WO2014168228A1

WO2014168228A1 - Composition for topical use

Info

Publication number: WO2014168228A1
Application number: PCT/JP2014/060453
Authority: WO
Inventors: 木戸　裕子; 磨耶子交久瀬; 栄次郎堀沢; 史紀鳴海
Original assignee: マルホ株式会社
Priority date: 2013-04-12
Filing date: 2014-04-11
Publication date: 2014-10-16

Abstract

The purpose of the present invention is to provide a pregabalin-containing composition that can produce satisfactory drug efficacy through topical administration. This composition is characterized in that the composition is one for topical application to the skin, the pregabalin is contained in a water-containing base, and the pregabalin content is 0.2-3 wt% with respect to total composition weight. The composition exhibits satisfactory drug efficacy despite the low pregabalin content (3 wt% or less) and the fact that pregabalin is the sole active ingredient. The pregabalin is preferably present in a water-dissolved form, and the form of the composition is preferably a solution lotion, emulsion lotion, spray, gel, water-in-oil type cream, or oil-in-water type cream.

Description

Topical composition

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 α ₂ δ 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 α ₂ δ subunit present in the pre-neural synapse, thereby suppressing excessive release of excitatory transmitters. It is thought to exert analgesic action. In other words, 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).

In recent years, the following

Patent Documents

1 and 2 and Non-Patent Documents 1 to 3 have been reported as documents for examining administration methods other than oral administration.
Non-Patent Document 1 is a document disclosing a transdermal absorption patch as a transdermal drug delivery system (TDDS) of pregabalin. 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. As can be seen from the disclosure of a patch containing pregabalin in an amount (75 mg) used in an orally administered preparation, 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. In Examples of Patent Document 1, 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. In Examples of 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 A gel containing 40.25-70.75% by weight and 0-2.75% by weight of Krisgel is disclosed. Further, Patent Document 2 states that it is common that 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.

Further, 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.

As described above, Patent Document 1 uses gabapentin prodrug, Patent Document 2 uses NMDA antagonist and gabapentin in combination, and 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.
However, for the treatment of neuropathic pain, one of the important needs is that the effect develops quickly and the patient can be quickly released from the pain. In addition, 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 α ₂ δ ligand-containing composition capable of rapidly exerting sufficient efficacy with local administration of a small amount of drug.

International Publication No. 2005/089872 International Publication No. 2010/036937

Accordingly, an object of the present invention is to provide a calcium channel α ₂ δ 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.

In order to solve the above problems, the present inventors have repeatedly studied on a skin composition containing a calcium channel α ₂ δ 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. In addition, when 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. As a result, it was found that 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.

Therefore, 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. In the composition according to the present invention, the base means a composition obtained by removing the active ingredient (pregabalin) from the composition according to the present invention.

The composition according to the present invention can exhibit excellent medicinal effects even if the pregabalin content is small (0.2 to 3% by weight). In the present specification, “% by weight” means the ratio of the weight of each component to the total weight of the composition.
Moreover, the composition which concerns on this invention can exhibit sufficient medicinal effect, even if an active ingredient is only pregabalin.

As a preferred example of the composition according to the present invention, a composition substantially free from oily components as a pregabalin solubilizer can be mentioned.
In the composition according to the present invention, pregabalin is preferably present in a form dissolved in water.

Favorable 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 include solution lotions, sprays or gels containing 70% by weight or more of water.

The 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.
Examples of said 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.

The 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. The structure and chemical name of pregabalin are as follows.

In this specification, “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). In the present specification, “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, 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 can include non-toxic salts obtained from bases including metal cations, such as alkali metal or alkaline earth metal cations, and amines. Examples of 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.
Examples of the solvate include hydrate and ethanolate.

The composition according to the present invention preferably contains the pregabalin itself. In addition, 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. In the present specification, 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. . For example, when the composition according to the present invention is intended for the treatment of pain, 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.

In the composition according to the present invention, 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. In Non-Patent Document 2, a composition containing 10% pregabalin is considered to be the most effective. In

Patent Document

2, 6% by weight of gabapentin is used together with 15% by weight or more of NMDA antagonist. On the other hand, 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. In addition, 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.

In the composition according to the present invention, 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.

