JP2004217566A - Method for enhancing gel strength of pharmaceutical preparation and sustained release pharmaceutical preparation - Google Patents

Abstract

An object of the present invention is to provide a method for enhancing the gel strength of a preparation and the like.
The present invention relates to the following (1) to (3).
(1) A method for enhancing the gel strength of a preparation, which comprises adding hydroxypropylcellulose and hydroxypropylmethylcellulose to the preparation.
(2) The method for enhancing gel strength of a preparation according to (1), wherein the content of hydroxypropylmethylcellulose is 5 to 45% by weight based on the whole preparation.
(3) The method according to (1) or (2), wherein the content of hydroxypropylcellulose is 5 to 45% by weight based on the whole preparation.
[Selection diagram] None

Description

【００５４】
表中、メトローズ（９０ＳＨ１００）、メトローズ（９０ＳＨ４０００）およびメトローズ（９０ＳＨ１５０００）は、信越化学工業（株）製の製品である。また、日曹ＨＰＣ（ＨＰＣ−Ｍ）および日曹ＨＰＣ（ＨＰＣ−Ｈ）は日本曹達（株）製の製品である。
【００５５】
試験例１（溶出試験）
実施例１〜４で得た錠剤および比較例１、２で得た錠剤を用い、第１４局改正日本薬局方溶出試験法の第２法（パドル法）に従って溶出試験を行った。回転数は毎分５０回転とし、試験液としては水９００ｍｌを用いた。溶出試験開始後、経時的にサンプリングし、高速液体クロマトグラフィー（ＨＰＬＣ）分析によってバルプロ酸の溶出量を求めた。
【００５６】
ＨＰＬＣ分析条件は以下の通りである。
カラム：デベロシル（Ｄｅｖｅｌｏｓｉｌ ＯＤＳ−ＵＧ−５：野村科学株式会社製） ４．６ｍｍ Ｉ．Ｄ．×１５０ｍｍ
カラム温度：２５℃
展開溶媒：０．０５ｍｏｌ／Ｌリン酸二水素ナトリウム試液（ｐＨ３．０）／アセトニトリル混液（１：１）
展開溶媒の流量：バルプロ酸の保持時間が約６分になるように調整（１．０ｍＬ／分）
検出器：紫外吸光光度計 （測定波長：２１０ｎｍ）
以下の試験例２についても、同様のＨＰＬＣ分析条件で分析した。
【００５７】
溶出試験の結果を図１に示した。図１より、ＨＰＣおよびＨＰＭＣを含有する製剤では、ＨＰＣとＨＰＭＣの種類および添加量により溶出速度を任意に制御できることが分かる。これに対し、比較例１、２で得たＨＰＭＣのみを含有する製剤では添加したＨＰＭＣの種類や添加量に関わらず、類似した溶出挙動を示している。
【００５８】
試験例２（ビーズを用いた溶出試験）
ゲル強度の評価のため、実施例２、４で得た錠剤および比較例１で得た錠剤について、ビーズを用いた溶出試験を行った。溶出試験器のビーカー中に試験液（水２５０ｍｌ）、ポリスチレンビーズ（径 約６．５ｍｍ、和光純薬工業（株）製）２０００個（約２８０ｇ）および試験錠剤を投入しパドルを毎分２５回転とし溶出試験を行った。溶出試験開始後、経時的にサンプリングし、ＨＰＬＣ分析によってバルプロ酸の溶出量を求めた。
【００５９】
ビーズを用いた溶出試験の結果を図２に示した。比較例１で得た錠剤ではパドルを用いた溶出試験において、試験開始後２〜４時間で活性成分のバースト傾向が観察された。ゲル強度の評価は、通常の溶出試験（試験例１）とビーズを用いた溶出試験（試験例２）での結果を比較することにより行った。表２に実施例２、４および比較例１で得られた錠剤の各時間（４、６、１２時間）における溶出率の差を示した。溶出速度に差がないものほど、生体内での機械的運動に対し抵抗力のあるゲルマトリックスを形成していると考えられる。
【００６０】
溶出率の差は以下の式により算出した。
【００６１】
【数１】

【００６２】
【表２】

【００６３】
表２より、比較例１で得た錠剤では溶出率の差が３０〜４５％になっているのに対し、実施例２、４で得た錠剤では溶出率の差は２０％程度であり、ゲル強度が有意に改善されていることがわかる。
【００６４】
【発明の効果】
本発明により、製剤のゲル強度の増強方法、ゲル強度に優れたバルプロ酸もしくはバルプロ酸誘導体またはそれらの塩を含む徐放性製剤などが提供される。
【図面の簡単な説明】
【図１】図１は、試験例１の錠剤の溶出試験の結果を示したものである。
【符号の説明】
−■−：実施例１の錠剤を用いた試験例１の場合の溶出率を表す。
−○−：実施例２の錠剤を用いた試験例１の場合の溶出率を表す。
−△−：実施例３の錠剤を用いた試験例１の場合の溶出率を表す。
−□−：実施例４の錠剤を用いた試験例１の場合の溶出率を表す。
−●−：比較例１の錠剤を用いた試験例１の場合の溶出率を表す。
−▲−：比較例２の錠剤を用いた試験例１の場合の溶出率を表す。
【図２】図２は、試験例２のビーズを用いた錠剤の溶出試験の結果を示したものである。
【符号の説明】
−○−：実施例２の錠剤を用いた試験例２の場合の溶出率を表す。
−□−：実施例４の錠剤を用いた試験例２の場合の溶出率を表す。
−●−：比較例１の錠剤を用いた試験例２の場合の溶出率を表す。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for enhancing the gel strength of a preparation and the like.
