JP6854639B2 - Pharmaceutical composition containing rapamycin derivative and method for producing the same - Google Patents
Pharmaceutical composition containing rapamycin derivative and method for producing the same Download PDFInfo
- Publication number
- JP6854639B2 JP6854639B2 JP2016248834A JP2016248834A JP6854639B2 JP 6854639 B2 JP6854639 B2 JP 6854639B2 JP 2016248834 A JP2016248834 A JP 2016248834A JP 2016248834 A JP2016248834 A JP 2016248834A JP 6854639 B2 JP6854639 B2 JP 6854639B2
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- Prior art keywords
- rapamycin
- derivative
- pharmaceutical composition
- everolimus
- solution
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 72
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- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 claims description 90
- 229960002930 sirolimus Drugs 0.000 claims description 90
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 claims description 54
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Description
本発明は、ラパマイシン又はその誘導体の安定性を向上させた医薬製剤組成物に関する。ラパマイシン又はその誘導体は、酸素、光及び水分に対して非常に不安定であり、保存安定性に課題がある。そのような化合物に対する保存安定性を、医薬組成物の成分及び製造方法を最適化することにより、現在報告されているあらゆる製造方法で得られる医薬組成物よりも、長期安定性に優れた医薬製剤組成物を提供する技術である。 The present invention relates to a pharmaceutical pharmaceutical composition having improved stability of rapamycin or a derivative thereof. Rapamycin or a derivative thereof is extremely unstable to oxygen, light and moisture, and has a problem in storage stability. By optimizing the components and production method of the pharmaceutical composition, the storage stability for such a compound is superior to that of the pharmaceutical composition obtained by any of the currently reported production methods. It is a technique for providing a composition.
ラパマイシン（シロリムス）は、放線菌の代謝産物から見出されたマクロライド系抗生物質であり、免疫抑制作用を有することが知られている。ラパマイシンは細胞の分裂や増殖、生存などを調節する哺乳類ラパマイシン標的タンパク質（ｍａｍｍａｌｉａｎ ｔａｒｇｅｔ ｏｆ ｒａｐａｍｙｃｉｎ；ｍＴＯＲ）の阻害作用を有する。このｍＴＯＲは、増殖因子や栄養素などによる刺激により蛋白質の合成を調節する主要なセリン・スレオニンキナーゼであり、細胞の成長、増殖、生存及び血管新生を調節することが知られている。そこで、ラパマイシンのｍＴＯＲ阻害作用に着目して、その誘導体合成が試みられ、エベロリムスとテムシロリムスが抗腫瘍剤として見出されている。 Rapamycin (sirolimus) is a macrolide antibiotic found in metabolites of actinomycetes and is known to have an immunosuppressive effect. Rapamycin has an inhibitory effect on the mammalian target of rapamycin (mTOR), which regulates cell division, proliferation, survival, and the like. This mTOR is a major serine / threonine kinase that regulates protein synthesis by stimulation with growth factors and nutrients, and is known to regulate cell growth, proliferation, survival and angiogenesis. Therefore, focusing on the mTOR inhibitory effect of rapamycin, its derivative synthesis has been attempted, and everolimus and temsirolimus have been found as antitumor agents.
ラパマイシン又はその誘導体を含む医薬品を提供するための、医薬製剤が報告されている。特許文献１は、ラパマイシン類、ヒドロキシプロピルメチルセルロース及び乳糖等の混合物を含む溶液を調製し、溶媒溜去することで得られる固体分散体を製剤化することを記載している。また、特許文献２には、ラパマイシン類であるエベロリムス、崩壊剤であるクロスポビドン、コロイド状二酸化ケイ素及び乳糖を含有する錠剤が記載されている。 Pharmaceutical formulations for providing pharmaceuticals containing rapamycin or its derivatives have been reported. Patent Document 1 describes that a solution containing a mixture of rapamycins, hydroxypropylmethylcellulose, lactose and the like is prepared, and a solid dispersion obtained by distilling off the solvent is formulated. Further, Patent Document 2 describes tablets containing everolimus, which is a rapamycin, crospovidone, which is a disintegrant, colloidal silicon dioxide, and lactose.
ラパマイシン又はその誘導体は、酸化に対して非常に不安定な物性であることが知られている。そこで、ラパマイシン類を有効成分とする医薬品製剤には、抗酸化剤が添加されている。例えば、ラパマイシン製剤（ラパリムス（登録商標）錠）及びテムシロリムス製剤（トーリセル（登録商標）点滴静注液）ではトコフェロールが添加されている。また、エベロリムス製剤（アフィニト−ル（登録商標）錠及びサーティカン（登録商標）錠）には、ジブチルヒドロキシトルエン（ＢＨＴ）が使用されている。
ラパマイシン誘導体の安定化方法について、特許文献３では、エベロリムスと抗酸化剤であるＢＨＴを含む混合溶液を調製し、その後溶媒を除去することで、安定化されたエベロリムス固体が得られることが報告されている。
一方、特許文献４は、エベロリムスのエタノール溶液をヒプロメロース等の水溶性高分子に添加し造粒して調製した固体分散体をエベロリムス製剤に適用することを記載している。
Rapamycin or its derivatives are known to have very unstable physical properties against oxidation. Therefore, an antioxidant is added to the pharmaceutical preparation containing rapamycins as an active ingredient. For example, tocopherol is added to rapamycin preparations (Laparimus (registered trademark) tablets) and temsirolimus preparations (Torisel (registered trademark) intravenous drip infusion). In addition, dibutylhydroxytoluene (BHT) is used for everolimus preparations (Affinitol (registered trademark) tablets and Certican (registered trademark) tablets).
Regarding the method for stabilizing a rapamycin derivative, Patent Document 3 reports that a stabilized everolimus solid can be obtained by preparing a mixed solution containing everolimus and BHT, which is an antioxidant, and then removing the solvent. ing.
On the other hand, Patent Document 4 describes that a solid dispersion prepared by adding an ethanol solution of everolimus to a water-soluble polymer such as hypromellose and granulating it is applied to an everolimus preparation.
