JP2021084905A - Oral pharmaceutical preparation and method for producing the same - Google Patents
Oral pharmaceutical preparation and method for producing the same Download PDFInfo
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- JP2021084905A JP2021084905A JP2019217346A JP2019217346A JP2021084905A JP 2021084905 A JP2021084905 A JP 2021084905A JP 2019217346 A JP2019217346 A JP 2019217346A JP 2019217346 A JP2019217346 A JP 2019217346A JP 2021084905 A JP2021084905 A JP 2021084905A
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- oral pharmaceutical
- pharmaceutical preparation
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Images
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Abstract
Description
本発明は経口医薬製剤およびその製造方法に関し、より詳細には薬剤の溶出性に優れる経口医薬製剤およびその製造方法に関する。 The present invention relates to an oral pharmaceutical preparation and a method for producing the same, and more particularly to an oral pharmaceutical preparation having excellent drug dissolution and a method for producing the same.
酸に不安定な薬剤については、服用後の胃酸による失活を防ぐために薬剤に腸溶層を被覆して顆粒を作製し、これをカプセルに充填することにより製剤化されることがある。例えば、セロトニン・ノルアドレナリン再取り込み阻害剤（ＳＮＲＩ）であるデュロキセチン塩酸塩は、酸に不安定であるため、薬剤（デュロキセチン塩酸塩）と添加物とを含む内容物に対して腸溶性コーティングが施され、該内容物（顆粒）を硬カプセルに充填したカプセル剤の剤形で市販されている（非特許文献１）。このような腸溶性コーティングが施されたデュロキセチン塩酸塩の顆粒を製造するために、腸溶層をヒドロキシプロピルメチルセルロースアセテートサクシネート（ＨＰＭＣＡＳ）で形成する方法が報告されている（特許文献１）。 Acid-labile drugs may be formulated by coating the drug with an enteric layer to prepare granules and filling them in capsules in order to prevent inactivation due to gastric acid after administration. For example, since duloxetine hydrochloride, which is a serotonin-noradrenaline reuptake inhibitor (SNRI), is unstable to acid, an enteric coating is applied to the contents containing the drug (duloxetine hydrochloride) and additives. , The content (granule) is commercially available in the form of a capsule filled in a hard capsule (Non-Patent Document 1). In order to produce granules of duloxetine hydrochloride having such an enteric coating, a method of forming an enteric layer with hydroxypropylmethylcellulose acetate succinate (HPMCAS) has been reported (Patent Document 1).
一般に、こうしたカプセル剤は嚥下し難く服用性に欠く点が指摘されている。そのため、服用が容易な錠剤としての製剤化が所望されている。 In general, it has been pointed out that these capsules are difficult to swallow and lack ease of administration. Therefore, it is desired to formulate the tablet as an easy-to-take tablet.
しかし、腸溶性ポリマーはその種類に関わらずベタつきが強いため、最外層に腸溶性コーティングが施された顆粒は、錠剤として製剤化すべく打錠すると、顆粒同士が必要以上に凝集する傾向にある。そのため、打錠して得られた錠剤は、薬剤の溶出率が低下する点が指摘されていた。 However, since enteric polymers are highly sticky regardless of their type, granules having an enteric coating on the outermost layer tend to aggregate more than necessary when they are tableted to be formulated as tablets. Therefore, it has been pointed out that the tablet obtained by tableting has a reduced dissolution rate of the drug.
また、特許文献１では、腸溶層の外側に、ヒドロキシプロピルメチルセルロースやポリビニルピロリドンなどの重合物質で形成されるフィニッシング層を設けてもよいことが開示されている。しかし、このような重合物質は水溶性高分子であるため、腸溶層をこれらで被覆してもベタつきは解消されず、依然として打錠によって顆粒が凝集し易い。そのため、薬剤の溶出率が低下するという点は、依然として回避することが困難であった。 Further, Patent Document 1 discloses that a finishing layer formed of a polymer substance such as hydroxypropyl methylcellulose or polyvinylpyrrolidone may be provided outside the enteric layer. However, since such a polymer substance is a water-soluble polymer, the stickiness is not eliminated even if the enteric layer is coated with these, and the granules are still easily aggregated by tableting. Therefore, it is still difficult to avoid the point that the dissolution rate of the drug decreases.
本発明は、上記問題の解決を課題とするものであり、その目的とするところは、酸に不安定な薬剤を含有する経口医薬製剤において、錠剤の剤形であっても、腸溶層を備えた薬剤含有粒子の凝集を抑制し、優れた溶出性を有する経口医薬製剤およびその製造方法を提供することにある。 An object of the present invention is to solve the above-mentioned problems, and an object of the present invention is to provide an enteric layer in an oral pharmaceutical preparation containing an acid-labile drug, even in the form of a tablet. An object of the present invention is to provide an oral pharmaceutical preparation having excellent dissolution property by suppressing aggregation of the provided drug-containing particles and a method for producing the same.
本発明は以下を包含する：
（１）薬剤粒子と腸溶層と被覆層とをこの順で備える被覆粒子を含有する経口医薬製剤であって、
該薬剤粒子が酸に不安定な薬剤を含有し、
該被覆層が低置換度ヒドロキシプロピルセルロースおよび結合剤を含有する、経口医薬製剤。
The present invention includes:
(1) An oral pharmaceutical preparation containing coating particles including drug particles, an enteric layer, and a coating layer in this order.
The drug particles contain a drug that is unstable to acid and
An oral pharmaceutical preparation in which the coating layer contains low-degree-of-substitution hydroxypropyl cellulose and a binder.
（２）錠剤の剤形を有する、（１）に記載の経口医薬製剤。 (2) The oral pharmaceutical preparation according to (1), which has a tablet dosage form.
（３）上記錠剤が口腔内崩壊錠である、（２）に記載の経口医薬製剤。 (3) The oral pharmaceutical preparation according to (2), wherein the tablet is an orally disintegrating tablet.
（４）上記被覆層が、上記低置換度ヒドロキシプロピルセルロース１００質量部に対して０．５質量部から１０質量部の前記結合剤を含有する、（１）から（３）のいずれかに記載の経口医薬製剤。 (4) The method according to any one of (1) to (3), wherein the coating layer contains 0.5 parts by mass to 10 parts by mass of the binder with respect to 100 parts by mass of the low-degree-of-substitution hydroxypropyl cellulose. Oral pharmaceutical preparation.
（５）上記被覆層が、上記低置換度ヒドロキシプロピルセルロース１００質量部に対して０．５質量部から３．５質量部の前記結合剤を含有する、（３）に記載の経口医薬製剤。 (5) The oral pharmaceutical preparation according to (3), wherein the coating layer contains 0.5 to 3.5 parts by mass of the binder with respect to 100 parts by mass of the low-degree-of-substitution hydroxypropyl cellulose.
（６）上記被覆層が、上記被覆粒子の総質量に対して４．５質量％以上２０質量％以下の割合で構成されている、（１）から（５）のいずれかに記載の経口医薬製剤。 (6) The oral preparation according to any one of (1) to (5), wherein the coating layer is composed of 4.5% by mass or more and 20% by mass or less with respect to the total mass of the coating particles. Formulation.
（７）上記結合剤がポリビニルアルコールである、（１）から（６）のいずれかに記載の経口医薬製剤。 (7) The oral pharmaceutical preparation according to any one of (1) to (6), wherein the binder is polyvinyl alcohol.
（８）経口医薬製剤の製造方法であって、
酸に不安定な薬剤を含有する薬剤粒子を作製する工程、
該薬剤粒子に腸溶層を形成して腸溶性粒子を得る工程、および
該腸溶性粒子に被覆層を形成して被覆粒子を得る工程、
を包含し、
該被覆層が、低置換度ヒドロキシプロピルセルロースおよび結合剤を含有する懸濁液を該腸溶性粒子に付着させることにより形成される、方法。
(8) A method for producing an oral pharmaceutical product.
The process of producing drug particles containing a drug that is unstable to acid,
A step of forming an enteric layer on the drug particles to obtain enteric particles, and a step of forming a coating layer on the enteric particles to obtain coated particles.
Including,
A method in which the coating layer is formed by adhering a suspension containing low degree of substitution hydroxypropyl cellulose and a binder to the enteric particles.
（９）さらに、上記被覆粒子を圧縮成形する工程を包含する、（８）に記載の方法。 (9) The method according to (8), further comprising a step of compression molding the coated particles.
本発明によれば、酸に不安定な薬剤を含有する経口医薬製剤において、錠剤の剤形であっても、薬剤の溶出性を良好に保持することができる。本発明の経口医薬製剤は、例えば口腔内崩壊錠や普通錠などの錠剤の剤形に製造することができるため、カプセル剤よりも嚥下し易く、服用が容易である。 According to the present invention, in an oral pharmaceutical preparation containing an acid-unstable drug, the dissolution property of the drug can be well maintained even in the dosage form of a tablet. Since the oral pharmaceutical preparation of the present invention can be produced in the dosage form of tablets such as orally disintegrating tablets and ordinary tablets, it is easier to swallow and take than capsules.
