JP2023184497A - Pharmaceutical compositions and methods for improving elution properties - Google Patents
Pharmaceutical compositions and methods for improving elution properties Download PDFInfo
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- JP2023184497A JP2023184497A JP2023098965A JP2023098965A JP2023184497A JP 2023184497 A JP2023184497 A JP 2023184497A JP 2023098965 A JP2023098965 A JP 2023098965A JP 2023098965 A JP2023098965 A JP 2023098965A JP 2023184497 A JP2023184497 A JP 2023184497A
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- acid
- pharmaceutical composition
- nintedanib
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- 238000000034 method Methods 0.000 title claims abstract description 29
- 238000010828 elution Methods 0.000 title 1
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- 229960004378 nintedanib Drugs 0.000 claims abstract description 61
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- 238000004090 dissolution Methods 0.000 claims abstract description 34
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- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 18
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
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- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical group C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
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- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Abstract
Description
本発明は、医薬組成物及び溶出性改善方法に関する。より詳細には、ニンテダニブを含有する医薬組成物及びその溶出性を改善する方法に関する。 The present invention relates to a pharmaceutical composition and a method for improving dissolution properties. More specifically, the present invention relates to a pharmaceutical composition containing nintedanib and a method for improving its dissolution properties.
ニンテダニブは下記の式（１）で表される低分子チロシンキナーゼ阻害剤であり、特発性肺線維症、全身性強皮症に伴う間質性肺疾患、進行性線維化を伴う間質性肺疾患の治療に効果を有し、エタンスルホン酸塩として製造販売されている（非特許文献１、２）。 Nintedanib is a small molecule tyrosine kinase inhibitor represented by the following formula (1), and is used to treat idiopathic pulmonary fibrosis, interstitial lung disease associated with systemic sclerosis, and interstitial lung disease associated with progressive fibrosis. It is effective in treating diseases and is manufactured and sold as ethanesulfonate (Non-patent Documents 1 and 2).
ニンテダニブエタンスルホン酸塩は、軟カプセル剤として製造販売されている。軟カプセル剤は安定性や服用性が不充分であり、錠剤の開発が望まれる。
ニンテダニブの錠剤としては、造粒法で製造されたものが知られている（特許文献１）。
Nintedanib ethanesulfonate is manufactured and sold as a soft capsule. Soft capsules have insufficient stability and ease of administration, and the development of tablets is desired.
Nintedanib tablets manufactured by a granulation method are known (Patent Document 1).
ニンテダニブ含有錠剤について本発明者が検討を行ったところ、ニンテダニブの溶出性が不充分であることが判明した。また、崩壊性も不充分であることが分かった。
本発明の課題は、ニンテダニブ含有医薬組成物のニンテダニブ溶出性を改善する技術を提供することにある。
When the present inventor conducted a study on tablets containing nintedanib, it was found that the dissolution properties of nintedanib were insufficient. It was also found that the disintegrability was insufficient.
An object of the present invention is to provide a technique for improving the dissolution of nintedanib in a pharmaceutical composition containing nintedanib.
本発明者は上記課題を解決すべく鋭意検討した結果、ニンテダニブ若しくはその薬学的に許容される塩又はそれらの溶媒和物に、ｐＨ調整剤を組み合わせて医薬組成物とすることによって、ニンテダニブ溶出性を改善できることを見出し、本発明を完成した。 As a result of intensive studies to solve the above problems, the present inventors have found that by combining nintedanib, a pharmaceutically acceptable salt thereof, or a solvate thereof with a pH adjuster to form a pharmaceutical composition, the dissolution rate of nintedanib can be improved. The present invention has been completed based on the discovery that this can be improved.
すなわち、本発明は、以下の＜１＞～＜８＞を提供するものである。
＜１＞ 以下の成分（Ａ）及び（Ｂ）を含有する、医薬組成物。
（Ａ）ニンテダニブ若しくはその薬学的に許容される塩又はそれらの溶媒和物
（Ｂ）ｐＨ調整剤
＜２＞ 成分（Ｂ）として酸性ｐＨ調整剤を含有する、＜１＞に記載の医薬組成物。
＜３＞ 成分（Ｂ）として、フマル酸、アジピン酸、マロン酸、酒石酸、クエン酸、コハク酸、アスコルビン酸、リンゴ酸、リン酸、パラオキシ安息香酸エステル及びそれらの薬学的に許容される塩並びにそれらの溶媒和物からなる群から選択される少なくとも１種を含有する、＜１＞に記載の医薬組成物。
＜４＞ 成分（Ｂ）としてフマル酸及びその薬学的に許容される塩並びにそれらの溶媒和物からなる群から選択される少なくとも１種を含有する、＜１＞～＜３＞のいずれかに記載の医薬組成物。
That is, the present invention provides the following <1> to <8>.
<1> A pharmaceutical composition containing the following components (A) and (B).
(A) Nintedanib or a pharmaceutically acceptable salt thereof or a solvate thereof (B) pH adjuster <2> Pharmaceutical composition according to <1>, containing an acidic pH adjuster as component (B) .
<3> Component (B) includes fumaric acid, adipic acid, malonic acid, tartaric acid, citric acid, succinic acid, ascorbic acid, malic acid, phosphoric acid, paraoxybenzoic acid esters and pharmaceutically acceptable salts thereof, and The pharmaceutical composition according to <1>, containing at least one selected from the group consisting of solvates thereof.
<4> Any one of <1> to <3>, containing as component (B) at least one member selected from the group consisting of fumaric acid, its pharmaceutically acceptable salts, and solvates thereof. Pharmaceutical compositions as described.
＜５＞ さらに担体を含有し、且つ当該担体中に成分（Ａ）が分散している、＜１＞～＜４＞のいずれかに記載の医薬組成物。
＜６＞ 成分（Ａ）に対する成分（Ｂ）の含有質量比〔（Ｂ）／（Ａ）〕が０．０１以上５以下である、＜１＞～＜５＞のいずれかに記載の医薬組成物。
＜７＞ 固形製剤である、＜１＞～＜６＞のいずれかに記載の医薬組成物。
<5> The pharmaceutical composition according to any one of <1> to <4>, further comprising a carrier, and the component (A) is dispersed in the carrier.
<6> The pharmaceutical composition according to any one of <1> to <5>, wherein the content mass ratio [(B)/(A)] of component (B) to component (A) is 0.01 or more and 5 or less. thing.
<7> The pharmaceutical composition according to any one of <1> to <6>, which is a solid preparation.
＜８＞ ニンテダニブ若しくはその薬学的に許容される塩又はそれらの溶媒和物を含有する医薬組成物に、ｐＨ調整剤を含有せしめる工程を含む、ニンテダニブ若しくはその薬学的に許容される塩又はそれらの溶媒和物の溶出性を改善する方法。 <8> Nintedanib, a pharmaceutically acceptable salt thereof, or a solvate thereof, including a step of incorporating a pH adjuster into a pharmaceutical composition containing nintedanib, a pharmaceutically acceptable salt thereof, or a solvate thereof. A method for improving the dissolution properties of solvates.
本発明によれば、ニンテダニブ含有医薬組成物のニンテダニブ溶出性を改善できる。 According to the present invention, the dissolution of nintedanib in a pharmaceutical composition containing nintedanib can be improved.
本発明の医薬組成物は、以下の成分（Ａ）及び（Ｂ）を含有する。
（Ａ）ニンテダニブ若しくはその薬学的に許容される塩又はそれらの溶媒和物
（Ｂ）ｐＨ調整剤
The pharmaceutical composition of the present invention contains the following components (A) and (B).
(A) Nintedanib or a pharmaceutically acceptable salt thereof or a solvate thereof (B) pH adjuster
（成分（Ａ））
ニンテダニブ（化学名：（３Ｚ）－３－［（｛４－［Ｎ－メチル－２－（４－メチルピペラジン－１－イル）アセトアミド］フェニル｝アミノ）（フェニル）メチリデン］－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－６－カルボン酸メチル）は、下記式（１）で表される化合物である。
(Component (A))
Nintedanib (chemical name: (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2 , 3-dihydro-1H-indole-6-methyl carboxylate) is a compound represented by the following formula (1).
