JPWO2004110448A1 - Benidipine hydrochloride-containing pharmaceutical composition - Google Patents
Benidipine hydrochloride-containing pharmaceutical composition Download PDFInfo
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- JPWO2004110448A1 JPWO2004110448A1 JP2005505044A JP2005505044A JPWO2004110448A1 JP WO2004110448 A1 JPWO2004110448 A1 JP WO2004110448A1 JP 2005505044 A JP2005505044 A JP 2005505044A JP 2005505044 A JP2005505044 A JP 2005505044A JP WO2004110448 A1 JPWO2004110448 A1 JP WO2004110448A1
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- benidipine hydrochloride
- pharmaceutical composition
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- functional additive
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Classifications
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
本発明は、主薬である塩酸ベニジピンの速やかな吸収を促進するための、速やかな溶出性を有する塩酸ベニジピン医薬組成物等を提供することを目的として、体積平均粒子径１．０〜５０．０μｍの塩酸ベニジピン結晶、または塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する体積平均粒子径１．０〜５０．０μｍの粉粒体を含有することを特徴とする塩酸ベニジピン医薬組成物等を提供する。The present invention aims to provide a pharmaceutical composition of benidipine hydrochloride having a rapid dissolution property for promoting rapid absorption of benidipine hydrochloride as a main agent, and the like, and a volume average particle size of 1.0 to 50.0 μm. Benidipine hydrochloride crystal comprising benidipine hydrochloride crystal, or a granule having a volume average particle size of 1.0 to 50.0 μm, containing benidipine hydrochloride crystal and a functional additive having water solubility or water affinity Pharmaceutical compositions and the like are provided.
Description
本発明は、主薬である塩酸ベニジピンの速やかな吸収を促進するための、速やかな溶出性を有する塩酸ベニジピン含有医薬組成物等に関する。 The present invention relates to a pharmaceutical composition containing benidipine hydrochloride having a rapid dissolution property for promoting rapid absorption of benidipine hydrochloride as a main drug.
ジヒドロピリジン系カルシウム拮抗剤である塩酸ベニジピンは高血圧症、腎実質性高血圧症、狭心症等の治療薬として特に有用であり、安全性も高いとして汎用されている。また塩酸ベニジピンはニフェジピンやアムロジピン等、他のカルシウム拮抗剤とは異なり、造骨細胞および骨芽細胞に作用し、骨形成を損なうことなく、骨保護作用を示すことが知られており、さらに造骨活性の指標として広く知られているアルカリホスファターゼ活性を増加させ、骨代謝に作用し骨芽細胞機能を刺激していることが知られている。しかし前記のニフェジピンやアムロジピンではこれらの作用は知られていない［カルシファイド・ティシュー・インターナショナル（Ｃａｌｃｉｆｉｅｄ Ｔｉｓｓｕｅ Ｉｎｔｅｒｎａｔｉｏｎａｌ）、１９９８年、第６２巻、ｐ．５５４−５５６］。加えてラットの骨粗しょう症モデルにおいても、塩酸ベニジピンは、骨量増加作用および骨強度の増加作用を示し、さらに骨量増加についてはＸ線検査によっても観察されている。すなわち塩酸ベニジピンは骨代謝バランスのうち、骨保護側に優位に働くことが示唆されている［新薬と臨床、第４２巻、第１１号別冊（平成５年１１月）、ｐ．５８（２２９８）−６６（２３０６）］。これら一連の塩酸ベニジピンの骨保護作用は、骨代謝に関与する副甲状腺ホルモン（ＰＴＨ）等のカルシウム代謝調節ホルモンを介した作用と考えられ、塩酸ベニジピンの速やかな吸収と速やかな代謝により達成される血中ＰＴＨの一過性の上昇が骨形成側に優位に働いていることが示唆されている。しかしながら、血中ＰＴＨの長時間の上昇は、骨代謝に悪影響を及ぼすことが知られている。
以上の理由から、骨代謝への悪影響という副作用を回避するために、速やかな吸収を促進するための、速やかな溶出性を有する塩酸ベニジピン含有医薬組成物の開発が望まれている。
一方、塩酸ベニジピンの一般的な製剤例が知られている（特公平２−５１５２５号公報）。また、塩酸ベニジピンは、水性溶媒への溶解度が非常に低いために経口投与の場合には消化管液中で薬物が医薬組成物から速やかに溶出するような工夫が必要である。Benidipine hydrochloride, which is a dihydropyridine calcium antagonist, is particularly useful as a therapeutic agent for hypertension, renal parenchymal hypertension, angina pectoris, etc., and is widely used because of its high safety. Benidipine hydrochloride, unlike other calcium antagonists such as nifedipine and amlodipine, is known to act on osteoblasts and osteoblasts, exhibiting bone protective effects without impairing bone formation. It is known that alkaline phosphatase activity, which is widely known as an index of bone activity, is increased, acting on bone metabolism and stimulating osteoblast function. However, these effects are not known in the above-mentioned nifedipine and amlodipine [Calcified Tissue International, 1998, Vol. 62, p. 554-556]. In addition, in a rat osteoporosis model, benidipine hydrochloride exhibits an effect of increasing bone mass and an effect of increasing bone strength, and an increase in bone mass is also observed by X-ray examination. In other words, it has been suggested that benidipine hydrochloride works preferentially on the bone-protective side of the bone metabolic balance [New Drugs and Clinical, Vol. 42, No. 11 (November 1993), p. 58 (2298) -66 (2306)]. These series of bone protective effects of benidipine hydrochloride are thought to be mediated by calcium metabolism regulating hormones such as parathyroid hormone (PTH) involved in bone metabolism, and are achieved by rapid absorption and rapid metabolism of benidipine hydrochloride. It has been suggested that a transient increase in blood PTH works predominantly on the osteogenic side. However, it is known that a long rise in blood PTH has an adverse effect on bone metabolism.
For the above reasons, in order to avoid the side effect of adverse effects on bone metabolism, development of a pharmaceutical composition containing benidipine hydrochloride having a rapid dissolution property for promoting rapid absorption is desired.
On the other hand, a general formulation example of benidipine hydrochloride is known (Japanese Patent Publication No. 2-51525). In addition, since benidipine hydrochloride has a very low solubility in an aqueous solvent, in the case of oral administration, it is necessary to devise such that the drug is quickly eluted from the pharmaceutical composition in the gastrointestinal fluid.