本発明の目的は、ラパマイシン又はその誘導体を含有する医薬製剤に用いる、ラパマイシン又はその誘導体の酸化や分解に伴う有効成分含量の低減を抑制し、長期安定性が確保できる医薬組成物の製造方法を提供することである。また、医薬品として流通保存条件下における長期安定性が確保できるラパマイシン又はその誘導体を含有する医薬製剤を提供することである。 An object of the present invention is a method for producing a pharmaceutical composition used in a pharmaceutical preparation containing rapamycin or a derivative thereof, which suppresses a decrease in the active ingredient content due to oxidation or decomposition of rapamycin or a derivative thereof and can ensure long-term stability. To provide. Another object of the present invention is to provide a pharmaceutical preparation containing rapamycin or a derivative thereof that can ensure long-term stability under distribution and storage conditions as a pharmaceutical product.
本発明は、ラパマイシン又はその誘導体の溶液を、２５℃における臨界相対湿度が９５％以上の糖類に滴下して、その後、溶媒を除去することで製造されたラパマイシン又はその誘導体含有医薬組成物が、ラパマイシン又はその誘導体の安定化効果を長期間示すことを見出し、発明を完成させるに至った。すなわち、本願は以下［１］〜［７］の発明を要旨とする。 In the present invention, a rapamycin or a derivative-containing pharmaceutical composition produced by dropping a solution of rapamycin or a derivative thereof onto a saccharide having a critical relative humidity of 95% or more at 25 ° C. and then removing the solvent can be used. They have found that rapamycin or a derivative thereof has a stabilizing effect for a long period of time, and have completed the invention. That is, the present application is based on the inventions of [1] to [7] below.
［１］ ラパマイシン又はその誘導体を含有する溶液を、２５℃における臨界相対湿度が９５％以上の糖類に添加する工程を含む、ラパマイシン又はその誘導体を含有する医薬組成物の製造方法。
本発明では、医薬品の有効成分であるラパマイシン等を含む溶液を、固体状態にある吸湿性をほとんど示さない糖類へ添加して混合することにより調製される医薬組成物の製造方法に関する。本製造方法により得られる医薬組成物は、有効成分であるラパマイシン又はその誘導体の分解を抑制し、保存安定性に優れた医薬組成物を提供することができる。
［２］ ラパマイシン又はその誘導体１質量部に対し、２５℃における臨界相対湿度が９５％以上の糖類が０．５〜５０質量部である前記[１]に記載の医薬組成物の製造方法。
[1] A method for producing a pharmaceutical composition containing rapamycin or a derivative thereof, which comprises a step of adding a solution containing rapamycin or a derivative thereof to a saccharide having a critical relative humidity of 95% or more at 25 ° C.
The present invention relates to a method for producing a pharmaceutical composition prepared by adding and mixing a solution containing rapamycin or the like, which is an active ingredient of a pharmaceutical product, to a saccharide in a solid state that exhibits almost no hygroscopicity. The pharmaceutical composition obtained by this production method can suppress the decomposition of rapamycin, which is an active ingredient, or a derivative thereof, and can provide a pharmaceutical composition having excellent storage stability.
[2] The method for producing a pharmaceutical composition according to the above [1], wherein the amount of saccharides having a critical relative humidity of 95% or more at 25 ° C. is 0.5 to 50 parts by mass with respect to 1 part by mass of rapamycin or a derivative thereof.
［３］ ラパマイシン又はその誘導体を含有する溶液が、安定化剤を含有する前記［１］又は［２］に記載の医薬組成物の製造方法。
［４］ ラパマイシン又はその誘導体を含有する溶液が、水溶性高分子担体を含有する前記［１］〜［３］の何れか一項に記載の医薬組成物の製造方法。
［５］ ラパマイシン又はその誘導体を含有する溶液が、水溶性セルロース誘導体を含有する前記［１］〜［４］の何れか一項に記載の医薬組成物の製造方法。
本発明の製造方法において、ラパマイシン又はその誘導体を含有する溶液に、安定化剤や水溶性セルロース誘導体等の水溶性高分子担体を添加することにより、ラパマイシン等の分解抑制効果を一層向上させることができ、安定性に優れた医薬組成物を提供することを可能とする。
[3] The method for producing a pharmaceutical composition according to the above [1] or [2], wherein the solution containing rapamycin or a derivative thereof contains a stabilizer.
[4] The method for producing a pharmaceutical composition according to any one of the above [1] to [3], wherein the solution containing rapamycin or a derivative thereof contains a water-soluble polymer carrier.
[5] The method for producing a pharmaceutical composition according to any one of the above [1] to [4], wherein the solution containing rapamycin or a derivative thereof contains a water-soluble cellulose derivative.
In the production method of the present invention, by adding a water-soluble polymer carrier such as a stabilizer or a water-soluble cellulose derivative to a solution containing rapamycin or a derivative thereof, the effect of suppressing decomposition of rapamycin or the like can be further improved. It is possible to provide a pharmaceutical composition having excellent stability.
［６］ ラパマイシン又はその誘導体を含有する溶液を、２５℃における臨界相対湿度が９５％以上の糖類に添加することにより調製されるラパマイシン又はその誘導体を含有する医薬組成物。
本発明はラパマイシン又はその誘導体と前記糖類を含有する医薬組成物であるが、該ラパマイシン等を溶液として、該糖類に添加して調製される組成物が、極めて高い安定性を奏する。これは該ラパマイシン等と該糖類を物理的に混合した医薬組成物や、これらを共に含有した溶液から調製される医薬組成物とは異なる物性である。このような本発明に係る医薬組成物のより詳細な態様を、化学構造体や特性等により示すことが困難である。そこで、本発明で得られる医薬組成物は、前記［６］で示される製造方法により特定されるラパマイシン又はその誘導体と前記糖類を含有する医薬組成物として表すことが適当であり、発明の明確性の要件を充足しているものと考える。
［７］ 遮光下６０℃、相対湿度約４９％にて１４日保存した後において、ラパマイシン又はその誘導体の含有量が初期値に対して少なくとも８０％を含有する前記［６］に記載の医薬組成物。
本発明の医薬組成物は保存安定性に優れるものであり、より好ましい態様においては、前記保存安定性により特定される医薬組成物である。
[6] A pharmaceutical composition containing rapamycin or a derivative thereof, which is prepared by adding a solution containing rapamycin or a derivative thereof to a saccharide having a critical relative humidity of 95% or more at 25 ° C.