ニンテダニブの塩は、薬学的に許容されるものであればよく、例えば、塩酸塩、硫酸塩、硝酸塩等の無機酸塩；酢酸塩、酒石酸塩、乳酸塩、クエン酸塩、フマル酸塩、マレイン酸塩、コハク酸塩、メタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩等の有機酸塩等が挙げられる。また、溶媒和物としては、水和物、アルコール和物が挙げられる。 The salt of nintedanib may be any pharmaceutically acceptable salt, such as inorganic acid salts such as hydrochloride, sulfate, and nitrate; acetate, tartrate, lactate, citrate, fumarate, and maleic acid salt. Examples include organic acid salts such as acid salts, succinates, methanesulfonates, ethanesulfonates, benzenesulfonates, and toluenesulfonates. Furthermore, examples of solvates include hydrates and alcoholates.
これらの中でも、ニンテダニブのフリー体、ニンテダニブエタンスルホン酸塩が好ましく、ニンテダニブエタンスルホン酸塩がより好ましい。
なお、ニンテダニブ若しくはその薬学的に許容される塩又はそれらの溶媒和物は、非晶質でも結晶の状態でもよい。
Among these, the free form of nintedanib and nintedanib ethanesulfonate are preferred, and nintedanib ethanesulfonate is more preferred.
Note that nintedanib, a pharmaceutically acceptable salt thereof, or a solvate thereof may be in an amorphous or crystalline state.
成分（Ａ）の含有量は、不純物低減、崩壊性及びニンテダニブ溶出性等の観点から、本発明の医薬組成物中、５質量％以上８０質量％以下が好ましく、２０質量％以上７５質量％以下がより好ましく、３０質量％以上７０質量％以下が更に好ましく、４０質量％以上６０質量％以下が特に好ましい。成分（Ａ）の含有量を４０質量％以上とした場合に、ニンテダニブ溶出性と適度な硬度を両立させやすくなる。
ニンテダニブのフリー体として、１錠あたりに１５０ｍｇまたは１００ｍｇ含むことが好ましい。
The content of component (A) is preferably 5% by mass or more and 80% by mass or less, and 20% by mass or more and 75% by mass or less in the pharmaceutical composition of the present invention from the viewpoints of impurity reduction, disintegration properties, nintedanib dissolution properties, etc. is more preferable, 30% by mass or more and 70% by mass or less is still more preferable, and particularly preferably 40% by mass or more and 60% by mass or less. When the content of component (A) is 40% by mass or more, it becomes easier to achieve both nintedanib dissolution and appropriate hardness.
It is preferable that each tablet contains 150 mg or 100 mg of free nintedanib.
（成分（Ｂ））
ｐＨ調整剤としては、有機化合物系酸性ｐＨ調整剤、無機化合物系酸性ｐＨ調整剤、有機化合物系塩基性ｐＨ調整剤、無機化合物系塩基性ｐＨ調整剤が挙げられる。これらの中では、崩壊性、ニンテダニブ溶出性及び硬度等の観点から、有機化合物系酸性ｐＨ調整剤、無機化合物系酸性ｐＨ調整剤、有機化合物系塩基性ｐＨ調整剤が好ましく、有機化合物系酸性ｐＨ調整剤、無機化合物系酸性ｐＨ調整剤がより好ましく、有機化合物系酸性ｐＨ調整剤が特に好ましい。
有機化合物系酸性ｐＨ調整剤は、酸性ｐＨ調整剤のうち有機化合物であるものをいう。有機化合物系酸性ｐＨ調整剤としては、例えば、フマル酸、アジピン酸、マロン酸、酒石酸、クエン酸、コハク酸、アスコルビン酸、リンゴ酸などの有機酸、有機酸塩及び溶媒和物（無水クエン酸、クエン酸一水和物、クエン酸二水素ナトリウム等）の他、パラオキシ安息香酸エステル（パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル等）等が挙げられる。溶媒和物としては、水和物、アルコール和物が挙げられる。
無機化合物系酸性ｐＨ調整剤は、酸性ｐＨ調整剤のうち無機化合物であるものをいう。無機化合物系酸性ｐＨ調整剤としては、例えば、塩酸、硫酸、リン酸、リン酸二水素カリウム等が挙げられる。
有機化合物系塩基性ｐＨ調整剤は、塩基性ｐＨ調整剤のうち有機化合物であるものをいう。有機化合物系塩基性ｐＨ調整剤としては、例えば、ジイソプロパノールアミン、トリイソプロパノールアミン、モノエタノールアミンなどのアミン類；酒石酸ナトリウム二水和物、クエン酸ナトリウム、クエン酸三ナトリウム二水和物、コハク酸ナトリウム、酢酸ナトリウム水和物などの有機酸塩及びその溶媒和物が挙げられる。溶媒和物としては、水和物、アルコール和物が挙げられる。
無機化合物系塩基性ｐＨ調整剤は、塩基性ｐＨ調整剤のうち無機化合物であるものをいう。無機化合物系塩基性ｐＨ調整剤としては、例えば、水酸化カリウム、水酸化カルシウム、炭酸水素ナトリウム等が挙げられる。
酸性ｐＨ調整剤は、有機化合物系酸性ｐＨ調整剤と無機化合物系酸性ｐＨ調整剤とを含む。
(Component (B))
Examples of the pH adjuster include organic compound acidic pH adjusters, inorganic compound acidic pH adjusters, organic compound basic pH adjusters, and inorganic compound basic pH adjusters. Among these, from the viewpoint of disintegration, nintedanib dissolution, hardness, etc., organic compound-based acidic pH adjusters, inorganic compound-based acidic pH adjusters, and organic compound-based basic pH adjusters are preferred; The regulator is more preferably an inorganic compound-based acidic pH regulator, and an organic compound-based acidic pH regulator is particularly preferred.
The organic compound-based acidic pH adjuster refers to an acidic pH adjuster that is an organic compound. Examples of organic compound-based acidic pH adjusters include organic acids such as fumaric acid, adipic acid, malonic acid, tartaric acid, citric acid, succinic acid, ascorbic acid, and malic acid; organic acid salts; and solvates (citric acid anhydride). , citric acid monohydrate, sodium dihydrogen citrate, etc.), paraoxybenzoic acid esters (methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, etc.). Examples of solvates include hydrates and alcoholates.
The inorganic compound-based acidic pH adjuster refers to an acidic pH adjuster that is an inorganic compound. Examples of the inorganic compound acidic pH adjuster include hydrochloric acid, sulfuric acid, phosphoric acid, potassium dihydrogen phosphate, and the like.
The organic compound basic pH adjuster refers to a basic pH adjuster that is an organic compound. Examples of organic compound-based basic pH adjusters include amines such as diisopropanolamine, triisopropanolamine, and monoethanolamine; sodium tartrate dihydrate, sodium citrate, trisodium citrate dihydrate, and amber. Examples include organic acid salts such as sodium acid and sodium acetate hydrate, and solvates thereof. Examples of solvates include hydrates and alcoholates.
The inorganic compound basic pH adjuster refers to a basic pH adjuster that is an inorganic compound. Examples of the inorganic compound-based basic pH adjuster include potassium hydroxide, calcium hydroxide, sodium hydrogen carbonate, and the like.
The acidic pH adjuster includes an organic compound acidic pH adjuster and an inorganic compound acidic pH adjuster.