本発明の目的は、主薬である塩酸ベニジピンの速やかな吸収を促進するための、速やかな溶出性を有する塩酸ベニジピン含有医薬組成物等を提供することにある。
本発明は、下記の（１）〜（２０）に関する。
（１） 体積平均粒子径１．０〜５０．０μｍの塩酸ベニジピン結晶、または塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する体積平均粒子径１．０〜５０．０μｍの粉粒体を含有することを特徴とする塩酸ベニジピン含有医薬組成物。
（２） 体積平均粒子径および個数平均粒子径が４．５〜３０．０μｍの塩酸ベニジピン結晶、または塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する体積平均粒子径４．５〜５０．０μｍの粉粒体を含有することを特徴とする塩酸ベニジピン含有医薬組成物。
（３） 塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する粉粒体において、塩酸ベニジピン結晶と水溶性または水親和性を有する機能性添加剤との重量比が１：９９〜９９：１である前記（１）または（２）記載の医薬組成物。
（４） 塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する粉粒体において、水溶性または水親和性を有する機能性添加剤が水溶性または水親和性を有する賦形剤である前記（１）〜（３）のいずれかに記載の医薬組成物。
（５） 塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する粉粒体において、水溶性または水親和性を有する賦形剤がデンプン類、デンプン誘導体、糖類、糖アルコール類、セルロース類、セルロース誘導体またはデキストリンである前記（１）〜（４）のいずれかに記載の医薬組成物。
（６） 塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する粉粒体において、水溶性または水親和性を有する機能性添加剤が崩壊剤である前記（１）〜（３）のいずれかに記載の医薬組成物。
（７） 崩壊剤がデンプン類、デンプン誘導体、セルロース類またはセルロース誘導体である前記（６）記載の医薬組成物。
（８） 塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する粉粒体において、水溶性または水親和性を有する機能性添加剤が水溶性または水親和性を有する結合剤である前記（１）〜（３）のいずれかに記載の医薬組成物。
（９） 水溶性または水親和性を有する結合剤がセルロース類、セルロース誘導体、ポリビニルアルコール、部分けん化ポリビニルアルコールまたはポリビニルピロリドンである前記（８）記載の医薬組成物。
（１０） コーティングされていることを特徴とする前記（１）〜（９）のいずれかに記載の医薬組成物。
（１１） 塩酸ベニジピンを含有する医薬組成物において、塩酸ベニジピン結晶の体積平均粒子径を１．０〜５０．０μｍとする、または塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する粉粒体を含有する医薬組成物において、塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する粉粒体の体積平均粒子径を１．０〜５０．０μｍとすることを特徴とする、該医薬組成物からの塩酸ベニジピンの即溶出化方法。
（１２） 塩酸ベニジピンを含有する医薬組成物において、塩酸ベニジピン結晶の体積平均粒子径および個数平均径を４．５〜３０．０μｍとする、または塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する粉粒体を含有する医薬組成物において、塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する粉粒体の体積平均粒子径を４．５〜５０．０μｍとすることを特徴とする、該医薬組成物からの塩酸ベニジピンの即溶出化方法。
（１３） 塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する粉粒体において、塩酸ベニジピン結晶と水溶性または水親和性を有する機能性添加剤との重量比が１：９９〜９９：１である前記（１１）または（１２）記載の即溶出化方法。
（１４） 塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する粉粒体において、水溶性または水親和性を有する機能性添加剤が水溶性または水親和性を有する賦形剤である前記（１１）〜（１３）のいずれかに記載の即溶出化方法。
（１５） 塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する粉粒体において、水溶性または水親和性を有する賦形剤がデンプン類、デンプン誘導体、糖類、糖アルコール類、セルロース類、セルロース誘導体またはデキストリンである前記（１１）〜（１４）のいずれかに記載の即溶出化方法。
（１６） 塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する粉粒体において、水溶性または水親和性を有する機能性添加剤が崩壊剤である前記（１１）〜（１５）のいずれかに記載の即溶出化方法。
（１７） 崩壊剤がデンプン類、デンプン誘導体、セルロース類またはセルロース誘導体である前記（１６）記載の即溶出化方法。
（１８） 塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する粉粒体において、水溶性または水親和性を有する機能性添加剤が水溶性または水親和性を有する結合剤である前記（１１）〜（１５）のいずれかに記載の即溶出化方法。
（１９） 水溶性または水親和性を有する結合剤がセルロース類、セルロース誘導体、ポリビニルアルコール、部分けん化ポリビニルアルコールまたはポリビニルピロリドンである前記（１８）記載の即溶出化方法。
（２０） 医薬組成物がコーティングされている医薬組成物である前記（１１）〜（１９）のいずれかに記載の即溶出化方法。
本発明の医薬組成物は、塩酸ベニジピンを含有し、約４０％〜１００％のＤ３０ｍｉｎ値（溶出試験における３０分の時点での塩酸ベニジピンの溶出率）を示すことが好ましい。なおこの際の溶出試験の条件は、後記の試験例に記載の溶出試験における条件と同じである。
水親和性とは、静電相互作用や水素結合等の何らかの相互作用により、水分子と引き合う性質をいう。
本発明における塩酸ベニジピン結晶の体積平均粒子径は、１．０〜５０．０μｍであり、４．５〜５０．０μｍであるのが好ましく、４．５〜３０．０μｍであるのがより好ましい。また本発明における塩酸ベニジピンおよび水溶性または水親和性を有する機能性添加剤を含有する粉粒体の体積平均粒子径は、１．０〜５０．０μｍであり、４．５〜５０．０μｍであるのが好ましく、４．５〜３０．０μｍであるのがより好ましい。塩酸ベニジピンおよび水溶性または水親和性を有する機能性添加剤を含有する粉粒体を含有することを特徴とする塩酸ベニジピン含有医薬組成物において、塩酸ベニジピン結晶と水溶性または水親和性を有する機能性添加剤との重量比は１：９９〜９９：１であるのが好ましく、より好ましくは１：５０〜１：２であり、さらに好ましくは１：４０〜１：４である。
また、該塩酸ベニジピン結晶、ならびに塩酸ベニジピンおよび水溶性または水親和性を有する機能性添加剤を含有する粉粒体は、それぞれ個数平均粒子径１．０〜５０．０μｍであることが好ましく、４．５〜３０．０μｍであることがより好ましく、体積平均粒子径と個数平均粒子径の差が、体積平均粒子径に対して５０％以下の値であることがより好ましい。または、個数平均粒子径に関わらず、体積平均粒子径が１２〜５０．０μｍであるのが好ましい。これらの好ましい平均粒子径においては、塩酸ベニジピンの安定性、塩酸ベニジピンの含量均一性等の医薬組成物の品質をよりよく保つことができる。
水溶性または水親和性を有する機能性添加剤としては、例えば水溶性または水親和性を有する賦形剤、崩壊剤、水溶性または水親和性を有する結合剤等があげられる。
水溶性または水親和性を有する賦形剤としては、例えばコムギデンプン、コメデンプン、トウモロコシデンプン、バレイショデンプン等のデンプン類、α化デンプン、部分α化デンプン、ヒドロキシプロピルデンプン等のデンプン誘導体、ラクトース、グルコース、マルトース、プルラン等の糖類、Ｄ−マンニトール、ソルビトール、エリスリトール、キシリトール、ラクチトール、マルチトール等の糖アルコール類、結晶セルロース等のセルロース類、カルメロース、カルメロースナトリウム、クロスカルメロースナトリウム、メチルセルロース、エチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシエチルセルロース、カルボキシエチルメチルセルロース等のセルロース誘導体、デキストリン等があげられ、水溶性または水親和性を有する賦形剤の使用量としては、医薬組成物中４０〜９５質量％が好ましく、さらに好ましくは６０〜９５質量％である。
崩壊剤としては、例えばコムギデンプン、コメデンプン、トウモロコシデンプン、バレイショデンプン等のデンプン類、α化デンプン、部分α化デンプン、ヒドロキシプロピルデンプン等のデンプン誘導体、結晶セルロース等のセルロース類、カルメロース、カルメロースナトリウム、クロスカルメロースナトリウム、メチルセルロース、エチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシエチルセルロース、カルボキシエチルメチルセルロース等のセルロース誘導体等があげられ、水溶性または水親和性を有する崩壊剤の使用量としては、医薬組成物中１〜１０質量％が好ましく、さらに好ましくは２〜５質量％である。