[0002]
[Prior art]
Sustained-release preparations are highly useful preparations that can reduce the number of administrations, control drug concentration in the blood, and maintain drug efficacy. For example, a sustained-release preparation has a short elimination half-life in vivo such as sodium valproate, and requires twice a day to take a drug that needs to be taken three times a day, or a drug such as theophylline It is possible to control the blood concentration of a drug having a narrow effective therapeutic range to a predetermined concentration and maintain the drug effect. Many studies and reports have been made on matrix-type sustained-release preparations that use a water-soluble polymer that forms a gel upon contact with water as a sustained-release solid preparation and that sustain drug release from the preparation (eg, non- Patent Document 1). This matrix-type sustained-release preparation is simpler and cheaper to manufacture than the reservoir-type sustained-release preparation. In addition, matrix-type sustained-release preparations using hydroxypropylmethylcellulose (HPMC), which is a typical water-soluble polymer, have an effect that the dissolution of a drug is not affected by the environment in a living body, such as pH, and is affected by heat. It has many advantages, such as excellent elution stability over time, because it is not performed.
[0003]
As sustained release preparations using HPMC as a carrier, for example, the following are known.
(1) Patent Documents 1, 2, and 3 describe sustained-release preparations using HPMC having a hydroxypropoxyl group content of 9 to 12% and a methoxyl group content of 28 to 30% as a carrier.
(2) Patent Document 4 discloses that the average molecular weight is 50,000 or more, the viscosity of a 2% aqueous solution at 20 ° C. is about 800 cP or more, the methoxyl group content is 16 to 24%, and the hydroxypropoxyl group content is 4 to Tablets using 32% HPMC up to 25% of the total tablets are listed.
(3) Patent Document 5 discloses a formulation of a sustained-release preparation of sodium hydrogen divalproate based on HPMC. Specifically, 50 to 55% by weight of the active ingredient, 20 to 40% by weight of HPMC, 5 to 15% by weight of lactose, 4 to 6% by weight of crystalline cellulose, 1 to 5% by weight of a particle size of 1 to 10 μm. It is described as a tablet composed of light silicic anhydride.
(4) Patent Document 6 discloses a formulation containing HPMC as a formulation for improving the fluidity and compression moldability of a powder and gradually releasing an active ingredient such as a water-soluble drug in a formulation containing HPMC. There is a description of a sustained-release preparation obtained by tableting a powder component containing calcium phosphate and, if necessary, microcrystalline cellulose.
[0004]
It is known that the elution rate of an active ingredient from a gel matrix using HPMC as a carrier can be controlled by the type (viscosity) of HPMC and the amount added. However, in order to obtain a fast dissolution behavior, it is necessary to use a low-viscosity base material and / or reduce the amount of addition. However, when a substance having a low viscosity is used and / or the amount of the base material is reduced, the gel strength inherent in the gel matrix is reduced, and a dissolution test and a tendency of drug burst in vivo are observed. When a burst of a drug occurs in a living body, not only the drug effect cannot be sustained, but also the drug concentration exceeds the effective therapeutic range, and serious side effects may be caused. Conversely, if the gel strength is to be increased, a high-viscosity HPMC must be used in large quantities, making it difficult to control the elution rate of the active ingredient.
[0005]
Non-Patent Document 2 describes a sustained-release preparation using HPMC as a base material of a gel matrix. In this, the dissolution rate is controlled by the viscosity and the amount of HPMC added, but if the amount of HPMC added is reduced in order to increase the dissolution rate, the resulting formulation is susceptible to meals and the gel strength is reduced. It has been suggested that when a large amount of a highly viscous base material is used to increase the strength, the active ingredient is not completely eluted and is excreted outside the body.
[0006]
Non-Patent Document 3 describes a sustained-release preparation of theophylline using HPMC as a base material of a gel matrix. If HPMC is 10% by weight in the tablet, the dissolution rate can be controlled with other additives, but if HPMC in the tablet is 30 to 40% by weight, it is suggested that the dissolution rate is difficult to control. I have.
The following are known as sustained-release preparations containing HPMC and hydroxypropylcellulose (HPC).
(1) Patent Document 7 discloses a step of mixing a dry carrier composed of 80 to 95% HPMC and 20 to 5% HPC, a step of drying the carrier to a water content of 1% or less, Forming a dry preparation by mixing a therapeutically effective amount of a therapeutic agent with the HPMC and the HPC by 2%. A process for the preparation of a controlled-action, long-acting formulation is described which has a viscosity in aqueous solution at 50C in the range of 50 to 25000 centipoise.
(2) Patent Document 8 discloses that at least 50% by weight of HPC fine particles pass through a 100-mesh screen, a hydroxypropoxyl group content of 4 to 12%, a methoxyl group content of 19 to 30%, and a 2% aqueous solution viscosity of 400 to 100. A sustained release tablet comprising 2,000 cps HPMC is described. This publication also states that the amount of HPMC is from 5 to 75% by weight based on the total amount of the polymer mixture (HPC and HPMC) and that it can be used in combination with HPC in the range of up to 90% by weight of the tablet. .
(3) Patent Document 9 discloses that cisapride- (L) -tartrate: about 9% by weight, lactose: about 61% by weight, HPMC: 5.5 to 18%, HPC: : A controlled release formulation comprising: 5.5-18% and a lubricant; about 6.5% by weight, where the total weight% of the cellulose derivative is about 23.5%.
