JP5241511B2 - Pharmaceutical composition with improved dissolution - Google Patents
Pharmaceutical composition with improved dissolution Download PDFInfo
- Publication number
- JP5241511B2 JP5241511B2 JP2008551105A JP2008551105A JP5241511B2 JP 5241511 B2 JP5241511 B2 JP 5241511B2 JP 2008551105 A JP2008551105 A JP 2008551105A JP 2008551105 A JP2008551105 A JP 2008551105A JP 5241511 B2 JP5241511 B2 JP 5241511B2
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- JP
- Japan
- Prior art keywords
- pharmaceutical composition
- acid
- composition according
- olmesartan medoxomil
- polyvinyl alcohol
- Prior art date
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- 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
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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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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- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
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- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
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Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
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- Heart & Thoracic Surgery (AREA)
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- Vascular Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、オルメサルタンメドキソミル及びアゼルニジピンを含有する医薬組成物に関する。 The present invention relates to a pharmaceutical composition comprising olmesartan medoxomil and azelnidipine.
現在、アンジオテンシンII受容体拮抗剤及びカルシウムチャンネル拮抗剤は、高血圧症または心疾患等の治療もしくは予防のための医薬として広く用いられている。レニン−アンジオテンシン系の抑制薬であるアンジオテンシンII受容体拮抗剤は、レニン依存性の高血圧症に特に有効であり、心血管や腎臓の障害に対して保護作用を示す。また、カルシウムチャンネル拮抗剤は、血管拡張作用に加えナトリウム利尿作用を有することから、体液貯留性(レニン非依存性)の高血圧症にも有効である。したがって、アンジオテンシンII受容体拮抗剤とカルシウムチャンネル拮抗剤を併用すれば、アンジオテンシンII受容体拮抗剤によるレニン−アンジオテンシン系の抑制効果に加え、カルシウムチャンネル拮抗剤による血管平滑筋におけるカルシウムチャネル拮抗作用及び二次的なナトリウム排泄作用により,複数の高血圧の成因を同時に抑えることが可能となり、病因によらず安定かつ十分な高血圧症の治療もしくは予防効果を示すことが期待される。 Currently, angiotensin II receptor antagonists and calcium channel antagonists are widely used as medicaments for the treatment or prevention of hypertension or heart disease. Angiotensin II receptor antagonists, which are inhibitors of the renin-angiotensin system, are particularly effective for renin-dependent hypertension and have a protective effect against cardiovascular and renal damage. Further, since the calcium channel antagonist has a natriuretic action in addition to a vasodilatory action, it is also effective for fluid retention (renin-independent) hypertension. Therefore, when an angiotensin II receptor antagonist and a calcium channel antagonist are used in combination, in addition to the inhibitory effect of the renin-angiotensin system by an angiotensin II receptor antagonist, The next sodium excretion action makes it possible to simultaneously suppress the origin of multiple hypertension, and is expected to show a stable and sufficient hypertension treatment or prevention effect regardless of the etiology.
(5−メチル−2−オキソ−1,3−ジオキソレン−4−イル)メチル 4−(1−ヒドロキシ−1−メチルエチル)−2−プロピル−1−[2’−(1H−テトラゾール−5−イル)ビフェニル−4−イルメチル]イミダゾール−5−カルボキシレート(以下、オルメサルタンメドキソミルという)は、優れたアンジオテンシンII受容体拮抗剤であり、高血圧症および心疾患等の治療もしくは予防のための医薬として有用であることが知られている(特許第2082519号公報、米国特許第5,616,599号公報)。 (5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- [2 ′-(1H-tetrazole-5- Yl) biphenyl-4-ylmethyl] imidazole-5-carboxylate (hereinafter referred to as olmesartan medoxomil) is an excellent angiotensin II receptor antagonist and is useful as a medicament for the treatment or prevention of hypertension, heart disease and the like (Patent No. 2082519, US Pat. No. 5,616,599).
オルメサルタンメドキソミル
Olmesartan Medoxomil
オルメサルタンメドキソミルは、オルメテック(登録商標)錠として販売されており、有効成分としてオルメサルタンメドキソミル5mg、10mg、20mg又は40mgを含有し、添加物として低置換度ヒドロキシプロピルセルロース、ヒドロキシプロピルセルロース、結晶セルロース、乳糖、ステアリン酸マグネシウムを含有する。 Olmesartan medoxomil is sold as Olmetec (registered trademark) tablets, containing 5 mg, 10 mg, 20 mg or 40 mg of olmesartan medoxomil as an active ingredient, and low-substituted hydroxypropylcellulose, hydroxypropylcellulose, crystalline cellulose, lactose as additives And magnesium stearate.
また、(±)−2−アミノ−1,4−ジヒドロ−6−メチル−4−(3−ニトロフェニル)−3,5−ピリジンジカルボン酸 3−(1−ジフェニルメチルアゼチジン−3−イル)エステル5−イソプロピルエステル(以下、アゼルニジピンという)は、優れたカルシウムチャンネル拮抗剤であり、高血圧症および心疾患等の治療もしくは予防のための医薬として有用であることが知られている(特許第1666755号公報、米国特許第4,772,596号公報)。 (±) -2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3- (1-diphenylmethylazetidin-3-yl) Ester 5-isopropyl ester (hereinafter referred to as azelnidipine) is an excellent calcium channel antagonist and is known to be useful as a medicament for the treatment or prevention of hypertension, heart disease and the like (Japanese Patent No. 1666755). No., US Pat. No. 4,772,596).
アゼルニジピン
Azelnidipine
アゼルニジピンは、カルブロック(登録商標)錠として販売されており、有効成分としてアゼルニジピン8mg又は16mgを含有し、添加物としてD−マンニトール、カルメロースカルシウム、低置換度ヒドロキシプロピルセルロース、炭酸水素ナトリウム、ポリソルベート80、メタケイ酸アルミン酸マグネシウム、軽質無水ケイ酸、ヒドロキシプロピルセルロース、タルク、ステアリン酸マグネシウムを含有する。 Azelnidipine is sold as Calblock (registered trademark) tablets, containing 8 mg or 16 mg of azelnidipine as an active ingredient, and D-mannitol, carmellose calcium, low-substituted hydroxypropylcellulose, sodium bicarbonate, polysorbate as an additive 80, containing magnesium aluminate metasilicate, light anhydrous silicic acid, hydroxypropylcellulose, talc, magnesium stearate.
従来技術では、オルメサルタンメドキソミル及びアゼルニジピンを組み合わせた医薬が知られているが(国際公開第2004/067003号パンフレット)、本発明のオルメサルタンメドキソミル及びアゼルニジピンを含有する医薬組成物であって、さらにポリビニルアルコール及び/又はビニルアルコール系共重合体を配合し、溶出性をより改善した医薬組成物は知られていない。
本発明の課題は、(A)オルメサルタンメドキソミル、(B)アゼルニジピン及び(C)ポリビニルアルコール及び/又はビニルアルコール系共重合体を含有する溶出性の改善された医薬組成物を提供することにある。 An object of the present invention is to provide a pharmaceutical composition with improved dissolution, comprising (A) olmesartan medoxomil, (B) azelnidipine and (C) polyvinyl alcohol and / or a vinyl alcohol copolymer.