ｐＨ調整剤としては、崩壊性、ニンテダニブ溶出性及び硬度等の観点から、フマル酸、アジピン酸、マロン酸、酒石酸、クエン酸、コハク酸、アスコルビン酸、リンゴ酸、リン酸、パラオキシ安息香酸エステル及びそれらの薬学的に許容される塩並びにそれらの溶媒和物からなる群から選択される少なくとも１種が好ましく、フマル酸、アジピン酸、マロン酸、酒石酸、クエン酸、コハク酸、アスコルビン酸、リン酸、パラオキシ安息香酸エステル及びそれらの薬学的に許容される塩並びにそれらの溶媒和物からなる群から選択される少なくとも１種がより好ましく、フマル酸、アジピン酸、マロン酸、酒石酸、クエン酸、コハク酸、リン酸、パラオキシ安息香酸エステル及びそれらの薬学的に許容される塩並びにそれらの溶媒和物からなる群から選択される少なくとも１種が更に好ましく、フマル酸、アジピン酸、マロン酸、パラオキシ安息香酸エステル及びそれらの薬学的に許容される塩並びにそれらの溶媒和物からなる群から選択される少なくとも１種が更に好ましく、フマル酸、アジピン酸、パラオキシ安息香酸エステル及びそれらの薬学的に許容される塩並びにそれらの溶媒和物からなる群から選択される少なくとも１種が更に好ましく、フマル酸及びその薬学的に許容される塩並びにそれらの溶媒和物からなる群から選択される少なくとも１種が特に好ましい。
有機酸塩としては、有機酸のアルカリ金属塩、有機酸のアルカリ土類金属塩が挙げられる。フマル酸塩としては、フマル酸一ナトリウム、フマル酸二ナトリウム、フマル酸一カリウム、フマル酸二カリウム、フマル酸マグネシウム、フマル酸カルシウムが好ましい。リン酸塩としては、リン酸二水素カリウムが好ましい。パラオキシ安息香酸エステルとしては、パラオキシ安息香酸エチルが好ましい。
From the viewpoint of disintegration, nintedanib dissolution, hardness, etc., pH adjusting agents include fumaric acid, adipic acid, malonic acid, tartaric acid, citric acid, succinic acid, ascorbic acid, malic acid, phosphoric acid, paraoxybenzoic acid ester, and At least one selected from the group consisting of pharmaceutically acceptable salts thereof and solvates thereof is preferred, including fumaric acid, adipic acid, malonic acid, tartaric acid, citric acid, succinic acid, ascorbic acid, and phosphoric acid. , paraoxybenzoic acid esters, their pharmaceutically acceptable salts, and their solvates are more preferable, and at least one selected from the group consisting of fumaric acid, adipic acid, malonic acid, tartaric acid, citric acid, and succinic acid is more preferable. At least one selected from the group consisting of acids, phosphoric acid, paraoxybenzoic acid esters, their pharmaceutically acceptable salts, and solvates thereof is more preferred, and fumaric acid, adipic acid, malonic acid, and paraoxybenzoic acid are more preferred. More preferred is at least one selected from the group consisting of acid esters, their pharmaceutically acceptable salts, and solvates thereof, and fumaric acid, adipic acid, paraoxybenzoic acid esters, and their pharmaceutically acceptable salts. More preferably, at least one selected from the group consisting of fumaric acid and its pharmaceutically acceptable salts and solvates thereof is more preferable, and at least one selected from the group consisting of fumaric acid, its pharmaceutically acceptable salts, and their solvates Particularly preferred.
Examples of organic acid salts include alkali metal salts of organic acids and alkaline earth metal salts of organic acids. Preferred fumarate salts include monosodium fumarate, disodium fumarate, monopotassium fumarate, dipotassium fumarate, magnesium fumarate, and calcium fumarate. As the phosphate, potassium dihydrogen phosphate is preferred. As the paraoxybenzoic acid ester, ethyl paraoxybenzoate is preferred.
ｐＨ調整剤としては、崩壊性、ニンテダニブ溶出性及び硬度等の観点から、飽和水溶液としたときの２５℃におけるｐＨが０以上６以下のｐＨ調整剤が好ましく、飽和水溶液としたときの２５℃におけるｐＨが０．１以上５以下のｐＨ調整剤が好ましく、飽和水溶液としたときの２５℃におけるｐＨが０．５以上４以下のｐＨ調整剤がより好ましく、飽和水溶液としたときの２５℃におけるｐＨが０．５以上２．７５以下のｐＨ調整剤が更に好ましく、飽和水溶液としたときの２５℃におけるｐＨが２以上２．７５以下のｐＨ調整剤が更に好ましく、飽和水溶液としたときの２５℃におけるｐＨが２．２以上２．７５以下のｐＨ調整剤が特に好ましい。
飽和水溶液としたときの２５℃におけるｐＨが２．７５以下のものを用いた場合に、崩壊性、ニンテダニブ溶出性及び硬度が特に良好なものとなる。
As the pH adjuster, from the viewpoint of disintegration, nintedanib dissolution, hardness, etc., a pH adjuster having a pH of 0 or more and 6 or less at 25°C when made into a saturated aqueous solution is preferable; A pH adjuster with a pH of 0.1 or more and 5 or less is preferable, and a pH adjuster with a pH of 0.5 or more and 4 or less at 25°C when made into a saturated aqueous solution is more preferable, and a pH at 25°C when made into a saturated aqueous solution. is more preferably a pH adjuster having a pH of 0.5 or more and 2.75 or less, and even more preferably a pH adjuster having a pH of 2 or more and 2.75 or less at 25°C when made into a saturated aqueous solution, and when made into a saturated aqueous solution at 25°C. A pH adjuster having a pH of 2.2 or more and 2.75 or less is particularly preferred.
When a saturated aqueous solution having a pH of 2.75 or less at 25° C. is used, particularly good disintegration properties, nintedanib dissolution properties, and hardness are obtained.
なお、ｐＨ調整剤は、１種のみを単独で使用しても２種以上を組み合わせて使用してもよい。 Note that the pH adjusters may be used alone or in combination of two or more.
成分（Ｂ）の含有量は、崩壊性、ニンテダニブ溶出性及び硬度等の観点から、本発明の医薬組成物中、１質量％以上３０質量％以下が好ましく、２質量％以上２０質量％以下がより好ましく、３質量％以上１５質量％以下が更に好ましく、７．５質量％以上１５質量％以下が特に好ましい。 The content of component (B) is preferably 1% by mass or more and 30% by mass or less, and 2% by mass or more and 20% by mass or less in the pharmaceutical composition of the present invention from the viewpoints of disintegration, nintedanib dissolution, hardness, etc. It is more preferably 3% by mass or more and 15% by mass or less, and particularly preferably 7.5% by mass or more and 15% by mass or less.
医薬組成物中の成分（Ａ）に対する成分（Ｂ）の含有質量比〔（Ｂ）／（Ａ）〕は特に限定されないが、崩壊性、ニンテダニブ溶出性及び硬度等の観点から、０．０１以上５以下が好ましく、０．０２以上３以下がより好ましく、０．０３以上１以下が更に好ましく、０．０５以上０．７５以下が更に好ましく、０．１以上０．５以下が更に好ましく、０．１５以上０．５以下が特に好ましい。 The content mass ratio of component (B) to component (A) in the pharmaceutical composition [(B)/(A)] is not particularly limited, but from the viewpoint of disintegration, nintedanib dissolution, hardness, etc., it is 0.01 or more. It is preferably 5 or less, more preferably 0.02 or more and 3 or less, even more preferably 0.03 or more and 1 or less, even more preferably 0.05 or more and 0.75 or less, even more preferably 0.1 or more and 0.5 or less, and 0. Particularly preferred is .15 or more and 0.5 or less.
本発明の医薬組成物には、その剤形に応じて、上記成分以外に製剤添加物を加えてもよい。こうした製剤添加物としては、例えば、賦形剤、滑沢剤、崩壊剤、流動化剤、結合剤、界面活性剤、コーティング剤、可塑剤、抗酸化剤、甘味剤、矯味剤、着香剤・香料、安定化剤等が挙げられる。これらのうち１種のみを単独で使用しても２種以上を組み合わせて使用してもよい。 In addition to the above-mentioned components, additives may be added to the pharmaceutical composition of the present invention, depending on its dosage form. Examples of such formulation additives include excipients, lubricants, disintegrants, flow agents, binders, surfactants, coating agents, plasticizers, antioxidants, sweeteners, flavoring agents, and flavoring agents. - Includes fragrances, stabilizers, etc. One of these may be used alone or two or more may be used in combination.
賦形剤としては、例えば、マンニトール、エリスリトール、ソルビトール、マルチトール、ラクチトール、キシリトール等の糖アルコール系賦形剤；トウモロコシデンプン、バレイショデンプン、アルファー化デンプン、部分アルファー化デンプン等のデンプン系賦形剤の他、リン酸水素カルシウム水和物、無水リン酸水素カルシウム、ケイ酸カルシウム、乳糖、乳糖水和物、無水乳糖、果糖、白糖、ブドウ糖、結晶セルロース、粉末セルロース等が挙げられる。これらのうち１種のみを単独で使用しても２種以上を組み合わせて使用してもよい。
賦形剤の含有量は、崩壊性、ニンテダニブ溶出性及び硬度等の観点から、本発明の医薬組成物中、１質量％以上６０質量％以下が好ましく、５質量％以上３０質量％以下がより好ましい。
Examples of excipients include sugar alcohol excipients such as mannitol, erythritol, sorbitol, maltitol, lactitol, and xylitol; starch excipients such as corn starch, potato starch, pregelatinized starch, and partially pregelatinized starch. Other examples include calcium hydrogen phosphate hydrate, anhydrous calcium hydrogen phosphate, calcium silicate, lactose, lactose hydrate, anhydrous lactose, fructose, sucrose, glucose, crystalline cellulose, powdered cellulose, and the like. One of these may be used alone or two or more may be used in combination.