(4) Patent Document 10 discloses that as an active substance-containing preparation, an active substance is used as a carrier substance, a) 10 to 90% by weight of a water-soluble polymer A having a viscosity Va of 1000 to 12000 cps, b) a viscosity Vb of 1 to 500 cps. A water-soluble polymer consisting of 10 to 90% by weight of a water-soluble polymer B of the formula (wherein the viscosities Va and Vb are each a 2% by weight aqueous solution measured at 20 ° C. according to the capillary method ASTM D-2363-7); There is a description of a solid particulate active substance-containing preparation obtained by intimately mixing and processing and molding this melt into particles. As examples of the water-soluble polymer A, HPMC and HPC are water-soluble. As an example of the polymer B, HPC is mentioned.
[0007]
However, conventionally, it is not known to enhance the gel strength of a preparation by including HPMC and HPC in the preparation.
[0008]
[Patent Document 1]
JP-A-62-149632
[0009]
[Patent Document 2]
Japanese Patent Publication No. 5-9413
[0010]
[Patent Document 3]
Japanese Patent Publication No. 7-57726
[0011]
[Patent Document 4]
Japanese Patent Publication No. 4-5208
[0012]
[Patent Document 5]
WO 00/37055 pamphlet
[0013]
[Patent Document 6]
JP-A-10-17497
[0014]
[Patent Document 7]
Japanese Patent Publication No. 4-43001
[0015]
[Patent Document 8]
Patent No. 2134343
[0016]
[Patent Document 9]
Patent No. 3182423
[0017]
[Patent Document 10]
JP-A-6-172160
[0018]
[Non-patent document 1]
DA Alderman, "International Journal of Pharmaceutical Technology and Product Manufacturing (Int. J. Pharm. Tech. & Prod. Mfr.)" 1984, Vol. 5, No. 3, p. 1-9
[0019]
[Non-patent document 2]
Hirokazu Y., "Biological and Pharmaceutical Britain", 1995, Vol. 18, No. 10, p. 1409-1416
[0020]
[Non-Patent Document 3]
Clara I. Vargas, "Drug Development and Industrial Pharmacy", 1999, Vol. 25, No. 9, p. 1045-1050
[0021]
[Problems to be solved by the invention]
An object of the present invention is to provide a method for enhancing the gel strength of a preparation and the like.
[0022]
[Means for Solving the Problems]
The present invention relates to the following (1) to (14).
(1) A method for enhancing the gel strength of a preparation, which comprises adding hydroxypropylcellulose and hydroxypropylmethylcellulose to the preparation.
(2) The method for enhancing gel strength of a preparation according to (1), wherein the content of hydroxypropylmethylcellulose is 5 to 45% by weight based on the whole preparation.
(3) The method according to (1) or (2), wherein the content of hydroxypropylcellulose is 5 to 45% by weight based on the whole preparation.
(4) The method according to any one of (1) to (3), wherein the combined content of hydroxypropylcellulose and hydroxypropylmethylcellulose is 10 to 50% by weight based on the whole preparation.
(5) The method for enhancing the gel strength of the preparation according to any one of (1) to (4), wherein the preparation contains an active ingredient.
(6) An agent for enhancing the gel strength of a preparation comprising hydroxypropylcellulose and hydroxypropylmethylcellulose.
(7) The gel strength enhancer according to (6), wherein the ratio of hydroxypropylcellulose to hydroxypropylmethylcellulose is 1: 1.2 to 1: 5 (weight ratio).
(8) A sustained-release preparation containing hydroxypropylcellulose, hydroxypropylmethylcellulose and valproic acid or a valproic acid derivative or a salt thereof.
(9) The sustained-release preparation according to (8), wherein the valproic acid or the valproic acid derivative or a salt thereof is sodium divalproate.
(10) The sustained-release preparation according to (8) or (9), wherein the content of hydroxypropylmethylcellulose is 5 to 45% by weight based on the whole preparation.
(11) The sustained-release preparation according to any one of (8) to (10), wherein the content of hydroxypropylcellulose is 5 to 45% by weight based on the whole preparation.
(12) The sustained-release preparation according to any of (8) to (11), wherein the total content of hydroxypropylcellulose and hydroxypropylmethylcellulose is 10 to 50% by weight based on the whole preparation.
(13) The sustained-release preparation according to any one of (8) to (12), wherein the content of valproic acid, a valproic acid derivative or a salt thereof is 50% by weight or more based on the whole preparation.
(14) The sustained-release preparation according to any one of (8) to (13), wherein the sustained-release preparation is a monolayer sustained-release preparation.
[0023]
BEST MODE FOR CARRYING OUT THE INVENTION
[Method of Increasing Gel Strength of Formulation, Including HPC and HPMC in Formulation]
In the method for enhancing the gel strength of the preparation of the present invention, examples of the preparation include pharmaceutical preparations and food preparations.
[0024]
In the method for enhancing the gel strength of the preparation of the present invention, the preparation is preferably a sustained-release preparation.
In the method for enhancing the gel strength of a preparation of the present invention, the preparation preferably contains an active ingredient.
Hereinafter, each component in the preparation will be described.
(1) Active ingredient
The formulation in the method for enhancing the gel strength of the formulation of the present invention preferably contains the active ingredient in an amount of 50% by weight or more, more preferably 50 to 70% by weight, still more preferably 50 to 60% by weight, based on the whole formulation. .