The present invention is a pharmaceutical composition containing rapamycin or a derivative thereof and the saccharide, and the composition prepared by adding the saccharide to the rapamycin or the like as a solution exhibits extremely high stability. This is a physical characteristic different from that of a pharmaceutical composition in which the rapamycin or the like and the saccharide are physically mixed, or a pharmaceutical composition prepared from a solution containing both of them. It is difficult to show such a more detailed aspect of the pharmaceutical composition according to the present invention by means of a chemical structure, properties, or the like. Therefore, it is appropriate that the pharmaceutical composition obtained in the present invention is represented as a pharmaceutical composition containing rapamycin or a derivative thereof specified by the production method shown in the above [6] and the saccharide, and the clarification of the invention. It is considered that the requirements of
[7] The pharmaceutical composition according to the above [6], wherein the content of rapamycin or a derivative thereof is at least 80% of the initial value after storage at 60 ° C. in the dark and at a relative humidity of about 49% for 14 days. Stuff.
The pharmaceutical composition of the present invention is excellent in storage stability, and in a more preferable embodiment, it is a pharmaceutical composition specified by the storage stability.
本発明により、ラパマイシン又はその誘導体の酸化や分解に伴う有効成分含量の低減を抑制し、長期安定性が確保できるラパマイシン又はその誘導体を含有する医薬組成物を製造することができる。 INDUSTRIAL APPLICABILITY According to the present invention, it is possible to produce a pharmaceutical composition containing rapamycin or a derivative thereof, which can suppress a decrease in the active ingredient content due to oxidation or decomposition of rapamycin or a derivative thereof and can secure long-term stability.
本発明の医薬組成物は、ラパマイシン又はその誘導体を含有する溶液を、２５℃における臨界相対湿度が９５％以上の糖類に添加する工程を含む、ラパマイシン又はその誘導体を含有する医薬組成物の製造方法、並びに該製造方法により調製される医薬組成物に関する。以下にその詳細を説明する。 The pharmaceutical composition of the present invention is a method for producing a pharmaceutical composition containing rapamycin or a derivative thereof, which comprises a step of adding a solution containing rapamycin or a derivative thereof to a saccharide having a critical relative humidity of 95% or more at 25 ° C. , And the pharmaceutical composition prepared by the production method. The details will be described below.
本発明は、有効成分としてラパマイシン又はその誘導体を含有する。
ラパマイシン（一般名 シロリムス）は、イースター島の土壌から分離された放線菌Ｓｔｒｅｐｔｏｍｙｃｅｓ Ｈｙｇｒｏｓｃｏｐｉｃｕｓの代謝産物から単離されたマクロライド骨格を有する化合物である。
ラパマイシン誘導体とは、ラパマイシンを母格として化学修飾を施したものを指す。ラパマイシン誘導体としては、例えば、１６−Ｏ−置換ラパマイシン（例えばＷＯ９４／０２２１３６を参照）、４０−Ｏ−置換ラパマイシン（例えばＵＳ５２５８３８９、ＷＯ９４／０９０１０を参照）、カルボン酸エステル置換ラパマイシン（例えばＷＯ９２／０５１７９を参照）、アミド置換ラパマイシン（例えばＵＳ５１１８６７７を参照）、フッ素置換ラパマイシン（例えばＵＳ５１００８８３を参照）、アセタール置換ラパマイシン（例えばＵＳ５１５１４１３を参照）等が挙げられる。本発明のラパマイシン又はその誘導体は、これらの化合物に限定されるものではないが、適用する好ましい化合物として挙げることができる。
ラパマイシン誘導体としては、ラパマイシンのシクロヘキシル基の４０位ヒドロキシル基がヒドロキシアルキル基、ヒドロキシアルコキシアルキル基、アシルアミノアルキル基及びアミノアルキル基、ヒロドキシ置換アシル基で置換されている４０−Ｏ−置換ラパマイシン誘導体が好ましい。
より好ましいラパマイシン誘導体としては、４０−Ｏ−(２−ヒドロキシエチル)ラパマイシン（エベロリムス）であり、４０−Ｏ−［３−ヒドロキシ−２−（ヒドロキシメチル）−２−メチルプロパノエート］ラパマイシン（テムシロリムス）である。
The present invention contains rapamycin or a derivative thereof as an active ingredient.
Rapamycin (generic name sirolimus) is a compound having a macrolide skeleton isolated from a metabolite of the actinomycete Streptomyces Hygroscopicus isolated from the soil of Easter Island.
The rapamycin derivative refers to a derivative obtained by chemically modifying rapamycin as a mother. Examples of rapamycin derivatives include 16-O-substituted rapamycin (see, eg, WO94 / 02213), 40-O-substituted rapamycin (see, eg, US525389, WO94 / 09010), and carboxylic acid ester-substituted rapamycin (eg, WO92 / 05179). Included), amide-substituted rapamycin (see, eg, US5118677), fluorine-substituted rapamycin (see, eg, US510883), acetal-substituted rapamycin (see, eg, US5151413) and the like. The rapamycin or its derivative of the present invention is not limited to these compounds, but can be mentioned as a preferable compound to be applied.
Examples of the rapamycin derivative include a 40-O-substituted rapamycin derivative in which the hydroxyl group at the 40-position of the cyclohexyl group of rapamycin is substituted with a hydroxyalkyl group, a hydroxyalkoxyalkyl group, an acylaminoalkyl group and an aminoalkyl group, and a hirodoxy-substituted acyl group. preferable.
More preferred rapamycin derivatives are 40-O- (2-hydroxyethyl) rapamycin (everolimus) and 40-O- [3-hydroxy-2- (hydroxymethyl) -2-methylpropanoate] rapamycin (temsirolimus). ).
本発明のラパマイシン又はその誘導体としては、ラパマイシン（シロリムス）、エベロリムス、テムシロリムスを用いることが好ましい。
ラパマイシン又はその誘導体は、医薬品として用いることができる品質レベルの化合物を用いることが好ましい。
As rapamycin or a derivative thereof of the present invention, it is preferable to use rapamycin (sirolimus), everolimus, and temsirolimus.