The content of the excipient in the pharmaceutical composition of the present invention is preferably 1% by mass or more and 60% by mass or less, more preferably 5% by mass or more and 30% by mass or less, from the viewpoints of disintegration, nintedanib dissolution, hardness, etc. preferable.
滑沢剤としては、例えば、硬化油、ステアリン酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、フマル酸ステアリルナトリウム、タルク等が挙げられる。これらのうち１種のみを単独で使用しても２種以上を組み合わせて使用してもよい。
滑沢剤の含有量は、崩壊性、ニンテダニブ溶出性及び硬度等の観点から、本発明の医薬組成物中、０．１質量％以上５質量％以下が好ましく、０．３質量％以上２質量％以下がより好ましい。
Examples of the lubricant include hydrogenated oil, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, and talc. One of these may be used alone or two or more may be used in combination.
The content of the lubricant is preferably 0.1% by mass or more and 5% by mass or less, and 0.3% by mass or more and 2% by mass in the pharmaceutical composition of the present invention from the viewpoints of disintegration, nintedanib dissolution, hardness, etc. % or less is more preferable.
崩壊剤としては、例えば、カルメロース、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、クロスポビドン、クロスカルメロースナトリウム等が挙げられる。これらのうち１種のみを単独で使用しても２種以上を組み合わせて使用してもよい。これらの中では、崩壊性、ニンテダニブ溶出性及び硬度等の観点から、低置換度ヒドロキシプロピルセルロース、クロスポビドンが好ましく、低置換度ヒドロキシプロピルセルロースがより好ましい。
崩壊剤の含有量は、崩壊性、ニンテダニブ溶出性及び硬度等の観点から、本発明の医薬組成物中、０質量％以上４０質量％以下が好ましく、１質量％以上３０質量％以下がより好ましく、３質量％以上２５質量％以下が更に好ましく、５質量％以上２０質量％以下が更に好ましく、１０質量％以上１５質量％以下が特に好ましい。
崩壊剤の含有量を１０質量％以上とした場合に、崩壊性、ニンテダニブ溶出性及び硬度が特に良好なものとなる。
Examples of the disintegrant include carmellose, carmellose calcium, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, and the like. One of these may be used alone or two or more may be used in combination. Among these, low-substituted hydroxypropylcellulose and crospovidone are preferred, and low-substituted hydroxypropylcellulose is more preferred, from the viewpoint of disintegration, nintedanib dissolution, hardness, and the like.
The content of the disintegrant is preferably 0% by mass or more and 40% by mass or less, more preferably 1% by mass or more and 30% by mass or less in the pharmaceutical composition of the present invention, from the viewpoints of disintegration properties, nintedanib dissolution properties, hardness, etc. , more preferably 3% by mass or more and 25% by mass or less, further preferably 5% by mass or more and 20% by mass or less, particularly preferably 10% by mass or more and 15% by mass or less.
When the content of the disintegrant is 10% by mass or more, the disintegration properties, nintedanib dissolution properties, and hardness are particularly good.
流動化剤としては、例えば、軽質無水ケイ酸、含水二酸化ケイ素、トウモロコシデンプン、メタケイ酸アルミン酸マグネシウム、合成ケイ酸アルミニウム等が挙げられるが、好ましくは軽質無水ケイ酸、含水二酸化ケイ素、トウモロコシデンプン、合成ケイ酸アルミニウムである。これらのうち１種のみを単独で使用しても２種以上を組み合わせて使用してもよい。
流動化剤の含有量は、崩壊性、ニンテダニブ溶出性及び硬度等の観点から、本発明の医薬組成物中、０．１質量％以上５質量％以下が好ましく、０．３質量％以上２質量％以下がより好ましい。
Examples of the fluidizing agent include light anhydrous silicic acid, hydrated silicon dioxide, corn starch, magnesium aluminate metasilicate, synthetic aluminum silicate, etc., but preferably light silicic anhydride, hydrated silicon dioxide, corn starch, It is a synthetic aluminum silicate. One of these may be used alone or two or more may be used in combination.
The content of the fluidizing agent is preferably 0.1% by mass or more and 5% by mass or less, and 0.3% by mass or more and 2% by mass in the pharmaceutical composition of the present invention from the viewpoints of disintegration, nintedanib dissolution, hardness, etc. % or less is more preferable.
結合剤としては、例えば、ヒドロキシプロピルセルロース、メチルセルロース、ポビドン等が挙げられる。これらのうち１種のみを単独で使用しても２種以上を組み合わせて使用してもよい。
結合剤の含有量は、崩壊性、ニンテダニブ溶出性及び硬度等の観点から、本発明の医薬組成物中、０．１質量％以上１０質量％以下が好ましく、０．５質量％以上５質量％以下がより好ましい。
Examples of the binder include hydroxypropylcellulose, methylcellulose, povidone, and the like. One of these may be used alone or two or more may be used in combination.
The content of the binder in the pharmaceutical composition of the present invention is preferably 0.1% by mass or more and 10% by mass or less, and 0.5% by mass or more and 5% by mass from the viewpoints of disintegration, nintedanib dissolution, hardness, etc. The following are more preferred.
界面活性剤としては、例えば、ラウリル硫酸ナトリウム、大豆レシチン、ショ糖脂肪酸エステル、ポリソルベート８０、モノステアリン酸ソルビタン等が挙げられる。これらのうち１種のみを単独で使用しても２種以上を組み合わせて使用してもよい。
界面活性剤の含有量は、崩壊性、ニンテダニブ溶出性及び硬度等の観点から、本発明の医薬組成物中、０．０１質量％以上５質量％以下が好ましく、０．１質量％以上２質量％以下がより好ましい。
Examples of the surfactant include sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 80, sorbitan monostearate, and the like. One of these may be used alone or two or more may be used in combination.
The content of the surfactant is preferably 0.01% by mass or more and 5% by mass or less, and 0.1% by mass or more and 2% by mass in the pharmaceutical composition of the present invention from the viewpoints of disintegration, nintedanib dissolution, hardness, etc. % or less is more preferable.
コーティング剤としては、例えば、ヒプロメロース酢酸エステルコハク酸エステル、ヒプロメロースフタル酸エステル、アクリル酸エチル・メタクリル酸メチルコポリマー、アミノアルキルメタクリレートコポリマーＥ、アミノアルキルメタクリレートコポリマーＲＳ、アンモニオアルキルメタクリレートコポリマー、カルボキシビニルポリマー、メタクリル酸コポリマーＳ、メタクリル酸コポリマーＬ、メタクリル酸コポリマーＬＤ、カルナウバロウ等が挙げられる。これらのうち１種のみを単独で使用しても２種以上を組み合わせて使用してもよい。 Examples of coating agents include hypromellose acetate succinate, hypromellose phthalate, ethyl acrylate/methyl methacrylate copolymer, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, ammonioalkyl methacrylate copolymer, carboxyvinyl polymer, methacrylic acid copolymer S, methacrylic acid copolymer L, methacrylic acid copolymer LD, carnauba wax, and the like. One of these may be used alone or two or more may be used in combination.
また、本発明の医薬組成物としては、ニンテダニブ由来の不純物含有量を低減させる観点から、以下の成分（Ａ）、（Ｂ）及び（Ｃ）を含有し、且つ成分（Ｃ）中に成分（Ａ）が分散している、医薬組成物が好ましく、以下の成分（Ａ）、（Ｂ）及び（Ｃ）を含有し、且つ成分（Ｃ）中に成分（Ａ）が分散した固体分散体を含む医薬組成物がより好ましく、成分（Ｃ）中に成分（Ａ）が分散した固体分散体と添加物層とを含み、当該添加物層中に前記固体分散体が分散しており、固体分散体及び添加物層の少なくとも一方が成分（Ｂ）を含む、錠剤が特に好ましい。
（Ａ）ニンテダニブ若しくはその薬学的に許容される塩又はそれらの溶媒和物
（Ｂ）ｐＨ調整剤
（Ｃ）担体
In addition, from the viewpoint of reducing the content of impurities derived from nintedanib, the pharmaceutical composition of the present invention contains the following components (A), (B), and (C), and in component (C), component ( Preferably, a pharmaceutical composition in which A) is dispersed contains the following components (A), (B) and (C), and a solid dispersion in which component (A) is dispersed in component (C). More preferably, the pharmaceutical composition comprises a solid dispersion in which component (A) is dispersed in component (C) and an additive layer, the solid dispersion is dispersed in the additive layer, and the solid dispersion is Particularly preferred are tablets in which at least one of the body and the additive layer comprises component (B).