[0025]
The active ingredient may be any of the poorly water-soluble active ingredients, hydrophilic or water-soluble active ingredients. Active ingredients include (human) pharmaceutical active ingredients such as pharmaceuticals and quasi-drugs; animal drug active ingredients; pesticide active ingredients such as fungicides, insecticides, herbicides, rodenticides, repellents, plant growth regulators; amino acids , Peptides, nucleic acids, organic acids, and other components contained in foods. Pharmaceutical active ingredients include, for example, drugs for central nervous system such as hypnotic sedatives, antiepileptics, antipyretic analgesics and antiphlogistics, antiparkinson agents, agents for psychiatric nerves; Drugs; Cardiovascular drugs such as cardiotonic, arrhythmic, diuretic, antihypertensive, and vasodilators; Respiratory drugs such as bronchodilators and antitussives; Digestion of stomachic, intestinals, antacids, etc. Active ingredients contained in organ drugs; hormone drugs; antihistamine drugs; vitamin drugs; anti-ulcer drugs; antibiotics; chemotherapeutic drugs;
[0026]
As the active ingredient, an active ingredient which requires sustained drug effect is preferable, for example, an active ingredient contained in an antiepileptic agent or an active ingredient contained in an antiparkinson agent, and an active ingredient for a cold medicine or an active ingredient for rhinitis. Is mentioned.
Examples of the active ingredients contained in the antiepileptic agent include phenasemide-based active ingredients, hydantoin-based active ingredients, oxazolidine-based active ingredients, barbituric acid-based active ingredients, primidone-based active ingredients, aminobutyric acid-based active ingredients, and sulfonamide-based active ingredients And the like.
[0027]
Examples of the active ingredient contained in the antiparkinson agent include amantadine, biperiden, profenamine, levodopa and the like.
Examples of active ingredients for cold medicine include active ingredients contained in antipyretic analgesic anti-inflammatory, bronchodilator, antihistamine, antitussive, antitussive, antitussive and antitussive, vitamins, herbal extract, etc., and active for rhinitis. Examples of the component include an active component contained in a sympathetic stimulant, a parasympathetic blocker, an antiallergic / antiinflammatory agent, and the like.
[0028]
Examples of the active ingredient contained in the antipyretic analgesic anti-inflammatory include, for example, aniline derivatives such as acetaminophen, phenacetin, refetamine hydrochloride; salicylic acid such as methyl salicylate, phenyl salicylate, sodium salicylate, choline salicylate, aspirin, aspirin aluminum, ethenzamide, and sazapyrine. Derivatives; pyrazolone derivatives such as isopropylantipyrine, sulpyrine, phenylbutazone, ketophenylbutazone, antipyrine and aminopyrine; propionic acid derivatives such as ibuprofen, ketoprofen, naproxen, oxacipronine, fenoprofen calcium, thiaprofenic acid; fenbufen, diclofenac Phenylacetic acid derivatives such as sodium and ampenac sodium; indomethacin, indomethacin Indoleacetic acid derivatives such as arnesyl, programatasin maleate, and tolmetin sodium; anthranilic acid derivatives such as mefenamic acid, flufenamic acid, and tolfenamic acid; oxicam derivatives such as piroxicam, ampiroxicam, and tenoxicam; benzidamine hydrochloride, epilizole (mepyrizole); Examples include tiaramid hydrochloride and tinolidine hydrochloride. Further, examples of the active ingredient contained in the antipyretic analgesic anti-inflammatory agent include an active ingredient contained in an anti-inflammatory enzyme agent {such as serrapeptase [seratiothiopeptidase (trade name)] and lysozyme chloride}. The active ingredients contained in these antipyretic analgesics and anti-inflammatory agents can be used alone or in combination of two or more.
[0029]
Examples of the active ingredient contained in the bronchodilator include ephedrine hydrochloride, dl-methylephedrine hydrochloride, dl-methylephedrine saccharinate, isoprenaline hydrochloride, isoproterenol sulfate, methoxyphenamine hydrochloride, orciprenaline sulfate, chlorprenaline hydrochloride , Trimethoquinol hydrochloride, salbutamol sulfate, terbutaline sulfate, hexoprenaline sulfate, formoterol fumarate, fenoterol hydrobromide, procaterol hydrochloride, purbuterol hydrochloride, clenbuterol hydrochloride, mabuterol hydrochloride; xanthine derivatives such as aminophylline, theophylline, diprofylline, proxyphilin Anticholinergic agents such as ipratropium bromide, flutropium bromide and oxitropium bromide.
[0030]
Examples of the active ingredient contained in the antihistamine include, for example, an active ingredient contained in an ethanolamine-based antihistamine such as diphenhydramine or a salt thereof (eg, hydrochloride); dl-chlorpheniramine maleate, d-chlorpheniramine maleate, and the like. Active ingredients contained in propylamine-based antihistamines of the following; active ingredients contained in phenothiazine-based antihistamines such as alimemazine tartrate, isotipendyl hydrochloride, promethazine hydrochloride, mequitazine; diphenylpyralin or a salt thereof (eg, hydrochloride, teocoleate, etc.), maleic acid Carbinoxamine acid, clemastine fumarate, iproheptin hydrochloride, homochlorcyclidine hydrochloride, cyproheptadine hydrochloride, dimethindene maleate, triprolidine hydrochloride and the like.
[0031]
The active ingredient contained in the antitussive includes, for example, codeines (eg, codeine phosphate, dihydrocodeine phosphate, etc.), dextromethorphan hydrobromide, cloperastine or a salt thereof (hydrochloride, fendizate, etc.), noscapine or Salts thereof (eg, hydrochloride), dimemorphan or salts thereof (eg, phosphates, sulfates, etc.), oxerazine or salts thereof (eg, tannates, citrates, etc.), pentoxiverine citrate, epradinone hydrochloride, Clobutinol hydrochloride, isoaminyl citrate, hominoben hydrochloride, clofedanol hydrochloride, benproperin phosphate, sodium dibnate, hydrocotarnine and the like can be mentioned.