As rapamycin or a derivative thereof, it is preferable to use a compound having a quality level that can be used as a pharmaceutical product.
本発明において、ラパマイシン又はその誘導体の溶液を調製するための溶媒は、ラパマイシンを溶解できれば特に限定されることなく適用することができる。例えば、水、メタノール、エタノール、１−プロパノール、２−プロパノール、１−ブタノール、２−ブタノール、２−メチル−１−プロパノール、３−メチル−１−ブタノール、１−ペンタノール、エチレングリコール、グリセリン、ギ酸、酢酸、アセトン、メチルエチルケトン、メチルイソブチルケトン、アニソール、酢酸メチル、酢酸エチル、ギ酸エチル、酢酸プロピル、酢酸イソプロピル、酢酸ｎ−ブチル、酢酸イソブチル、アセトニトリル、ジエチルエーテル、ｔ−ブチルメチルエーテル、テトラヒドロフラン、１，４−ジオキサン、ジイソプロピルエーテル、ペンタン、ヘキサン、ヘプタン、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチルピロリドン、１，３−ジメチル−２−イミダゾリジノン、ジメチルスルホキシド、ジクロロメタン、クロロホルム等が挙げられる。
これらの溶媒は単独で用いても良く、２種類以上の溶媒を用いた混合溶媒でもよい。本発明は上記の溶媒の使用に限定されるものではないが、適用する好ましい溶媒として挙げることができる。
In the present invention, the solvent for preparing a solution of rapamycin or a derivative thereof can be applied without particular limitation as long as rapamycin can be dissolved. For example, water, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 3-methyl-1-butanol, 1-pentanol, ethylene glycol, glycerin, Formic acid, acetic acid, acetone, methyl ethyl ketone, methyl isobutyl ketone, anisole, methyl acetate, ethyl acetate, ethyl formate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, acetonitrile, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, diisopropyl ether, pentane, hexane, heptane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethylsulfoxide, dichloromethane , Chloroform and the like.
These solvents may be used alone or may be a mixed solvent using two or more kinds of solvents. The present invention is not limited to the use of the above solvents, but may be mentioned as preferred solvents to be applied.
該溶媒は後に除去することを考慮すると、温和な条件で溜去することが可能である沸点が１２０℃以下の溶媒を用いることが好ましい。例えば、水、メタノール、エタノール、１−プロパノール、２−プロパノール、アセトニトリル、アセトン、メチルエチルケトン、酢酸エチル、酢酸エチル、酢酸イソプロピル、酢酸イソブチル、テトラヒドロフラン、１，４−ジオキサン、ペンタン、へプタン、ジエチルエーテル、ｔ−ブチルメチルエーテルが好ましい。
また、本発明で用いる溶媒は、後述する２５℃における臨界相対湿度が９５％以上である糖類が不溶性又は難溶性の溶媒を用いることが好ましい。したがって、上記の好ましい溶媒において、メタノール、エタノール、１−プロパノール、２−プロパノール、アセトン、酢酸イソプロピル、酢酸エチルを用いることが特に好ましい。これらの溶媒をそれぞれ単独で用いても良く、併用して用いても良い。
Considering that the solvent will be removed later, it is preferable to use a solvent having a boiling point of 120 ° C. or lower, which can be distilled off under mild conditions. For example, water, methanol, ethanol, 1-propanol, 2-propanol, acetonitrile, acetone, methyl ethyl ketone, ethyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, tetrahydrofuran, 1,4-dioxane, pentane, heptane, diethyl ether, t-Butyl methyl ether is preferred.
Further, as the solvent used in the present invention, it is preferable to use a solvent in which the saccharide having a critical relative humidity of 95% or more at 25 ° C. described later is insoluble or sparingly soluble. Therefore, it is particularly preferable to use methanol, ethanol, 1-propanol, 2-propanol, acetone, isopropyl acetate, and ethyl acetate in the above preferred solvents. Each of these solvents may be used alone or in combination.
該溶媒の使用量は、ラパマイシン又はその誘導体が完全に溶解すれば良く、適宜、使用量を調整することができる。好ましくはラパマイシン又はその誘導体含有濃度として、１〜１０００ｍｇ／ｍＬ以下の溶液を調製することであり、好ましくは、１０〜５００ｍｇ／ｍＬの溶液である。
また溶液調製において、適宜加温を行いラパマイシン又はその誘導体の溶解を促しても良い。溶液調製時の溶液温度は、特に限定されるものではないが、ラパマイシン又はその誘導体の安定性を考慮して０〜８０℃で溶液を調製することが好ましい。
The amount of the solvent used may be adjusted as appropriate, as long as rapamycin or a derivative thereof is completely dissolved. It is preferable to prepare a solution having a rapamycin or a derivative-containing concentration of 1 to 1000 mg / mL or less, and a solution of 10 to 500 mg / mL is preferable.
Further, in the solution preparation, heating may be appropriately performed to promote the dissolution of rapamycin or a derivative thereof. The solution temperature at the time of preparing the solution is not particularly limited, but it is preferable to prepare the solution at 0 to 80 ° C. in consideration of the stability of rapamycin or a derivative thereof.
本発明は、医薬組成物の担体として２５℃における臨界相対湿度が９５％以上である糖類を用いる。「２５℃における臨界相対湿度が９５％以上である」とは、２５℃における相対湿度が９５％以下の保存環境において、ほとんど吸湿しない物性であることを示す。臨界相対湿度は、例えば文献、Ｅｕｒｏｐｅａｎ Ｊｏｕｒｎａｌ ｏｆ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｓｃｉｅｎｃｅｓ ４１ （２０１０）３８３−３８７記載の方法で測定することができる。
本発明は、２５℃における臨界相対湿度が９５％以上である糖類であれば特に限定されずに適用することができる。このような物性の糖類は単糖類、オリゴ糖等において見出すことができ、当業者において低吸湿性の糖類として通常認知されている。
当該２５℃における臨界相対湿度が９５％以上である糖類としては、糖アルコール又は二糖類が好ましく、マンニトール、乳糖、トレハロース及びマルトースからなる群から選択される１種以上の糖類が好ましい。これらの糖類はそれぞれ単独で用いても良く、２種類以上を併用して用いても良い。乳糖を用いることが特に好ましい。
The present invention uses a saccharide having a critical relative humidity of 95% or more at 25 ° C. as a carrier of the pharmaceutical composition. "The critical relative humidity at 25 ° C. is 95% or more" indicates that the physical property hardly absorbs moisture in a storage environment where the relative humidity at 25 ° C. is 95% or less. The critical relative humidity can be measured, for example, by the method described in the literature, European Journal of Pharmaceutical Sciences 41 (2010) 383-387.