以下、本発明について詳述する。 Hereinafter, the present invention will be described in detail.
（経口医薬製剤）
本発明の経口医薬製剤は、薬剤粒子と腸溶層と被覆層とをこの順で備える被覆粒子を含有する。
(Oral pharmaceutical product)
The oral pharmaceutical preparation of the present invention contains coating particles including drug particles, an enteric layer and a coating layer in this order.
被覆粒子を構成する薬剤粒子は、酸に不安定な薬剤を含有する。 The drug particles constituting the coating particles contain a drug that is unstable to acid.
本明細書において、用語「酸に不安定な薬剤」とは、酸性物質を含有する水溶液または固体が存在する環境下において、変質（例えば、分解、置換、付加、脱離、重縮合、酸化、還元または中和、あるいはそれらの組み合わせによる化学反応を包含する）を通じてその物理的性質および／または化学的性質が経時的に変化する薬剤化合物を総称していう。１つの実施形態では、酸に不安定な薬剤としては、胃酸のような強酸性物質の存在下で変質し得る薬剤、例えばｐＨ１〜６、好ましくはｐＨ１〜４、より好ましくはｐＨ１〜３、さらにより好ましくはｐＨ１〜１．５の水溶液の存在下で変質し得る薬剤が挙げられる。 As used herein, the term "acid-labile agent" refers to alteration (eg, decomposition, substitution, addition, desorption, polycondensation, oxidation, etc.) in the presence of an aqueous solution or solid containing an acidic substance. A generic term for a drug compound whose physical and / or chemical properties change over time through reduction or neutralization, or a chemical reaction resulting from a combination thereof. In one embodiment, the acid-labile agent includes agents that can be altered in the presence of strongly acidic substances such as gastric acid, such as pH 1-6, preferably pH 1-4, more preferably pH 1-3, and further. More preferably, a drug that can be altered in the presence of an aqueous solution having a pH of 1 to 1.5 can be mentioned.
酸に不安定な薬剤としては、必ずしも限定されないが、例えば、デュロセキチン、エソメプラゾール、オメプラゾール、ラベプラゾール、ランソプラゾール、ジダノシン、ジゴキシン、エリスロマイシン、パンクレアチン、およびプラバスタチン；ならびにこれらの薬学的に許容し得る塩（例えば、塩酸塩、ナトリウム塩、カリウム塩、リチウム塩、カルシウム塩、マグネシウム塩、アルミニウム塩、アンモニウム塩、トリメチルアンモニウム塩、トリエチルアンモニウム塩、モノエタノールアンモニウム塩、トリエタノールアンモニウム塩、ピリジニウム塩、置換ピリジニウム塩などの医薬的に許容し得るアルカリ金属塩、アルカリ土類金属塩、非毒性金属塩、アンモニウム塩および置換アンモニウム塩）および水和物等が挙げられる。うつ病；うつ状態；糖尿病性神経障害、線維筋痛症、慢性腰痛症などに伴う疼痛；に対する治療または予防に加え、糖尿病性ニューロパチー、腹圧性尿失禁、全般性不安障害に対する治療または予防への適用も知られており、有用性および汎用性が期待されている点から、デュロセキチン塩酸塩が好ましい。 Acid-labile agents include, but are not necessarily limited to, for example, durosekitin, esomeprazole, omeprazole, labeprazole, lansoprazole, didanosine, digoxin, erythromycin, pancreatin, and pravastatin; and pharmaceutically acceptable salts thereof. (For example, hydrochloride, sodium salt, potassium salt, lithium salt, calcium salt, magnesium salt, aluminum salt, ammonium salt, trimethylammonium salt, triethylammonium salt, monoethanolammonium salt, triethanolammonium salt, pyridinium salt, substituted pyridinium Pharmaceutically acceptable alkali metal salts such as salts, alkaline earth metal salts, non-toxic metal salts, ammonium salts and substituted ammonium salts) and hydrates and the like can be mentioned. Depression; Depression; Pain associated with diabetic neuropathy, fibromyalgia, chronic lumbar pain, etc.; in addition to treatment or prevention, treatment or prevention for diabetic neuropathy, stress urinary incontinence, general anxiety disorder Durosecitine hydrochloride is preferred because its application is known and its usefulness and versatility are expected.
本発明における酸に不安定な薬剤の含有量は、含有される薬剤の種類や用量等に応じて変動するため必ずしも限定されないが、経口医薬製剤の全体質量を基準にして、０．５質量％〜５０質量％、好ましくは１質量％〜２０質量％である。薬剤の含有量が０．５質量％を下回ると、１回の投与に要する経口医薬製剤の全体量が増大して患者に過度の服用負担を与えることがある。薬剤の含有量が５０質量％を上回ると、所望の剤形を保持することが困難となる場合がある。 The content of the drug unstable to acid in the present invention is not necessarily limited because it varies depending on the type and dose of the drug contained, but is 0.5% by mass based on the total mass of the oral pharmaceutical preparation. It is ~ 50% by mass, preferably 1% by mass to 20% by mass. If the content of the drug is less than 0.5% by mass, the total amount of the oral pharmaceutical preparation required for one administration may increase, which may impose an excessive burden on the patient. If the content of the drug exceeds 50% by mass, it may be difficult to maintain the desired dosage form.
薬剤粒子は、１）上記酸に不安定な薬剤そのものであってもよいし、２）上記酸に不安定な薬剤と薬理学的に許容される添加物（例えば、後述する各剤など）との混合物を造粒したものであってもよいし、３）コア粒子の表面に上記酸に不安定な薬剤を含む薬物層が形成されたものであってもよい。薬剤粒子は、３）コア粒子の表面に上記酸に不安定な薬剤を含む薬物層が形成されたものであることが好ましい。 The drug particles may be 1) the acid-labile drug itself, or 2) the acid-labile drug and pharmacologically acceptable additives (eg, each drug described below). The mixture may be granulated, or 3) a drug layer containing the acid-unstable drug may be formed on the surface of the core particles. The drug particles are preferably those in which a drug layer containing the above-mentioned acid-unstable drug is formed on the surface of 3) core particles.
コア粒子としては、薬理学的に不活性な粒子が好ましく、例えば製薬分野にて一般に使用されている賦形剤を用いることができる。賦形剤の例としては、乳糖・結晶セルロース球状顆粒、精製白糖球状顆粒、白糖・デンプン球状顆粒、Ｄ−マンニトール、エリスリトール、キシリトール、ソルビトール、イソマルト、マルチトール、ショ糖、ブドウ糖、トウモロコシデンプン、バレイショデンプン、コメデンプン、コムギデンプン、ヒドロキシプロピルスターチ、アルファー化デンプン、部分アルファー化デンプン、カルボキシメチルスターチナトリウム、デキストリン等が挙げられる。コア粒子は１種のみであってもよいし、２種以上であってもよい。 As the core particles, pharmacologically inert particles are preferable, and for example, excipients generally used in the pharmaceutical field can be used. Examples of excipients include lactose / crystalline cellulose spherical granules, purified sucrose spherical granules, sucrose / starch spherical granules, D-mannitol, erythritol, xylitol, sorbitol, isomalt, martitol, sucrose, glucose, corn starch, potato. Examples thereof include starch, rice starch, wheat starch, hydroxypropyl starch, pregelatinized starch, partially pregelatinized starch, sodium carboxymethyl starch, dextrin and the like. The core particles may be of only one type or of two or more types.
コア粒子の平均粒子径は、必ずしも限定されないが、好ましくは直径５０μｍ〜８５０μｍ、より好ましくは直径１００μｍ〜７００μｍである。 The average particle size of the core particles is not necessarily limited, but is preferably 50 μm to 850 μm in diameter, and more preferably 100 μm to 700 μm in diameter.
薬剤層は、上記酸に不安定な薬剤とともに第１のコーティング剤を含有し得る。 The drug layer may contain a first coating agent along with the acid-labile agent.
第１のコーティング剤としては、例えば、ヒドロキシプロピルメチルセルロース（ヒプロメロース）、エチルセルロース、ヒドロキシメチルセルロース、ヒドロキシプロピルセルロース、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、ポリビニルアルコール、ポリエチレングリコール、メタクリル酸コポリマー、アクリル酸エチル・メタクリル酸メチルコポリマー、タルク、および酸化チタン、ならびにそれらの組み合わせ等が挙げられる。薬剤層に含まれる第１のコーティング剤の含有量は、例えば、酸に不安定な薬剤の含有量、コア粒子の平均粒子径およびその含有量等に応じて当業者によって適切に選択され得る。 Examples of the first coating agent include hydroxypropylmethyl cellulose (hypromellose), ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyvinyl alcohol, polyethylene glycol, methacrylic acid copolymer, and acrylic. Examples thereof include ethyl acetate / methyl methacrylate copolymer, talc, and titanium oxide, and combinations thereof. The content of the first coating agent contained in the drug layer can be appropriately selected by those skilled in the art depending on, for example, the content of the drug which is unstable to acid, the average particle size of the core particles and the content thereof.