[0032]
Examples of active ingredients contained in expectorants include potassium guaiacol sulfonate; cysteine derivatives such as carbocysteine, L-ethylcysteine hydrochloride, L-methylcysteine hydrochloride, and acetylcysteine; bromhexine or a salt thereof (such as hydrochloride), hydrochloric acid Ambroxol and the like.
The active ingredients contained in the antitussive expectorant include, for example, guaifenesin, tipepidine or a salt thereof (hibenzate, citrate, etc.), oxymethebanol, alloclamide hydrochloride, carbetapentane phenate, trimethoquinol hydrochloride, methoxy hydrochloride Phenamine and the like.
[0033]
As vitamins, for example, vitamin B ₁ Or a derivative thereof or a salt thereof (eg, fursultiamine, fursultiamine hydrochloride, prosultiamine, octiamine, thiamine disulfide, bisbenthamine, bisbutiamine, bisbutiamine, benfotiamine, cettiamine hydrochloride, etc.), Vitamin B ₂ Or a derivative thereof or a salt thereof (eg, riboflavin, sodium riboflavin phosphate, sodium flavin adenine dinucleotide, riboflavin butyrate, etc.), and vitamin C.
[0034]
Examples of the herbal medicine extract include extracts of licorice, saiko, cinnamon bark, kakkon, kyounin, midsummer, ginger, ginseng, cinnamon and the like.
Examples of the active ingredient contained in the sympathetic stimulant (α receptor stimulant) include an active ingredient contained in a decongestant, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, phenylephrine hydrochloride and the like. The active ingredient contained in the parasympathetic blocker includes, for example, belladonna total alkaloid, and the active ingredient contained in the antiallergic / anti-inflammatory agent includes, for example, tranexamic acid. These active ingredients are appropriately selected from the group consisting of the same or different strains, and can be used alone or in combination of two or more. The active ingredient may be, if necessary, caffeine (eg, anhydrous caffeine, sodium benzoate caffeine, caffeine silate, caffeine (monohydrate), etc.), an antacid or a mucosal protective agent. Active ingredients contained in, for example, magnesium hydroxide, magnesium oxide, magnesium carbonate, magnesium silicate, aluminum sulfate, synthetic aluminum silicate, synthetic hydrotalcite [eg, Alkamac (trade name)], dihydroaluminum aminoacetic acid Salts, aluminum hydroxide gel, magnesium metasilicate aluminate, aluminum hydroxide / sodium bicarbonate coprecipitate [for example, cumulite (trade name)], sucralfate and the like, minerals, amino acids and the like may be used in combination.
[0035]
The active ingredient is more preferably a water-soluble active ingredient. Examples of the water-soluble active ingredient include inorganic acid salts (eg, salts with hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, etc.) and organic acid salts (eg, salts with acetic acid, trifluoroacetic acid, etc.). And particularly preferred are organic acid salts. The solubility of the water-soluble active ingredient in water (temperature: 20 ° C.) is preferably 1 mg / ml or more, more preferably 10 mg / ml or more, and further preferably 50 mg / ml or more.
[0036]
Further, as the active ingredient, valproic acid or a valproic acid derivative or a salt thereof is preferable.
Valproic acid or a valproic acid derivative or a salt thereof is useful for treating epilepsy (small seizures, focal seizures, psychomotor seizures and mixed seizures, etc.) and personality and behavioral disorders associated with epilepsy (gruminess, irritability, etc.). It is also used for the treatment of mania and manic states of manic depression.
[0037]
Examples of the valproic acid derivative include valproic acid amide.
Examples of the salt of valproic acid or a valproic acid derivative include salts of valproic acid or a valproic acid derivative with an alkali metal such as lithium, sodium, and potassium, and an alkaline earth metal such as beryllium, magnesium, and calcium. Sodium hydrogen valproate is most preferably used.
[0038]
Valproic acid is commercially available.
As a valproic acid derivative, for example, valproic acid amide can be obtained according to a known method, for example, by converting valproic acid into an acid chloride and further reacting the acid with ammonia.
Valproic acid or a salt of a valproic acid derivative can be produced according to a known method (eg, Japanese Patent Publication No. 64-3178).
[0039]
(2) HPMC
In the method for enhancing the gel strength of the preparation of the present invention, the content of HPMC in the preparation is, for example, 5 to 45% by weight based on the whole preparation when the preparation is a monolayer sustained-release preparation. Preferably, it is 5 to 30% by weight, more preferably 5 to 20% by weight.
[0040]
The methoxyl group content in HPMC is preferably 15 to 35%, and the hydroxypropoxyl group content is preferably 2 to 15%.
As HPMC, for example, Japanese Pharmacopoeia hydroxypropyl methylcellulose 2208 [methoxyl group content 19 to 24% (average degree of substitution of methoxy group about 1.1 to 2.0), hydroxypropoxy group content 4 to 12% (hydroxypropoxyl group) Average substitution degree of about 0.1 to 0.34)], hydroxypropyl methylcellulose 2906 [methoxy group content 27 to 30%, hydroxypropoxyl group content 4 to 7.5%], hydroxypropyl methylcellulose 2910 [JP] Methoxyl group content: 28 to 30%, hydroxypropoxyl group content: 7 to 12%]. These HPMCs can be used alone or in combination of two or more.
[0041]
The viscosity of a 2% by weight aqueous solution of HPMC at 20 ° C. is preferably 10 to 100,000 cps, more preferably 100 to 30,000 cps, and still more preferably 100 to 4000 cps.
Further, the pH of a 1% (weight / volume) aqueous solution of HPMC is preferably 5 to 8.
[0042]
HPMC may be prepared by a known method, for example, a method of reacting methyl chloride and propylene oxide with alkali cellulose, but it is also available as a commercial product.