(A) Nintedanib or its pharmaceutically acceptable salt or solvate thereof (B) pH adjuster (C) Carrier
固体分散体は、そのまま又は他の成分と組み合わせて医薬組成物とすることができる。なお、「固体分散体」とは、不活性な担体中に薬物が分散した固体状態のものをいう。このような固体分散体を含む医薬組成物とした場合に薬物の溶解性やバイオアベイラビリティが改善され、また放出制御や安定化（凝集制御など）が可能となる。 The solid dispersion can be used as a pharmaceutical composition as it is or in combination with other ingredients. Note that the term "solid dispersion" refers to a solid state in which a drug is dispersed in an inert carrier. When a pharmaceutical composition containing such a solid dispersion is prepared, the solubility and bioavailability of the drug can be improved, and release control and stabilization (such as aggregation control) can be achieved.
成分（Ａ）を分散させる担体としては、上記した製剤添加物や他の製剤添加物が挙げられるが、ニンテダニブ由来の不純物含有量を低減させる観点から、糖アルコール、ヒプロメロースエステル類、（メタ）アクリル酸系重合体類、硬化油、カルナウバロウ、ポリアルキレングリコール類、ショ糖脂肪酸エステル、高級脂肪酸及び高級脂肪酸塩からなる群から選択される少なくとも１種が好ましく、糖アルコール、硬化油、高級脂肪酸及び高級脂肪酸塩からなる群から選択される少なくとも１種がより好ましく、糖アルコール、高級脂肪酸及び高級脂肪酸塩からなる群から選択される少なくとも１種が特に好ましい。なお、大豆レシチン、モノステアリン酸ソルビタンなどの界面活性剤を更に用いてもよい。 Examples of carriers for dispersing component (A) include the above-mentioned formulation additives and other formulation additives, but from the viewpoint of reducing the content of impurities derived from nintedanib, sugar alcohols, hypromellose esters, (meth) ) Preferably at least one selected from the group consisting of acrylic acid polymers, hydrogenated oils, carnauba wax, polyalkylene glycols, sucrose fatty acid esters, higher fatty acids, and higher fatty acid salts; sugar alcohols, hydrogenated oils, and higher fatty acids. At least one selected from the group consisting of and higher fatty acid salts is more preferable, and at least one selected from the group consisting of sugar alcohols, higher fatty acids, and higher fatty acid salts is particularly preferable. Incidentally, a surfactant such as soybean lecithin or sorbitan monostearate may also be used.
糖アルコールとしては、不純物低減、非晶質化容易性の観点から、炭素数４～６の糖アルコールが好ましく、炭素数４～５の糖アルコールがより好ましく、炭素数４の糖アルコールが特に好ましい。糖アルコールとしては、例えば、マンニトール、エリスリトール、ソルビトール、マルチトール、ラクチトール、キシリトールが挙げられる。糖アルコールの中では、不純物低減の観点から、マンニトール、エリスリトール、キシリトールが好ましく、エリスリトール、キシリトールがより好ましく、エリスリトールが特に好ましい。糖アルコールは、１種を単独で用いても２種以上を組み合わせて用いてもよい。 As the sugar alcohol, from the viewpoint of impurity reduction and ease of amorphization, sugar alcohols having 4 to 6 carbon atoms are preferred, sugar alcohols having 4 to 5 carbon atoms are more preferred, and sugar alcohols having 4 carbon atoms are particularly preferred. . Examples of sugar alcohols include mannitol, erythritol, sorbitol, maltitol, lactitol, and xylitol. Among the sugar alcohols, from the viewpoint of impurity reduction, mannitol, erythritol, and xylitol are preferred, erythritol and xylitol are more preferred, and erythritol is particularly preferred. One type of sugar alcohol may be used alone or two or more types may be used in combination.
ヒプロメロースエステル類としては、不純物低減の観点から、ヒプロメロース酢酸エステルコハク酸エステル、ヒプロメロースフタル酸エステルが好ましい。ヒプロメロース酢酸エステルコハク酸エステルは、ヒプロメロースの酢酸及びモノコハク酸の混合エステルである。 As the hypromellose esters, from the viewpoint of reducing impurities, hypromellose acetate succinate and hypromellose phthalate are preferable. Hypromellose acetate succinate is a mixed ester of acetic acid and monosuccinic acid of hypromellose.
（メタ）アクリル酸系重合体類としては、不純物低減の観点から、アクリル酸エチル・メタクリル酸メチルコポリマー、アミノアルキルメタクリレートコポリマーＥ、アミノアルキルメタクリレートコポリマーＲＳ、アンモニオアルキルメタクリレートコポリマー、カルボキシビニルポリマー、メタクリル酸コポリマーＳ、メタクリル酸コポリマーＬ及びメタクリル酸コポリマーＬＤよりなる群から選ばれる１種以上が好ましい。 From the viewpoint of impurity reduction, (meth)acrylic acid polymers include ethyl acrylate/methyl methacrylate copolymer, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, ammonioalkyl methacrylate copolymer, carboxyvinyl polymer, methacrylate One or more selected from the group consisting of acid copolymer S, methacrylic acid copolymer L, and methacrylic acid copolymer LD is preferred.
硬化油は、魚油又は他の動物性若しくは植物性の脂肪油に水素を添加して得た脂肪である。
カルナウバロウは、カルナウバヤシの葉から得たロウである。
ポリアルキレングリコール類としては、不純物低減の観点から、マクロゴール、ポリプロピレングリコール、ポリオキシエチレンポリオキシプロピレングリコールが好ましい。
ショ糖脂肪酸エステルは、ショ糖（砂糖）と植物油由来の脂肪酸から作られるシュガーエステルである。脂肪酸としては、例えば、ラウリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、オレイン酸、ベヘニン酸、エルカ酸等が挙げられる。
Hydrogenated oils are fats obtained by hydrogenating fish oil or other fatty oils of animal or vegetable origin.
Carnauba wax is a wax obtained from the leaves of the carnauba palm.
As the polyalkylene glycols, from the viewpoint of reducing impurities, macrogol, polypropylene glycol, and polyoxyethylene polyoxypropylene glycol are preferable.
Sucrose fatty acid ester is a sugar ester made from sucrose (sugar) and fatty acids derived from vegetable oils. Examples of fatty acids include lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, behenic acid, and erucic acid.
高級脂肪酸、高級脂肪酸塩としては、ステアリン酸、ステアリン酸亜鉛、ステアリン酸アルミニウム、ステアリン酸マグネシウム、ステアリン酸カルシウム、ミリスチン酸、ミリスチン酸ナトリウム、パルミチン酸、パルミチン酸ナトリウム、オレイン酸、オレイン酸ナトリウム、ベヘニン酸、ベヘニン酸ナトリウム等が挙げられる。高級脂肪酸、高級脂肪酸塩は、１種を単独で用いても２種以上を組み合わせて用いてもよい。 Higher fatty acids and higher fatty acid salts include stearic acid, zinc stearate, aluminum stearate, magnesium stearate, calcium stearate, myristic acid, sodium myristate, palmitic acid, sodium palmitate, oleic acid, sodium oleate, behenic acid. , sodium behenate, and the like. Higher fatty acids and higher fatty acid salts may be used alone or in combination of two or more.
成分（Ａ）を分散させる担体の含有量は、不純物低減の観点から、本発明の医薬組成物中、０．１質量％以上４０質量％以下が好ましく、１０質量％以上３０質量％以下がより好ましい。 From the viewpoint of impurity reduction, the content of the carrier in which component (A) is dispersed is preferably 0.1% by mass or more and 40% by mass or less, more preferably 10% by mass or more and 30% by mass or less. preferable.
成分（Ａ）に対するそれを分散させる成分（Ｃ）の含有質量比〔（Ｃ）／（Ａ）〕は特に限定されないが、不純物低減の観点から、０．１以上３以下が好ましく、０．４以上１．５以下がより好ましい。 The content mass ratio [(C)/(A)] of component (C) for dispersing component (A) is not particularly limited, but from the viewpoint of reducing impurities, it is preferably 0.1 or more and 3 or less, and 0.4 More preferably, it is 1.5 or less.
