this, it was found that the analgesic effect of gabapentin reached a peak at a concentration of about 1%, and even if the concentration was increased above 1%, no enhancement of the medicinal effect could be expected.
  • Example 3 Comparison of the efficacy of pregabalin and gabapentin A lotion preparation (aqueous solution) prepared by dissolving pregabalin or gabapentin in purified water containing 0.1 vol% Tween 80 was prepared, and a rat spinal nerve ligation model was prepared in the same manner as in Example 2. Then, the analgesic effect by transdermal administration was examined. The test procedure is as described in Example 2. Each test was performed using 5 rats. Table 7 and FIG. 3 show values obtained by averaging the maximum pain threshold values of each individual (maximum pain threshold values).
  • the analgesic effects of the pregabalin 0.2% preparation and the gabapentin 1% preparation were equivalent.
  • the analgesic effect of gabapentin reaches a peak at 1%. Therefore, it was found that if pregabalin was used, the maximum analgesic effect obtained with gabapentin was obtained with a content of only 0.2%. Moreover, it turned out that the analgesic effect exceeding the maximum analgesic effect obtained with gabapentin is acquired by making the content rate of pregabalin higher.
  • Example 4 Concentration-dependent pregabalin drug content
  • the pregabalin content is 0.3, 1, and 3% by weight, and a gel having the same composition as in Table 2 was prepared.
  • a spinal nerve ligation model the analgesic effect by transdermal administration was examined.
  • the test was performed in the same procedure as in Example 2 except that von Frey filament was used instead of Dynamic Plantar Aesthesiometer (37400, Ugobasil) for the pain threshold measurement.
  • As the von Frey filament for measuring the pain threshold 0.4 g, 0.6 g, 1.0 g, 1.4 g, 2.0 g, 4.0 g, 6.0 g, 8.0 g, 10.0 g, 15.0 g and 26.0 g filaments were used.
  • the measurement starting filament was 1.0 g.
  • stimulation was performed with a one-step heavy filament, and when a pain response was observed, stimulation was performed with a one-step lighter filament. Stimulation was performed until a pain response was observed twice in succession, and the number of grams of filaments in which the pain response was observed twice in succession was taken as a pain threshold.
  • Each test was performed using 8 rats.
  • Table 8 and FIG. 4 show values obtained by averaging the maximum pain threshold values of each individual (maximum pain threshold values).
  • Table 9 shows the average pain threshold value at each measurement time.
  • Example 5 Comparison of central side effects between oral administration and predermal administration of pregabalin Using the Beam walking method (test for evaluating ability to walk on thin beams) known as an evaluation system for central action The effects of oral or transdermal administration of pregabalin on locomotor activity were evaluated. SD rats were trained to cross a rectangular wooden beam in advance, and only individuals whose time to cross a practice beam (length 1.5 m) was 10 seconds or less were used for the test. On the test day, pregabalin was orally or transdermally administered to rats, and 2 hours after administration, the rats were allowed to walk a 2.5 m long beam and the number of times the limb was slid.
  • the site of transdermal administration was the rat's left footpad as in the drug efficacy evaluation of Example 2.
  • the results are shown in Table 10 and FIG. The more times a rat slides its limb, the more severe the central side effects. Each test was performed using 5 rats.
  • Example 6 Changes in plasma concentration after oral administration or precutaneous administration of pregabalin
  • pregabalin oral administration dose (10 mg / kg) and transdermal administration dose (1 % Preparation) the drug concentration in plasma after administration was measured.
  • Pregabalin is orally administered to the SD rat or dermally to the left footpad, 15, 30, 45, 60, 120, 240, 360 minutes after oral administration and 15, 30, 45, 60, 90, 120, after dermal administration
  • heparinized blood was collected by jugular vein blood collection.
  • unchanged pregabalin was quantified with a liquid chromatography tandem mass spectrometer (LC / MS / MS). Each test was performed using 3 rats. The results are shown in Table 11 and FIG.
  • Example 7 Comparison of the analgesic effect of the composition according to the present invention and the analgesic effect of the anhydrous composition
  • Table 12 An anhydrous composition (0.3% ointment) was prepared. The numerical values in the table indicate% by weight. In this 0.3% ointment, each component shown in Table 12 was weighed and heated (80 ° C.), and after confirming that components other than pregabalin were dissolved and melted, the mixture was stirred until the product temperature reached 30 ° C. It was prepared by cooling while cooling. Since pregabalin does not dissolve in the ointment base, it exists in the ointment in a suspended state.
  • anhydrous composition in Table 12 and the water-containing composition (dissolution type preparation) according to the present invention
  • Pain threshold was measured.
  • Table 13 and FIG. 7 show the average value of the pain threshold value at each measurement time and the average value of the maximum pain threshold value of each individual (maximum pain threshold value).
  • 0.3% ointment is the anhydrous composition of Table 12
  • 0.3% gel is the 0.3% formulation (dissolved preparation of pregabalin containing water) described in Table 2.
  • the placebo (ointment) and the placebo (gel) are compositions having the same composition as the 0.3% ointment and 0.3% gel, respectively, except that they do not contain pregabalin.
  • the group administered with the 0.3% ointment which is an anhydrous composition
  • the 0.3% ointment showed significant analgesia compared to the untreated group and each placebo formulation administered group even after 1.5 hours had elapsed after administration. There was no effect.
  • the group applied with a 0.3% gel which is a water-containing composition
  • a significant analgesic effect was observed at 1 hour after administration, and the analgesic effect after 1 hour and 1.5 hours was 0.3% ointment and each It was much higher than the placebo group.
  • the composition according to the present invention containing pregabalin in the base containing water has a significantly higher efficacy than the composition of the same concentration containing gabapentin in the base containing water. It turns out to have.
  • the pregabaline-containing composition according to the present invention has a concentration higher than that of the composition containing gabapentin in the base, which reaches a peak at 1% and does not vary even when the concentration is increased further. Even if it exceeds 1%, the drug efficacy increases in a dose-dependent manner, and it has been found that by increasing the concentration, a formulation with higher drug efficacy can be obtained.
  • the pregabalin-containing composition according to the present invention can achieve a sufficient medicinal effect even when the pregabalin dose is much smaller than that of the orally administered preparation, since the medicinal effect comparable to that of the orally administered preparation is obtained.
  • the drug concentration in the blood when the composition according to the present invention is transdermally administered is clearly lower than when pregabalin is orally administered, pregabalin is acting without intervening systemic circulation blood, That is, it was found that the effect was exerted in the skin local area that was the administration site. Further, when the composition according to the present invention was administered transdermally, no central side effects were observed since it was not circulated through the systemic circulating blood.
  • composition according to the present invention showed a significant analgesic effect 1 to 1.5 hours after administration, and thus was found to be excellent in immediate effect.
  • composition according to the present invention has the same degree of effectiveness as an oral preparation, but has a lower risk of developing central side effects, and thus has higher utility than conventional pregabalin oral preparations, such as postherpetic neuralgia. It is an excellent therapeutic drug.