The present invention can be applied without particular limitation as long as it is a saccharide having a critical relative humidity of 95% or more at 25 ° C. Sugars having such physical characteristics can be found in monosaccharides, oligosaccharides and the like, and are usually recognized as low hygroscopic sugars by those skilled in the art.
As the saccharide having a critical relative humidity of 95% or more at 25 ° C., a sugar alcohol or a disaccharide is preferable, and one or more saccharides selected from the group consisting of mannitol, lactose, trehalose and maltose are preferable. Each of these sugars may be used alone, or two or more kinds may be used in combination. It is particularly preferable to use lactose.
本発明における２５℃における臨界相対湿度が９５％以上である糖類の添加量は、ラパマイシン又はその誘導体が１質量部に対し、０．５質量部以上を用いれば良い。好ましくは、１質量部以上を用いれば良く、更に好ましくは２質量部以上の使用である。５質量部以上を用いれば十分量である。本発明において、２５℃における臨界相対湿度が９５％以上である糖類は安全上特に問題ないことから、その使用量の上限は特になく、医薬品として実用可能な使用量において設定されるべきである。
ラパマイシン又はその誘導体の安定性確保と、医薬品添加剤の現実的な使用量を考慮すると、ラパマイシン又はその誘導体１質量部に対し、当該糖類は０．５〜１００質量部で用いることが好ましい。好ましくは０．５〜５０質量部であり、より好ましくは１〜５０質量部であり、更に好ましくは２〜５０質量部である。
The amount of the saccharide having a critical relative humidity of 95% or more at 25 ° C. in the present invention may be 0.5 parts by mass or more with respect to 1 part by mass of rapamycin or a derivative thereof. It is preferable to use 1 part by mass or more, and more preferably 2 parts by mass or more. It is a sufficient amount if 5 parts by mass or more is used. In the present invention, since there is no particular safety problem with saccharides having a critical relative humidity of 95% or more at 25 ° C., there is no particular upper limit on the amount of saccharides used, and the amount used should be set to a practical amount as a pharmaceutical product.
Considering the stability of rapamycin or its derivative and the practical amount of the pharmaceutical additive used, it is preferable to use the saccharide in an amount of 0.5 to 100 parts by mass with respect to 1 part by mass of rapamycin or its derivative. It is preferably 0.5 to 50 parts by mass, more preferably 1 to 50 parts by mass, and further preferably 2 to 50 parts by mass.
本発明のより好ましい態様として、ラパマイシン又はその誘導体を含有する溶液は、更に安定化剤が含有した溶液を用いることが挙げられる。
安定化剤とは、ラパマイシン又はその誘導体に添加することでラパマイシン又はその誘導体の酸化や光分解、加水分解を抑制して、安定性を持続させるものであれば特に限定されない。このような安定化剤としては、ラパマイシン及びその誘導体の安定化効果を示す公知の抗酸化剤や安定化剤を用いることができる。
例えば、亜硝酸、アスコルビン酸、アスコルビン酸ナトリウム、アスコルビン酸ステアリン酸エステル、アスコルビン酸パルミチン酸エステル、亜硫酸、アルファチオグリセリン、エデト酸、エリソルビン酸、塩酸システイン、クエン酸、クエン酸ナトリウム、クエン酸水素二ナトリウム、クエン酸二水素ナトリウム、ジクロルイソシアヌール酸、ジブチルヒドロキシトルエン（ＢＨＴ）、チオグリコール酸、チオリンゴ酸、トコフェロール、トレハロース、ピロ亜硫酸、ブチルヒドロキシアニソール、１，３−ブチレングリコール、ペンタエリトリトールテトラキス［３−（３，５−ジ−ｔ−ブチル４−ヒドロキシフェニル）プロピオナート］ベンゾトリアゾール、没食子酸イソプロピル、２−メルカプトベンズイミダゾール、レシチン等が挙げられる。該安定化剤としては、これらの化合物に限定されるものではないが、本発明に適用することが好ましい安定化剤として挙げることができる。前記安定化剤をそれぞれ単独で用いても良く、併用して用いても良い。
安定化剤としてより好ましくは、アスコルビン酸ナトリウム、アスコルビン酸ステアリン酸エステル、クエン酸水素二ナトリウム、クエン酸二水素ナトリウム、ジブチルヒドロキシトルエン（ＢＨＴ）、トコフェロール、トレハロース、ブチルヒドロキシアニソール、没食子酸イソプロピル、レシチンが挙げられる。最も好ましくはアスコルビン酸ナトリウム、アスコルビン酸ステアリン酸エステル、クエン酸水素二ナトリウム、ジブチルヒドロキシトルエン（ＢＨＴ）、トコフェロール、トレハロース、レシチンが挙げられる。
As a more preferable embodiment of the present invention, as the solution containing rapamycin or a derivative thereof, a solution further containing a stabilizer may be used.
The stabilizer is not particularly limited as long as it is added to rapamycin or a derivative thereof to suppress oxidation, photodecomposition and hydrolysis of rapamycin or a derivative thereof to maintain stability. As such a stabilizer, a known antioxidant or stabilizer that exhibits a stabilizing effect on rapamycin and its derivative can be used.