成分（Ｃ）中に成分（Ａ）が分散した固体分散体の含有量の合計は特に限定されないが、本発明の医薬組成物中、５０質量％以上１００質量％以下が好ましく、７０質量％以上１００質量％以下がより好ましい。 The total content of the solid dispersion in which component (A) is dispersed in component (C) is not particularly limited, but is preferably 50% by mass or more and 100% by mass or less, and 70% by mass or more in the pharmaceutical composition of the present invention. More preferably, it is 100% by mass or less.
次に、上記添加物層について説明する。
添加物層としては、成分（Ｂ）を含有するものが好ましい。添加物層に成分（Ｂ）を含有せしめる場合において、成分（Ｂ）の含有量は、添加物層中、５０質量％以上１００質量％以下が好ましく、７０質量％以上１００質量％以下がより好ましい。
成分（Ｂ）以外の添加物としては、上記した製剤添加物（賦形剤、滑沢剤、崩壊剤、流動化剤、結合剤、界面活性剤、コーティング剤、可塑剤、抗酸化剤、甘味剤、矯味剤、着香剤・香料、安定化剤等）や他の製剤添加物が挙げられる。これらの中でも、添加物層に用いる添加物としては、崩壊剤、滑沢剤が特に好ましい。
Next, the additive layer will be explained.
The additive layer preferably contains component (B). When the additive layer contains component (B), the content of component (B) in the additive layer is preferably 50% by mass or more and 100% by mass or less, more preferably 70% by mass or more and 100% by mass or less. .
Additives other than component (B) include the above-mentioned formulation additives (excipients, lubricants, disintegrants, fluidizing agents, binders, surfactants, coating agents, plasticizers, antioxidants, sweeteners). agents, flavoring agents, flavoring agents/fragrances, stabilizers, etc.) and other formulation additives. Among these, disintegrants and lubricants are particularly preferred as additives used in the additive layer.
本発明の医薬組成物は、経口投与用製剤でも非経口投与用製剤でもよいが、好ましくは経口投与用製剤である。また、本発明の医薬組成物としては、固形製剤が好ましく、経口投与用固形製剤がより好ましい。
経口投与用固形製剤の剤形としては、例えば、顆粒剤、細粒剤、散剤、錠剤、丸剤、カプセル剤（ソフトカプセル剤を含む）、ドライシロップ剤等が挙げられる。これらの中でも、顆粒剤、細粒剤、錠剤、カプセル剤が好ましく、錠剤がより好ましい。錠剤としては、素錠、フィルムコーティング錠、糖衣錠、口腔内崩壊錠、チュアブル錠等が挙げられる。本発明の医薬組成物は、剤形が錠剤の場合であっても、崩壊性、ニンテダニブ溶出性及び硬度が良好である。
The pharmaceutical composition of the present invention may be a preparation for oral administration or a preparation for parenteral administration, but is preferably a preparation for oral administration. Furthermore, the pharmaceutical composition of the present invention is preferably a solid preparation, more preferably a solid preparation for oral administration.
Examples of dosage forms of solid preparations for oral administration include granules, fine granules, powders, tablets, pills, capsules (including soft capsules), and dry syrups. Among these, granules, fine granules, tablets, and capsules are preferred, and tablets are more preferred. Examples of tablets include plain tablets, film-coated tablets, sugar-coated tablets, orally disintegrating tablets, and chewable tablets. The pharmaceutical composition of the present invention has good disintegration, nintedanib dissolution, and hardness even when the dosage form is a tablet.
本発明の医薬組成物は、（Ａ）ニンテダニブ若しくはその薬学的に許容される塩又はそれらの溶媒和物及び（Ｂ）ｐＨ調整剤を混合する工程を含む製造方法によって製造できる。例えば錠剤の場合、成分（Ａ）及び（Ｂ）並びに必要に応じて製剤添加物を混合した後、打錠することよって、又は成分（Ａ）及び（Ｂ）並びに必要に応じて製剤添加物を混合して造粒し、得られた顆粒に対して製剤添加物を混合し、打錠することによって製造できる。
上記各混合は、容器回転式混合機、機械攪拌式混合機等を用いて常法に従って行えばよい。なお、顆粒と製剤添加物とを混合する前又は混合した後に、顆粒及び／又は製剤添加物の粒子径を、粉砕等の手法により整えることが好ましい。この操作によって、錠剤の含量均一性を改善することができる。
また、打錠は、ロータリー打錠機、単発打錠機等を用いて常法に従って行えばよい。本発明によれば、ニンテダニブ錠剤を直接打錠法や湿式造粒法で製造した場合でも崩壊性や溶出性を満足させることができる。
なお、錠剤は、外部滑沢法を用いなくとも圧縮成型が可能であるが、外部滑沢法を用いて成型することもできる。この場合には、滑沢剤を除く成分を混合した後、滑沢剤を杵臼に噴霧しながら打錠を行うか、あるいは、滑沢剤の一部を、滑沢剤を除く成分とあらかじめ混合しておいた後、残りの滑沢剤を杵臼に噴霧しながら打錠を行えばよい。
The pharmaceutical composition of the present invention can be manufactured by a manufacturing method including the step of mixing (A) nintedanib or a pharmaceutically acceptable salt thereof or a solvate thereof and (B) a pH adjuster. For example, in the case of tablets, components (A) and (B) and, if necessary, pharmaceutical additives are mixed and then tableted, or components (A) and (B) and, if necessary, pharmaceutical additives are mixed. It can be manufactured by mixing and granulating the resulting granules, mixing formulation additives with the resulting granules, and then tableting.
The above-mentioned mixing may be carried out according to a conventional method using a container rotary mixer, a mechanical stirring mixer, or the like. Note that, before or after mixing the granules and the pharmaceutical additive, it is preferable to adjust the particle size of the granules and/or the pharmaceutical additive by a method such as pulverization. This operation can improve the content uniformity of the tablets.
Moreover, tableting may be carried out according to a conventional method using a rotary tableting machine, a single-shot tableting machine, or the like. According to the present invention, even when a nintedanib tablet is manufactured by a direct compression method or a wet granulation method, it is possible to satisfy disintegration properties and dissolution properties.
Although tablets can be compression molded without using the external lubrication method, they can also be molded using the external lubrication method. In this case, after mixing the ingredients excluding the lubricant, tableting is performed while spraying the lubricant into a punch or die, or a part of the lubricant is mixed in advance with the ingredients other than the lubricant. After this, the remaining lubricant may be sprayed into a punch and die to form tablets.
また、成分（Ａ）、（Ｂ）及び（Ｃ）を含有し、且つ成分（Ｃ）中に成分（Ａ）が分散した固体分散体を含む医薬組成物を製造する場合は、ホットメルトエクストルーダー法（以下、「ＨＭＥ法」ともいう。）、スプレードライ法（以下、「ＳＤ法」ともいう。）等により固体分散体を得て、必要に応じて造粒、製剤添加物の混合及び打錠等を行えばよい。固体分散体の製造方法としては、ＨＭＥ法が好ましい。ＨＭＥ法で製造した場合でもニンテダニブ由来の不純物含有量を低減させることができる。また、無溶媒で製造可能であり、固体分散体中の成分分布が均一となりやすい。
成分（Ｂ）は、成分（Ａ）とともに成分（Ｃ）中に分散させる手法、固体分散体を造粒した後に製剤添加物とともに混合する手法、又はこれら両方の手法の組み合わせによって、医薬組成物に含有せしめることができる。
In addition, when producing a pharmaceutical composition containing components (A), (B), and (C) and a solid dispersion in which component (A) is dispersed in component (C), a hot melt extruder is used. (hereinafter also referred to as "HME method"), spray drying method (hereinafter also referred to as "SD method"), etc. to obtain a solid dispersion, and if necessary, granulate it, mix it with formulation additives, and pound it. All you have to do is lock it. As a method for producing the solid dispersion, the HME method is preferred. Even when produced by the HME method, the content of impurities derived from nintedanib can be reduced. Moreover, it can be produced without a solvent, and the component distribution in the solid dispersion tends to be uniform.
Component (B) can be added to a pharmaceutical composition by dispersing it in component (C) together with component (A), by granulating a solid dispersion and then mixing it with pharmaceutical additives, or by a combination of both methods. It can be made to contain.