水溶性または水親和性を有する結合剤としては、例えば結晶セルロース等のセルロース類、カルメロース、カルメロースナトリウム、クロスカルメロースナトリウム、メチルセルロース、エチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシエチルセルロース、カルボキシエチルメチルセルロース等のセルロース誘導体、ポリビニルアルコール、部分けん化ポリビニルアルコール、ポリビニルピロリドン等があげられ、水溶性または水親和性を有する結合剤の使用量としては、医薬組成物中０．１〜１０質量％が好ましく、さらに好ましくは０．５〜５質量％である。
本発明の医薬組成物においては、前記水溶性または水親和性を有する機能性添加剤が、前記粉粒体以外の医薬組成物中に含有されていることが好ましい。前記粉粒体以外の医薬組成物中に含有される水溶性または水親和性を有する機能性添加剤の量としては、例えば水溶性または水親和性を有する賦形剤では、前記粉粒体中と、前記粉粒体以外の医薬組成物中とで合わせて医薬組成物の４０〜９５質量％であるのが好ましく、さらに好ましくは６０〜９５質量％であり、崩壊剤では、前記粉粒体中と、前記粉粒体以外の医薬組成物中とで合わせて医薬組成物の１〜３０質量％であるのが好ましく、さらに好ましくは２〜１５質量％であり、水親和性を有する賦形剤では、前記粉粒体中と、前記粉粒体以外の医薬組成物中とで合わせて医薬組成物の０．１〜３０質量％であるのが好ましく、さらに好ましくは０．５〜１５質量％である。
本発明の医薬組成物には、前記の水溶性または水親和性を有する機能性添加剤に加え、製剤の分野で一般に用いられる他の製剤用添加物、例えば滑沢剤、発泡剤、甘味剤、香料、着色剤等を加えることもできる。
滑沢剤としては、例えばステアリン酸、ステアリン酸カルシウム、ステアリン酸マグネシウム、ステアリン酸ポリオキシル４０、タルク、セタノール、ラブリワックス、無水ケイ酸、パラフィン、ホウ酸、ロイシン、ポリオキシエチレン脂肪酸エステル、安息香酸ナトリウム等があげられる。滑沢剤の使用量としては、医薬組成物中０．０１〜１質量％が好ましく、さらに好ましくは０．０１〜０．５質量％である。
発泡剤としては、例えば炭酸水素ナトリウム、炭酸ナトリウム、炭酸カルシウム等があげられる。
甘味剤としては、例えばアスパルテーム（登録商標）、サッカリン、グリチルリチン等があげられる。
香料としては、例えばレモン、オレンジ、パイン、ミント、メントール等があげられる。
着色剤としては、例えば黄色三二酸化鉄、三二酸化鉄、タール色素等があげられる。
コーティングとしては、例えば糖衣、フィルムコーティング、ポリマーコーティング等があげられ、コーティングを行う目的としては、例えば矯味、胃溶性または腸溶性の付与、薬物の酸化や加水分解等による変質防止等があげられる。
矯味のためのコーティングに用いられるコーティング剤としては、例えばメチルセルロース、エチルセルロース、ヒドロキシエチルメチルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、メタクリル酸メチル・メタクリル酸ブチル・メタクリル酸ジメチルアミノエチル・コポリマー（Ｅ）、アクリル酸エチル・メタクリル酸メチル・メタクリル酸塩化トリメチルアンモニウムエチル・コポリマー（ＲＳ）等があげられる。
胃溶性の付与のためのコーティングに用いられるコーティング剤としては、例えばメタクリル酸メチル・メタクリル酸ブチル・メタクリル酸ジメチルアミノエチル・コポリマー（Ｅ）、ポリビニルアセタールジエチルアミノアセテート（ＡＥＡ）等があげられる。
腸溶性の付与のためのコーティングに用いられるコーティング剤としては、例えばメタクリル酸・メタクリル酸メチル・コポリマー（Ｌ）、メタクリル酸・アクリル酸エチル・コポリマー（ＬＤ）、酢酸セルロース、酢酸フタル酸セルロース、カルボキシメチルエチルセルロース、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、ヒドロキシプロピルメチルセルロースフタレート等があげられる。
なお前記の矯味または胃溶性もしくは腸溶性の付与のためのコーティングに用いられるコーティング剤によってコーティングすることにより、同時に薬物の酸化や加水分解等による変質防止等の目的を達成することが可能な場合もある。
次に、本発明の塩酸ベニジピン含有医薬組成物の好ましい製造法について、錠剤を例に説明する。なお、本発明の塩酸ベニジピン含有医薬組成物の形態としては、錠剤の他、顆粒剤、散剤、丸剤等があげられる。
（１）塩酸ベニジピン結晶の粉砕および造粒工程
塩酸ベニジピン結晶の粉砕に用いられる粉砕機は特に限定されないが、好ましくはハンマーミル、ジェットミル等が用いられる。この粉砕工程において、塩酸ベニジピンを体積平均粒子径１．０〜５０．０μｍ、好ましくは４．５〜５０．０μｍ、より好ましくは４．５〜３０．０μｍとなるよう加工することができる。
また、前記粉砕工程において、好ましくは個数平均粒子径１．０〜５０．０μｍ、より好ましくは４．５〜３０．０μｍとし、さらに好ましくは体積平均粒子径と個数平均粒子径の差が、体積平均粒子径に対して５０％以下の値となるよう加工することができる。または、個数平均粒子径に関わらず、体積平均粒子径が１２〜５０．０μｍとなるよう加工することができる。
また粉砕の代わりに、篩過、晶析、スプレードライ等によって塩酸ベニジピンを体積平均粒子径１．０〜５０．０μｍとなるように加工することもできる。
塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する粉粒体は、塩酸ベニジピン結晶に前記の水溶性もしくは水親和性を有する機能性添加剤を加えた後に、粉砕、篩過、晶析、スプレードライ等によって体積平均粒子径１．０〜５０．０μｍ、好ましくは４．５〜５０．０μｍ、より好ましくは４．５〜３０．０μｍとなるよう加工することができる。
また、前記粉砕、篩過、晶析、スプレードライ等によって、好ましくは個数平均粒子径１．０〜５０．０μｍ、より好ましくは４．５〜３０．０μｍとし、さらに好ましくは体積平均粒子径と個数平均粒子径の差が、体積平均粒子径に対して５０％以下の値となるよう加工することができる。または、個数平均粒子径に関わらず、体積平均粒子径が１２〜５０．０μｍとなるよう加工することができる。
続いて、体積平均粒子径１．０〜５０．０μｍとなるよう加工された塩酸ベニジピン結晶または塩酸ベニジピンおよび水溶性もしくは水親和性を有する機能性添加剤を含有する粉粒体に、必要により前記の各種製剤用添加物を加えて造粒を行い、造粒物を得る。造粒の方法としては、特に種類を問わないが、好ましくは湿式造粒が用いられる。造粒機としては、例えば流動層造粒機、転動攪拌造粒機、押し出し造粒機等が用いられる。
本発明の塩酸ベニジピン含有医薬組成物における塩酸ベニジピンの使用量としては、投与量等により異なるが、錠剤中０．０１〜５０質量％が好ましく、さらに好ましくは０．０１〜３０質量％である。
（２）塩酸ベニジピンを含有する錠剤の製造工程
前記（１）で得られた造粒物を乾燥後、滑沢剤を加えて混合し圧縮成形する。このとき、前記の各種製剤用添加物を加えることもできる。
圧縮成形に用いる打錠機は、特に限定されないが、ロータリー打錠機を用いるのが好ましく、圧縮成形圧力は、３００ｋｇ〜５０００ｋｇであることが好ましい。
また、矯味、胃溶性または腸溶性の付与等のために、医薬組成物にコーティングを行うこともできるが、これには造粒物即ち圧縮成形前の素顆粒にコーティングを行う方法と、圧縮成形後の錠剤にコーティングを行う方法等があげられる。
圧縮成形前の素顆粒にコーティングを行う方法としては、例えばコーティング装置中で、ラクトースまたは結晶セルロースの球形顆粒に結合剤とともに活性成分である塩酸ベニジピン結晶を付着させ、静置棚式乾燥機、流動層乾燥機等で乾燥して、塩酸ベニジピン結晶を含有した素顆粒を得る。さらに、コーティング装置中で、コーティング剤を適当な溶媒、例えば水、メタノール、エタノール、２−プロパノール、酢酸エチル、乳酸エチル、アセトン、塩化メチレン、１，１，１−トリクロロエタン等またはこれらの混合溶媒等で溶解または分散させたコーティング剤液を素顆粒にスプレーしてコーティングし、静置棚式乾燥機または流動層乾燥機等で乾燥して、コーティングされた粉粒体を得る。この時のコーティング装置は、特に限定されるものではないが、好ましくは流動層コーティング乾燥装置、遠心流動造粒装置、転動流動コーティング乾燥装置等が用いられる。
また、圧縮成形後の錠剤にコーティングを行う際のコーティング装置は、特に限定されるものではないが、好ましくはドラム式フィルムコーティング乾燥装置または流動層コーティング装置が用いられる。
本発明の医薬組成物からの塩酸ベニジピンの即溶出化は、塩酸ベニジピンを含有する医薬組成物において、塩酸ベニジピン結晶の体積平均粒子径を１．０〜５０．０μｍ、好ましくは体積平均粒子径および個数平均粒子径を４．５〜３０．０μｍとする、または塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する粉粒体を含有する医薬組成物において、塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する粉粒体の体積平均粒子径を１．０〜５０．０μｍ、好ましくは４．５〜５０．０μｍとすることにより行うことができ、例えば、上記した本発明の医薬組成物の製造法により塩酸ベニジピン含有医薬組成物を製造することによって行うことができる。
次に、本発明を実施例でさらに詳しく説明するが、本発明はこれらに限定されるものではない。An object of the present invention is to provide a pharmaceutical composition containing benidipine hydrochloride having a rapid dissolution property for promoting rapid absorption of benidipine hydrochloride as a main drug.
The present invention relates to the following (1) to (20).