For example, nitrite, ascorbic acid, sodium ascorbate, ascorbic acid stearate, ascorbic acid palmitate, sulfite, alphathioglycerin, edetic acid, erythorbic acid, cysteine hydrochloride, citric acid, sodium citrate, dihydrogen citrate. Sodium, sodium dihydrogen citrate, dichloroisocyanuric acid, dibutylhydroxytoluene (BHT), thioglycolic acid, thioannic acid, tocopherol, trehalose, pyrosulfite, butylhydroxyanisole, 1,3-butylene glycol, pentaerythritol tetrakis [ 3- (3,5-di-t-butyl4-hydroxyphenyl) propionate] benzotriazole, isopropyl citrate, 2-mercaptobenzimidazole, lecithin and the like can be mentioned. The stabilizer is not limited to these compounds, but can be mentioned as a preferred stabilizer to be applied to the present invention. The stabilizers may be used alone or in combination.
More preferably as a stabilizer, sodium ascorbate, ascorbic acid stearate, disodium hydrogen citrate, sodium dihydrogen citrate, dibutylhydroxytoluene (BHT), tocopherol, trehalose, butylhydroxyanisole, isopropyl castorate, lecithin. Can be mentioned. Most preferably, sodium ascorbate, stearic acid ester ascorbic acid, disodium hydrogen citrate, dibutylhydroxytoluene (BHT), tocopherol, trehalose, lecithin can be mentioned.
前記安定化剤は、ラパマイシン又はその誘導体の安定性を損なわない程度の量で適宜用いることができる。前記安定化剤の添加量としては、ラパマイシン又はその誘導体１質量部に対し、安定化剤は０．０００１〜１０質量部で用いることが好ましい。より好ましくは０．０００５〜１．０質量部であり、更に好ましくは０．００１〜１．０質量部である。
なお、前記安定化剤はラパマイシン又はその誘導体溶液に加えられ、完全に溶解した状態で適用することが好ましい。
The stabilizer can be appropriately used in an amount that does not impair the stability of rapamycin or a derivative thereof. The amount of the stabilizer added is preferably 0.0001 to 10 parts by mass with respect to 1 part by mass of rapamycin or a derivative thereof. It is more preferably 0.0005 to 1.0 part by mass, and further preferably 0.001 to 1.0 part by mass.
The stabilizer is preferably added to a rapamycin or a derivative solution thereof and applied in a completely dissolved state.
本発明のより好ましい態様として、ラパマイシン又はその誘導体を含有する溶液に、更に水溶性高分子担体を含有した溶液を用いることが挙げられる。
水溶性高分子担体とは、医薬品の添加剤として適用な可能な水溶性高分子担体であれば特に限定されるものではなく、適用することができる。該水溶性高分子担体としては、例えば水溶性合成高分子誘導体担体、水溶性セルロース誘導体担体、等が挙げられる。
水溶性合成高分子誘導体担体としては、ポビドン、マクロゴール、ポリビニルアルコール、メタクリル酸コポリマー等が挙げられる。これらの水溶性合成高分子誘導体担体は、それぞれ単独で用いても良く、併用して用いても良い。
As a more preferable embodiment of the present invention, a solution containing a water-soluble polymer carrier is used as a solution containing rapamycin or a derivative thereof.
The water-soluble polymer carrier is not particularly limited as long as it is a water-soluble polymer carrier that can be applied as an additive for pharmaceutical products, and can be applied. Examples of the water-soluble polymer carrier include a water-soluble synthetic polymer derivative carrier, a water-soluble cellulose derivative carrier, and the like.
Examples of the water-soluble synthetic polymer derivative carrier include povidone, macrogol, polyvinyl alcohol, and methacrylic acid copolymer. These water-soluble synthetic polymer derivative carriers may be used alone or in combination.
本発明における前記水溶性高分子担体は、水溶性セルロース誘導体を用いることが好ましい。前記水溶性セルロース誘導体とは、セルロースの水酸基の水素原子の一部を、メチル基、エチル基、プロピル基、ヒドロキシプロピル基、カルボキシメチル基等の置換基で置換した水溶性高分子である。
本発明で使用される水溶性セルロース誘導体としては、医薬品添加剤として許容されるものであることが好ましく、具体的には、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、メチルセルロース、エチルセルロース、ヒドロキシエチルセルロース、ヒドロキシメチルエチルセルロース、セラセフェート、ヒドロキシプロピルメチルセルロースフタレート、ヒプロメロースアセテートスクシネート、ヒプロメロースフタル酸エステル、カルボキシメチルセルロース、及びこれらのナトリウム塩、カリウム塩等のアルカリ金属塩等が挙げられる。好ましくは、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、メチルセルロース、エチルセルロース、ヒプロメロースフタル酸エステルが挙げられ、最も好ましくはヒドロキシプロピルメチルセルロースである。
As the water-soluble polymer carrier in the present invention, it is preferable to use a water-soluble cellulose derivative. The water-soluble cellulose derivative is a water-soluble polymer in which a part of hydrogen atoms of the hydroxyl group of cellulose is substituted with a substituent such as a methyl group, an ethyl group, a propyl group, a hydroxypropyl group or a carboxymethyl group.
The water-soluble cellulose derivative used in the present invention is preferably one that is acceptable as a pharmaceutical additive, and specifically, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl ethyl cellulose. , Ceracelate, hydroxypropylmethylcellulose phthalate, hypromellose acetate succinate, hypromellose phthalate, carboxymethylcellulose, and alkali metal salts such as sodium salts and potassium salts thereof. Preferred are hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, hypromellose phthalate, and most preferably hydroxypropylmethylcellulose.
本発明における水溶性高分子担体の添加量は、ラパマイシン又はその誘導体１質量部に対し、０．１質量部以上を用いることが好ましい。より好ましくは、０．５質量部以上を用いることが良い。すなわち、前記水溶性高分子担体は、ラパマイシン又はその誘導体の安定性を損なわない程度の量で適宜用いることができる。前記安定化剤の添加量としては、ラパマイシン又はその誘導体１質量部に対し、該水溶性高分子担体は０．１〜１０質量部で用いることが好ましい。より好ましくは０．１〜５．０質量部であり、更に好ましくは０．５〜５．０質量部である。
なお、前記水溶性高分子担体はラパマイシン又はその誘導体溶液に加えられ、完全に溶解した状態であっても良く、該水溶性高分子担体が懸濁した状態であっても良く、何れの態様で用いても良い。
The amount of the water-soluble polymer carrier added in the present invention is preferably 0.1 part by mass or more with respect to 1 part by mass of rapamycin or a derivative thereof. More preferably, 0.5 parts by mass or more is used. That is, the water-soluble polymer carrier can be appropriately used in an amount that does not impair the stability of rapamycin or a derivative thereof. The amount of the stabilizer added is preferably 0.1 to 10 parts by mass with respect to 1 part by mass of rapamycin or a derivative thereof. It is more preferably 0.1 to 5.0 parts by mass, and even more preferably 0.5 to 5.0 parts by mass.