薬剤層には、第１のコーティング剤とともに、酸に不安定な薬剤の変質を抑制し類縁物質の生成を回避するための安定剤を含有させることができる。安定剤としては、例えば、無機系アルカリ化剤および有機系アルカリ化剤、ならびにそれらの組み合わせ等が挙げられる。 The drug layer may contain, together with the first coating agent, a stabilizer for suppressing the alteration of the acid-labile drug and avoiding the formation of related substances. Examples of the stabilizer include an inorganic alkalizing agent and an organic alkalizing agent, and a combination thereof.
無機系アルカリ化剤は、無機化合物により構成されており、上記酸に不安定な薬剤と共存させることにより、水溶液中でのｐＨを調節する等の役割を果たし、酸性条件下での当該薬剤の変質を防止することができる。さらに、無機系アルカリ化剤は、経口医薬製剤の保管の間に生じ得る、上記薬剤成分の変質による類縁物質の形成を抑制することができる。 The inorganic alkalizing agent is composed of an inorganic compound, and by coexisting with the above-mentioned acid-unstable agent, it plays a role of adjusting the pH in an aqueous solution and the like, and the agent under acidic conditions. Deterioration can be prevented. Furthermore, the inorganic alkalizing agent can suppress the formation of related substances due to the alteration of the above-mentioned drug components, which may occur during the storage of the oral pharmaceutical preparation.
無機系アルカリ化剤としては、特に限定されないが、例えば、アルカリ金属またはアルカリ土類金属元素を含む炭酸塩、重炭酸塩、水酸化物塩、または酸化物、あるいはそれらの組み合わせ等が挙げられる。無機系アルカリ化剤を構成し得るアルカリ金属の例としては、ナトリウムおよびカリウム等が挙げられる。無機系アルカリ化剤を構成し得るアルカリ土類金属の例としては、マグネシウムおよびカルシウム等が挙げられる。無機系アルカリ化剤のより具体的な例としては、炭酸マグネシウム、炭酸カリウム、炭酸ナトリウム、酸化マグネシウム、水酸化マグネシウム、炭酸カルシウム、および炭酸水素ナトリウム、ならびにそれらの組み合わせが挙げられる。例えば、上記酸に不安定な薬剤としてデュロキセチン塩酸塩を用いた場合、当該デュロキセチン塩酸塩の安定性を最も効果的に保持し得るとの理由から、炭酸マグネシウムを用いることが好ましい。 The inorganic alkalizing agent is not particularly limited, and examples thereof include carbonates containing alkali metals or alkaline earth metal elements, bicarbonates, hydroxide salts, oxides, or combinations thereof. Examples of alkali metals that can constitute an inorganic alkalizing agent include sodium and potassium. Examples of alkaline earth metals that can constitute an inorganic alkalizing agent include magnesium and calcium. More specific examples of the inorganic alkalizing agent include magnesium carbonate, potassium carbonate, sodium carbonate, magnesium oxide, magnesium hydroxide, calcium carbonate, and sodium hydrogen carbonate, and combinations thereof. For example, when duloxetine hydrochloride is used as the drug unstable to the acid, magnesium carbonate is preferably used because the stability of the duloxetine hydrochloride can be maintained most effectively.
有機系アルカリ化剤は、必ずしも限定されないが、例えばメグルミン、アルギニン、ヒスチジン、リジン、およびアミノアルキルメタクリレートコポリマーＥ（例えば、Ｅｕｄｒａｇｉｔ（登録商標）（Ｅｖｏｎｉｋ社製））、ならびにそれらの組み合わせ等が挙げられる。 Examples of the organic alkalizing agent include, but are not limited to, meglumine, arginine, histidine, lysine, aminoalkyl methacrylate copolymer E (for example, Eudragit (registered trademark) (manufactured by Evonik)), and combinations thereof. ..
薬剤層における安定剤の含有量は、上記酸に不安定な薬剤１質量部に対して、好ましくは０．０００１質量部〜１０質量部、より好ましくは０．００１質量部〜５質量部である。安定剤の含有量が０．０００１質量部を下回ると、上記薬剤の変質に伴う類縁物質の形成を充分に抑制できない場合がある。安定剤の含有量が１０質量部を上回ると、もはや類縁物質の形成抑制にはそれ以上の変化は見られず、むしろ経口医薬製剤としての生産性を低下させるおそれがある。 The content of the stabilizer in the drug layer is preferably 0.0001 parts by mass to 10 parts by mass, and more preferably 0.001 parts by mass to 5 parts by mass with respect to 1 part by mass of the acid-unstable drug. .. If the content of the stabilizer is less than 0.0001 parts by mass, the formation of related substances due to the alteration of the drug may not be sufficiently suppressed. When the content of the stabilizer exceeds 10 parts by mass, no further change is observed in the suppression of the formation of related substances, but rather the productivity as an oral pharmaceutical preparation may be lowered.
薬剤粒子は、必要に応じて中間層で覆われていてもよい。 The drug particles may be covered with an intermediate layer, if desired.
中間層は、例えば薬剤粒子（例えば、上記薬剤層）上に直接配置される層であり、薬剤と腸溶層とが直接接触するのを避けるための層である。中間層は、第２のコーティング剤と、必要に応じて、帯電防止剤等を含有させることができる。第２のコーティング剤は、通常、非腸溶性のコーティング剤であり、具体的な例としては、上記薬剤層を構成する第１のコーティング剤に例示したものが挙げられる。本発明において、第２のコーティング剤は第１のコーティング剤と同一であってもよいし異なっていてもよい。 The intermediate layer is, for example, a layer directly arranged on the drug particles (for example, the above-mentioned drug layer), and is a layer for avoiding direct contact between the drug and the enteric layer. The intermediate layer may contain a second coating agent and, if necessary, an antistatic agent or the like. The second coating agent is usually a non-enteric coating agent, and specific examples thereof include those exemplified for the first coating agent constituting the drug layer. In the present invention, the second coating agent may be the same as or different from the first coating agent.
中間層に含まれる帯電防止剤の例としては、軽質無水ケイ酸、含水二酸化ケイ素、タルク、およびステアリン酸マグネシウム、ならびにそれらの組み合わせ等が挙げられる。中間層を構成する第２のコーティング剤および帯電防止剤の含有量は特に限定されず、当業者によって適切な含有量が選択され得る。 Examples of the antistatic agent contained in the intermediate layer include light silicic anhydride, hydrous silicon dioxide, talc, magnesium stearate, and combinations thereof. The contents of the second coating agent and the antistatic agent constituting the intermediate layer are not particularly limited, and an appropriate content can be selected by those skilled in the art.
本発明において、腸溶層は、薬剤粒子の表面（例えば上記中間層が設けられている場合は当該中間層の外側表面、上記中間層が設けられていない場合には薬剤層の外側表面）上にされている。 In the present invention, the enteric layer is on the surface of the drug particles (for example, the outer surface of the intermediate layer when the intermediate layer is provided, or the outer surface of the drug layer when the intermediate layer is not provided). Has been made.
腸溶層は、主に腸溶性のコーティング剤（第３のコーティング剤ともいう）から構成されている。第３のコーティング剤は、腸溶性ポリマーを含有していればよく、必要に応じて、クエン酸トリエチルなどの可塑剤、タルク等の付着防止剤、酸化チタンなどの遮光剤、その他各種添加剤ならびにそれらの組み合わせを含有し得る。腸溶性ポリマーの例としては、ヒプロメロース酢酸エステルコハク酸エステル、メタクリル酸共重合体、セルロースアセテートフタレート、セルロースアセテートブチレート、ヒプロメロースフタレート、ポリビニルアセテートフタレート、セルロースアセテートトリメリテート、およびカルボキシメチルエチルセルロース、ならびにそれらの組み合わせ等が挙げられる。 The enteric layer is mainly composed of an enteric coating agent (also referred to as a third coating agent). The third coating agent may contain an enteric polymer, and if necessary, a plasticizer such as triethyl citrate, an adhesion inhibitor such as talc, a light-shielding agent such as titanium oxide, and various other additives. It may contain a combination thereof. Examples of enteric polymers include hypromellose acetate succinate, methacrylic acid copolymer, cellulose acetate phthalate, cellulose acetate butyrate, hypromellose phthalate, polyvinyl acetate phthalate, cellulose acetate trimellitate, and carboxymethyl ethyl cellulose. And combinations thereof and the like.