(1) A volume average particle size of 1.0 to 50.0 μm containing a benidipine hydrochloride crystal having a volume average particle size of 1.0 to 50.0 μm, or a benidipine hydrochloride crystal and a water-soluble or water-soluble functional additive. A medicinal composition containing benidipine hydrochloride, comprising:
(2) Volume average particle size 4 containing a benidipine hydrochloride crystal having a volume average particle size and a number average particle size of 4.5 to 30.0 μm, or a benidipine hydrochloride crystal and a functional additive having water solubility or water affinity. A medicinal composition containing benidipine hydrochloride, characterized by containing 5 to 50.0 μm powder particles.
(3) In a granule containing a benidipine hydrochloride crystal and a water-soluble or water-soluble functional additive, the weight ratio of the benidipine hydrochloride crystal to the water-soluble or water-soluble functional additive is 1: The pharmaceutical composition according to the above (1) or (2), which is 99 to 99: 1.
(4) In a granule containing a benidipine hydrochloride crystal and a water-soluble or water-soluble functional additive, the water-soluble or water-compatible functional additive is water-soluble or water-compatible The pharmaceutical composition according to any one of (1) to (3), which is an agent.
(5) In a granule containing a benidipine hydrochloride crystal and a functional additive having water solubility or water affinity, excipients having water solubility or water affinity are starches, starch derivatives, sugars, sugar alcohols Pharmaceutical composition in any one of said (1)-(4) which is cellulose, cellulose derivatives, or dextrin.
(6) In the granule containing the benidipine hydrochloride crystal and the water-soluble or water-soluble functional additive, the water-soluble or water-compatible functional additive is a disintegrant. The pharmaceutical composition according to any one of 3).
(7) The pharmaceutical composition according to the above (6), wherein the disintegrant is starch, starch derivative, cellulose or cellulose derivative.
(8) A binder comprising a benidipine hydrochloride crystal and a water-soluble or water-soluble functional additive, wherein the water-soluble or water-compatible functional additive has water solubility or water affinity. The pharmaceutical composition according to any one of (1) to (3) above.
(9) The pharmaceutical composition according to the above (8), wherein the binder having water solubility or affinity is celluloses, cellulose derivatives, polyvinyl alcohol, partially saponified polyvinyl alcohol or polyvinyl pyrrolidone.
(10) The pharmaceutical composition according to any one of (1) to (9), which is coated.
(11) A pharmaceutical composition containing benidipine hydrochloride, wherein the volume average particle size of the benidipine hydrochloride crystals is 1.0 to 50.0 μm, or a functional additive having benidipine hydrochloride crystals and water-solubility or water affinity. In the pharmaceutical composition containing the contained granular material, the volume average particle size of the granular material containing the benidipine hydrochloride crystal and the water-soluble or water-soluble functional additive is 1.0 to 50.0 μm. A method for immediately eluting benidipine hydrochloride from the pharmaceutical composition.
(12) In the pharmaceutical composition containing benidipine hydrochloride, the volume average particle diameter and number average diameter of the benidipine hydrochloride crystals are 4.5 to 30.0 μm, or the benidipine hydrochloride crystals and the water-soluble or water-affinity function In the pharmaceutical composition containing the granular material containing the functional additive, the volume average particle size of the granular material containing the functional additive having benidipine hydrochloride crystals and water-soluble or water-affinity is 4.5 to 50 A method for immediately eluting benidipine hydrochloride from the pharmaceutical composition, characterized in that the thickness is 0.0 μm.
(13) In a granule containing a benidipine hydrochloride crystal and a water-soluble or water-soluble functional additive, the weight ratio of the benidipine hydrochloride crystal to the water-soluble or water-soluble functional additive is 1: The immediate elution method according to the above (11) or (12), which is 99 to 99: 1.
(14) In a granule containing a benidipine hydrochloride crystal and a water-soluble or water-soluble functional additive, the water-soluble or water-compatible functional additive is water-soluble or water-compatible The immediate elution method according to any one of (11) to (13), which is an agent.
(15) In a granule containing a benidipine hydrochloride crystal and a functional additive having water solubility or water affinity, excipients having water solubility or water affinity are starches, starch derivatives, sugars, sugar alcohols , The instant elution method according to any one of (11) to (14), which is a cellulose, a cellulose derivative, or a dextrin.
(16) In the granule containing a benidipine hydrochloride crystal and a water-soluble or water-soluble functional additive, the water-soluble or water-compatible functional additive is a disintegrant. The immediate elution method according to any one of 15).
(17) The immediate elution method according to the above (16), wherein the disintegrant is a starch, a starch derivative, a cellulose or a cellulose derivative.
(18) A binder comprising a benidipine hydrochloride crystal and a functional additive having water solubility or water affinity, wherein the functional additive having water solubility or affinity has water solubility or water affinity. The immediate elution method according to any one of the above (11) to (15).
(19) The immediate elution method according to the above (18), wherein the water-soluble or water-affinity binder is celluloses, cellulose derivatives, polyvinyl alcohol, partially saponified polyvinyl alcohol or polyvinylpyrrolidone.
(20) The immediate elution method according to any one of (11) to (19), wherein the pharmaceutical composition is a coated pharmaceutical composition.
The pharmaceutical composition of the present invention preferably contains benidipine hydrochloride and exhibits a D30min value (dissolution rate of benidipine hydrochloride at 30 minutes in the dissolution test) of about 40% to 100%. In this case, the conditions for the dissolution test are the same as the conditions for the dissolution test described in the following test examples.
Water affinity refers to a property that attracts water molecules by some kind of interaction such as electrostatic interaction or hydrogen bond.
The volume average particle diameter of the benidipine hydrochloride crystal in the present invention is 1.0 to 50.0 μm, preferably 4.5 to 50.0 μm, and more preferably 4.5 to 30.0 μm. Moreover, the volume average particle diameter of the granular material containing the functional additive having benidipine hydrochloride and water-soluble or water-affinity in the present invention is 1.0 to 50.0 μm, and 4.5 to 50.0 μm. It is preferable that it is 4.5 to 30.0 μm. A benidipine hydrochloride-containing pharmaceutical composition comprising a benidipine hydrochloride and a water-soluble or water-soluble functional additive, wherein the benidipine hydrochloride crystal and water-soluble or water-affinity function The weight ratio with the sex additive is preferably 1:99 to 99: 1, more preferably 1:50 to 1: 2, and still more preferably 1:40 to 1: 4.
Moreover, it is preferable that the granule containing the benidipine hydrochloride crystal and the benidipine hydrochloride and the functional additive having water solubility or water affinity each have a number average particle size of 1.0 to 50.0 μm. More preferably, the difference between the volume average particle diameter and the number average particle diameter is more preferably 50% or less with respect to the volume average particle diameter. Or it is preferable that a volume average particle diameter is 12-50.0 micrometers irrespective of a number average particle diameter. In these preferable average particle sizes, the quality of the pharmaceutical composition such as the stability of benidipine hydrochloride and the content uniformity of benidipine hydrochloride can be better maintained.
Examples of the functional additive having water solubility or water affinity include an excipient having water solubility or water affinity, a disintegrant, a binder having water solubility or water affinity, and the like.
Examples of excipients having water solubility or water affinity include starches such as wheat starch, rice starch, corn starch, and potato starch, starch derivatives such as pregelatinized starch, partially pregelatinized starch, and hydroxypropyl starch, lactose, Sugars such as glucose, maltose and pullulan, sugar alcohols such as D-mannitol, sorbitol, erythritol, xylitol, lactitol and maltitol, celluloses such as crystalline cellulose, carmellose, carmellose sodium, croscarmellose sodium, methylcellulose, ethylcellulose , Cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxyethylmethylcellulose, dextst The amount of the excipient having water solubility or water affinity, such as phosphorus, is preferably 40 to 95% by mass, more preferably 60 to 95% by mass in the pharmaceutical composition.
Examples of the disintegrant include starches such as wheat starch, rice starch, corn starch and potato starch, starch derivatives such as pregelatinized starch, partially pregelatinized starch and hydroxypropyl starch, celluloses such as crystalline cellulose, carmellose and carmellose Examples include sodium derivatives such as sodium, croscarmellose sodium, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxyethyl methyl cellulose, and the use amount of a disintegrant having water solubility or water affinity. 1-10 mass% is preferable in a pharmaceutical composition, More preferably, it is 2-5 mass%.