近年、高血圧症患者はより確実な血圧コントロールを達成するため、作用機序の異なる複数の降圧薬を併用する傾向にある。中でも、アンジオテンシンII受容体拮抗剤であるオルメサルタンメドキソミルとカルシウムチャンネル拮抗剤であるアゼルニジピンは、より確実な高血圧治療効果が期待できる組合せとして医療現場で広く併用されている。しかし、オルメサルタンメドキソミルとアゼルニジピンは相互作用して難溶性化合物を生じ、オルメサルタンメドキソミルの溶出性が低下してしまうことが分かった。 In recent years, hypertensive patients tend to use a plurality of antihypertensive drugs having different mechanisms of action in order to achieve more reliable blood pressure control. Among them, olmesartan medoxomil, which is an angiotensin II receptor antagonist, and azelnidipine, which is a calcium channel antagonist, are widely used in the medical field as a combination that can be expected to have a more reliable therapeutic effect on hypertension. However, it was found that olmesartan medoxomil and azelnidipine interact with each other to form a poorly soluble compound, and the dissolution property of olmesartan medoxomil decreases.
本発明者らは、上記の課題を解決すべく鋭意研究を行った結果、ポリビニルアルコール又はビニルアルコール系共重合体を配合することにより溶出性の改善された医薬組成物が得られることを見出して、本発明を完成するに至った。 As a result of intensive studies to solve the above problems, the present inventors have found that a pharmaceutical composition with improved dissolution can be obtained by blending polyvinyl alcohol or a vinyl alcohol copolymer. The present invention has been completed.
本発明は、(A)オルメサルタンメドキソミル、(B)アゼルニジピン及び(C)ポリビニルアルコール及び/又はビニルアルコール系共重合体を含有する医薬組成物(特に、高血圧症の予防又は治療のための組成物)、上記医薬組成物(特に、高血圧症の予防又は治療のための組成物)を製造するためのオルメサルタンメドキソミル及びアゼルニジピンの使用、オルメサルタンメドキソミル及びアゼルニジピンの薬理学的な有効量を含有する前記医薬組成物を温血動物(特に、ヒト)に投与する疾病(特に、高血圧症)の予防又は治療方法、オルメサルタンメドキソミル及びアゼルニジピンを含有する医薬組成物(特に、高血圧症の治療又は予防のための組成物)の溶出性改善方法等を提供する。 The present invention relates to a pharmaceutical composition comprising (A) olmesartan medoxomil, (B) azelnidipine, and (C) polyvinyl alcohol and / or a vinyl alcohol copolymer (particularly, a composition for preventing or treating hypertension). Use of olmesartan medoxomil and azelnidipine for the preparation of the above pharmaceutical composition (particularly, a composition for the prevention or treatment of hypertension), the pharmaceutical composition comprising a pharmacologically effective amount of olmesartan medoxomil and azelnidipine For the prevention or treatment of diseases (especially hypertension) administered to warm-blooded animals (especially humans), pharmaceutical compositions containing olmesartan medoxomil and azelnidipine (especially compositions for the treatment or prevention of hypertension) A method for improving the dissolution property of
すなわち、本発明は、
(1)(A)オルメサルタンメドキソミル;(B)アゼルニジピン;及び(C)ポリビニルアルコール及びビニルアルコール系共重合体から選択される化合物の1種又は2種以上を含有する医薬組成物、
(2)成分(C)が、ポリビニルアルコール、ポリビニルアルコール−ポリエチレングリコールグラフトコポリマー、ポリビニルアルコール−アクリル酸−メタクリル酸メチルコポリマーから選択される化合物の1種又は2種以上である(1)に記載の医薬組成物、
(3)成分(C)が、ポリビニルアルコールである(1)に記載の医薬組成物、
(4)医薬組成物を単一製剤に配合した(1)乃至(3)のいずれかに記載の医薬組成物、
(5)製剤が、固形製剤である(4)に記載の医薬組成物、
(6)製剤が、散剤、細粒剤、顆粒剤、カプセル剤又は錠剤である(4)に記載の医薬組成物、
(7)製剤が、錠剤である(4)に記載の医薬組成物、
(8)コーティングを施してなる(1)乃至(7)のいずれかに記載の医薬組成物、
(9)成分(C)が、コーティング中に含有されている(8)に記載の医薬組成物、
(10)高血圧症治療又は予防のための(1)乃至(9)のいずれかに記載の医薬組成物、
(11)(1)乃至(10)のいずれかに記載の医薬組成物を用いたオルメサルタンメドキソミルの溶出性改善方法等を提供するものである。That is, the present invention
(1) (A) olmesartan medoxomil; (B) azelnidipine; and (C) a pharmaceutical composition containing one or more compounds selected from polyvinyl alcohol and vinyl alcohol copolymers,
(2) The component (C) is one or more compounds selected from polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer. Pharmaceutical composition,
(3) The pharmaceutical composition according to (1), wherein component (C) is polyvinyl alcohol,
(4) The pharmaceutical composition according to any one of (1) to (3), wherein the pharmaceutical composition is blended into a single preparation,
(5) The pharmaceutical composition according to (4), wherein the preparation is a solid preparation,
(6) The pharmaceutical composition according to (4), wherein the preparation is a powder, fine granules, granules, capsules or tablets,
(7) The pharmaceutical composition according to (4), wherein the preparation is a tablet,
(8) The pharmaceutical composition according to any one of (1) to (7), which is coated;
(9) The pharmaceutical composition according to (8), wherein component (C) is contained in the coating,
(10) The pharmaceutical composition according to any one of (1) to (9) for treating or preventing hypertension,
(11) A method for improving the dissolution property of olmesartan medoxomil using the pharmaceutical composition according to any one of (1) to (10).
本発明によれば、(A)オルメサルタンメドキソミル、(B)アゼルニジピン及び(C)ポリビニルアルコール及び/又はビニルアルコール系共重合体を含有する、溶出性の改善された医薬組成物を提供することが可能となる。 According to the present invention, it is possible to provide a pharmaceutical composition with improved dissolution, comprising (A) olmesartan medoxomil, (B) azelnidipine and (C) polyvinyl alcohol and / or a vinyl alcohol copolymer. It becomes.
本発明の医薬組成物の有効成分は、オルメサルタンメドキソミルとアゼルニジピンである。 The active ingredients of the pharmaceutical composition of the present invention are olmesartan medoxomil and azelnidipine.
本発明の医薬組成物における有効成分の一つであるオルメサルタンメドキソミルは、特許第2082519号公報(米国特許第5,616,599号公報)等に記載の方法に従い容易に製造することができる。 Olmesartan medoxomil, which is one of the active ingredients in the pharmaceutical composition of the present invention, can be easily produced according to the method described in Japanese Patent No. 2082519 (US Pat. No. 5,616,599) and the like.