本発明において、被覆層は、腸溶層の外側表面上、すなわち当該腸溶層の外側表面の一部または全体を覆って形成されている。本発明においては、被覆粒子を構成する被覆層は腸溶層の外側表面の全体を覆って付与されていることが好ましい。これにより、被覆粒子表面への腸溶層の露出が防止され、被覆粒子のベタつきによる薬剤の溶出性低下を回避することができる。 In the present invention, the coating layer is formed on the outer surface of the enteric layer, that is, covering a part or the whole of the outer surface of the enteric layer. In the present invention, it is preferable that the coating layer constituting the coating particles is applied so as to cover the entire outer surface of the enteric layer. As a result, the exposure of the enteric layer to the surface of the coated particles can be prevented, and the decrease in elution of the drug due to the stickiness of the coated particles can be avoided.
被覆層は、低置換度ヒドロキシプロピルセルロースおよび結合剤を含有する。一般に、粒子のコーティングには水溶性ポリマーが用いられるところ、本発明においては、敢えて、水不溶性の低置換度ヒドロキシプロピルセルロースを使用する。これにより、被覆粒子の表面は水不溶性の微小な凹凸形状となるので、打錠された場合にも被覆粒子（顆粒）同士の凝集を防止することができる。 The coating layer contains low degree of substitution hydroxypropyl cellulose and a binder. Generally, a water-soluble polymer is used for coating particles, but in the present invention, water-insoluble low-degree-of-substitution hydroxypropyl cellulose is intentionally used. As a result, the surface of the coated particles has a minute uneven shape that is insoluble in water, so that it is possible to prevent the coated particles (granule) from aggregating with each other even when the tablet is locked.
低置換度ヒドロキシプロピルセルロースは、極めて少量のヒドロキシプロピル基（−ＯＣ３Ｈ６ＯＨ）をグルコース環に導入したものであり、通常所定の平均粒子径（例えば１０μｍ〜６０μｍ、好ましくは１５μｍ〜４０μｍ）を有する粒子（例えば、微粉状、重質、繊維状、または長繊維状の形態）である。 Low-substituted hydroxypropylcellulose is for a very small amount of hydroxypropyl groups (-OC 3 H 6 OH) was introduced into the glucose ring, usually predetermined average particle size (e.g. 10 m to 60 m, preferably 15Myuemu～40myuemu) Particles having (eg, fine powder, heavy, fibrous, or long fibrous form).
低置換度ヒドロキシプロピルセルロースはまた、そのモル置換度（１グルコースあたりのヒドロキシプロピル基の数）が例えば０．２〜０．４であるものを包含する。これに対し、一般的なヒドロキシプロピルセルロース（ＨＰＣ）の当該モル置換度は約３より大きい。このモル置換度の相違により、低置換度ヒドロキシプロピルセルロースは、一般的なヒドロキシプロピルセルロース（ＨＰＣ）とは異なる性質を有する。例えば、ヒドロキシプロピルセルロース（ＨＰＣ）は水溶性およびアルコール可溶性であるのに対し、低置換度ヒドロキシプロピルセルロースは嵩高く、水または水溶液に対して不溶性の性質を有する。 Low degree of substitution hydroxypropyl cellulose also includes those having a degree of molar substitution (the number of hydroxypropyl groups per glucose), for example 0.2-0.4. In contrast, the degree of molar substitution of common hydroxypropyl cellulose (HPC) is greater than about 3. Due to this difference in molar substitution, low-substituted hydroxypropyl cellulose has properties different from general hydroxypropyl cellulose (HPC). For example, hydroxypropyl cellulose (HPC) is water-soluble and alcohol-soluble, whereas low-degree-of-substitution hydroxypropyl cellulose is bulky and insoluble in water or aqueous solutions.
このように、低置換度ヒドロキシプロピルセルロースは、ヒドロキシプロピルセルロース（ＨＰＣ）とは全く別異の化合物として明確に区別される。 Thus, low-degree-of-substitution hydroxypropyl cellulose is clearly distinguished as a completely different compound from hydroxypropyl cellulose (HPC).
さらに、低置換度ヒドロキシプロピルセルロースは、例えば日本薬局方に記載のセルロースの低置換度ヒドロキシプロピルエーテルであり、換算した乾燥物を基準として好ましくは５％〜１６％、より好ましくは７％〜１４％、さらにより好ましくは９％〜１２％のヒドロキシプロポキシ基を有する。ヒドロキシプロポキシ基の割合が上記範囲であれば、所望の嵩高さを有し、かつ水不溶性であるという低置換度ヒドロキシプロピルセルロースの特性を発揮する。 Further, the low-degree-of-substitution hydroxypropyl cellulose is, for example, the low-degree-of-substitution hydroxypropyl ether of cellulose described in the Japanese Pharmacopoeia, and is preferably 5% to 16%, more preferably 7% to 14% based on the converted dried product. %, More preferably 9% to 12% of hydroxypropoxy groups. When the proportion of hydroxypropoxy groups is in the above range, it exhibits the characteristics of low-degree-of-substitution hydroxypropyl cellulose having a desired bulkiness and being water-insoluble.
本発明において、低置換度ヒドロキシプロピルセルロースは崩壊剤の１種として機能し得る。 In the present invention, low degree of substitution hydroxypropyl cellulose can function as one of the disintegrants.
被覆層に含有される低置換度ヒドロキシプロピルセルロースの平均粒子径は、特に限定されないが、好ましくは１０μｍ〜６０μｍ、より好ましくは２０μｍ〜５５μｍである。低置換度ヒドロキシプロピルセルロースの平均粒子径が１０μｍ未満であると、被覆粒子の表面に凹凸を形成し難くなることがあり、一方、６０μｍを上回ると、腸溶性粒子の表面に付着させ難くなることがある。 The average particle size of the low-degree-of-substitution hydroxypropyl cellulose contained in the coating layer is not particularly limited, but is preferably 10 μm to 60 μm, and more preferably 20 μm to 55 μm. If the average particle size of the low-substitution hydroxypropyl cellulose is less than 10 μm, it may be difficult to form irregularities on the surface of the coated particles, while if it exceeds 60 μm, it may be difficult to adhere to the surface of the enteric particles. There is.
なお、低置換度ヒドロキシプロピルセルロースの平均粒子径は、例えば、レーザー回折式粒度分布測定装置などにより測定することができる。 The average particle size of the low-degree-of-substitution hydroxypropyl cellulose can be measured by, for example, a laser diffraction type particle size distribution measuring device.
結合剤は、腸溶層で覆われた薬剤粒子上で上記低置換度ヒドロキシプロピルセルロースの粒子を接着させる機能を果たす。 The binder serves to bond the particles of the low degree of substitution hydroxypropyl cellulose onto the drug particles covered with an enteric layer.
結合剤としては、例えば、ポリビニルアルコール（ＰＶＡ）（ここで、ＰＶＡは部分けん化物および完全けん化物のいずれであってもよい）、ヒドロキシプロピルセルロース（ＨＰＣ）、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ；ヒプロメロース）、ポリビニルピロリドン（ＰＶＰ；ポビドン）、メチルセルロース、およびエチルセルロース、ならびにそれらの組み合わせが挙げられる。低置換度ヒドロキシプロピルセルロースの粒子を少量で強固に接着することができるという点から、ポリビニルアルコールが好ましく、ポリビニルアルコールの部分けん化物がさらに好ましい。結合剤としてポリビニルアルコールの部分けん化物が用いられる場合、そのけん化度は、好ましくは８５モル％〜９０モル％である。 Examples of the binder include polyvinyl alcohol (PVA) (where PVA may be either a partially saponified product or a completely saponified product), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC; hypromellose), and the like. Polyvinylpyrrolidone (PVP; povidone), methylcellulose, and ethylcellulose, and combinations thereof can be mentioned. Polyvinyl alcohol is preferable, and a partially saponified product of polyvinyl alcohol is more preferable, because particles of hydroxypropyl cellulose having a low degree of substitution can be firmly adhered with a small amount. When a partially saponified product of polyvinyl alcohol is used as the binder, the degree of saponification is preferably 85 mol% to 90 mol%.
本発明の経口医薬製剤において、被覆層に含まれる結合剤の含有量は、低置換度ヒドロキシプロピルセルロース１００質量部に対して、好ましくは０．５質量部〜１０質量部、より好ましくは１質量部〜５質量部である。結合剤の含有量が０．５質量部を下回ると、腸溶層で覆われた薬剤粒子上で低置換度ヒドロキシプロピルセルロースを十分に接着して強固な被膜層を形成することができないことがある。結合剤の含有量が１０質量部を上回ると、被覆粒子（顆粒）同士の凝集が起こることがある。 In the oral pharmaceutical preparation of the present invention, the content of the binder contained in the coating layer is preferably 0.5 parts by mass to 10 parts by mass, more preferably 1 part by mass with respect to 100 parts by mass of low-substituted hydroxypropyl cellulose. Parts to 5 parts by mass. If the content of the binder is less than 0.5 parts by mass, it may not be possible to sufficiently adhere the low-substitution hydroxypropyl cellulose on the drug particles covered with the enteric layer to form a strong coating layer. is there. If the content of the binder exceeds 10 parts by mass, agglomeration of the coated particles (granule) may occur.