(3) HPC
In the method for enhancing the gel strength of the preparation of the present invention, the content of HPC in the preparation is, for example, 5 to 45% by weight based on the whole preparation when the preparation is a monolayer sustained-release preparation. Preferably, it is 10 to 45% by weight, more preferably 15 to 30% by weight.
[0043]
The hydroxypropoxyl group content in HPC is preferably from 53.4 to 77.5%.
The viscosity of a 2% by weight aqueous solution of HPC at 20 ° C. is preferably 6 to 5000 cps, more preferably 150 to 5000 cps, and still more preferably 150 to 4000 cps.
[0044]
The pH of a 2% (weight / volume) aqueous solution of HPC is preferably between 5.0 and 7.5.
HPC can be prepared by a known method, for example, by reacting propylene oxide with alkali cellulose, or may be obtained as a commercial product.
The combined content of HPMC and HPC is preferably from 10 to 50% by weight, more preferably from 15 to 40% by weight, based on the whole preparation.
[0045]
The content ratio between HPMC and HPC in the preparation is preferably 1: 1.2 to 1: 5 (weight ratio), more preferably 1: 1.5 to 1: 3 (weight ratio). preferable.
[0046]
(4) Other components in the preparation
The formulation in the method of enhancing the gel strength of the formulation of the present invention may contain other components such as excipients (eg, starches such as corn starch, lactose, powdered sugar, granulose, glucose, mannitol, light anhydrous silicic acid, Talc, magnesium carbonate, calcium carbonate, etc.), binders [eg, sucrose, gelatin, gum arabic powder, methylcellulose, carboxymethylcellulose, crystalline cellulose / carboxymethylcellulose sodium (eg, Avicel RC, manufactured by Asahi Kasei Corporation), polyvinylpyrrolidone , Pullulan, dextrin, tragacanth, sodium alginate, pregelatinized starch, etc.], disintegrant [for example, carboxymethylcellulose calcium (for example, ECG505, manufactured by Nichirin Chemical Co., Ltd.), croscarmellose sodium (for example, Asahi Kasei ( ), Cross-linked polyvinylpyrrolidone (eg, BASF Corp., Kollidon CL), low-substituted hydroxypropylcellulose (eg, Shin-Etsu Chemical Co., Ltd., L-HPC), starches, etc.], lubricant (Eg, magnesium stearate, talc, stearic acid, calcium stearate, etc.), fluidizing agents (eg, light anhydrous silicic acid, etc.), surfactants (eg, anionic surfactants such as sodium alkyl sulfate, polyoxyethylene) Nonionic surfactants such as sorbitan fatty acid esters, polyoxyethylene fatty acid esters and polyoxyethylene castor oil derivatives, etc.), lipids (eg, hydrocarbons, waxes, higher fatty acids and their salts, higher alcohols, fatty acid esters, hardening) Oils, etc.), coloring agents (for example, tar dyes, Preservatives such as ramel, red iron oxide, titanium oxide, etc., flavoring agents (eg, sweeteners, flavors, etc.), fillers, bulking agents, adsorbents, preservatives, buffers, wetting agents, antistatic agents, disintegration extenders Etc. may be included.
[0047]
In the method for enhancing the gel strength of the preparation of the present invention, when the preparation is a sustained release preparation, the sustained release preparation may be in the form of fine granules, granules, etc. In order to obtain a solid preparation efficiently, it is preferably in the form of a tablet. The tablet may be a single-layer tablet or a laminated tablet or a dry-coated tablet (compressed-encapsulated tablet) composed of a plurality of layers. The laminated tablet and the dry coated tablet are not particularly limited as long as they have at least one sustained release layer (sustained release part), but a solid having at least one sustained release part and an immediate release part composed of an active ingredient, HPMC, HPC, etc. It is effective to be a preparation. That is, when at least one sustained-release layer (sustained-release part) and at least one fast-release layer (fast-release part) are combined, not only can the medicinal effect be rapidly developed, but also the medicinal effect can be maintained. It is.
[0048]
When the preparation in the method for enhancing gel strength of the preparation of the present invention is a sustained release preparation, the sustained release preparation may be formed into a coating tablet by forming a coating layer, if necessary, The feeling may be improved or the stability may be improved. The coated tablets include, for example, sugar-coated tablets, film-coated tablets, etc., and the coating layer is made of calcium carbonate, sucrose, calcium phosphate, talc, gum arabic, hydroxypropylmethylcellulose, polyethylene glycol, polyoxyethylene [105] poly. Oxypropylene [5] glycol, polyoxyethylene [160] polyoxypropylene [30] glycol, glycol, ethylcellulose coating, methacrylic acid copolymer, polyvinyl alcohol, stearic acid-containing hydroxypropylcellulose, enteric polymer (eg, hydroxypropylmethylcellulose) Phthalate, cellulose acetate phthalate, carboxymethylethylcellulose, etc.), coloring agent (titanium oxide, yellow Ngara, ferric oxide, etc. food dyes) with a coating composition composed of such can be formed in a conventional manner.
(5) Method for enhancing gel strength of preparation
The method for enhancing the gel strength of the preparation of the present invention can be carried out, for example, when the preparation is a sustained release preparation, by tableting a powder component containing the active ingredient, HPMC and HPC. The powder component may further contain other components in the preparation exemplified in the above (4). A sustained-release preparation or a sustained-release part may be formed by a simple method of directly compressing and compression-molding the powder component, or a granulated material previously wet- or dry-granulated from the powder component The sustained release preparation or sustained release part may be formed by tableting a tableting component containing The tableting pressure is, for example, 300 to 3000 kg / cm. ² It can be appropriately selected from the range of the degree. When the sustained-release preparation is a tablet, the size of the tablet is not particularly limited, and for example, is preferably 20 to 3000 mg per tablet.