本発明の医薬組成物における有効成分の一つであるアゼルニジピンは、特許第1666755号公報(米国特許第4,772,596号公報)等に記載の方法に従い容易に製造することができる。アゼルニジピンは酸付加塩を形成することができ、これらの酸付加塩も本発明に包含される。アゼルニジピンの酸付加塩の酸部分は、アゼルニジピンと酸付加塩を形成し得る酸であれば特に限定はなく、そのような酸としては、例えば、塩酸、臭化水素酸、沃化水素酸、硫酸、硝酸、リン酸、酢酸、シュウ酸、マロン酸、フマル酸、マレイン酸、酒石酸、コハク酸、クエン酸、メタンスルホン酸、ベンゼンスルホン酸、p‐トルエンスルホン酸、または、ナフタレンスルホン酸であり得、好適には、塩酸、臭化水素酸、硫酸、リン酸、フマル酸、酒石酸、クエン酸、メタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸、又は、ナフタレンスルホン酸であり、より好適には、臭化水素酸、クエン酸、メタンスルホン酸、ベンゼンスルホン酸、p‐トルエンスルホン酸、または、ナフタレンスルホン酸であり、さらに好適には、臭化水素酸、メタンスルホン酸、または、p‐トルエンスルホン酸であり、さらにより好適には、臭化水素酸またはメタンスルホン酸であり、最も好適には、臭化水素酸である。 Azelnidipine which is one of the active ingredients in the pharmaceutical composition of the present invention can be easily produced according to the method described in Japanese Patent No. 1666755 (US Pat. No. 4,772,596) and the like. Azelnidipine can form acid addition salts, and these acid addition salts are also encompassed by the present invention. The acid part of the acid addition salt of azelnidipine is not particularly limited as long as it is an acid that can form an acid addition salt with azelnidipine. Examples of such acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and the like. , Nitric acid, phosphoric acid, acetic acid, oxalic acid, malonic acid, fumaric acid, maleic acid, tartaric acid, succinic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or naphthalenesulfonic acid , Preferably hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, tartaric acid, citric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or naphthalenesulfonic acid, more preferably Is hydrobromic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or naphthalenesulfonic acid, more preferably Hydrobromic acid, methanesulfonic acid, or p-toluenesulfonic acid, still more preferably hydrobromic acid or methanesulfonic acid, and most preferably hydrobromic acid.
本発明の医薬組成物における「ポリビニルアルコール及び/又はビニルアルコール系共重合体」としては、例えば、ポリビニルアルコール(カラコン社製OPADRY II 85F18422等)、ポリビニルアルコール−ポリエチレングリコールグラフトコポリマー(BASF社製コリコートIR等)、ポリビニルアルコール−アクリル酸−メタクリル酸メチルコポリマー(大同化成工業社製POVACOAT(登録商標)等)であり、好適にはポリビニルアルコールである。本発明においては、これらを単独で用いることもできるし、又は2種以上を組み合わせて用いることもできる。医薬組成物中のポリビニルアルコール及び/又はビニルアルコール系共重合体の配合量は特に限定されるものではないが、好適には処方重量の1〜90重量%、より好適には5〜85重量%範囲内で配合することができる。ポリビニルアルコール及び/又はビニルアルコール系共重合体は、製剤全体に均一に含まれていてもよく、製剤の一部に含まれていてもよい。フィルムコーティング層を設ける場合には、フィルムコーティング層中に含まれていてもよい。 Examples of the “polyvinyl alcohol and / or vinyl alcohol copolymer” in the pharmaceutical composition of the present invention include, for example, polyvinyl alcohol (OPADRY II 85F18422 manufactured by Colorcon), polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat IR manufactured by BASF). Etc.), polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer (POVACOAT (registered trademark) manufactured by Daido Kasei Kogyo Co., Ltd.), and preferably polyvinyl alcohol. In the present invention, these can be used alone or in combination of two or more. The blending amount of polyvinyl alcohol and / or vinyl alcohol copolymer in the pharmaceutical composition is not particularly limited, but is preferably 1 to 90% by weight, more preferably 5 to 85% by weight of the formulation weight. It can mix | blend within the range. The polyvinyl alcohol and / or the vinyl alcohol copolymer may be uniformly contained in the whole preparation or may be contained in a part of the preparation. When providing a film coating layer, it may be contained in the film coating layer.
本発明の医薬組成物は、さらに必要に応じて、適宜の薬理学的に許容される賦形剤、滑沢剤、結合剤、崩壊剤、乳化剤、安定剤、矯味矯臭剤、希釈剤等の添加剤を含むことができる。 The pharmaceutical composition of the present invention further comprises, as necessary, appropriate pharmacologically acceptable excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, flavoring agents, diluents, and the like. Additives can be included.
使用される「賦形剤」としては、例えば、乳糖、白糖、葡萄糖、マンニトール若しくはソルビトールのような糖誘導体;トウモロコシデンプン、バレイショデンプン、α−澱粉若しくはデキストリンのような澱粉誘導体;結晶セルロースのようなセルロース誘導体;アラビアゴム;デキストラン;又はプルランのような有機系賦形剤;或いは、軽質無水珪酸、合成珪酸アルミニウム、珪酸カルシウム若しくはメタ珪酸アルミン酸マグネシウムのような珪酸塩誘導体;燐酸水素カルシウムのような燐酸塩;炭酸カルシウムのような炭酸塩;又は、硫酸カルシウムのような硫酸塩等の無機系賦形剤を挙げることができる。 “Excipients” used include, for example, sugar derivatives such as lactose, sucrose, sucrose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, α-starch or dextrin; Cellulose derivatives; gum arabic; dextran; or organic excipients such as pullulan; or silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate or magnesium metasilicate aluminate; such as calcium hydrogen phosphate An inorganic excipient such as phosphate; carbonate such as calcium carbonate; or sulfate such as calcium sulfate can be mentioned.
使用される「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若しくはステアリン酸マグネシウムのようなステアリン酸金属塩;タルク;コロイドシリカ;ビーズワックス若しくはゲイ蝋のようなワックス類;硼酸;アジピン酸;硫酸ナトリウムのような硫酸塩;グリコール;フマル酸;安息香酸ナトリウム;D,L−ロイシン;ラウリル硫酸ナトリウム若しくはラウリル硫酸マグネシウムのようなラウリル硫酸塩;無水珪酸若しくは珪酸水和物のような珪酸類;又は、上記澱粉誘導体を挙げることができる。 Examples of “lubricants” used include stearic acid; metal stearates such as calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as bead wax or gay wax; boric acid; adipic acid Sulfates such as sodium sulfate; glycols; fumaric acid; sodium benzoate; D, L-leucine; lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acids such as anhydrous silicic acid or silicic acid hydrates; Or the above starch derivatives.
使用される「結合剤」としては、例えば、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、ポリビニルピロリドン、マクロゴール、又は、前記賦形剤と同様の化合物を挙げることができる。 Examples of the “binder” used include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, or the same compound as the excipient.
使用される「崩壊剤」としては、例えば、低置換度ヒドロキシプロピルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム若しくは内部架橋カルボキシメチルセルロースナトリウムのようなセルロース誘導体;架橋ポリビニルピロリドン;又は、カルボキシメチルスターチ若しくはカルボキシメチルスターチナトリウムのような化学修飾されたデンプン・セルロース類を挙げることができる。 “Disintegrants” used include, for example, cellulose derivatives such as low substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium or sodium carboxymethylcellulose; crosslinked polyvinylpyrrolidone; or carboxymethyl starch or carboxymethyl starch Mention may be made of starch and cellulose modified chemically such as sodium.
使用される「乳化剤」としては、例えば、ベントナイト若しくはビーガムのようなコロイド性粘土;水酸化マグネシウム若しくは水酸化アルミニウムのような金属水酸化物;ラウリル硫酸ナトリウム若しくはステアリン酸カルシウムのような陰イオン界面活性剤;塩化ベンザルコニウムのような陽イオン界面活性剤;又は、ポリオキシエチレンアルキルエーテル、ポリオキシエチレンソルビタン脂肪酸エステル若しくはショ糖脂肪酸エステルのような非イオン界面活性剤を挙げることができる。 “Emulsifiers” used include, for example, colloidal clays such as bentonite or bee gum; metal hydroxides such as magnesium hydroxide or aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate A cationic surfactant such as benzalkonium chloride; or a nonionic surfactant such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester or sucrose fatty acid ester.