さらに本発明の経口医薬製剤が口腔崩壊錠である場合、被覆層に含まれる結合剤の含有量は、低置換度ヒドロキシプロピルセルロース１００質量部に対して、好ましくは０．５質量部〜７質量部、より好ましくは１質量部〜３．５質量部である。被膜層に含まれる結合剤がこのような範囲の含有量で含まれていることにより、得られる経口医薬製剤（口腔内崩壊錠）は、口の中での唾液や少量の水による速やかな崩壊性を可能にするとともに、当該製剤からの酸に不安定な薬剤の溶出性の低下を防止することができる。 Further, when the oral pharmaceutical preparation of the present invention is an orally disintegrating tablet, the content of the binder contained in the coating layer is preferably 0.5 parts by mass to 7 parts by mass with respect to 100 parts by mass of low-substituted hydroxypropyl cellulose. Parts, more preferably 1 part by mass to 3.5 parts by mass. When the binder contained in the coating layer is contained in such a range, the obtained oral pharmaceutical preparation (orally disintegrating tablet) is rapidly disintegrated by saliva or a small amount of water in the mouth. In addition to enabling sex, it is possible to prevent a decrease in the dissolution property of an acid-unstable drug from the preparation.
本発明において、被覆層は、被覆粒子の総質量に対して、好ましくは４．５質量％以上５０質量％以下、より好ましくは４．５質量％以上２０質量％以下の割合で含有されている。被覆層の割合が４．５質量％未満であると、得られる被覆粒子は互いに凝集し易くなり、それを用いて作製した経口医薬製剤からの薬剤の溶出性は低下することがある。被覆層の割合が５０質量％を上回ると、被覆粒子が大きくなり、それに応じて錠剤自体も大きくなるため、服用性が低下するおそれがある。 In the present invention, the coating layer is preferably contained in a proportion of 4.5% by mass or more and 50% by mass or less, more preferably 4.5% by mass or more and 20% by mass or less, based on the total mass of the coating particles. .. When the proportion of the coating layer is less than 4.5% by mass, the obtained coating particles tend to aggregate with each other, and the dissolution property of the drug from the oral pharmaceutical preparation prepared by using the coating particles may decrease. If the proportion of the coating layer exceeds 50% by mass, the coating particles become large, and the tablet itself becomes large accordingly, so that the ingestibility may decrease.
被覆層には、上記低置換度ヒドロキシプロピルセルロースおよび結合剤による効果を阻害しない範囲において他の添加剤が含まれていてもよい。しかし、より強固な層を形成するためには、被膜層は、上記低置換度ヒドロキシプロピルセルロースおよび結合剤のみで構成されていてもよい。 The coating layer may contain the above-mentioned low-degree-of-substitution hydroxypropyl cellulose and other additives as long as the effects of the binder are not impaired. However, in order to form a stronger layer, the coating layer may be composed only of the low degree of substitution hydroxypropyl cellulose and the binder.
本発明の経口医薬製剤は、上記被覆粒子とともに他の添加剤を含有していてもよい。 The oral pharmaceutical preparation of the present invention may contain other additives together with the coating particles.
被覆粒子とともに添加され得る他の添加剤としては、例えば、賦形剤、崩壊剤、流動化剤、矯味剤、香料、および滑沢剤、ならびにそれらの組み合わせが挙げられる。 Other additives that can be added with the coated particles include, for example, excipients, disintegrants, fluidizers, flavoring agents, fragrances, and lubricants, and combinations thereof.
被覆粒子とともに添加され得る賦形剤の例としては、乳糖、結晶セルロース、Ｄ−マンニトール、エリスリトール、キシリトール、ソルビトール、イソマルト、マルチトール、白糖、ショ糖、ブドウ糖、トウモロコシデンプン、バレイショデンプン、コメデンプン、コムギデンプン、ヒドロキシプロピルスターチ、アルファー化デンプン、部分アルファー化デンプン、カルボキシメチルスターチナトリウム、およびデキストリン、ならびにそれらの組み合わせ等が挙げられる。経口医薬製剤における当該賦形剤の含有量は、当業者によって適宜選択され得る。 Examples of excipients that can be added with the coating particles include lactose, crystalline cellulose, D-mannitol, erythritol, xylitol, sorbitol, isomalt, martitol, sucrose, sucrose, glucose, corn starch, potato starch, rice starch, etc. Examples thereof include wheat starch, hydroxypropyl starch, pregelatinized starch, partially pregelatinized starch, sodium carboxymethyl starch, and dextrin, and combinations thereof. The content of the excipient in the oral pharmaceutical preparation can be appropriately selected by those skilled in the art.
被覆粒子とともに添加され得る崩壊剤の例としては、カルメロース、カルメロースカルシウム、カルメロースナトリウム、ヒドロキシプロピルスターチ、カルボキシメチルスターチナトリウム、およびクロスポビドン、ならびにそれらの組み合わせ等が挙げられる。経口医薬製剤における当該崩壊剤の含有量は、当業者によって適宜選択され得る。 Examples of disintegrants that can be added with the coated particles include carmellose, carmellose calcium, carmellose sodium, hydroxypropyl starch, carboxymethyl starch sodium, and crospovidone, and combinations thereof. The content of the disintegrant in the oral pharmaceutical preparation can be appropriately selected by those skilled in the art.
被覆粒子とともに添加され得る流動化剤の例としては、含水二酸化ケイ素、軽質無水ケイ酸、タルク、合成ケイ酸アルミニウム、酸化チタン、ステアリン酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、メタケイ酸アルミン酸マグネシウム、ならびにそれらの組合せ等が挙げられる。経口医薬製剤における当該流動化剤の含有量は、当業者によって適宜選択され得る。 Examples of fluidizers that can be added with the coating particles include hydrous silicon dioxide, light anhydrous silicic acid, talc, synthetic aluminum silicate, titanium oxide, stearic acid, magnesium stearate, calcium stearate, magnesium aluminometasilicate, as well. Examples thereof include a combination thereof. The content of the fluidizing agent in the oral pharmaceutical preparation can be appropriately selected by those skilled in the art.
被覆粒子とともに添加され得る矯味剤の例としては、アスコルビン酸、Ｌ−アスパラギン酸、アスパルテーム、スクラロース、アセスルファムカリウム、およびソーマチン、ならびにそれらの組み合わせ等が挙げられる。経口医薬製剤における当該矯味剤の含有量は、当業者によって適宜選択され得る。 Examples of flavoring agents that can be added with the coating particles include ascorbic acid, L-aspartic acid, aspartame, sucralose, acesulfame potassium, and thaumatin, and combinations thereof. The content of the flavoring agent in the oral pharmaceutical preparation can be appropriately selected by those skilled in the art.
被覆粒子とともに添加され得る香料の例としては、ミント、レモン香料、オレンジコートン、パイナップルフレーバー、およびｌ−メントール、ならびにそれらの組み合わせ等が挙げられる。経口医薬製剤における当該香料の含有量は、当業者によって適宜選択され得る。 Examples of flavors that can be added with the coating particles include mint, lemon flavors, orange corton, pineapple flavors, and l-menthol, and combinations thereof. The content of the fragrance in the oral pharmaceutical preparation can be appropriately selected by those skilled in the art.
被覆粒子とともに添加され得る滑沢剤の例としては、軽質無水ケイ酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、フマル酸ステアリルナトリウム、タルク、および硬化油、ならびにそれらの組み合わせ等が挙げられる。経口医薬製剤における当該滑沢剤の含有量は、当業者によって適宜選択され得る。 Examples of lubricants that can be added with the coated particles include light anhydrous silicic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, and hydrogenated oils, and combinations thereof. The content of the lubricant in the oral pharmaceutical preparation can be appropriately selected by those skilled in the art.