ＨＭＥ法としては、成分（Ａ）を成分（Ｃ）（必要に応じて更に成分（Ｂ）等の他の成分）と溶融混錬する溶融混錬工程と、当該溶融混錬工程で得られた溶融物を固化させる固化工程とを含む方法が挙げられる。より具体的には、成分（Ａ）及び成分（Ｃ）（必要に応じて更に成分（Ｂ）等の他の成分）を混合して固形状組成物を得る混合工程と、得られた固形状組成物を溶融混錬する溶融混錬工程と、当該溶融混錬工程で得られた溶融物を固化させる固化工程とを含む方法が挙げられる。 The HME method involves a melt-kneading step in which component (A) is melt-kneaded with component (C) (further as necessary, other components such as component (B)), and Examples include a method including a solidification step of solidifying the molten material. More specifically, a mixing step of mixing component (A) and component (C) (and further other components such as component (B) as necessary) to obtain a solid composition; Examples include a method including a melt-kneading step of melt-kneading the composition, and a solidification step of solidifying the molten material obtained in the melt-kneading step.
溶融混錬工程としては、具体的に、成分（Ａ）と成分（Ｃ）（必要に応じて更に成分（Ｂ）等の他の成分）を加熱しながら混錬押出する工程が挙げられる。溶融混錬工程は、慣用される溶融混錬装置（例えば２軸エクストルーダー）を用いて行うことができる。押出部の形状によって、棒状、シート状、顆粒状及びカプセル状など任意の形態の固体分散体が得られる。
溶融混錬工程の温度は通常成分（Ｃ）の融点又はガラス転移点以上であり、好ましくは９０℃以上、より好ましくは１００℃以上であり、また、好ましくは２５０℃以下、より好ましくは２２０℃以下、更に好ましくは２００℃以下である。
溶融混錬時間は、装置に投入する組成物の総量に応じて適宜設定すればよいが、通常１～３０分間、好ましくは１～１０分間である。
Specifically, the melt-kneading step includes a step of kneading and extruding component (A) and component (C) (further, if necessary, other components such as component (B)) while heating them. The melt-kneading process can be performed using a commonly used melt-kneader (for example, a twin-screw extruder). Depending on the shape of the extrusion section, a solid dispersion in any form such as a rod, sheet, granule, or capsule can be obtained.
The temperature in the melt-kneading step is usually higher than the melting point or glass transition point of component (C), preferably 90°C or higher, more preferably 100°C or higher, and preferably 250°C or lower, more preferably 220°C. The temperature is preferably below 200°C.
The melting and kneading time may be appropriately set depending on the total amount of the composition to be charged into the apparatus, but is usually 1 to 30 minutes, preferably 1 to 10 minutes.
固化工程としては、例えば、溶融混錬工程で得られた溶融物を冷却する手法が挙げられる。冷却温度は、通常３～４０℃である。
また、固化工程で得られた固化物を整粒する整粒工程を含んでいてもよい。
このようにして得られた固体分散体をそのまま、或いは必要に応じて造粒、製剤添加物の混合及び打錠等することによって、固体分散体を含む医薬組成物を製造できる。
Examples of the solidification step include a method of cooling the molten material obtained in the melt-kneading step. The cooling temperature is usually 3 to 40°C.
Further, the method may include a sizing step of sizing the solidified material obtained in the solidification step.
A pharmaceutical composition containing the solid dispersion can be produced by using the solid dispersion thus obtained as it is, or by granulating it, mixing formulation additives, tabletting, etc. as necessary.
そして、上記のようにして、ニンテダニブ溶出性が改善された医薬組成物を製造できる。 Then, as described above, a pharmaceutical composition with improved nintedanib dissolution properties can be produced.
また本発明は、ニンテダニブ若しくはその薬学的に許容される塩又はそれらの溶媒和物を含有する医薬組成物に、ｐＨ調整剤を含有せしめる工程を含む、ニンテダニブ若しくはその薬学的に許容される塩又はそれらの溶媒和物の溶出性を改善する方法を提供する。この態様の発明において、各種文言の意義、各成分の配合量等は全て本発明の医薬組成物について説明したのと同様である。 The present invention also provides a pharmaceutical composition containing nintedanib, a pharmaceutically acceptable salt thereof, or a solvate thereof, which comprises a step of containing a pH adjuster. A method of improving the dissolution properties of these solvates is provided. In this aspect of the invention, the meanings of various words, the amounts of each component, etc. are all the same as described for the pharmaceutical composition of the invention.
以下、実施例を挙げて本発明を詳細に説明するが、本発明はこれら実施例に限定されるものではない。 EXAMPLES Hereinafter, the present invention will be explained in detail with reference to Examples, but the present invention is not limited to these Examples.
本実施例において使用した成分は、特に明示しない限り以下のものである。
乳糖：Ｐｈａｒｍａｔｏｓｅ２００Ｍ（ＤＦＥファーマ社製）
エリスリトール：エリスリトールＴ微粉（三菱ケミカルフーズ社製）
硬化油：ラブリワックス－１０１（フロイント社製）、ラブリワックス－１０３（フロイント社製）
ステアリン酸：ＮＦ－ＧｅｎＡＲ（ＡＶＡＮＴＯＲ社製）
大豆レシチン：ＳＬＰ－ホワイト（辻製油社製）
結晶セルロース：セオラスＵＦ－７０２（旭化成社製）
トウモロコシデンプン：ＳＴ－Ｃ（日澱化学社製）
ヒドロキシプロピルセルロース：ＨＰＣ－Ｌ（日本曹達社製）
フマル酸：（扶桑化学工業社製）
アジピン酸：（富士フィルム和光純薬社製）
アスコルビン酸：（富士フィルム和光純薬社製）
マロン酸：（富士フィルム和光純薬社製）
酒石酸：（富士フィルム和光純薬社製）
クエン酸：（富士フィルム和光純薬社製）
コハク酸：（富士フィルム和光純薬社製）
リンゴ酸：（富士フィルム和光純薬社製）
パラオキシ安息香酸エチル：（富士フィルム和光純薬社製）
リン酸二水素カリウム：（富士フィルム和光純薬社製）
フマル酸一ナトリウム：（扶桑化学工業株式会社社製）
低置換度ヒドロキシプロピルセルロース：ＮＢＤ－０２０（信越化学社製）
軽質無水ケイ酸：アドソリダー‐１０１（フロイント産業製）
含水二酸化ケイ素：アドソリダー‐１０２（フロイント産業製）
メタケイ酸アルミン酸マグネシウム：ノイシリンＵＦＬ２（富士化学工業社製）
無水リン酸水素カルシウム：軽質無水リン酸水素カルシウム（協和化学工業社製）
ケイ酸カルシウム：フローライトＲ（富田製薬社製）
合成ケイ酸アルミニウム：軽質合成ケイ酸アルミニウム（協和化学工業社製）
クロスポビドン：Ｋｏｌｉｄｏｎ ＣＬ（ＢＡＳＦ社製）
ステアリン酸マグネシウム：植物性ステアリン酸マグネシウム（太平化学産業社製）
The components used in this example are as follows unless otherwise specified.
Lactose: Pharmatose 200M (manufactured by DFE Pharma)
Erythritol: Erythritol T fine powder (manufactured by Mitsubishi Chemical Foods)
Hardened oil: Loveriwax-101 (manufactured by Freund), Loveriwax-103 (manufactured by Freund)
Stearic acid: NF-GenAR (manufactured by AVANTOR)
Soy lecithin: SLP-White (manufactured by Tsuji Oil Co., Ltd.)
Crystalline cellulose: Ceolus UF-702 (manufactured by Asahi Kasei Corporation)
Corn starch: ST-C (manufactured by Nippon Star Chemical Co., Ltd.)
Hydroxypropyl cellulose: HPC-L (manufactured by Nippon Soda Co., Ltd.)
Fumaric acid: (manufactured by Fuso Chemical Industry Co., Ltd.)
Adipic acid: (manufactured by Fuji Film Wako Pure Chemical Industries)
Ascorbic acid: (manufactured by Fuji Film Wako Pure Chemical Industries)
Malonic acid: (manufactured by Fuji Film Wako Pure Chemical Industries)
Tartaric acid: (manufactured by Fuji Film Wako Pure Chemical Industries)
Citric acid: (manufactured by Fuji Film Wako Pure Chemical Industries)
Succinic acid: (manufactured by Fuji Film Wako Pure Chemical Industries)
Malic acid: (manufactured by Fuji Film Wako Pure Chemical Industries)
Ethyl paraoxybenzoate: (manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.)
Potassium dihydrogen phosphate: (manufactured by Fuji Film Wako Pure Chemical Industries)
Monosodium fumarate: (manufactured by Fuso Chemical Industry Co., Ltd.)