Examples of binders having water solubility or affinity include celluloses such as crystalline cellulose, carmellose, carmellose sodium, croscarmellose sodium, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxyethylmethylcellulose. Cellulose derivatives such as polyvinyl alcohol, partially saponified polyvinyl alcohol, polyvinyl pyrrolidone and the like. The amount of the water-soluble or water-soluble binder used is preferably 0.1 to 10% by mass in the pharmaceutical composition, More preferably, it is 0.5-5 mass%.
In the pharmaceutical composition of the present invention, it is preferable that the functional additive having water solubility or affinity is contained in a pharmaceutical composition other than the granular material. The amount of the water-soluble or water-compatible functional additive contained in the pharmaceutical composition other than the powder is, for example, an additive having water-solubility or water-affinity in the powder And 40 to 95% by mass of the pharmaceutical composition, and more preferably 60 to 95% by mass, in the pharmaceutical composition other than the granular material. It is preferable that it is 1 to 30% by mass of the pharmaceutical composition, and more preferably 2 to 15% by mass of the pharmaceutical composition other than the powder and granule, and has water affinity In an agent, it is preferable that it is 0.1-30 mass% of pharmaceutical composition combining in the said granular material and in pharmaceutical compositions other than the said granular material, More preferably, it is 0.5-15 mass%. %.
In the pharmaceutical composition of the present invention, in addition to the above-mentioned functional additives having water solubility or water affinity, other pharmaceutical additives generally used in the field of pharmaceutical preparations such as lubricants, foaming agents, sweeteners , Fragrances, colorants and the like can also be added.
Examples of lubricants include stearic acid, calcium stearate, magnesium stearate, polyoxyl 40 stearate, talc, cetanol, love wax, silicic anhydride, paraffin, boric acid, leucine, polyoxyethylene fatty acid ester, sodium benzoate, etc. Is given. As the usage-amount of a lubricant, 0.01-1 mass% is preferable in a pharmaceutical composition, More preferably, it is 0.01-0.5 mass%.
Examples of the foaming agent include sodium bicarbonate, sodium carbonate, calcium carbonate and the like.
Examples of the sweetening agent include aspartame (registered trademark), saccharin, glycyrrhizin and the like.
Examples of the fragrances include lemon, orange, pine, mint, menthol and the like.
Examples of the colorant include yellow ferric oxide, ferric oxide, and tar dye.
Examples of the coating include sugar coating, film coating, polymer coating, and the like. Examples of the purpose of coating include imparting taste, gastric or enteric properties, and preventing alteration due to drug oxidation or hydrolysis.
Examples of the coating agent used for coating for taste masking include methyl cellulose, ethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer (E), acrylic Examples include ethyl acetate, methyl methacrylate, methacrylate trimethylammonium ethyl copolymer (RS), and the like.
Examples of the coating agent used for coating for imparting gastric solubility include methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer (E), polyvinyl acetal diethylaminoacetate (AEA), and the like.
Examples of the coating agent used for coating for enteric property include methacrylic acid / methyl methacrylate copolymer (L), methacrylic acid / ethyl acrylate copolymer (LD), cellulose acetate, cellulose acetate phthalate, carboxy Examples thereof include methyl ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, and hydroxypropyl methyl cellulose phthalate.
In addition, by coating with the coating agent used for the above-mentioned taste-masking or gastro- or enteric coating, it may be possible to simultaneously achieve the purpose of preventing alteration due to drug oxidation or hydrolysis. is there.
Next, a preferred method for producing the pharmaceutical composition containing benidipine hydrochloride of the present invention will be described taking tablets as an example. The form of the pharmaceutical composition containing benidipine hydrochloride of the present invention includes granules, powders, pills and the like in addition to tablets.
(1) Grinding and granulating step for benidipine hydrochloride crystals The grinder used for grinding the benidipine hydrochloride crystals is not particularly limited, but a hammer mill, jet mill or the like is preferably used. In this pulverization step, benidipine hydrochloride can be processed to have a volume average particle size of 1.0 to 50.0 μm, preferably 4.5 to 50.0 μm, more preferably 4.5 to 30.0 μm.
In the pulverization step, the number average particle size is preferably 1.0 to 50.0 μm, more preferably 4.5 to 30.0 μm, and still more preferably the difference between the volume average particle size and the number average particle size is the volume. It can be processed so as to have a value of 50% or less with respect to the average particle diameter. Or it can process so that a volume average particle diameter may be set to 12-50.0 micrometers irrespective of a number average particle diameter.
Further, instead of pulverization, benidipine hydrochloride can be processed to have a volume average particle size of 1.0 to 50.0 μm by sieving, crystallization, spray drying or the like.
A granule containing a benidipine hydrochloride crystal and a water-soluble or water-soluble functional additive is added to the benidipine hydrochloride crystal after adding the water-soluble or water-compatible functional additive, and then pulverized and sieved. The volume average particle diameter can be processed to be 1.0 to 50.0 μm, preferably 4.5 to 50.0 μm, and more preferably 4.5 to 30.0 μm by excess, crystallization, spray drying, or the like.
The number average particle size is preferably 1.0 to 50.0 μm, more preferably 4.5 to 30.0 μm, and more preferably the volume average particle size by pulverization, sieving, crystallization, spray drying and the like. Processing can be performed so that the difference in number average particle diameter is 50% or less of the volume average particle diameter. Or it can process so that a volume average particle diameter may be set to 12-50.0 micrometers irrespective of a number average particle diameter.
Subsequently, the powder containing benidipine hydrochloride crystals or benidipine hydrochloride processed to have a volume average particle diameter of 1.0 to 50.0 μm and a granular material containing a functional additive having water solubility or water affinity, if necessary. The granules for various preparations are added and granulated to obtain a granulated product. The granulation method is not particularly limited, but wet granulation is preferably used. As the granulator, for example, a fluidized bed granulator, a rolling stirring granulator, an extrusion granulator, or the like is used.
The amount of benidipine hydrochloride used in the pharmaceutical composition containing benidipine hydrochloride of the present invention is preferably 0.01 to 50% by mass, more preferably 0.01 to 30% by mass, although it varies depending on the dose.
(2) Manufacturing process of tablet containing benidipine hydrochloride After drying the granulated product obtained in the above (1), a lubricant is added and mixed and compression molded. At this time, the above-mentioned various additives for preparation can also be added.
Although the tableting machine used for compression molding is not particularly limited, it is preferable to use a rotary tableting machine, and the compression molding pressure is preferably 300 kg to 5000 kg.
In addition, for imparting taste-masking, gastric or enteric properties, etc., the pharmaceutical composition can also be coated. This includes a method of coating the granulated product, ie, the raw granule before compression molding, and compression molding. For example, a method of coating the subsequent tablets.
As a method of coating the elementary granules before compression molding, for example, in a coating apparatus, the benidipine hydrochloride crystal as an active ingredient is attached to a spherical granule of lactose or crystalline cellulose together with a binder, and a stationary shelf type dryer, fluidized Dry with a layer dryer or the like to obtain elementary granules containing benidipine hydrochloride crystals. Further, in the coating apparatus, the coating agent may be a suitable solvent such as water, methanol, ethanol, 2-propanol, ethyl acetate, ethyl lactate, acetone, methylene chloride, 1,1,1-trichloroethane, or a mixed solvent thereof. The coating agent solution dissolved or dispersed in is sprayed onto the elementary granules to be coated, and dried with a stationary shelf dryer or a fluidized bed dryer to obtain coated powder particles. The coating apparatus at this time is not particularly limited, but a fluidized bed coating drying apparatus, a centrifugal fluidized granulator, a rolling fluidized coating drying apparatus, or the like is preferably used.
In addition, a coating apparatus for coating the tablets after compression molding is not particularly limited, but a drum type film coating drying apparatus or a fluidized bed coating apparatus is preferably used.
Immediate elution of benidipine hydrochloride from the pharmaceutical composition of the present invention is carried out in the pharmaceutical composition containing benidipine hydrochloride, wherein the volume average particle size of the benidipine hydrochloride crystals is 1.0 to 50.0 μm, preferably the volume average particle size and In a pharmaceutical composition comprising a number average particle diameter of 4.5 to 30.0 μm, or a benidipine hydrochloride crystal and a granule containing a functional additive having water solubility or water affinity, It can be carried out by setting the volume average particle size of the granular material containing a functional additive having water solubility or water affinity to 1.0 to 50.0 μm, preferably 4.5 to 50.0 μm, For example, it can be carried out by producing a benidipine hydrochloride-containing pharmaceutical composition by the above-described method for producing a pharmaceutical composition of the present invention.