使用される「安定剤」としては、例えば、メチルパラベン若しくはプロピルパラベンのようなパラヒドロキシ安息香酸エステル類;クロロブタノール、ベンジルアルコール若しくはフェニルエチルアルコールのようなアルコール類;塩化ベンザルコニウム;フェノール若しくはクレゾールのようなフェノール類;チメロサール;デヒドロ酢酸;又は、ソルビン酸を挙げることができる。 “Stabilizers” used include, for example, parahydroxybenzoates such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenol or cresol Such phenols; thimerosal; dehydroacetic acid; or sorbic acid.
使用される「矯味矯臭剤」としては、例えば、サッカリンナトリウム若しくはアスパルテームのような甘味料;クエン酸、リンゴ酸若しくは酒石酸のような酸味料;又は、メントール、レモン若しくはオレンジのような香料を挙げることができる。 Examples of the “flavoring agent” used include sweeteners such as sodium saccharin or aspartame; acidifiers such as citric acid, malic acid or tartaric acid; or flavors such as menthol, lemon or orange. it can.
使用される「希釈剤」としては、例えば、ラクトース、マンニトール、グルコース、スクロース、硫酸カルシウム、リン酸カルシウム、ヒドロキシプロピルセルロース、微結晶性セルロース、水、エタノール、ポリエチレングリコール、プロピレングリコール、グリセロール、デンプン、ポリビニルピロリドン、メタケイ酸アルミン酸マグネシウム又はこれらの混合物を挙げることができる。 Examples of the “diluent” used include lactose, mannitol, glucose, sucrose, calcium sulfate, calcium phosphate, hydroxypropyl cellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, starch, and polyvinylpyrrolidone. And magnesium aluminate metasilicate or mixtures thereof.
本発明における医薬組成物は、(A)オルメサルタンメドキソミル、(B)アゼルニジピン及び(C)ポリビニルアルコール及び/又はビニルアルコール系共重合体とが別々の製剤となっていてもよく、均一に混合された配合剤(単一製剤)であってもよい。好適には配合剤である。 In the pharmaceutical composition of the present invention, (A) olmesartan medoxomil, (B) azelnidipine, and (C) polyvinyl alcohol and / or a vinyl alcohol copolymer may be in separate preparations and mixed uniformly. A compounding agent (single preparation) may be used. A compounding agent is preferred.
本発明における医薬組成物は固形製剤であることが好ましく、例えば、錠剤(舌下錠、口腔内崩壊錠を含む)、カプセル剤(ソフトカプセル、マイクロカプセルを含む)、顆粒剤、細粒剤、散剤、丸剤、チュワブル剤、トローチ剤等を挙げることができ、好適には散剤、細粒剤、顆粒剤、カプセル剤又は錠剤であり、より好適には錠剤であり、さらに好適には(A)、(B)及び(C)が別々の層に配合された多層錠である。 The pharmaceutical composition in the present invention is preferably a solid preparation. For example, tablets (including sublingual tablets and orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, fine granules, and powders Pills, chewables, troches and the like, preferably powders, fine granules, granules, capsules or tablets, more preferably tablets, and even more preferably (A). , (B) and (C) are multi-layer tablets formulated in separate layers.
本発明における製剤の製造方法としては、Powder Technology and Pharmaceutical Processes (D. Chulia他, Elsevier Science Pub Co (December 1, 1993))のような刊行物に記載されている一般的な方法を用いて製造すればよく、特別な制限は設けない。 As a method for producing the preparation in the present invention, a general method described in a publication such as Powder Technology and Pharmaceutical Processes (D. Chulia et al., Elsevier Science Pub Co (December 1, 1993)) is used. There are no special restrictions.
本発明の錠剤は、例えば、それ自体公知の方法で主薬を賦形剤、結合剤等とともに造粒、乾燥、整粒し、滑沢剤等を加えて混合し、製錠することにより錠剤を得る。ここで、造粒は、湿式造粒法、乾式造粒法あるいは加熱造粒法のいずれの方法によっても行うことができ、具体的には、高速攪拌造粒機、流動造粒乾燥機、押し出し造粒機、ローラーコンパクターなどを用いて行われる。また、造粒の後、必要により乾燥、整粒などの操作を行ってもよい。主薬と賦形剤、結合剤、滑沢剤等の混合物を直接打錠することもできる。また、本発明の錠剤には少なくとも1層のフィルムコーティングを設けてもよい。 The tablet of the present invention is prepared by, for example, granulating, drying, and sizing the active ingredient together with excipients, binders, etc. by a method known per se, adding a lubricant, etc., mixing, and tableting. obtain. Here, the granulation can be carried out by any of wet granulation, dry granulation, and heat granulation methods. Specifically, a high-speed agitation granulator, a fluidized granulator / dryer, an extrusion It is performed using a granulator, a roller compactor, etc. In addition, after granulation, operations such as drying and sizing may be performed as necessary. A mixture of the active ingredient and excipient, binder, lubricant, etc. can also be directly compressed. The tablet of the present invention may be provided with at least one film coating.
コーティングは、例えば、フィルムコーティング装置を用いて行われ、フィルムコーティング基剤としては、例えば、糖衣基剤、水溶性フィルムコーティング基剤、腸溶性フィルムコーティング基剤、徐放性フィルムコーティング基剤などが挙げられる。 Coating is performed using, for example, a film coating apparatus, and examples of the film coating base include sugar coating base, water-soluble film coating base, enteric film coating base, sustained-release film coating base, and the like. Can be mentioned.
糖衣基剤としては、白糖が用いられ、さらに、タルク、沈降炭酸カルシウム、リン酸カルシウム、硫酸カルシウム、ゼラチン、アラビアゴム、ポリビニルピロリドン、プルラン、などから選ばれる1種または2種以上を組み合わせて用いることもできる。 As the sugar coating base, sucrose is used, and one or more kinds selected from talc, precipitated calcium carbonate, calcium phosphate, calcium sulfate, gelatin, gum arabic, polyvinylpyrrolidone, pullulan and the like may be used in combination. it can.
水溶性フィルムコーティング基剤としては、例えば、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、メチルヒドロキシエチルセルロース、カルボキシメチルセルロースナトリウムなどのセルロース誘導体;ポリビニルアセタールジエチルアミノアセテート、アミノアルキルメタクリレートコポリマー、ポリビニルピロリドンなどの合成高分子;プルランなどの多糖類などが挙げられる。 Examples of water-soluble film coating bases include cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, sodium carboxymethylcellulose; synthetic polymers such as polyvinylacetal diethylaminoacetate, aminoalkylmethacrylate copolymer, and polyvinylpyrrolidone. Molecule: polysaccharides such as pullulan.
腸溶性フィルムコーティング基剤としては、例えば、ヒドロキシプロピルメチルセルロースフタレート、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、カルボキシメチルエチルセルロース、酢酸フタル酸セルロースなどのセルロース誘導体;メタアクリル酸コポリマーL、メタアクリル酸コポリマーLD、メタアクリル酸コポリマーSなどのアクリル酸誘導体;セラックなどの天然物などが挙げられる。 Examples of enteric film coating bases include cellulose derivatives such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic Acrylic acid derivatives such as acid copolymer S; natural products such as shellac.
徐放性フィルムコーティング基剤としては、例えば、エチルセルロースなどのセルロース誘導体;アミノアルキルメタクリレートコポリマーRS、アクリル酸エチル・メタクリル酸メチル・共重合体乳濁液などのアクリル酸誘導体などが挙げられる。 Examples of the sustained-release film coating base include cellulose derivatives such as ethyl cellulose; acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS, ethyl acrylate / methyl methacrylate / copolymer emulsion, and the like.