The water-soluble polymer carrier may be added to rapamycin or a derivative solution thereof and completely dissolved, or the water-soluble polymer carrier may be suspended. You may use it.
本発明は、ラパマイシン又はその誘導体溶液に、本発明の効果を妨げない範囲で医薬品製剤を調製するために通常用いられる他の添加剤を含んでいても良い。例えば、ｐＨ調整剤、無機塩類等を適用しても良い。
ｐＨ調整剤としては、例えば塩酸、硫酸、リン酸、クエン酸、酒石酸、リンゴ酸、メシル酸、トシル酸、ベシル酸等を挙げることができる。これらの酸性添加剤を主成分として、これにアルカリ金属塩、アルカリ土類金属塩、アンモニウム塩を含んだ緩衝剤を用いても良い。
無機塩類としては塩化カルシウム、塩化ナトリウム、酸化カルシウム、硫酸マグネシウム等が挙げられる。
前記他の添加剤を用いる場合は、ラパマイシン又はその誘導体１質量部に対し、０．０１〜１０質量部で用いることが好ましい。
なお、前記他の添加剤はラパマイシン又はその誘導体溶液に加えられ、完全に溶解した状態であっても良く、懸濁した状態であっても良く、何れの態様で用いても良い。
In the present invention, rapamycin or a derivative solution thereof may contain other additives usually used for preparing a pharmaceutical preparation without interfering with the effects of the present invention. For example, a pH adjuster, inorganic salts and the like may be applied.
Examples of the pH adjuster include hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, malic acid, mesylic acid, tosylic acid, besilic acid and the like. A buffer agent containing these acidic additives as a main component and containing an alkali metal salt, an alkaline earth metal salt, and an ammonium salt may be used.
Examples of inorganic salts include calcium chloride, sodium chloride, calcium oxide, magnesium sulfate and the like.
When the other additive is used, it is preferably used in an amount of 0.01 to 10 parts by mass with respect to 1 part by mass of rapamycin or a derivative thereof.
The other additive may be added to rapamycin or a derivative solution thereof and may be in a completely dissolved state or a suspended state, and may be used in any embodiment.
本発明の医薬組成物は、前記ラパマイシン又はその誘導体等を含有する溶液を、固体状態にある２５℃における臨界相対湿度が９５％以上である糖類へ添加して、混合することにより調製される。
前記固体状態の２５℃における臨界相対湿度が９５％以上である糖類は、該糖類のみであることが好ましいが、本発明の効果を妨げない範囲で医薬品製剤を調製するために通常用いられる他の添加剤を含んでいても良い。すなわち、本発明は２５℃における臨界相対湿度が９５％以上である糖類を含有する固体担体に対して、ラパマイシン又はその誘導体を含有する溶液を添加することを要旨として含む。
The pharmaceutical composition of the present invention is prepared by adding a solution containing the rapamycin or a derivative thereof and the like to a saccharide having a critical relative humidity of 95% or more at 25 ° C. in a solid state and mixing them.
The saccharide having a critical relative humidity of 95% or more at 25 ° C. in the solid state is preferably only the saccharide, but other saccharides usually used for preparing a pharmaceutical preparation within a range that does not interfere with the effects of the present invention. It may contain additives. That is, the gist of the present invention is to add a solution containing rapamycin or a derivative thereof to a solid carrier containing a saccharide having a critical relative humidity of 95% or more at 25 ° C.
他の添加剤としては、例えば、賦形剤、崩壊剤、結合剤、滑沢剤、ｐＨ調整剤、無機塩類等を適用しても良い。
賦形剤としては、スクロース、エリスリトール、ソルビトール、フコース、キシリトール、フルクトース、イノシトール、デンプン等の糖類を挙げることができる。
崩壊剤としては、カルメロース、クロスポビドン、低置換ヒドロキシプロピルセルロース、デンプングリコール酸ナトリウム、カルメロースカルシウム、クロスカルメロースナトリウム等を挙げることができる。
結合剤としては、ヒドロキシプロピルセルロース、ピプロメロース、ポリビニルアルコール、ポリビニルピロリドン等を挙げることができる。
滑沢剤としては、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、ショ糖脂肪酸エステル等を挙げることができる。
ｐＨ調整剤としては、例えば塩酸、硫酸、リン酸、クエン酸、酒石酸、リンゴ酸、メシル酸、トシル酸、ベシル酸等を挙げることができる。これらの酸性添加剤を主成分として、これにアルカリ金属塩、アルカリ土類金属塩、アンモニウム塩を含んだ緩衝剤を用いても良い。
無機塩類としては塩化カルシウム、塩化ナトリウム、酸化カルシウム、硫酸マグネシウム等が挙げられる。
これらの添加剤は、医薬品製剤用途で許容される純度であれば特に制限されることなく用いることができる。これらの添加剤は１種のみを用いても良く、これらの混合物として用いても良い。当該医薬組成物又は医薬製剤を調製する際に、任意に使用される。
As other additives, for example, excipients, disintegrants, binders, lubricants, pH adjusters, inorganic salts and the like may be applied.
Examples of the excipient include sugars such as sucrose, erythritol, sorbitol, fucose, xylitol, fructose, inositol, and starch.
Examples of the disintegrant include carmellose, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate, carmellose calcium, croscarmellose sodium and the like.
Examples of the binder include hydroxypropyl cellulose, pipromerose, polyvinyl alcohol, polyvinylpyrrolidone and the like.
Examples of the lubricant include magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, and sucrose fatty acid ester.