EXAMPLES Next, although an Example demonstrates this invention further in detail, this invention is not limited to these.
（塩酸ベニジピン原薬の粉砕）
塩酸ベニジピン原薬（ロットＰ−０１０、協和発酵製、体積平均粒子径６５．０μｍ、個数平均粒子径１０．３μｍ）５０００ｇを粉砕機サンプルミル（ＫＩＩＷＧ−１Ｆ型、不二パウダル製）による１回粉砕処理に付した。さらに、得られた粉砕された塩酸ベニジピン結晶をジェットミル粉砕機（ＰＪＭ−１００ＳＰ、日本ニューマチック工業社製）による１回粉砕処理に付し、粉砕された塩酸ベニジピン結晶を得た。粉砕された塩酸ベニジピン結晶の平均粒子径は、流動パラフィン懸濁による湿式法で顕微鏡下イメージアナライザー（オリンパスＳＰ−５００型）にて測定した。その結果、粉砕された塩酸ベニジピン結晶は、体積平均粒子径９．４μｍ、個数平均粒子径４．９μｍであった。
（粉砕された塩酸ベニジピン結晶を用いた錠剤製造）
上記の粉砕された塩酸ベニジピン結晶を用いて、以下の処方および製造法により、錠剤を得た。
（錠剤処方）
粉砕された塩酸ベニジピン結晶、ラクトースおよびバレイショデンプンをポリビニルアルコールの水溶液を噴霧下、流動層造粒機にて造粒し、さらに、滑沢剤としてステアリン酸マグネシウムをＶ型混合機にて混合し、打錠用顆粒を得た。この打錠用顆粒を用いて、錠剤径７ｍｍφ、錠剤重量１３０ｍｇの錠剤を得た。(Crushing of benidipine hydrochloride drug substance)
Benigpine hydrochloride drug substance (Lot P-010, manufactured by Kyowa Hakko, volume average particle size 65.0 μm, number average particle size 10.3 μm) 5000 g once by pulverizer sample mill (KIIWG-1F type, manufactured by Fuji Powder) It was subjected to a grinding process. Furthermore, the pulverized benidipine hydrochloride crystals thus obtained were subjected to a pulverization process once by a jet mill pulverizer (PJM-100SP, manufactured by Nippon Pneumatic Kogyo Co., Ltd.) to obtain crushed benidipine hydrochloride crystals. The average particle size of the pulverized benidipine hydrochloride crystals was measured with an image analyzer (Olympus SP-500 type) under a microscope by a wet method using liquid paraffin suspension. As a result, the ground benidipine hydrochloride crystal had a volume average particle size of 9.4 μm and a number average particle size of 4.9 μm.
(Manufacture of tablets using ground benidipine hydrochloride crystals)
Using the pulverized benidipine hydrochloride crystals, tablets were obtained by the following formulation and production method.
(Tablet prescription)
The ground benidipine hydrochloride crystals, lactose and potato starch are granulated in a fluidized bed granulator while spraying an aqueous solution of polyvinyl alcohol, and further magnesium stearate as a lubricant is mixed in a V-type mixer, Granules for tableting were obtained. Tablets having a tablet diameter of 7 mmφ and a tablet weight of 130 mg were obtained using the granules for tableting.
（塩酸ベニジピン原薬の粉砕）
塩酸ベニジピン原薬（ロットＰ−０１０、協和発酵製、体積平均粒子径６５．０μｍ、個数平均粒子径１０．３μｍ）５０００ｇを粉砕機サンプルミル（ＫＩＩＷＧ−１Ｆ型、不二パウダル製）による１回粉砕処理に付し、粉砕された塩酸ベニジピン結晶を得た。粉砕された塩酸ベニジピン結晶の平均粒子径は、流動パラフィン懸濁による湿式法で顕微鏡下イメージアナライザー（オリンパスＳＰ−５００型）にて測定した。その結果、粉砕された塩酸ベニジピン結晶は、体積平均粒子径１４．５μｍ、個数平均粒子径６．２μｍであった。
（粉砕された塩酸ベニジピン結晶を用いた錠剤製造）
上記の粉砕された塩酸ベニジピン結晶を用いて、以下の処方および製造法により、錠剤を得た。
（錠剤処方）
粉砕された塩酸ベニジピン結晶、ラクトースおよびバレイショデンプンをポリビニルアルコールの水溶液を噴霧下、流動層造粒機にて造粒し、さらに、滑沢剤としてステアリン酸マグネシウムをＶ型混合機にて混合し、打錠用顆粒を得た。この打錠用顆粒を用いて、錠剤径７ｍｍφ、錠剤重量１３０ｍｇの錠剤を得た。(Crushing of benidipine hydrochloride drug substance)
Benigpine hydrochloride drug substance (Lot P-010, manufactured by Kyowa Hakko, volume average particle size 65.0 μm, number average particle size 10.3 μm) 5000 g once by pulverizer sample mill (KIIWG-1F type, manufactured by Fuji Powder) A pulverized benidipine hydrochloride crystal was obtained by pulverization. The average particle size of the pulverized benidipine hydrochloride crystals was measured with an image analyzer (Olympus SP-500 type) under a microscope by a wet method using liquid paraffin suspension. As a result, the ground benidipine hydrochloride crystal had a volume average particle size of 14.5 μm and a number average particle size of 6.2 μm.
(Manufacture of tablets using ground benidipine hydrochloride crystals)
Using the pulverized benidipine hydrochloride crystals, tablets were obtained by the following formulation and production method.
(Tablet prescription)
The ground benidipine hydrochloride crystals, lactose and potato starch are granulated in a fluidized bed granulator while spraying an aqueous solution of polyvinyl alcohol, and further magnesium stearate as a lubricant is mixed in a V-type mixer, Granules for tableting were obtained. Tablets having a tablet diameter of 7 mmφ and a tablet weight of 130 mg were obtained using the granules for tableting.