本発明の経口医薬製剤は、錠剤、顆粒剤、細粒剤、丸剤、カプセル剤、ドライシロップ剤、トローチ剤、末剤および散剤等の固形製剤であれば特に限定されないが、打錠した場合であっても凝集せず溶出性を損なわないという上記被覆粒子の優位性を活かす上では、錠剤の剤形であることが好ましい。錠剤のより具体的な例としては、普通錠、口腔内崩壊錠、チュアブル錠、発泡錠、分散錠、および溶解錠等が挙げられる。このような錠剤であれば、カプセル剤と比較して嚥下し易く服用者への負担を低減することができる。服用性の点では、中でも特に、口腔内崩壊錠の形態を有することがより好ましい。さらに、本発明の経口医薬製剤は、口腔内崩壊錠または普通錠のような錠剤の形態を有している場合、これらの錠剤は素錠のままであってもよく、あるいは当該技術分野において公知のコーティング剤を用いてフィルムコーティングされた錠剤（フィルムコーティング錠）であってもよい。 The oral pharmaceutical preparation of the present invention is not particularly limited as long as it is a solid preparation such as tablets, granules, fine granules, pills, capsules, dry syrups, troches, powders and powders, but it may be tableted. In order to take advantage of the coating particles, which do not aggregate and impair the elution property even if they are present, the dosage form of tablets is preferable. More specific examples of tablets include ordinary tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersion tablets, dissolution tablets and the like. Such tablets are easier to swallow than capsules and can reduce the burden on the user. In terms of ease of administration, it is more preferable to have the form of an orally disintegrating tablet. Further, when the oral pharmaceutical preparation of the present invention has the form of tablets such as an orally disintegrating tablet or an ordinary tablet, these tablets may remain uncoated tablets or are known in the art. It may be a tablet (film-coated tablet) film-coated with the coating agent of.
（経口医薬製剤の製造方法）
本発明の経口医薬製剤は、例えば以下のようにして製造される。
(Manufacturing method of oral pharmaceutical product)
The oral pharmaceutical preparation of the present invention is produced, for example, as follows.
まず、酸に不安定な薬剤を含有する薬剤粒子が作製される。以下では、薬剤粒子が、コア粒子の表面に酸に不安定な薬剤を含む薬物層が形成されたものである場合の作製方法について説明する。なお、薬剤粒子が、酸に不安定な薬剤と薬理学的に許容される添加物（例えば、後述する各剤など）との混合物を造粒したものである場合の混合方法および造粒方法については、特に制限されるものではなく、公知の方法を適宜採用することができる。 First, drug particles containing a drug that is unstable to acid are produced. Hereinafter, a method for producing the drug particles will be described when a drug layer containing an acid-unstable drug is formed on the surface of the core particles. Regarding the mixing method and the granulation method when the drug particles are obtained by granulating a mixture of an acid-labile drug and a pharmacologically acceptable additive (for example, each agent described later). Is not particularly limited, and a known method can be appropriately adopted.
薬剤粒子の作製では、上記のようなコア粒子に、酸に不安定と薬剤を、例えば第１のコーティング剤および必要に応じて安定剤を含む懸濁液または溶液を付与（例えばスプレー）し、必要に応じて乾燥することにより、コア粒子上に薬剤層が形成する。さらに、中間層を設ける場合には、薬剤層の外側表面に、第２のコーティング剤を含む懸濁液または溶液を付与（例えばスプレー）し、必要に応じて乾燥することにより、中間層が配置される。 In the preparation of the drug particles, the core particles as described above are imparted (eg, sprayed) with a suspension or solution containing an acid-labile and drug, eg, a first coating agent and, if necessary, a stabilizer. By drying as needed, a drug layer is formed on the core particles. Further, when an intermediate layer is provided, the intermediate layer is arranged by applying a suspension or solution containing a second coating agent (for example, spraying) to the outer surface of the drug layer and drying it if necessary. Will be done.
次いで、薬剤粒子に腸溶層が形成され、腸溶性粒子が作製される。 Next, an enteric layer is formed on the drug particles to produce enteric particles.
具体的には、薬剤粒子に、上記第３のコーティング剤を含む懸濁液または溶液を付与（例えばスプレー）し、必要に応じて乾燥することにより、腸溶層を有する腸溶性粒子を得ることができる。 Specifically, enteric particles having an enteric layer are obtained by applying (for example, spraying) a suspension or solution containing the above-mentioned third coating agent to the drug particles and drying them if necessary. Can be done.
その後、得られた腸溶性粒子に被覆層が形成され被覆粒子が作製される。 Then, a coating layer is formed on the obtained enteric particles to prepare coated particles.
具体的には、腸溶性粒子に、上記低置換度ヒドロキシプロピルセルロースおよび結合剤を含む懸濁液を付与（例えばスプレー）し、必要に応じて乾燥することにより、被覆層が形成される。 Specifically, a coating layer is formed by applying (for example, spraying) a suspension containing the above-mentioned low-degree-of-substitution hydroxypropyl cellulose and a binder to enteric particles and drying the particles as necessary.
ここで、上記薬剤粒子（薬剤層および中間層の形成を含む）、腸溶性粒子および被覆粒子の一連の作製には、流動層造粒法、微粒子コーティング法などの従来の造粒方法を適用することができる。本発明においては、特に市販の転動流動層コーティング装置による微粒子コーティング法を採用することによって、薬剤粒子から被覆粒子までの作製を同一の装置内で行ってもよい。 Here, a conventional granulation method such as a fluidized bed granulation method or a fine particle coating method is applied to a series of preparation of the above-mentioned drug particles (including the formation of a drug layer and an intermediate layer), enteric particles and coated particles. be able to. In the present invention, particularly by adopting a fine particle coating method using a commercially available rolling fluidized bed coating device, the production of drug particles to coated particles may be carried out in the same device.
また、こうして得られた被覆粒子は、必要に応じて他の添加剤と混合され、打錠機によって圧縮成形され、錠剤（素錠）の剤形に加工されることが好ましい。ここで、他の添加剤は、圧縮成形の前にあらかじめ被覆粒子とともに造粒物に成形されていてもよい。ただし、他の添加剤のうち滑沢剤については、造粒物とは別に混合することが望ましい。加えて、必要に応じてこの錠剤に当業者に公知の手段を用いてフィルムコーティングが行われてもよい。 Further, it is preferable that the coated particles thus obtained are mixed with other additives as necessary, compression-molded by a tableting machine, and processed into a tablet (uncoated tablet) dosage form. Here, the other additives may be previously molded into the granulated product together with the coated particles before compression molding. However, among other additives, it is desirable to mix the lubricant separately from the granulated product. In addition, if necessary, the tablet may be film-coated using means known to those skilled in the art.
このようにして本発明の経口医薬製剤を製造することができる。 In this way, the oral pharmaceutical preparation of the present invention can be produced.
本発明の経口医薬製剤は、その薬効成分として含有される上記薬剤の種類に応じて、種々の用法および用量にて患者に投与される。また、この投与が行われるまでの期間は、例えば冷暗所に保管され得る。本発明の経口医薬製剤は、顆粒（被覆粒子）がベタつきにより凝集することがないので、打錠して圧縮成形したとしても、薬剤の溶出性を低下させることがない。 The oral pharmaceutical preparation of the present invention is administered to a patient in various dosages and administrations depending on the type of the above-mentioned drug contained as a medicinal ingredient thereof. In addition, the period until this administration is performed can be stored in a cool and dark place, for example. In the oral pharmaceutical preparation of the present invention, since the granules (coated particles) do not aggregate due to stickiness, the elution of the drug does not decrease even if the granules are tableted and compression-molded.
以下、実施例により本発明をより具体的に説明するが、本発明はこれらの実施例により限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.
（実施例１：錠剤（Ｅ１）の作製）
表１および２に示す組成となるように、デュロキセチン塩酸塩２２．４ｍｇ（デュロキセチンとして２０ｍｇ）を含有する錠剤を以下のようにして作製した。
(Example 1: Preparation of tablet (E1))
Tablets containing 22.4 mg of duloxetine hydrochloride (20 mg as duloxetine) were prepared as follows so as to have the compositions shown in Tables 1 and 2.
＜第１の薬剤粒子の作製＞
デュロキセチン塩酸塩、炭酸マグネシウムおよびタルクを少量の精製水に分散させた後、ヒプロメロース添加して溶解させて第１の懸濁液を得た。転動流動層コーティング機（株式会社パウレック製ＭＰ−０１）を使用し、この第１の懸濁液を乳糖・結晶セルロース球状顆粒にスプレーして、コア粒子を薬剤層で被覆した第１の薬剤粒子を得た。
<Preparation of first drug particles>
Duloxetine hydrochloride, magnesium carbonate and talc were dispersed in a small amount of purified water, and then hypromellose was added and dissolved to obtain a first suspension. Using a rolling fluidized bed coating machine (MP-01 manufactured by Paulec Co., Ltd.), this first suspension was sprayed on lactose / crystalline cellulose spherical granules, and the core particles were coated with a drug layer. Obtained particles.