上記コーティング基剤は、その2種以上を適宜の割合で混合して用いてもよい。また、さらに必要に応じて、適宜の薬理学的に許容される可塑剤、賦形剤、滑沢剤、隠蔽剤、着色剤、防腐剤等の添加剤を含むことができる。 Two or more kinds of the coating bases may be mixed and used at an appropriate ratio. Further, if necessary, additives such as appropriate pharmacologically acceptable plasticizers, excipients, lubricants, masking agents, coloring agents, preservatives and the like can be contained.
本発明の医薬組成物の溶出性は、日局一般試験法の溶出試験法第2法(パドル法)に従い、測定される。例えば、パドル回転数は毎分75回転、試験液として日局第2液(JP‐2、pH6.8)900mLを用い、試験開始から30分後の試験液を採取し、0.45μm孔径のメンブランフィルターを用いて濾過し、濾液を高速液体クロマトグラフィーを用いて定量することにより、オルメサルタンメドキソミルの溶出率を算出することができる。 The dissolution property of the pharmaceutical composition of the present invention is measured according to the second dissolution test method (paddle method) of the JP General Test Method. For example, the paddle rotation speed is 75 rotations per minute, 900 mL of JP II second liquid (JP-2, pH 6.8) is used as the test liquid, and the test liquid is collected 30 minutes after the start of the test, and has a pore diameter of 0.45 μm. The elution rate of olmesartan medoxomil can be calculated by filtering using a membrane filter and quantifying the filtrate using high performance liquid chromatography.
本発明の医薬組成物の有効成分であるオルメサルタンメドキソミルとアゼルニジピンの投与量と投与比率は、個々の薬剤の活性、患者の症状、年齢、体重等の種々の条件により変化し得る。その投与量は症状、年齢等により異なるが、経口投与の場合には、成人一日あたりオルメサルタンメドキソミル5mg−80mg(好適には10mg−40mg)、アゼルニジピン8mg−32mg(好適には8mg−16mg)を一日1乃至6回(好適には一日1回)症状に応じて投与することができる。 The dosage and administration ratio of olmesartan medoxomil and azelnidipine, which are the active ingredients of the pharmaceutical composition of the present invention, can vary depending on various conditions such as the activity of individual drugs, patient symptoms, age, body weight and the like. The dose varies depending on symptoms, age, etc., but in the case of oral administration, olmesartan medoxomil 5 mg-80 mg (preferably 10 mg-40 mg), azelnidipine 8 mg-32 mg (preferably 8 mg-16 mg) per day for adults. It can be administered 1 to 6 times a day (preferably once a day) according to symptoms.
また、本発明の医薬組成物の有効成分であるオルメサルタンメドキソミルとアゼルニジピンの投与量の比率も、また、大幅に変わりうるが、例えばオルメサルタンメドキソミルとアゼルニジピンの投与量比率は、重量比で、1:50乃至50:1の範囲内であり得、好適には、1:5乃至5:1 である。最も好適な形態としては、オルメサルタンメドキソミル/アゼルニジピンを20mg/16mg又は10mg/8mg含有する錠剤である。 In addition, the dose ratio of olmesartan medoxomil and azelnidipine, which are the active ingredients of the pharmaceutical composition of the present invention, can also vary greatly. For example, the dose ratio of olmesartan medoxomil and azelnidipine is 1:50 by weight. Up to 50: 1, and preferably 1: 5 to 5: 1. The most preferred form is a tablet containing 20 mg / 16 mg or 10 mg / 8 mg of olmesartan medoxomil / azelnidipine.
本発明の医薬組成物は、例えば、高血圧症又は高血圧症に由来する疾患(より具体的には、高血圧症、心臓疾患[狭心症、心筋梗塞、不整脈、心不全若しくは心肥大]、腎臓疾患[糖尿病性腎症、糸球体腎炎若しくは腎硬化症]又は脳血管性疾患[脳梗塞若しくは脳出血])等の予防又は治療に有効である。 The pharmaceutical composition of the present invention includes, for example, hypertension or a disease derived from hypertension (more specifically, hypertension, heart disease [angina, myocardial infarction, arrhythmia, heart failure or cardiac hypertrophy], kidney disease [ It is effective for the prevention or treatment of diabetic nephropathy, glomerulonephritis or nephrosclerosis] or cerebrovascular disease [cerebral infarction or cerebral hemorrhage]).
以下、実施例等により本発明をさらに詳細に説明するが、本発明はこれに限定されるものではない。
(実施例1)
以下の表1に示す成分とそれらの量を用いて、混合顆粒1を作製した。オルメサルタンメドキソミル、低置換度ヒドロキシプロピルセルロース、ヒドロキシプロピルセルロース、乳糖を高速撹拌造粒機(VG-10、パウレック、約2kgスケール)を用いて5分間混合した後、精製水を注加し3分間撹拌し、造粒した。得られた造粒物をスクリーニングミル(フィオーレミニ、徳寿工作所、φ10mm角の目開き篩装着)を用いて製顆し、入風温度90℃の流動層乾燥機(Glatt WST-5、パウレック)にて乾燥させた後、スクリーニングミル(コーミル 197S、パウレック、φ1.143mmのメッシュ装着)にて整粒し、顆粒1を得た。顆粒1、結晶セルロースおよびステアリン酸マグネシウムを表1に示す割合にて秤量し、V型混合機を用いて混合して混合顆粒1を得た。EXAMPLES Hereinafter, although an Example etc. demonstrate this invention further in detail, this invention is not limited to this.
Example 1
A mixed granule 1 was prepared using the components shown in Table 1 below and their amounts. Olmesartan medoxomil, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, and lactose were mixed for 5 minutes using a high-speed agitation granulator (VG-10, Paulek, approximately 2 kg scale), then purified water was added and the mixture was stirred for 3 minutes. And granulated. The resulting granulated product is made into a condyle using a screening mill (Fiore mini, Deoksugaku Kosakusho, φ10mm square sieve sieve), and a fluidized bed dryer (Glatt WST-5, Paulek) with an inlet temperature of 90 ° C. And dried with a screening mill (Comil 197S, Paulek, equipped with a mesh of φ1.143 mm), and granules 1 were obtained. Granule 1, crystalline cellulose, and magnesium stearate were weighed in the proportions shown in Table 1, and mixed using a V-type mixer to obtain mixed granule 1.