[0049]
The sustained-release preparation is not limited to a monolayer tablet, and may be produced as a laminated tablet, a dry coated tablet or the like.
[Enhancer of gel strength of formulation comprising HPC and HPMC]
The present invention also provides an agent for enhancing the gel strength of a preparation comprising HPC and HPMC. When using the enhancer, the gel strength of the preparation is characterized in that the preparation contains HPC and HPMC. The conditions can be set in the same manner as described in the description of “Method of enhancing”.
[0050]
In the gel strength enhancer of a preparation comprising HPC and HPMC, HPC and HPMC need not necessarily be present in a mixed state, and a form in which HPC and HPMC are present separately is also included in the enhancer.
[Sustained-release preparation containing HPC, HPMC and valproic acid or a valproic acid derivative or a salt thereof]
The present invention also provides a sustained-release preparation containing HPC, HPMC, and valproic acid or a valproic acid derivative or a salt thereof. The method can be carried out by setting the conditions in the same manner as described in the section “Method for enhancing the gel strength of the preparation, characterized in that the preparation is carried out. The sustained-release preparation of the present invention is a sustained-release preparation excellent in gel strength against mechanical movement in a living body and the like.
[0051]
Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.
[0052]
【Example】
Example 1
Tablets were prepared as follows according to the formulation in Table 1. That is, 37.4 g of sodium divalproate [manufactured by Kyowa Hakko Kogyo Co., Ltd.], 6.8 g of HPMC [manufactured by Shin-Etsu Chemical Co., Ltd., Metroze, 90SH-100], HPC [manufactured by Nippon Soda Co., Ltd., Nisso 13.6 g of HPC, HPC-M], 3.4 g of crystalline cellulose [Abicel PH101 manufactured by Asahi Kasei Corporation], and 4.76 g of lactose (Parmatose, 200M Lactose, manufactured by DMV) in a sample mill [SK-M-1700 separate mold] , Manufactured by Kyoritsu Riko Co., Ltd.], and then 4.5 ml of water was added dropwise and kneaded. The obtained kneaded product was dried in a thermostat at 60 ° C. overnight, and the dried product was pulverized using a spatula and a 30-mesh sieve to give a sized powder. To 9.7 g of the sized powder, 0.3 g of light anhydrous silicic acid [Adsolder 101, manufactured by Freund Corporation] was added and mixed using a 2 L plastic bag to obtain a mixed powder. A tableting machine [Collect 12, manufactured by Kikusui Seisakusho Co., Ltd.] was used to make tablets using the obtained mixed powder. The tablet weight was 680 mg, and the tablet shape was oblong (17.5 × 7.0 mm).
Example 2
According to the formulation in Table 1, tablets were prepared in the same manner as in Example 1 except that 6.8 g of HPMC [manufactured by Shin-Etsu Chemical Co., Ltd., Metrose, 90SH-4000] was used.
Example 3
According to the formulation of Table 1, a tablet was prepared in the same manner as in Example 1 except that 6.8 g of HPMC [manufactured by Shin-Etsu Chemical Co., Ltd., Metrose, 60SH-4000] was used.
Example 4
Except for using 6.8 g of HPMC (manufactured by Shin-Etsu Chemical Co., Ltd., Metrosh, 90SH-4000) and 13.6 g of HPC [manufactured by Nippon Soda Co., Ltd., Nisso HPC, HPC-H] according to the formulation in Table 1. In the same manner as in Example 1, a tablet was prepared.
Comparative Example 1
According to the prescription of Table 1, 20.4 g of HPMC [Shin-Etsu Chemical Co., Ltd., Metrose, 90SH-4000] is used, except that the amount of water used for kneading is 5.0 ml without using HPC. A tablet was prepared in the same manner as in Example 1.
Comparative Example 2
According to the prescription of Table 1, 20.4 g of HPMC [Shin-Etsu Chemical Co., Ltd., Metrose, 90SH-15000] was used, except that the amount of water used for kneading was 5.0 ml without using HPC. It was prepared in the same manner as in Example 1.
[0053]
[Table 1]

[0054]
In the table, Metrolose (90SH100), Metrolose (90SH4000) and Metrolose (90SH15000) are products manufactured by Shin-Etsu Chemical Co., Ltd. Nisso HPC (HPC-M) and Nisso HPC (HPC-H) are products manufactured by Nippon Soda Co., Ltd.
[0055]
Test example 1 (dissolution test)
Using the tablets obtained in Examples 1 to 4 and the tablets obtained in Comparative Examples 1 and 2, a dissolution test was conducted according to the second method (paddle method) of the Japanese Pharmacopoeia, 14th Edition, dissolution test method. The number of revolutions was 50 revolutions per minute, and 900 ml of water was used as a test solution. After the start of the dissolution test, sampling was performed over time, and the amount of valproic acid dissolved was determined by high performance liquid chromatography (HPLC) analysis.
[0056]
The HPLC analysis conditions are as follows.
Column: Develosil ODS-UG-5: manufactured by Nomura Science Co., Ltd. 4.6 mm D. × 150mm
Column temperature: 25 ° C
Developing solvent: 0.05 mol / L sodium dihydrogen phosphate TS (pH 3.0) / acetonitrile mixed solution (1: 1)
Flow rate of developing solvent: adjusted so that the retention time of valproic acid is about 6 minutes (1.0 mL / min)
Detector: UV absorption photometer (measurement wavelength: 210 nm)
The following Test Example 2 was also analyzed under the same HPLC analysis conditions.