＜中間層の形成（第２の薬剤粒子の作製）＞
タルクおよび酸化チタンを少量の精製水に分散させた後、エタノールおよびヒプロメロースを添加して第２の懸濁液を得た。次いで、上記と同様の転動流動層コーティング機内でこの第２の懸濁液を第１の薬剤粒子にスプレーして、第１の薬剤粒子を中間層で被覆した第２の薬剤粒子を得た。
<Formation of intermediate layer (preparation of second drug particle)>
After dispersing talc and titanium oxide in a small amount of purified water, ethanol and hypromellose were added to obtain a second suspension. Next, the second suspension was sprayed on the first drug particles in the same rolling fluidized bed coating machine as described above to obtain the second drug particles in which the first drug particles were coated with the intermediate layer. ..
＜腸溶層の形成（腸溶性粒子の作製）＞
タルクおよび酸化チタンを少量の精製水に分散させた後、エタノール、クエン酸トリエチル、およびヒプロメロース酢酸エステルコハク酸エステルを添加して第３の懸濁液を得た。次いで、上記と同様の転動流動層コーティング機内でこの第３の懸濁液を第２の薬剤粒子にスプレーして、第２の薬剤粒子を腸溶層で被覆した腸溶性粒子を得た。
<Formation of enteric layer (preparation of enteric particles)>
After dispersing talc and titanium oxide in a small amount of purified water, ethanol, triethyl citrate, and hypromellose acetate succinate were added to obtain a third suspension. Next, the third suspension was sprayed on the second drug particles in the same rolling fluidized bed coating machine as described above to obtain enteric particles in which the second drug particles were coated with the enteric layer.
＜被覆層の形成（被覆粒子の作製）＞
低置換度ヒドロキシプロピルセルロース（信越化学工業(株)製Ｌ−ＨＰＣ（登録商標）ＬＨ−３１；ヒドロキシプロポキシ基含量１１％、平均粒子径２０μｍ）を少量の精製水に分散させた後、８０℃に加温した精製水に溶解させたポリビニルアルコール（三菱ケミカル(株)製ゴーセノールＥＧ−０３Ｐ；けん化度８６．５〜８９．０モル％（部分けん化物））を添加して、第４の懸濁液を得た。次いで、上記と同様の転動流動層コーティング機内で、この第４の懸濁液を腸溶性粒子に対してスプレーして、腸溶性粒子を被覆層で被覆した被覆粒子を得た。
<Formation of coating layer (preparation of coating particles)>
Low degree of substitution Hydroxypropyl cellulose (L-HPC (registered trademark) LH-31 manufactured by Shin-Etsu Chemical Industry Co., Ltd .; hydroxypropoxy group content 11%, average particle size 20 μm) was dispersed in a small amount of purified water and then 80 ° C. Polyvinyl alcohol (Gosenol EG-03P manufactured by Mitsubishi Chemical Co., Ltd .; saponification degree 86.5-89.0 mol% (partially saponified)) dissolved in purified water was added to the fourth suspension. A turbid liquid was obtained. Then, in the same rolling fluidized bed coating machine as described above, the fourth suspension was sprayed on the enteric particles to obtain coated particles in which the enteric particles were coated with a coating layer.
なお、実施例１で得られた被覆粒子における被覆層の割合は４．７質量％であった。被覆層における結合剤（ポリビニルアルコール）の量は低置換度ヒドロキシプロピルセルロース１００質量部に対して３．１質量部であった。 The proportion of the coating layer in the coating particles obtained in Example 1 was 4.7% by mass. The amount of the binder (polyvinyl alcohol) in the coating layer was 3.1 parts by mass with respect to 100 parts by mass of low-degree-of-substitution hydroxypropyl cellulose.
＜打錠（錠剤の作製）＞
被覆粒子に、Ｄ−マンニトール、結晶セルロース、クロスポビドン、スクラロース、軽質無水ケイ酸、ｌ−メントール、およびフマル酸ステアリルナトリウムを添加かつ混合して、打錠用顆粒を得た。その後、この打錠用顆粒を単発打錠機内で圧縮成形して、錠剤（Ｅ１）（重量４００．４ｍｇ、錠剤径９．５ｍｍ、錠剤厚み５．２ｍｍおよび硬度６５Ｎ）を得た。
<Locking (preparation of tablets)>
D-mannitol, crystalline cellulose, crospovidone, sucralose, light silicic anhydride, l-menthol, and sodium stearyl fumarate were added to and mixed with the coated particles to obtain granules for tableting. Then, the tableting granules were compression-molded in a single-shot tableting machine to obtain tablets (E1) (weight 400.4 mg, tablet diameter 9.5 mm, tablet thickness 5.2 mm and hardness 65 N).
なお、実施例１で作製した被覆粒子および腸溶性粒子の表面状態を、走査型電子顕微鏡（(株)日立ハイテクノロジーズ製ＴＭ３０３０Ｐｌｕｓ）により観察した。被覆粒子の電子顕微鏡写真を図１の（ａ）に、腸溶性粒子の電子顕微鏡写真を図１の（ｂ）に、それぞれ示す。 The surface states of the coated particles and enteric-coated particles produced in Example 1 were observed with a scanning electron microscope (TM3030Plus, manufactured by Hitachi High-Technologies Corporation). An electron micrograph of the coated particles is shown in FIG. 1 (a), and an electron micrograph of the enteric particles is shown in FIG. 1 (b).
図１（ａ）と図１（ｂ）の対比より、被覆粒子の表面は微小な凹凸で形成される被覆層で略完全に覆われていることが分かった。本発明の医薬製剤は、この微少な凹凸が存在することにより、打錠された場合にも被覆粒子（顆粒）同士の凝集を防止することができる。 From the comparison between FIGS. 1 (a) and 1 (b), it was found that the surface of the coated particles was almost completely covered with a coating layer formed of minute irregularities. The pharmaceutical preparation of the present invention can prevent the coating particles (granule) from agglomerating with each other even when the tablet is locked due to the presence of these fine irregularities.
（実施例２：錠剤（Ｅ２）の作製）
錠剤の被覆層に含まれる低置換度ヒドロキシプロピルセルロースの含有量を１２．８ｍｇ（２倍）、当該被覆層に含まれるポリビニルアルコールの含有量を０．４ｍｇ（２倍）に変更し、かつ打錠の際、被覆粒子とともに添加したＤ−マンニトールの含有量を１３１．６ｍｇに変更したこと以外は、実施例１と同様にして錠剤（Ｅ２）（重量４００．４ｍｇ、錠剤径９．５ｍｍ、錠剤厚み５．２ｍｍおよび硬度６５Ｎ）を得た。
(Example 2: Preparation of tablet (E2))
The content of low-substituted hydroxypropyl cellulose contained in the coating layer of the tablet was changed to 12.8 mg (double), and the content of polyvinyl alcohol contained in the coating layer was changed to 0.4 mg (double), and the tablet was beaten. Tablets (E2) (weight 400.4 mg, tablet diameter 9.5 mm, tablets) in the same manner as in Example 1 except that the content of D-mannitol added together with the coating particles was changed to 131.6 mg at the time of tableting. A thickness of 5.2 mm and a hardness of 65 N) were obtained.
なお、実施例２で得られた被覆粒子における被覆層の割合は９．１質量％であった。被覆層における結合剤（ポリビニルアルコール）の量は低置換度ヒドロキシプロピルセルロース１００質量部に対して３．１質量部であった。 The proportion of the coating layer in the coating particles obtained in Example 2 was 9.1% by mass. The amount of the binder (polyvinyl alcohol) in the coating layer was 3.1 parts by mass with respect to 100 parts by mass of low-degree-of-substitution hydroxypropyl cellulose.
（実施例３：錠剤（Ｅ３）の作製）
錠剤の被覆層に含まれる低置換度ヒドロキシプロピルセルロースの含有量を１７．９２ｍｇ（２．８倍）、当該被覆層に含まれるポリビニルアルコールの含有量を０．５６ｍｇ（２．８倍）に変更し、かつ打錠の際、被覆粒子とともに添加したＤ−マンニトールの含有量を１２６．３ｍｇに変更したこと以外は、実施例１と同様にして錠剤（Ｅ３）（重量４００．４ｍｇ、錠剤径９．５ｍｍ、錠剤厚み５．２ｍｍおよび硬度６５Ｎ）を得た。
(Example 3: Preparation of tablet (E3))
The content of low-substituted hydroxypropyl cellulose contained in the tablet coating layer was changed to 17.92 mg (2.8 times), and the content of polyvinyl alcohol contained in the coating layer was changed to 0.56 mg (2.8 times). However, the tablet (E3) (weight 400.4 mg, tablet diameter 9) was obtained in the same manner as in Example 1 except that the content of D-mannitol added together with the coating particles was changed to 126.3 mg at the time of tableting. 5.5 mm, tablet thickness 5.2 mm and hardness 65 N) were obtained.