次に、以下の表2に示す成分とそれらの量を用いて、混合顆粒2を作製した。アゼルニジピンとD−マンニトールを各々1:1(重量比)秤量し、高速撹拌造粒機(ヘンシェルミキサーFM-20、三井三池製作所)を用いて5分間混合後、混合物をハンマーミル(サンプルミル K II WG-1、不二パウダル)にて粉砕した。また、メタケイ酸アルミン酸マグネシウム、軽質無水ケイ酸を高速撹拌造粒機(ヘンシェルミキサー FM20、三井三池製作所)を用いて混合した後、この混合物にポリソルベート80を注加し、ポリソルベート80吸着末を得た。得られたアゼルニジピン粉砕品、ポリソルベート80吸着末、D−マンニトール、カルメロースカルシウム、低置換度ヒドロキシプロピルセルロース、炭酸水素ナトリウム、軽質無水ケイ酸を高速撹拌造粒機(VG-10、パウレック、約2kgスケール)にて混合し、ヒドロキシプロピルセルロースの水溶液(固形分濃度6.5%)を加え高速撹拌造粒機(VG-10、パウレック)にて7.5分間造粒を行った。得られた練合物をスクリーニングミル(トーネードミル、F.J. Stokes Corp.、φ10mm角の目開き篩装着)を用いて製顆し、入風温度90℃の流動層乾燥機(Glatt WST-5、パウレック)にて乾燥させた後、スクリーニングミル(トーネードミル、F.J. Stokes Corp.、φ1.143mmのメッシュ装着)にて顆粒を整粒し、顆粒2を得た。顆粒2、メタケイ酸アルミン酸マグネシウム、軽質無水ケイ酸、タルク、ステアリン酸マグネシウムを表2に示す割合にて秤量し、V型混合機(徳寿工作所)を用いて混合することにより混合顆粒2を得た。 Next, the mixed granule 2 was produced using the components and their amounts shown in Table 2 below. Azelnidipine and D-mannitol were weighed 1: 1 (weight ratio), mixed for 5 minutes using a high-speed stirring granulator (Henschel mixer FM-20, Mitsui Miike Seisakusho), and the mixture was then hammer milled (sample mill K II). WG-1, Fuji powder). Moreover, after mixing magnesium aluminate metasilicate and light anhydrous silicic acid using a high-speed agitation granulator (Henschel mixer FM20, Mitsui Miike Seisakusho Co., Ltd.), polysorbate 80 is added to this mixture to obtain a polysorbate 80 adsorption powder. It was. The obtained azelnidipine pulverized product, polysorbate 80 adsorbed powder, D-mannitol, carmellose calcium, low-substituted hydroxypropylcellulose, sodium hydrogen carbonate, light anhydrous silicic acid, high speed stirring granulator (VG-10, Paulek, about 2 kg) (Scale), an aqueous solution of hydroxypropyl cellulose (solid content concentration 6.5%) was added, and granulation was performed for 7.5 minutes with a high-speed agitation granulator (VG-10, Paulek). The resulting kneaded product was made into a condyle using a screening mill (tornado mill, FJ Stokes Corp., equipped with a φ10 mm square mesh sieve), and a fluidized bed dryer (Glatt WST-5, Paulek, with an inlet temperature of 90 ° C). ), And the granules were sized using a screening mill (tornado mill, FJ Stokes Corp., φ1.143 mm mesh) to obtain granules 2. Granule 2, magnesium aluminate metasilicate, light anhydrous silicic acid, talc, magnesium stearate are weighed in the proportions shown in Table 2 and mixed using a V-type mixer (Tokuju Kogakusho). Obtained.
次に表3に示す処方にて、乳糖(造粒粉末)、ステアリン酸マグネシウムを秤量し、V型混合機(徳寿工作所)にて10分間混合することにより混合顆粒3を得た。 Next, with the formulation shown in Table 3, lactose (granulated powder) and magnesium stearate were weighed and mixed for 10 minutes with a V-type mixer (Tokuju Kogakusho) to obtain mixed granules 3.
次に、混合顆粒2を1層目に260mg、混合顆粒3を2層目に100mg、混合顆粒1を3層目に120mgとなるよう充填調整し、ロータリー打錠機にて長径15mm、短径7.3mmの異型杵を用いて、2.5トンの圧縮圧で成形打錠した。 Next, the mixed granule 2 was adjusted to be filled with 260 mg in the first layer, the mixed granule 3 with 100 mg in the second layer, and the mixed granule 1 with 120 mg in the third layer. Using a 7.3 mm variant punch, the tablet was molded with a compression pressure of 2.5 tons.
得られた錠剤にPVAを含むコーティング基剤であるOPADRY II 85F18422(カラコン社製)をコーティングし(パンコーティング機(パウレック)を使用)、フィルムコート錠1を得た。 The obtained tablets were coated with OPADRY II 85F18422 (Colorcon Co., Ltd.), which is a coating base containing PVA (using a pan coating machine (Paurec)), and film-coated tablets 1 were obtained.
得られたフィルムコート錠の溶出性(30分後のオルメサルタンメドキソミル溶出率)を評価した。結果を表4に示す。
(比較例1)
実施例1に示した製法にて得られた錠剤(素錠)の溶出性(30分後のオルメサルタンメドキソミル溶出率)を評価した。結果を表4に示す。
(比較例2)
実施例1に示した製法にて得られた錠剤にHPMCを含むOPADRY II 33K28628(カラコン社製)でフィルムコートを施し、フィルムコート錠2を得た。得られたフィルムコート錠の溶出性(30分後のオルメサルタンメドキソミル溶出率)を評価した。結果を表4に示す。The dissolution property (olmesartan medoxomil dissolution rate after 30 minutes) of the obtained film-coated tablet was evaluated. The results are shown in Table 4.
(Comparative Example 1)
The dissolution properties (dissolution rate of olmesartan medoxomil after 30 minutes) of the tablets (plain tablets) obtained by the production method shown in Example 1 were evaluated. The results are shown in Table 4.
(Comparative Example 2)
The tablets obtained by the production method shown in Example 1 were subjected to film coating with OPADRY II 33K28628 (manufactured by Colorcon) containing HPMC to obtain film-coated tablets 2. The dissolution property (olmesartan medoxomil dissolution rate after 30 minutes) of the obtained film-coated tablet was evaluated. The results are shown in Table 4.
(実施例2)
表3に示す処方にて、結晶セルロース・軽質無水珪酸 スプレードライ品、ステアリン酸マグネシウムを秤量し、V型混合機(徳寿工作所)にて10分間混合することにより混合顆粒4を得た。
(Example 2)
In the formulation shown in Table 3, crystalline cellulose / light anhydrous silicic acid spray-dried product and magnesium stearate were weighed and mixed for 10 minutes with a V-type mixer (Tokuju Kogakusho) to obtain mixed granules 4.
実施例1で示した混合顆粒2を1層目に260mg、混合顆粒4を2層目に100mg、混合顆粒1を3層目に120mgとなるよう充填調整し、ロータリー打錠機にて長径15mm、短径7.3mmの異型杵を用いて、2.5トンの圧縮圧で成形打錠した。得られた錠剤にPVAを含むコーティング基剤であるOPADRY II 85F18422をコーティングし(パンコーティング機(パウレック)を使用)、フィルムコート錠3を得た。 The mixed granule 2 shown in Example 1 was adjusted to 260 mg in the first layer, the mixed granule 4 to 100 mg in the second layer, and the mixed granule 1 to 120 mg in the third layer, and the major axis was 15 mm with a rotary tableting machine. The tablet was molded and compressed with a compression pressure of 2.5 tons using a variant punch with a minor axis of 7.3 mm. The resulting tablet was coated with OPADRY II 85F18422 which is a coating base containing PVA (using a pan coating machine (Paurec)) to obtain film-coated tablet 3.
得られたフィルムコート錠の溶出性(30分後のオルメサルタンメドキソミル溶出率)を評価した。結果を表4に示す。 The dissolution property (olmesartan medoxomil dissolution rate after 30 minutes) of the obtained film-coated tablet was evaluated. The results are shown in Table 4.