Low-substituted hydroxypropyl cellulose: NBD-020 (manufactured by Shin-Etsu Chemical Co., Ltd.)
Light silicic anhydride: Ad Solider-101 (manufactured by Freund Sangyo)
Hydrous silicon dioxide: Ad Solider-102 (manufactured by Freund Sangyo)
Magnesium metasilicate aluminate: Neusilin UFL2 (manufactured by Fuji Chemical Industry Co., Ltd.)
Anhydrous calcium hydrogen phosphate: Light anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry Co., Ltd.)
Calcium silicate: Fluorite R (manufactured by Tomita Pharmaceutical Co., Ltd.)
Synthetic aluminum silicate: Light synthetic aluminum silicate (manufactured by Kyowa Chemical Industry Co., Ltd.)
Crospovidone: Kolidon CL (manufactured by BASF)
Magnesium stearate: Vegetable magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.)
（実施例１ 錠剤）
以下の工程により、ニンテダニブエタンスルホン酸塩を１錠あたりに１８０．６０ｍｇ含有する錠剤（質量３６０ｍｇ）を得た。
１）混合工程（１）：ニンテダニブエタンスルホン酸塩とステアリン酸とエリスリトールと大豆レシチンを質量比５０．２：２２．６：２．５：０．５で混合して混合物１００ｇを得た。
２）溶融混錬工程、冷却工程：上記１）で得られた混合物を、２軸エクストルーダー（サーモフィッシャーサイエンティフィック社製Ｐｈａｒｍａ１１）により１３５℃で約４分間溶融混錬した後、２０℃に冷却した。
３）整粒工程：上記２）で得られた混錬物を、整粒機（ダルトン社製パワーミルＰ－０２Ｓ）を用いて整粒することで、ニンテダニブ固体分散体を得た。
４）混合工程（２）：上記３）で得られたニンテダニブ固体分散体及び表１の「混合顆粒」に示す成分を表１に示す組成になるように混合した。
５）打錠工程：単発式打錠機（市橋精機社製ＨＡＮＤＴＡＢ－２００）を用いて打錠することで、実施例１の錠剤を得た。
(Example 1 tablet)
Tablets (mass: 360 mg) each containing 180.60 mg of nintedanib ethanesulfonate were obtained through the following steps.
1) Mixing step (1): Nintedanib ethanesulfonate, stearic acid, erythritol, and soybean lecithin were mixed at a mass ratio of 50.2:22.6:2.5:0.5 to obtain 100 g of a mixture. .
2) Melting and kneading process, cooling process: The mixture obtained in 1) above was melted and kneaded at 135°C for about 4 minutes using a twin-screw extruder (Pharma 11 manufactured by Thermo Fisher Scientific), and then heated to 20°C. Cooled.
3) Particle sizing step: The kneaded product obtained in 2) above was sized using a sizing machine (Power Mill P-02S manufactured by Dalton) to obtain a solid dispersion of nintedanib.
4) Mixing step (2): The nintedanib solid dispersion obtained in 3) above and the components shown in "Mixed granules" in Table 1 were mixed to have the composition shown in Table 1.
5) Tablet compression process: Tablets of Example 1 were obtained by compression using a single-shot tablet machine (HANDTAB-200 manufactured by Ichihashi Seiki Co., Ltd.).
（実施例２～４１及び比較例１～６ 錠剤）
表１～１１に記載の処方及び製剤重量に従う以外は、実施例１と同様にして錠剤を得た。
(Examples 2 to 41 and Comparative Examples 1 to 6 tablets)
Tablets were obtained in the same manner as in Example 1, except that the formulations and formulation weights listed in Tables 1 to 11 were followed.
（比較例７～１１ 錠剤）
以下の工程により、ニンテダニブエタンスルホン酸塩を含有する錠剤を得た。
表１２の「混合造粒」に示す成分を、乳鉢を用いて表１２に示す組成になるように造粒した。得られた造粒物に、表１２の「混合顆粒」に示す成分を添加して、単発式打錠機（市橋精機社製ＨＡＮＤＴＡＢ－２００）を用いて打錠することで、比較例７～１１の錠剤を得た。
(Comparative Examples 7 to 11 Tablets)
Tablets containing nintedanib ethanesulfonate were obtained through the following steps.
The components shown in "Mixed Granulation" in Table 12 were granulated using a mortar to give the composition shown in Table 12. Comparative Examples 7- 11 tablets were obtained.
（試験例１ 溶出性）
水９００ｍＬに錠剤１錠を加え、パドル法により毎分５０回転で溶出試験を行い、各採取時点（５分、１０分、１５分、３０分、４５分、６０分、９０分、１２０分、１８０分）に試験液を採取してニンテダニブの溶出率をＨＰＬＣで測定した。６０分後、９０分後、１２０分後のニンテダニブ溶出率の結果を表１～１２に示す。溶出率が高いほど溶出性が良好といえる。
（試験例２ 錠剤硬度）
錠剤硬度計（岡田精工社製ポータブルチェッカーＰＣ－３０）を用いて硬度を測定し、得られた硬度（Ｎ）を錠剤の破断面積（ｍｍ2）で除した値を錠剤硬度（Ｎ／ｍｍ2）とした。破断面積は、錠剤厚みと錠剤直径により算出した値である。結果を表１～１２に示す。１．０Ｎ／ｍｍ2以上の場合に硬度が良好といえる。
(Test Example 1 Dissolution)
One tablet was added to 900 mL of water, and a dissolution test was performed using the paddle method at 50 revolutions per minute. A test solution was collected at 180 minutes) and the dissolution rate of nintedanib was measured by HPLC. Tables 1 to 12 show the results of the dissolution rate of nintedanib after 60 minutes, 90 minutes, and 120 minutes. It can be said that the higher the dissolution rate, the better the dissolution property.
(Test Example 2 Tablet Hardness)
The hardness is measured using a tablet hardness meter (Portable Checker PC-30 manufactured by Okada Seiko Co., Ltd.), and the value obtained by dividing the obtained hardness (N) by the fracture area (mm 2 ) of the tablet is the tablet hardness (N/mm 2 ) . ). The fracture area is a value calculated from the tablet thickness and tablet diameter. The results are shown in Tables 1-12. When the hardness is 1.0 N/mm 2 or more, it can be said that the hardness is good.
（試験例３ 崩壊性）
実施例１～３の錠剤について、試験例１の溶出試験の各採取時点に目視観察を行った。試料が明らかに原形をとどめない軟質の物質となり（ゲル状化）、その軟質物質が試験容器（ベッセル）の底部に認められなくなったとき、試料は崩壊したものとし、その時間を記録した。結果を表１３に示す。なお、比較例１、３、４の錠剤についても、崩壊性を同様に評価したところ、試験時間（１８０分）中に試料は崩壊しなかった。
(Test Example 3 Disintegration)
The tablets of Examples 1 to 3 were visually observed at each collection point in the dissolution test of Test Example 1. The sample was considered to have disintegrated and the time was recorded when the sample became a clearly shapeless soft material (gelling) and the soft material was no longer visible at the bottom of the test vessel. The results are shown in Table 13. Note that the tablets of Comparative Examples 1, 3, and 4 were similarly evaluated for disintegration, and the samples did not disintegrate during the test time (180 minutes).
（試験例４ ｐＨ）
表１４に示すｐＨ調整剤の飽和水溶液を調製し、ｐＨ計（堀場アドバンスドテクノ製ｐＨメータＦ－７２）を用いて、２５℃におけるｐＨを測定した。結果を表１４に示す。なお、比較例１０の錠剤で使用した無水リン酸水素カルシウムについて、４質量％懸濁溶液の２５℃におけるｐＨを測定したところ６．２だった。
(Test Example 4 pH)
A saturated aqueous solution of the pH adjuster shown in Table 14 was prepared, and the pH at 25° C. was measured using a pH meter (pH meter F-72 manufactured by Horiba Advanced Techno). The results are shown in Table 14. Regarding the anhydrous calcium hydrogen phosphate used in the tablet of Comparative Example 10, the pH of a 4% by mass suspension at 25° C. was measured and found to be 6.2.
Claims (8)
（Ａ）ニンテダニブ若しくはその薬学的に許容される塩又はそれらの溶媒和物
（Ｂ）ｐＨ調整剤 A pharmaceutical composition containing the following components (A) and (B).
(A) Nintedanib or a pharmaceutically acceptable salt thereof or a solvate thereof (B) pH adjuster
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