（塩酸ベニジピン原薬の篩過）
塩酸ベニジピン原薬（ロットＰ−０１０、協和発酵製、体積平均粒子径６５．０μｍ、個数平均粒子径１０．３μｍ）５０００ｇを振動フルイ機［１００ｍｅｓｈ（１５０μｍ）篩過］にて処理し、篩過された塩酸ベニジピン結晶を得た。篩過された塩酸ベニジピン結晶の平均粒子径は、流動パラフィン懸濁による湿式法で顕微鏡下イメージアナライザー（オリンパスＳＰ−５００型）にて測定した。その結果、篩過された塩酸ベニジピン結晶は、体積平均平均粒子径２６．３μｍ、個数平均粒子径６．６μｍであった。
（篩過された塩酸ベニジピン結晶を用いた錠剤製造）
上記の篩過された塩酸ベニジピン結晶を用いて、以下の処方および製造法により、錠剤を得た。
（錠剤処方）
篩過された塩酸ベニジピン結晶、ラクトースおよびバレイショデンプンをポリビニルアルコールの水溶液を噴霧下、流動層造粒機にて造粒し、さらに滑沢剤としてステアリン酸マグネシウムをＶ型混合機にて混合し、打錠用顆粒を得た。この打錠用顆粒を用いて、錠剤径７ｍｍφ、錠剤重量１３０ｍｇの錠剤を得た。
比較例１
（未粉砕または未篩過塩酸ベニジピン結晶を用いた錠剤製造）
塩酸ベニジピン原薬（ロットＰ−０１０、協和発酵製、体積平均粒子径６５．０μｍ、個数平均粒子径１０．３μｍ）を用いて、以下の処方および製造法により、錠剤を得た。
（錠剤処方）
塩酸ベニジピン原薬（ロットＰ−０１０、協和発酵製、体積平均粒子径６５．０μｍ、個数平均粒子径１０．３μｍ）、ラクトースおよびバレイショデンプンをポリビニルアルコールの水溶液を噴霧下、流動層造粒機にて造粒し、さらに滑沢剤としてステアリン酸マグネシウムをＶ型混合機にて混合し、打錠用顆粒を得た。この打錠用顆粒を用いて、錠剤径７ｍｍφ、錠剤重量１３０ｍｇの錠剤を得た。
比較例２
（未粉砕または未篩過塩酸ベニジピン結晶を用いた錠剤製造）
塩酸ベニジピン原薬（ロットＰ−００５、協和発酵製、体積平均粒子径１４７．１μｍ、個数平均粒子径９．７μｍ）を用いて、以下の処方および製造法により、錠剤を得た。
（錠剤処方）
塩酸ベニジピン原薬（ロットＰ−００５、協和発酵製、体積平均粒子径１４７．１μｍ、個数平均粒子径９．７μｍ）、ラクトースおよびバレイショデンプンをポリビニルアルコールの水溶液を噴霧下、流動層造粒機にて造粒し、さらに滑沢剤としてステアリン酸マグネシウムをＶ型混合機にて混合し、打錠用顆粒を得た。この打錠用顆粒を用いて、錠剤径７ｍｍφ、錠剤重量１３０ｍｇの錠剤を得た。
実施例１、２、３および比較例１、２で用いた塩酸ベニジピン結晶の体積平均粒子径および個数平均粒子径を表１に示した。
溶出試験は日局第１法（回転バスケット法）に従い、試験液［ラウリル硫酸ナトリウムのｐＨ６．８リン酸ナトリウム緩衝液溶液（１→５００）］９００ｍｌを用いて行い、操作条件は、３７℃、５０ｒｐｍで実施した。試験開始１０、２０、３０、４５、６０分後にサンプリングされた溶出液を高速液体クロマトグラフィー法［カラム：ＹＭＣ Ａ−３０１−１（４．６φ×１００ｍｍ）、温度：４０℃、移動層：０．０５ｍｏｌ／Ｌリン酸二水素カリウム水溶液／アセトニトリル混液（５５：４５）＋１ｍｍｏｌ／Ｌラウリル硫酸ナトリウム水溶液］により定量し、溶出プロファイルとして評価した。
実施例１、２、３および比較例１、２で得られた錠剤の溶出試験結果を表２に示した。
Benigpine hydrochloride drug substance (Lot P-010, manufactured by Kyowa Hakko, volume average particle size 65.0 μm, number average particle size 10.3 μm) 5000 g was treated with a vibrating sieve [100 mesh (150 μm) sieve] and sieved. The obtained benidipine hydrochloride crystals were obtained. The average particle size of the sieved benidipine hydrochloride crystals was measured by a wet method using liquid paraffin suspension with an image analyzer (Olympus SP-500 type) under a microscope. As a result, the sieved benidipine hydrochloride crystals had a volume average average particle size of 26.3 μm and a number average particle size of 6.6 μm.
(Manufacture of tablets using sieved benidipine hydrochloride crystals)
A tablet was obtained by the following formulation and production method using the sieved benidipine hydrochloride crystals.
(Tablet prescription)
The sieved benidipine hydrochloride crystals, lactose and potato starch were granulated in a fluidized bed granulator while spraying an aqueous solution of polyvinyl alcohol, and further magnesium stearate as a lubricant was mixed in a V-type mixer, Granules for tableting were obtained. Tablets having a tablet diameter of 7 mmφ and a tablet weight of 130 mg were obtained using the granules for tableting.
Comparative Example 1
(Manufacture of tablets using unmilled or unsieved benidipine hydrochloride crystals)
Using benidipine hydrochloride drug substance (Lot P-010, manufactured by Kyowa Hakko, volume average particle size 65.0 μm, number average particle size 10.3 μm), tablets were obtained by the following formulation and production method.
(Tablet prescription)
Benidipine hydrochloride drug substance (Lot P-010, manufactured by Kyowa Hakko, volume average particle diameter 65.0 μm, number average particle diameter 10.3 μm), lactose and potato starch are sprayed with an aqueous solution of polyvinyl alcohol in a fluid bed granulator. Further, magnesium stearate as a lubricant was mixed with a V-type mixer to obtain granules for tableting. Tablets having a tablet diameter of 7 mmφ and a tablet weight of 130 mg were obtained using the granules for tableting.
Comparative Example 2
(Manufacture of tablets using unmilled or unsieved benidipine hydrochloride crystals)
Using benidipine hydrochloride drug substance (Lot P-005, manufactured by Kyowa Hakko, volume average particle size 147.1 μm, number average particle size 9.7 μm), tablets were obtained by the following formulation and manufacturing method.
(Tablet prescription)
Benidipine hydrochloride drug substance (Lot P-005, manufactured by Kyowa Hakko, volume average particle diameter 147.1 μm, number average particle diameter 9.7 μm), lactose and potato starch are sprayed with an aqueous solution of polyvinyl alcohol in a fluid bed granulator. Further, magnesium stearate as a lubricant was mixed with a V-type mixer to obtain granules for tableting. Tablets having a tablet diameter of 7 mmφ and a tablet weight of 130 mg were obtained using the granules for tableting.
Table 1 shows the volume average particle diameter and the number average particle diameter of the benidipine hydrochloride crystals used in Examples 1, 2, and 3 and Comparative Examples 1 and 2.
Table 2 shows the dissolution test results of the tablets obtained in Examples 1, 2, and 3 and Comparative Examples 1 and 2.
本発明により、主薬である塩酸ベニジピンの速やかな吸収を促進するための、速やかな溶出性を有する塩酸ベニジピン含有医薬組成物等が提供される。 INDUSTRIAL APPLICABILITY According to the present invention, there is provided a pharmaceutical composition containing benidipine hydrochloride having a rapid dissolution property for promoting rapid absorption of benidipine hydrochloride as a main drug.
【特許請求の範囲】
【請求項1】 塩酸ベニジピンを含有する医薬組成物において、塩酸ベニジピン結晶の体積平均粒子径を4.5〜50.0μmとする、または塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する粉粒体を含有する医薬組成物において、塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する粉粒体の体積平均粒子径を4.5〜50.0μmとすることを特徴とする、該医薬組成物からの塩酸ベニジピンの即溶出化方法。
【請求項2】 塩酸ベニジピンを含有する医薬組成物において、塩酸ベニジピン結晶の体積平均粒子径および個数平均粒子径を4.5〜30.0μmとする、または塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する粉粒体を含有する医薬組成物において、塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する粉粒体の体積平均粒子径を4.5〜50.0μmとすることを特徴とする、該医薬組成物からの塩酸ベニジピンの即溶出化方法。
【請求項3】 塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する医薬組成物において、塩酸ベニジピン結晶と水溶性または水親和性を有する機能性添加剤との重量比が1:99〜99:1である請求項1または2記載の即溶出化方法。
【請求項4】 塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する医薬組成物において、水溶性または水親和性を有する機能性添加剤が水溶性または水親和性を有する賦形剤である請求項1〜3のいずれかに記載の即溶出化方法。
【請求項5】 水溶性または水親和性を有する賦形剤がデンプン類、デンプン誘導体、糖類、糖アルコール類、セルロース類、セルロース誘導体またはデキストリンである請求項1〜3のいずれかに記載の即溶出化方法。
【請求項6】 塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する医薬組成物において、水溶性または水親和性を有する機能性添加剤が崩壊剤である請求項1〜3のいずれかに記載の即溶出化方法。
【請求項7】 崩壊剤がデンプン類、デンプン誘導体、セルロース類またはセルロース誘導体である請求項6記載の即溶出化方法。
【請求項8】 塩酸ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する医薬組成物において、水溶性または水親和性を有する機能性添加剤が水溶性または水親和性を有する結合剤である請求項1〜3のいずれかに記載の即溶出化方法。
【請求項9】 水溶性または水親和性を有する結合剤がセルロース類、セルロース誘導体、ポリビニルアルコール、部分けん化ポリビニルアルコールまたはポリビニルピロリドンである請求項8記載の即溶出化方法。
【請求項10】 医薬組成物が、該粉粒体以外で医薬組成物中に水溶性または水親和性を有する機能性添加剤を含有する医薬組成物である請求項1〜9のいずれかに記載の即溶出化方法。
【請求項11】 粉粒体以外で医薬組成物中に含有される水溶性または水親和性を有する機能性添加剤が水溶性または水親和性を有する賦形剤である請求項10記載の即溶出化方法。
【請求項12】 水溶性または水親和性を有する賦形剤がデンプン類、デンプン誘導体、糖類、糖アルコール類、セルロース類、セルロース誘導体またはデキストリンである請求項11記載の即溶出化方法。
【請求項13】 粉粒体以外で医薬組成物中に含有される水溶性または水親和性を有する機能性添加剤が崩壊剤である請求項10記載の即溶出化方法。
【請求項14】 崩壊剤がデンプン類、デンプン誘導体、セルロース類またはセルロース誘導体である請求項13記載の即溶出化方法。
【請求項15】 粉粒体以外で医薬組成物中に含有される水溶性または水親和性を有する機能性添加剤が水溶性または水親和性を有する結合剤である請求項10記載の即溶出化方法。
【請求項16】 水溶性または水親和性を有する結合剤がセルロース類、セルロース誘導体、ポリビニルアルコール、部分けん化ポリビニルアルコールまたはポリビニルピロリドンである請求項15記載の即溶出化方法。
【請求項17】 医薬組成物が錠剤であり、塩酸ベニジピンの含有量が錠剤中0.01〜50質量%である請求項1〜16のいずれかに記載の即溶出化方法。
【請求項18】 医薬組成物がコーティングされている医薬組成物である請求項1〜17のいずれかに記載の即溶出化方法。
[Claims]
Claim1In a pharmaceutical composition containing benidipine hydrochloride, the volume average particle size of the benidipine hydrochloride crystals is4.5 ~Functionality having benidipine hydrochloride crystals and water-solubility or water-affinity in a pharmaceutical composition containing 50.0 μm or benidipine hydrochloride crystals and water-soluble or water-soluble functional granules The volume average particle size of the powder containing the additive4.5 ~A method for immediately eluting benidipine hydrochloride from the pharmaceutical composition, characterized by comprising 50.0 μm.