なお、実施例３で得られた被覆粒子における被覆層の割合は１２．２質量％であった。被覆層における結合剤（ポリビニルアルコール）の量は低置換度ヒドロキシプロピルセルロース１００質量部に対して３．１質量部であった。 The proportion of the coating layer in the coating particles obtained in Example 3 was 12.2% by mass. The amount of the binder (polyvinyl alcohol) in the coating layer was 3.1 parts by mass with respect to 100 parts by mass of low-degree-of-substitution hydroxypropyl cellulose.
（比較例１：錠剤（Ｃ１）の作製）
腸溶性粒子に被覆層を設けなかったこと（すなわち、被覆粒子の代わりに腸溶性粒子を用いたこと）、および打錠の際、被覆粒子とともに添加したＤ−マンニトールの含有量を１４４．８ｍｇに変更したこと以外は、実施例１と同様にして錠剤（Ｃ１）を得た。
(Comparative Example 1: Preparation of tablet (C1))
No coating layer was provided on the enteric particles (that is, enteric particles were used instead of the coating particles), and the content of D-mannitol added together with the coating particles at the time of tableting was reduced to 144.8 mg. A tablet (C1) was obtained in the same manner as in Example 1 except that it was changed.
（試験例１：溶出性試験）
実施例１〜３および比較例１で得られた錠剤（Ｅ１）〜（Ｅ３）および（Ｃ１）について、日本薬局方溶出試験法第２法（パドル法）によるデュロキセチンの溶出性試験を行った。試験液として溶出試験液第２液（ｐＨ６．８）９００ｍＬを用い、それぞれパドル回転数７５ｒｐｍにて、１２０分間の溶出率（％）の経時変化を所定の時間毎に測定した。得られた結果を図２に示す。
(Test Example 1: Dissolution test)
The tablets (E1) to (E3) and (C1) obtained in Examples 1 to 3 and Comparative Example 1 were subjected to a duloxetine dissolution test by the Japanese Pharmacopoeia dissolution test method 2 (paddle method). 900 mL of the second elution test solution (pH 6.8) was used as the test solution, and the change over time in the elution rate (%) for 120 minutes was measured at a paddle rotation speed of 75 rpm. The obtained results are shown in FIG.
図２に示すように、実施例１〜３で得られた錠剤（Ｅ１）〜（Ｅ３）は、比較例１の錠剤（Ｃ１）と比較して試験開始後３０分の段階で既に高い溶出率を示し、いずれも優れた溶出性を有していた。特に、低置換度ヒドロキシプロピルセルロースおよび結合剤の濃度を高めた実施例３の錠剤（Ｅ３）では、試験開始後６０分近くで略１００％の溶出率を達成していた。
As shown in FIG. 2, the tablets (E1) to (E3) obtained in Examples 1 to 3 have an already
（実施例４：錠剤（Ｅ４）の作製）
錠剤に含まれる低置換度ヒドロキシプロピルセルロースの含有量を１７．０ｍｇに変更し、結合剤（ポリビニルアルコール）の含有量を０．５ｍｇに変更し、かつ打錠の際、被覆粒子とともに添加したＤ−マンニトールの含有量を１２７．３ｍｇに変更したこと以外は、実施例１と同様にして錠剤（Ｅ４）（重量４００．４ｍｇ、錠剤径９．５ｍｍ、錠剤厚み５．２ｍｍおよび硬度６５Ｎ）を作製した。
(Example 4: Preparation of tablet (E4))
The content of low-substituted hydroxypropyl cellulose contained in the tablets was changed to 17.0 mg, the content of the binder (polyvinyl alcohol) was changed to 0.5 mg, and D was added together with the coating particles at the time of tableting. -Tablets (E4) (weight 400.4 mg, tablet diameter 9.5 mm, tablet thickness 5.2 mm and hardness 65 N) were prepared in the same manner as in Example 1 except that the content of mannitol was changed to 127.3 mg. did.
なお、実施例４で得られた被覆粒子における被覆層の割合は１１．７質量％であった。被覆層における結合剤（ポリビニルアルコール）の量は低置換度ヒドロキシプロピルセルロース１００質量部に対して２．９質量部であった。 The proportion of the coating layer in the coating particles obtained in Example 4 was 11.7% by mass. The amount of binder (polyvinyl alcohol) in the coating layer was 2.9 parts by mass with respect to 100 parts by mass of low-degree-of-substitution hydroxypropyl cellulose.
（実施例５：錠剤（Ｅ５）の作製）
錠剤に含まれる低置換度ヒドロキシプロピルセルロースの含有量を１７．０ｍｇに変更し、結合剤（ポリビニルアルコール）の含有量を１．０ｍｇに変更し、かつ打錠の際、被覆粒子とともに添加したＤ−マンニトールの含有量を１２６．８ｍｇに変更したこと以外は、実施例１と同様にして錠剤（Ｅ５）（重量４００．４ｍｇ、錠剤径５．２ｍｍ、錠剤厚み５．２ｍｍおよび硬度６５Ｎ）を作製した。
(Example 5: Preparation of tablet (E5))
The content of low-substituted hydroxypropyl cellulose contained in the tablets was changed to 17.0 mg, the content of the binder (polyvinyl alcohol) was changed to 1.0 mg, and D was added together with the coating particles at the time of tableting. -Tablets (E5) (weight 400.4 mg, tablet diameter 5.2 mm, tablet thickness 5.2 mm and hardness 65 N) were prepared in the same manner as in Example 1 except that the content of mannitol was changed to 126.8 mg. did.
なお、実施例５で得られた被覆粒子における被覆層の割合は１２．０質量％であった。被覆層における結合剤（ポリビニルアルコール）の量は低置換度ヒドロキシプロピルセルロース１００質量部に対して５．９質量部であった。 The proportion of the coating layer in the coating particles obtained in Example 5 was 12.0% by mass. The amount of the binder (polyvinyl alcohol) in the coating layer was 5.9 parts by mass with respect to 100 parts by mass of low-degree-of-substitution hydroxypropyl cellulose.
（口腔内崩壊時間）
実施例４および５で得られた錠剤（Ｅ４）および（Ｅ５）を、それぞれ５人の被験者が服用し、服用後から錠剤が口腔内で崩壊したと感じられた時点までの時間を測定し、その平均値を算出した。結果を表３に示す。
(Intraoral collapse time)
The tablets (E4) and (E5) obtained in Examples 4 and 5 were taken by 5 subjects, respectively, and the time from the administration to the time when the tablets were felt to have disintegrated in the oral cavity was measured. The average value was calculated. The results are shown in Table 3.
表３に示すように、実施例４および５で得られた錠剤（Ｅ４）および（Ｅ５）はいずれも、口腔内で比較的短時間で崩壊可能であるが、特に、低置換度ヒドロキシプロピルセルロースの含有量に対して結合剤の含有量を低く抑えると（実施例４）、より短時間での口腔内崩壊を達成することができることが分かった。 As shown in Table 3, both tablets (E4) and (E5) obtained in Examples 4 and 5 can disintegrate in the oral cavity in a relatively short time, but in particular, low-substituted hydroxypropyl cellulose. It was found that if the content of the binder was kept low with respect to the content of (Example 4), oral disintegration in a shorter time could be achieved.
本発明によれば、酸に不安定な薬剤を有効成分とする医薬製剤を、錠剤、丸剤、カプセル剤、トローチ剤などの種々の剤形にて提供することができ、製薬分野において有用である。 According to the present invention, a pharmaceutical preparation containing an acid-labile drug as an active ingredient can be provided in various dosage forms such as tablets, pills, capsules, and troches, which is useful in the pharmaceutical field. is there.
Claims (9)
該薬剤粒子が酸に不安定な薬剤を含有し、
該被覆層が低置換度ヒドロキシプロピルセルロースおよび結合剤を含有する、経口医薬製剤。 An oral pharmaceutical preparation containing coating particles including drug particles, an enteric layer, and a coating layer in this order.
The drug particles contain a drug that is unstable to acid and
An oral pharmaceutical preparation in which the coating layer contains low-degree-of-substitution hydroxypropyl cellulose and a binder.
酸に不安定な薬剤を含有する薬剤粒子を作製する工程、
該薬剤粒子に腸溶層を形成して腸溶性粒子を得る工程、および
該腸溶性粒子に被覆層を形成して被覆粒子を得る工程、
を包含し、
該被覆層が、低置換度ヒドロキシプロピルセルロースおよび結合剤を含有する懸濁液を該腸溶性粒子に付着させることにより形成される、方法。 It is a method for manufacturing oral pharmaceutical products.
The process of producing drug particles containing a drug that is unstable to acid,
A step of forming an enteric layer on the drug particles to obtain enteric particles, and a step of forming a coating layer on the enteric particles to obtain coated particles.
Including,
A method in which the coating layer is formed by adhering a suspension containing low degree of substitution hydroxypropyl cellulose and a binder to the enteric particles.
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