When the dosage form of the composition according to the present invention is a solution lotion or gel, the aqueous solvent may be water alone or a mixture of water and a water-soluble solvent. Examples of 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. One kind or two or more kinds of solvents may be mentioned. 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.

When 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.
When the dosage form of the composition according to the present invention is an emulsion lotion or an oil-in-water cream, 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.
Examples of 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.
In addition, as a surfactant (emulsifier) for emulsifying and stabilizing an aqueous phase and an oil phase, cationic surfactants, anionic surfactants, amphoteric surfactants and nonionic surfactants One or more selected from the group consisting of can be used.

When 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.

In the composition according to the present invention, the content of water (preferably purified 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. Examples of 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. In the present invention, the pregabalin solubilizer means a component containing pregabalin dissolved therein. Further, “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.
As a preferred example of the 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. As a particularly preferred thickener, carboxyvinyl polymer can be mentioned.

The 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.

The composition according to the present invention may contain a preservative (preservative) and a stabilizer (thickening aid) in addition to the above components. In addition, additives commonly used in external preparations for skin can be included.

Examples of the preservative 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.

Examples of the stabilizer (thickening aid) 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.
In addition, 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).

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. Examples of pain that can be treated with the composition according to the present invention 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. In particular, 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.

In the preceding paragraph, preferred compound names of optional components that can be used in the composition of the present invention have been described. However, the 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. In addition, 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. .

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the examples. In the examples, “%” means “% by weight” unless otherwise specified. The pregabalin used in the examples is pregabalin itself represented by the structure of [Chemical Formula 1].

[Examination of base]
The solubility of pregabalin in various solubilizers was examined. The results are shown in Table 1. As can be seen from Table 1, pregabalin was hardly dissolved regardless of whether the dissolving agent was an oily solvent or an aqueous solvent.

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.

[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.

In accordance with the method ^{1) of} Chung et al., 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).
For the oral administration group, 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 μL / 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. For both oral administration and transdermal administration, 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). The greater the maximum pain threshold value, the higher the analgesic effect. Table 4 shows the average pain threshold value at each measurement time. In Table 4, the value “0” after administration means the measured value immediately before administration. SE in each table is an abbreviation for standard error.
¹⁾ 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.

As can be seen from Table 3 and FIG. 1, in oral administration, pregabalin at 10 mg / kg or 30 mg / kg increased the maximum pain threshold as compared with control, confirming the analgesic effect of pregabalin. For transdermal administration, 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). An analgesic effect equal to or higher than that of about 2 to 2.5 mg) was confirmed.

In addition, as can be seen from Table 4, when 0.3% or 1% pregabalin formulation was administered transdermally, a significant analgesic effect was observed at 1 hour after administration compared to immediately before administration (time 0 after administration). It was. The time for the pain threshold value to reach the peak was 2 hours after oral administration, whereas 1.5 hours after transdermal administration. When comparing the pain threshold at 1.5 hours after administration, the 0.3% or 1% transdermal preparation showed a higher value than the 10 mg / kg or 30 mg / kg oral preparation. From this, it can be seen that the analgesic effect of the pregabalin-containing composition according to the present invention is more effective than oral administration, and can reduce the patient's pain more quickly.

[Comparative Example 1] Comparison of analgesic effect between oral administration and percutaneous administration of gabapentin In the same manner as in Example 2, the spinal nerve of SD rats (left side of L5 and L6 nerves) was completely ligated and spinal nerve partial incision was performed. A ligation (Segmental spinal nerve ligation; SNL) model was prepared. Individuals with reduced

pain threshold

7 or 8 days after surgery were selected and gabapentin was orally administered (10 mg, 30 mg or 100 mg / kg body weight) or transdermally (active ingredient was gabapentin, containing active ingredient) Except that the rate is each% shown in Table 5, after applying a gel with the same composition as the pregabalin preparation in Table 2 to the left footpad (100 μL / site), pain due to mechanical stimulation on the left footpad (model foot) The threshold was evaluated. For both oral administration and transdermal administration, 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). Each test was performed using 5 rats. Table 5 and FIG. 2 show the average value (maximum pain threshold value) of the maximum pain threshold value of each individual. Table 6 shows the average pain threshold value at each measurement time.

As can be seen from Table 5 and FIG. 2, 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).