Claim2In a pharmaceutical composition containing benidipine hydrochloride, the volume average particle size and number average of benidipine hydrochloride crystalsparticleIn a pharmaceutical composition containing a granule having a diameter of 4.5 to 30.0 μm or containing a benidipine hydrochloride crystal and a functional additive having water solubility or water affinity, the benidipine hydrochloride crystal and water solubility or water affinity A method for instantly eluting benidipine hydrochloride from the pharmaceutical composition, wherein the volume average particle size of the granular material containing the functional additive having a pH of 4.5 to 50.0 μm is used.
ClaimThreeA pharmaceutical composition comprising benidipine hydrochloride crystals and a functional additive having water solubility or water affinity, wherein the weight ratio of the benidipine hydrochloride crystals and the functional additive having water solubility or water affinity is from 1:99 to 99: 1Claim 1 or 2The immediate elution method described.
ClaimFourA pharmaceutical composition comprising benidipine hydrochloride crystals and a functional additive having water solubility or water affinity, wherein the functional additive having water solubility or water affinity is an excipient having water solubility or water affinity. is thereClaims 1-3The immediate elution method according to any one of the above.
ClaimFiveWater-soluble or water-soluble excipients are starches, starch derivatives, sugars, sugar alcohols, celluloses, cellulose derivatives or dextrinsClaims 1-3The immediate elution method according to any one of the above.
Claim6In a pharmaceutical composition containing benidipine hydrochloride crystals and a functional additive having water solubility or water affinity, the functional additive having water solubility or water affinity is a disintegrant.Claims 1-3The immediate elution method according to any one of the above.
Claim7The disintegrant is a starch, starch derivative, cellulose or cellulose derivative.6The immediate elution method described.
Claim8In a pharmaceutical composition containing benidipine hydrochloride crystals and a functional additive having water solubility or affinity, the functional additive having water solubility or affinity is a binder having water solubility or affinity.Claims 1-3The immediate elution method according to any one of the above.
Claim9The water-soluble or water-soluble binder is celluloses, cellulose derivatives, polyvinyl alcohol, partially saponified polyvinyl alcohol or polyvinyl pyrrolidone.Claim 8The immediate elution method described.
[Claim 10] The immediate elution according to any one of claims 1 to 9, wherein the pharmaceutical composition is a pharmaceutical composition containing a functional additive having water solubility or water affinity in the pharmaceutical composition other than the granular material. Method.
[Claim 11] 11. The immediate elution method according to claim 10, wherein the functional additive having water solubility or water affinity contained in the pharmaceutical composition other than the powder is an excipient having water solubility or water affinity.
[Claim 12] 12. The immediate elution method according to claim 11, wherein the excipient having water solubility or affinity is starch, starch derivative, saccharide, sugar alcohol, cellulose, cellulose derivative or dextrin.
[Claim 13] 11. The immediate elution method according to claim 10, wherein the functional additive having water solubility or water affinity contained in the pharmaceutical composition other than the powder is a disintegrant.
[Claim 14] 14. The immediate elution method according to claim 13, wherein the disintegrant is a starch, a starch derivative, a cellulose or a cellulose derivative.
[Claim 15] 11. The immediate elution method according to claim 10, wherein the functional additive having water solubility or water affinity contained in the pharmaceutical composition other than the powder is a water soluble or water affinity binder.
[Claim 16] 16. The immediate elution method according to claim 15, wherein the water-soluble or water-affinity binder is celluloses, cellulose derivatives, polyvinyl alcohol, partially saponified polyvinyl alcohol or polyvinylpyrrolidone.
[Claim 17] The immediate elution method according to any one of claims 1 to 16, wherein the pharmaceutical composition is a tablet, and the content of benidipine hydrochloride is 0.01 to 50% by mass in the tablet.
Claim18The pharmaceutical composition is a coated pharmaceutical compositionClaims 1-17The immediate elution method according to any one of the above.
Claims (20)
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| JP2003171503 | 2003-06-17 | ||
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| PCT/JP2004/008821 WO2004110448A1 (en) | 2003-06-17 | 2004-06-17 | Medicinal composition containing benidipine hydrochloride |
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| JP2005178235A Division JP4606258B2 (en) | 2003-06-17 | 2005-06-17 | Pharmaceutical composition containing benidipine hydrochloride |
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| KR (1) | KR101060885B1 (en) |
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| US20070042049A1 (en) * | 2005-06-03 | 2007-02-22 | Elan Pharma International, Limited | Nanoparticulate benidipine compositions |
| JPWO2008117707A1 (en) * | 2007-03-23 | 2010-07-15 | 第一三共株式会社 | Crushed crystals of olmesartan medoxomil |
| BRPI0809205B8 (en) * | 2007-03-29 | 2021-05-25 | Daiichi Sankyo Co Ltd | pharmaceutical composition |
| KR101792299B1 (en) | 2010-03-19 | 2017-10-31 | 다이이찌 산쿄 가부시키가이샤 | Method for improving dissolution of anticoagulant agent |
| JP2014511867A (en) | 2011-04-18 | 2014-05-19 | 合肥貝霓医薬科技有限公司 | Purification of dihydropyridine calcium channel blocker and method for preparing nanoparticles thereof |
| JP5590228B2 (en) * | 2011-04-18 | 2014-09-17 | ヘフェイ ベイニ メディカル テクノロジー カンパニー リミテッド | Preparation method of nanoparticles of Benidipine hydrochloride |
| KR101940840B1 (en) | 2011-08-10 | 2019-01-21 | 다이이찌 산쿄 가부시키가이샤 | Pharmaceutical composition containing diamine derivative |
| CN102362865B (en) * | 2011-10-28 | 2013-06-26 | 山东司邦得制药有限公司 | Compound preparation containing benidipine hydrochloride and valsartan and application thereof |
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| JPS55129221A (en) * | 1979-03-29 | 1980-10-06 | Kaken Pharmaceut Co Ltd | Preparation of oral preparation containing hardly soluble medicine |
| JPS59137461A (en) * | 1983-01-27 | 1984-08-07 | Kyowa Hakko Kogyo Co Ltd | 1,4-dihydropyridine derivative |
| JPH06128147A (en) * | 1992-10-20 | 1994-05-10 | Masayasu Sugihara | Method for improving solubility of sparingly water-soluble medicine and medicine composition obtained thereby |
| JPH07126154A (en) * | 1993-10-29 | 1995-05-16 | Terumo Corp | Slightly soluble medicine-containing pharmaceutical preparation |
| JP2003104888A (en) * | 2001-09-28 | 2003-04-09 | Taiyo Yakuhin Kogyo Kk | Tablet of dihydropyridine derivative |
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| CN102166212A (en) | 2011-08-31 |
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| KR101060885B1 (en) | 2011-08-31 |
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