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Abstract

La présente invention vise à proposer une composition contenant de la prégabaline, qui peut produire une efficacité de médicament satisfaisante au moyen d'une administration topique. Cette composition est caractérisée en ce que la composition est conçue pour une application topique sur la peau, la prégabaline est contenue dans une base contenant de l'eau, et la teneur en prégabaline est comprise entre 0,2 et 3 % en poids par rapport au poids de composition total. La composition présente une efficacité de médicament satisfaisante malgré la faible teneur en prégabaline (3 % en poids ou moins) et le fait que la prégabaline est le seul principe actif. La prégabaline est, de préférence, présente sous une forme dissoute dans l'eau, et la forme de la composition est, de préférence, une lotion de solution, une lotion d'émulsion, un pulvérisateur, un gel, une crème du type eau dans l'huile ou une crème du type huile dans l'eau.
PCT/JP2014/060453 2013-04-12 2014-04-11 Composition pour usage topique WO2014168228A1 (fr)

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Cited By (6)

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Publication number Priority date Publication date Assignee Title
WO2016061328A1 (fr) * 2014-10-15 2016-04-21 Maruho Co., Ltd. Composition topique
US10485776B2 (en) 2013-01-18 2019-11-26 Kemphys Ltd. Medicament for therapeutic treatment of neuropathic disease
EP3593795A4 (fr) * 2016-12-14 2020-05-06 Cidat, S.A. De C.V. Combinaisons et procédés de traitement de la douleur neuropathique
WO2022157524A1 (fr) * 2021-01-22 2022-07-28 Egis Gyógyszergyár Zrt. Composition pharmaceutique topique contenant des phospholipides
WO2022157526A1 (fr) * 2021-01-22 2022-07-28 Egis Gyógyszergyár Zrt. Composition topique comprenant de la prégabaline
WO2022157525A1 (fr) * 2021-01-22 2022-07-28 Egis Gyógyszergyár Zrt. Formulation topique contenant des composés phospholipides modifiés

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10485776B2 (en) 2013-01-18 2019-11-26 Kemphys Ltd. Medicament for therapeutic treatment of neuropathic disease
WO2016061328A1 (fr) * 2014-10-15 2016-04-21 Maruho Co., Ltd. Composition topique
EP3593795A4 (fr) * 2016-12-14 2020-05-06 Cidat, S.A. De C.V. Combinaisons et procédés de traitement de la douleur neuropathique
WO2022157524A1 (fr) * 2021-01-22 2022-07-28 Egis Gyógyszergyár Zrt. Composition pharmaceutique topique contenant des phospholipides
WO2022157526A1 (fr) * 2021-01-22 2022-07-28 Egis Gyógyszergyár Zrt. Composition topique comprenant de la prégabaline
WO2022157525A1 (fr) * 2021-01-22 2022-07-28 Egis Gyógyszergyár Zrt. Formulation topique contenant des composés phospholipides modifiés
WO2022157527A1 (fr) * 2021-01-22 2022-07-28 Egis Gyógyszergyár Zrt. Formulation topique contenant de la prégabaline dispersée

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