(比較例3)
実施例2に示した製法にて得られた錠剤(素錠)の溶出性(30分後のオルメサルタンメドキソミル溶出率)を評価した。結果を表4に示す。
(比較例4)
実施例2に示した製法にて得られた錠剤にHPMCを含むOPADRY II 33K28628でフィルムコートを施し、フィルムコート錠4を得た。得られたフィルムコート錠の溶出性(30分後のオルメサルタンメドキソミル溶出率)を評価した。結果を表4に示す。
(実施例3)
表3に示す処方にて、乳糖(造粒粉末)、低置換度ヒドロキシプロピルセルロース、ヒドロキシプロピルセルロース、結晶セルロース、ステアリン酸マグネシウムを秤量し、V型混合機(徳寿工作所)にて10分間混合することにより混合顆粒5を得た。
(Comparative Example 3)
The dissolution properties (dissolution rate of olmesartan medoxomil after 30 minutes) of the tablets (plain tablets) obtained by the production method shown in Example 2 were evaluated. The results are shown in Table 4.
(Comparative Example 4)
The tablets obtained by the production method shown in Example 2 were film-coated with OPADRY II 33K28628 containing HPMC to obtain film-coated tablets 4. The dissolution property (olmesartan medoxomil dissolution rate after 30 minutes) of the obtained film-coated tablet was evaluated. The results are shown in Table 4.
(Example 3)
Lactose (granulated powder), low-substituted hydroxypropylcellulose, hydroxypropylcellulose, crystalline cellulose, and magnesium stearate are weighed according to the formulation shown in Table 3 and mixed for 10 minutes with a V-type mixer (Tokuju Kosakusho). As a result, a mixed granule 5 was obtained.
実施例1で示した混合顆粒2を1層目に260mg、混合顆粒5を2層目に100mg、混合顆粒1を3層目に120mgとなるよう充填調整し、ロータリー打錠機にて長径15mm、短径7.3mmの異型杵を用いて、2.5トンの圧縮圧で成形打錠した。得られた錠剤にPVAを含むコーティング基剤であるOPADRY II 85F18422をコーティングし(パンコーティング機(パウレック)を使用)、フィルムコート錠5を得た。 The mixed granule 2 shown in Example 1 was adjusted to be 260 mg in the first layer, the mixed granule 5 was 100 mg in the second layer, and the mixed granule 1 was 120 mg in the third layer, and the major axis was 15 mm with a rotary tableting machine. The tablet was molded and compressed with a compression pressure of 2.5 tons using a variant punch with a minor axis of 7.3 mm. The obtained tablets were coated with OPADRY II 85F18422, which is a coating base containing PVA (using a pan coating machine (Paurec)), and film-coated tablets 5 were obtained.
得られたフィルムコート錠の溶出性(30分後のオルメサルタンメドキソミル溶出率)を評価した。結果を表4に示す。 The dissolution property (olmesartan medoxomil dissolution rate after 30 minutes) of the obtained film-coated tablet was evaluated. The results are shown in Table 4.
(比較例5)
実施例3に示した製法にて得られた錠剤(素錠)の溶出性(30分後のオルメサルタンメドキソミル溶出率)を評価した。結果を表4に示す。
(比較例6)
実施例3に示した製法にて得られた錠剤にHPMCを含むOPADRY II 33K28628でフィルムコートを施し、フィルムコート錠6を得た。得られたフィルムコート錠の溶出性(30分後のオルメサルタンメドキソミル溶出率)を評価した。結果を表4に示す。
(実施例4)
表3に示す処方にて、乳糖(造粒粉末)、結晶セルロース・軽質無水珪酸 スプレードライ品、ステアリン酸マグネシウムを秤量し、V型混合機(徳寿工作所)にて10分間混合することにより混合顆粒6を得た。
(Comparative Example 5)
The dissolution properties (dissolution rate of olmesartan medoxomil after 30 minutes) of the tablets (plain tablets) obtained by the production method shown in Example 3 were evaluated. The results are shown in Table 4.
(Comparative Example 6)
The film obtained by the production method shown in Example 3 was film-coated with OPADRY II 33K28628 containing HPMC to obtain film-coated tablet 6. The dissolution property (olmesartan medoxomil dissolution rate after 30 minutes) of the obtained film-coated tablet was evaluated. The results are shown in Table 4.
Example 4
In the formulation shown in Table 3, weigh lactose (granulated powder), crystalline cellulose, light anhydrous silicic acid spray-dried product, and magnesium stearate, and mix by mixing for 10 minutes with a V-type mixer (Tokuju Kosakusho). Granule 6 was obtained.
実施例1で示した混合顆粒2を1層目に260mg、混合顆粒6を2層目に100mg、混合顆粒1を3層目に120mgとなるよう充填調整し、ロータリー打錠機にて長径15mm、短径7.3mmの異型杵を用いて、2.5トンの圧縮圧で成形打錠した。得られた錠剤にPVAを含むコーティング基剤であるOPADRY II 85F18422をコーティングし(パンコーティング機(パウレック)を使用)、フィルムコート錠7を得た。 The mixed granule 2 shown in Example 1 was adjusted to 260 mg in the first layer, the mixed granule 6 to 100 mg in the second layer, and the mixed granule 1 to 120 mg in the third layer, and the major axis was 15 mm with a rotary tableting machine. The tablet was molded and compressed with a compression pressure of 2.5 tons using a variant punch with a minor axis of 7.3 mm. The obtained tablet was coated with OPADRY II 85F18422 which is a coating base containing PVA (using a pan coating machine (Paurec)) to obtain film-coated tablet 7.
得られたフィルムコート錠の溶出性(30分後のオルメサルタンメドキソミル溶出率)を評価した。結果を表4に示す。 The dissolution property (olmesartan medoxomil dissolution rate after 30 minutes) of the obtained film-coated tablet was evaluated. The results are shown in Table 4.
(比較例7)
実施例4に示した製法にて得られた錠剤(素錠)の溶出性(30分後のオルメサルタンメドキソミル溶出率)を評価した。結果を表4に示す。
(比較例8)
実施例4に示した製法にて得られた錠剤にHPMCを含むOPADRY II 33K28628でフィルムコートを施し、フィルムコート錠8を得た。得られたフィルムコート錠の溶出性(30分後のオルメサルタンメドキソミル溶出率)を評価した。結果を表4に示す。
(実施例5)
表3に示す処方にて、乳糖(造粒粉末)、結晶セルロース・軽質無水珪酸 スプレードライ品、メタ珪酸アルミン酸マグネシウム、軽質無水珪酸、ステアリン酸マグネシウムを秤量し、V型混合機(徳寿工作所)にて10分間混合することにより混合顆粒7を得た。
(Comparative Example 7)
The dissolution properties (dissolution rate of olmesartan medoxomil after 30 minutes) of the tablets (plain tablets) obtained by the production method shown in Example 4 were evaluated. The results are shown in Table 4.
(Comparative Example 8)
The film obtained by the production method shown in Example 4 was film-coated with OPADRY II 33K28628 containing HPMC to obtain film-coated tablet 8. The dissolution property (olmesartan medoxomil dissolution rate after 30 minutes) of the obtained film-coated tablet was evaluated. The results are shown in Table 4.
(Example 5)
Lactose (granulated powder), crystalline cellulose / lightly anhydrous silicic acid spray-dried product, magnesium metasilicate aluminate, lightly anhydrous silicic acid, magnesium stearate were weighed according to the formulation shown in Table 3, and a V-type mixer (Tokuju Works) The mixed granule 7 was obtained by mixing for 10 minutes.