As shown in Table 7 and FIG. 3, the analgesic effects of the pregabalin 0.2% preparation and the gabapentin 1% preparation were equivalent. As shown in Comparative Example 1, 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. Using 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. When no pain reaction was observed, 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.

As shown in Comparative Example 1, in the case of gabapentin, the analgesic effect reached a peak at a concentration of 1%, and the analgesic effect of a preparation with a concentration higher than 1% was not different from the analgesic effect of a preparation with a concentration of 1%. On the other hand, as shown in Table 8 and FIG. 4, the analgesic effect of pregabalin was significantly higher in the concentration 3% formulation than in the concentration 1% formulation. From this, it was found that the analgesic effect of pregabalin increases in a concentration-dependent manner even when the concentration exceeds 1%, and therefore a formulation having a higher analgesic effect can be obtained by increasing the concentration.

[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.

As can be seen from Table 10 and FIG. 5, oral administration of pregabalin caused the rat to have impaired locomotor movement and increased the number of times the limb was slid from the beam in a dose-dependent manner. On the other hand, in the transdermal administration, the locomotor activity was not impaired even in the 0.3% preparation and the 1% preparation for which the analgesic effect was confirmed in Example 2. Therefore, central side effects are observed in oral administration, and the central side effects increase as the pregabalin dose increases, but central side effects are observed when the composition of the present invention is administered transdermally. I found that there was no.

[Example 6] Changes in plasma concentration after oral administration or precutaneous administration of pregabalin In Example 2, 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 At 240 minutes, heparinized blood was collected by jugular vein blood collection. After plasma deproteinization and extraction treatment, 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.

As can be seen from Table 11 and FIG. 6, in the transdermal administration, the amount of pregabalin incorporated into the plasma was very small and was significantly lower than that in the oral administration. From this, it was shown that the analgesic effect by transdermal administration of the composition according to the present invention is local. In addition, it was confirmed that central side effects do not occur with transdermal administration.

[Example 7] Comparison of the analgesic effect of the composition according to the present invention and the analgesic effect of the anhydrous composition In order to examine the influence of the presence or absence of water in the composition on the analgesic effect, the composition shown in Table 12 is used as a comparative example. 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.

In order to examine the analgesic effect of the anhydrous composition (suspension type preparation) in Table 12 and the water-containing composition (dissolution type preparation) according to the present invention, the same method as in Example 2 was used. 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).
In Table 13 and FIG. 7, 0.3% ointment is the anhydrous composition of Table 12, and 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.

As can be seen from Table 13 and FIG. 7, the group administered with the 0.3% ointment, which is an anhydrous composition, 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. In contrast, in 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.
From this test, when a water-containing composition containing pregabalin in dissolved form is applied to the skin topical area, an analgesic effect appears immediately after application, but when an anhydrous composition containing pregabalin in suspended form is used. It was found that no significant analgesic effect was observed even after 1.5 hours from administration.

From the results of each of the above examples, 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. In addition, 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. In addition, it was found that 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. Moreover, since 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. Furthermore, it is considered possible to develop a low-concentration preparation because a composition of 0.2 to 3.0% by weight shows an analgesic effect. In addition, the 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.

The 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.

Claims

A composition for topical application to the skin, comprising pregabalin in a base containing water and a pregabalin content of 0.2 to 3% by weight based on the total amount of the composition.
The composition according to claim 1, wherein the active ingredient contained in the composition is only pregabalin.
3. The composition according to claim 1 or 2, which contains substantially no oil component as a pregabalin solubilizer.
The composition according to any one of claims 1 to 3, wherein the pregabalin is present in a form dissolved in water.
The composition according to any one of claims 1 to 4, wherein the dosage form of the composition is a solution lotion, an emulsion lotion, a spray, a gel, a water-in-oil cream, or an oil-in-water cream. The composition as described.
The composition according to any one of claims 1 to 5, which is a solution lotion, spray or gel containing 70% by weight or more of water.
The composition according to any one of claims 1 to 6, wherein the composition is used as an analgesic external preparation that is applied to an affected skin area where neuropathic pain occurs, and reduces pain.
The neuropathic pain is selected from the group consisting of postherpetic neuralgia, diabetic neuralgia, acute herpes zoster pain, muscle fiber pain, complex local pain syndrome, neuropathy due to chemotherapy, trigeminal neuralgia and chronic joint pain The composition according to claim 7.