[0057]
The results of the dissolution test are shown in FIG. From FIG. 1, it can be seen that in the preparation containing HPC and HPMC, the dissolution rate can be arbitrarily controlled by the types and amounts of HPC and HPMC. In contrast, the preparations containing only HPMC obtained in Comparative Examples 1 and 2 show similar dissolution behavior regardless of the type and amount of HPMC added.
[0058]
Test example 2 (dissolution test using beads)
For the evaluation of gel strength, the tablets obtained in Examples 2 and 4 and the tablet obtained in Comparative Example 1 were subjected to a dissolution test using beads. A test solution (250 ml of water), 2000 polystyrene beads (about 6.5 mm in diameter, manufactured by Wako Pure Chemical Industries, Ltd.) (about 280 g) and test tablets are put into a beaker of a dissolution tester, and a paddle is rotated at 25 rpm. A dissolution test was performed. After the start of the dissolution test, sampling was performed over time, and the amount of valproic acid eluted was determined by HPLC analysis.
[0059]
FIG. 2 shows the results of the dissolution test using the beads. In the tablet obtained in Comparative Example 1, in the dissolution test using a paddle, a tendency of bursting the active ingredient was observed 2 to 4 hours after the start of the test. Evaluation of the gel strength was performed by comparing the results of a normal dissolution test (Test Example 1) and a dissolution test using beads (Test Example 2). Table 2 shows the difference in the dissolution rate of the tablets obtained in Examples 2 and 4 and Comparative Example 1 at each time (4, 6, and 12 hours). It is considered that a gel with a smaller difference in elution rate forms a gel matrix that is more resistant to mechanical movement in a living body.
[0060]
The difference in elution rate was calculated by the following equation.
[0061]
(Equation 1)

[0062]
[Table 2]

[0063]
From Table 2, the difference between the dissolution rates of the tablets obtained in Comparative Example 1 was 30 to 45%, whereas the difference between the dissolution rates of the tablets obtained in Examples 2 and 4 was about 20%. It can be seen that the gel strength is significantly improved.
[0064]
【The invention's effect】
According to the present invention, a method for enhancing the gel strength of a preparation, a sustained-release preparation containing valproic acid or a valproic acid derivative or a salt thereof excellent in gel strength, and the like are provided.
[Brief description of the drawings]
FIG. 1 shows the results of a dissolution test of a tablet of Test Example 1.
[Explanation of symbols]
-■-: Indicates the dissolution rate in the case of Test Example 1 using the tablet of Example 1.
-O-: represents the dissolution rate in the case of Test Example 1 using the tablet of Example 2.
-△-: Indicates the dissolution rate in the case of Test Example 1 using the tablet of Example 3.
-□-: Shows the dissolution rate in the case of Test Example 1 using the tablet of Example 4.
-●-: represents the dissolution rate in the case of Test Example 1 using the tablet of Comparative Example 1.
-▲-: represents the dissolution rate in the case of Test Example 1 using the tablet of Comparative Example 2.
FIG. 2 shows the results of a tablet dissolution test using the beads of Test Example 2.
[Explanation of symbols]
-O-: Indicates the dissolution rate in the case of Test Example 2 using the tablet of Example 2.
-□-: Shows the dissolution rate in Test Example 2 using the tablet of Example 4.
-●-: Shows the dissolution rate in Test Example 2 using the tablet of Comparative Example 1.

Claims (14)

A method for enhancing the gel strength of a preparation, which comprises adding hydroxypropylcellulose and hydroxypropylmethylcellulose to the preparation. The method for enhancing gel strength of a preparation according to claim 1, wherein the content of hydroxypropylmethylcellulose is 5 to 45% by weight based on the whole preparation. The method for enhancing gel strength of a preparation according to claim 1 or 2, wherein the content of hydroxypropylcellulose is 5 to 45% by weight based on the whole preparation. The method according to any one of claims 1 to 3, wherein the combined content of hydroxypropylcellulose and hydroxypropylmethylcellulose is 10 to 50% by weight based on the whole preparation. The method for enhancing gel strength of a preparation according to any one of claims 1 to 4, wherein the preparation contains an active ingredient. An agent for enhancing the gel strength of a preparation comprising hydroxypropylcellulose and hydroxypropylmethylcellulose. 7. The gel strength enhancer of the preparation according to claim 6, wherein the ratio of hydroxypropylcellulose to hydroxypropylmethylcellulose is from 1: 1.2 to 1: 5 (weight ratio). A sustained-release preparation containing hydroxypropylcellulose, hydroxypropylmethylcellulose and valproic acid or a valproic acid derivative or a salt thereof. 9. The sustained-release preparation according to claim 8, wherein the valproic acid or the valproic acid derivative or a salt thereof is sodium hydrogen divalproate. The sustained release preparation according to claim 8 or 9, wherein the content of hydroxypropylmethylcellulose is 5 to 45% by weight based on the whole preparation. The sustained-release preparation according to any one of claims 8 to 10, wherein the content of hydroxypropylcellulose is 5 to 45% by weight based on the whole preparation. The sustained-release preparation according to any one of claims 8 to 11, wherein the total content of hydroxypropylcellulose and hydroxypropylmethylcellulose is 10 to 50% by weight based on the whole preparation. The sustained-release preparation according to any one of claims 8 to 12, wherein the content of valproic acid or a valproic acid derivative or a salt thereof is 50% by weight or more based on the whole preparation. The sustained release preparation according to any one of claims 8 to 13, wherein the sustained release preparation is a monolayer sustained release preparation.

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