実施例1で示した混合顆粒2を1層目に260mg、混合顆粒7を2層目に100mg、混合顆粒1を3層目に120mgとなるよう充填調整し、ロータリー打錠機にて長径15mm、短径7.3mmの異型杵を用いて、2.5トンの圧縮圧で成形打錠した。得られた錠剤にPVAを含むコーティング基剤であるOPADRY II 85F18422をコーティングし(パンコーティング機(パウレック)を使用)、フィルムコート錠9を得た。 The mixed granule 2 shown in Example 1 was adjusted to be 260 mg in the first layer, the mixed granule 7 was 100 mg in the second layer, and the mixed granule 1 was 120 mg in the third layer, and the major axis was 15 mm with a rotary tableting machine. The tablet was molded and compressed with a compression pressure of 2.5 tons using a variant punch with a minor axis of 7.3 mm. The obtained tablet was coated with OPADRY II 85F18422, which is a coating base containing PVA (using a pan coating machine (Paurec)), and film-coated tablets 9 were obtained.
得られたフィルムコート錠の溶出性(30分後のオルメサルタンメドキソミル溶出率)を評価した。結果を表4に示す。 The dissolution property (olmesartan medoxomil dissolution rate after 30 minutes) of the obtained film-coated tablet was evaluated. The results are shown in Table 4.
(比較例9)
実施例5に示した製法にて得られた錠剤(素錠)の溶出性(30分後のオルメサルタンメドキソミル溶出率)を評価した。結果を表4に示す。
(比較例10)
実施例5に示した製法にて得られた錠剤にHPMCを含むOPADRY II 33K28628でフィルムコートを施し、フィルムコート錠10を得た。得られたフィルムコート錠の溶出性(30分後のオルメサルタンメドキソミル溶出率)を評価した。結果を表4に示す。
(実施例6)
市販されているオルメテック錠20mg、およびカルブロック錠16mgを1つのベッセル内に投入し、オルメサルタンメドキソミルの溶出性を評価した。この溶出性の評価は、日本薬局方第14改正の項に記載されている溶出試験法第2法(パドル法)に従い、毎分75回転、試験液としてポリビニルアルコールを100mg予め溶解または懸濁させた日局第2液(JP-2)900mLを用いた。試験開始から30分後の試験液を採取し、0.45μm孔径のメンブランフィルターを用いて濾過、濾液を高速液体クロマトグラフィーを用いて定量し、オルメサルタンメドキソミルの溶出率を算出した(Varian:溶出試験器、Agilent technoloies:高速液体クロマトグラフィー)。結果を表5に示す。
(Comparative Example 9)
The dissolution properties (dissolution rate of olmesartan medoxomil after 30 minutes) of the tablets (plain tablets) obtained by the production method shown in Example 5 were evaluated. The results are shown in Table 4.
(Comparative Example 10)
The film obtained by the production method shown in Example 5 was film-coated with OPADRY II 33K28628 containing HPMC to obtain film-coated tablet 10. The dissolution property (olmesartan medoxomil dissolution rate after 30 minutes) of the obtained film-coated tablet was evaluated. The results are shown in Table 4.
(Example 6)
Commercially available Olmetec tablets (20 mg) and Calblock tablets (16 mg) were placed in one vessel, and the dissolution properties of olmesartan medoxomil were evaluated. This dissolution evaluation was performed by dissolving or suspending 100 mg of polyvinyl alcohol in advance as a test solution at 75 revolutions per minute in accordance with the second dissolution test method (paddle method) described in the 14th revision of the Japanese Pharmacopoeia. JP2 (JP-2) 900 mL was used. A test solution 30 minutes after the start of the test was collected, filtered using a membrane filter having a pore size of 0.45 μm, the filtrate was quantified using high performance liquid chromatography, and the dissolution rate of olmesartan medoxomil was calculated (Varian: dissolution test). Instrument, Agilent technoloies: high performance liquid chromatography). The results are shown in Table 5.
(比較例11)
実施例6と同様、市販されているオルメテック錠20mg、およびカルブロック錠16mgを1つのベッセル内に投入し、オルメサルタンメドキソミルの溶出性を評価した。但し、試験液には、日局第2液(JP-2)900mLを用いた。結果を表5に示す。
(試験例)
日本薬局方第14改正の項に記載されている溶出試験法第2法(パドル法)に従い、毎分75回転、試験液として日局第2液(JP-2)900mLを用い、試験を行った。試験開始から30分後の試験液を採取し、0.45μm孔径のメンブランフィルターを用いて濾過し、濾液を高速液体クロマトグラフィーを用いて定量し、オルメサルタンメドキソミルの溶出率を算出した(Varian:溶出試験器、Agilent technoloies:高速液体クロマトグラフィー)。
(Comparative Example 11)
In the same manner as in Example 6, 20 mg of commercially available Olmetec tablet and 16 mg of Calblock tablet were placed in one vessel, and the dissolution property of olmesartan medoxomil was evaluated. However, 900 mL of JP 2nd liquid (JP-2) was used for the test liquid. The results are shown in Table 5.
(Test example)
In accordance with dissolution test method method 2 (paddle method) described in the 14th revision of the Japanese Pharmacopoeia, the test was conducted using 75 mL / min and 900 mL of JP2 solution (JP-2) as the test solution. It was. A test solution 30 minutes after the start of the test was collected and filtered using a membrane filter having a pore size of 0.45 μm, and the filtrate was quantified using high performance liquid chromatography to calculate the dissolution rate of olmesartan medoxomil (Varian: elution). Tester, Agilent technoloies: high performance liquid chromatography).
試験は3錠について行い、その平均値を示す。
The test is performed on 3 tablets, and the average value is shown.
表4、表5より、本発明の医薬組成物は、オルメサルタンメドキソミルの溶出性を改善している。
From Table 4 and Table 5, the pharmaceutical composition of this invention has improved the dissolution property of olmesartan medoxomil.
本発明によれば、(A)オルメサルタンメドキソミル、(B)アゼルニジピン及び(C)ポリビニルアルコール又はビニルアルコール系共重合体を含有する、溶出性の改善された医薬組成物が得られる。
ADVANTAGE OF THE INVENTION According to this invention, the pharmaceutical composition with improved elution property containing (A) olmesartan medoxomil, (B) azelnidipine, and (C) polyvinyl alcohol or a vinyl alcohol-type copolymer is obtained.
Claims (11)
(B)アゼルニジピン;及び
(C)ポリビニルアルコール及びビニルアルコール系共重合体から選択される化合物の
1種又は2種以上を含有する医薬組成物。(A) Olmesartan medoxomil;
(B) Azelnidipine; and (C) A pharmaceutical composition containing one or more compounds selected from polyvinyl alcohol and vinyl alcohol copolymers.
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KR101148884B1 (en) * | 2010-02-01 | 2012-05-29 | 동성제약주식회사 | Composition for prevention or treatment hypertension comprising olmesartan medoxomil with an increased dissolution rate |
JP5421945B2 (en) * | 2010-03-10 | 2014-02-19 | 大日本住友製薬株式会社 | Pharmaceutical composition containing irbesartan and amlodipine or a salt thereof |
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WO2002034263A1 (en) * | 2000-10-25 | 2002-05-02 | Takeda Chemical Industries, Ltd. | Preventives/remedies for portal hypertension |
WO2004067003A1 (en) * | 2003-01-31 | 2004-08-12 | Sankyo Company, Limited | Medicine for prevention of and treatment for arteriosclerosis and hypertension |
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JP5063370B2 (en) * | 2005-06-27 | 2012-10-31 | 第一三共株式会社 | Method for preparing wet granulated pharmaceutical |
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WO2002034263A1 (en) * | 2000-10-25 | 2002-05-02 | Takeda Chemical Industries, Ltd. | Preventives/remedies for portal hypertension |
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