Examples of the pH adjuster include hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, malic acid, mesylic acid, tosylic acid, besilic acid and the like. A buffer agent containing these acidic additives as a main component and containing an alkali metal salt, an alkaline earth metal salt, and an ammonium salt may be used.
Examples of inorganic salts include calcium chloride, sodium chloride, calcium oxide, magnesium sulfate and the like.
These additives can be used without particular limitation as long as the purity is acceptable for pharmaceutical preparation applications. Only one of these additives may be used, or a mixture thereof may be used. It is optionally used when preparing the pharmaceutical composition or pharmaceutical preparation.
前記ラパマイシン又はその誘導体等を含有する溶液を、固体状態にある前記糖類へ添加する方法としては、特に限定されるものではないが、前記ラパマイシン等溶液と前記糖類が均一に混合する添加方法を用いることが好ましく、該溶液を該糖類へ滴下する方法が好ましい。より好ましくは、該溶液を噴霧状に滴下することが好ましい。該糖類を混合しながら該溶液を滴下する方法がより好ましい。 The method for adding the solution containing rapamycin or a derivative thereof or the like to the saccharide in a solid state is not particularly limited, but an addition method in which the solution such as rapamycin or the saccharide is uniformly mixed is used. It is preferable, and a method of dropping the solution onto the saccharide is preferable. More preferably, the solution is dropped in the form of a spray. A method of dropping the solution while mixing the saccharides is more preferable.
本発明の医薬組成物は、前記ラパマイシン又はその誘導体等を含有する溶液を、固体状態にある前記糖類へ添加した後、溶媒を除去することが好ましい。例えば、前記溶液を加熱することで溶媒除去することができるが、その際、減圧条件とすることで温和な温度条件で溶媒を除去することができることから好ましい。また、乾燥機の中に空気や窒素等の不活性ガスを送風し乾燥させる、通風乾燥によっても固体混合物を得ることができる。 In the pharmaceutical composition of the present invention, it is preferable to add a solution containing the rapamycin or a derivative thereof or the like to the saccharide in a solid state, and then remove the solvent. For example, the solvent can be removed by heating the solution, but at that time, it is preferable to set the reduced pressure condition because the solvent can be removed under mild temperature conditions. A solid mixture can also be obtained by ventilation drying, in which an inert gas such as air or nitrogen is blown into the dryer to dry it.
本発明の医薬組成物は、有効成分であるラパマイシン又はその誘導体の酸化や分解を抑制し、これに伴う有効成分含量の低減を防止することができるため、保存安定性に優れた医薬組成物を調製することができる。本発明の保存安定性は、医薬品開発における物理化学的安定性に係る試験方法を用いて評価することができる。例えば、加速試験である、遮光下６０℃で、飽和塩化コバルト水溶液で相対湿度約４９％に調整した保存庫で、１４日保存した場合、ラパマイシン又はその誘導体の含有量が初期値に対して少なくとも８０％を含有する物性である。 The pharmaceutical composition of the present invention can suppress the oxidation and decomposition of rapamycin or a derivative thereof, which is an active ingredient, and prevent the accompanying reduction in the content of the active ingredient. Therefore, a pharmaceutical composition having excellent storage stability can be obtained. Can be prepared. The storage stability of the present invention can be evaluated using a test method relating to physicochemical stability in drug development. For example, when stored for 14 days in an accelerated test, a storage room adjusted to a relative humidity of about 49% with a saturated aqueous cobalt chloride solution at 60 ° C. under shading, the content of rapamycin or a derivative thereof is at least the initial value. It is a physical property containing 80%.
上述した方法により調製される本発明の医薬組成物は、これを用いて医薬製剤を調製することができる。すなわち、本発明の医薬組成物に、医薬品製剤を調製するために通常用いられる添加剤を併せて、医薬製剤を調製することができる。他の添加剤としては、例えば、賦形剤、崩壊剤、結合剤、滑沢剤、ｐＨ調整剤、無機塩類、溶剤等を適用しても良い。
賦形剤としては、ラクトース、マルトース、マンニトール、スクロース、エリスリトール、ソルビトール、フコース、キシリトール、フルクトース、イノシトール、デンプン等の糖類を挙げることができる。
崩壊剤としては、カルメロース、クロスポビドン、低置換ヒドロキシプロピルセルロース、デンプングリコール酸ナトリウム、カルメロースカルシウム、クロスカルメロースナトリウム等を挙げることができる。
結合剤としては、ヒドロキシプロピルセルロース、ピプロメロース、ポリビニルアルコール、ポリビニルピロリドン等を挙げることができる。
滑沢剤としては、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、ショ糖脂肪酸エステル等を挙げることができる。
ｐＨ調整剤としては、例えば塩酸、硫酸、リン酸、クエン酸、酒石酸、リンゴ酸、メシル酸、トシル酸、ベシル酸等を挙げることができる。これらの酸性添加剤を主成分として、これにアルカリ金属塩、アルカリ土類金属塩、アンモニウム塩を含んだ緩衝剤を用いても良い。
無機塩類としては塩化カルシウム、塩化ナトリウム、酸化カルシウム、硫酸マグネシウム等が挙げられる。
溶剤としては、通常、水、生理食塩水、５％ブドウ糖又はマンニトール水溶液、水溶性有機溶媒（例えば、グリセロール、エタノール、ジメチルスルホキシド、Ｎ−メチルピロリドン、ポリエチレングリコール、クレモフォア等の単一溶媒又はこれらの混合溶媒）、ポリエチレングリコール類（例えば、ポリエチレングリコール３００、ポリエチレングリコール４００、ポリエチレングリコール６００、ポリエチレングリコール４０００等）が挙げられる。
これらの添加剤は、医薬品製剤用途で許容される純度であれば特に制限されることなく用いることができる。これらの添加剤は１種のみを用いても良く、これらの混合物として用いても良い。当該医薬組成物又は医薬製剤を調製する際に、任意に使用される。
The pharmaceutical composition of the present invention prepared by the method described above can be used to prepare a pharmaceutical preparation. That is, a pharmaceutical preparation can be prepared by combining the pharmaceutical composition of the present invention with an additive usually used for preparing the pharmaceutical preparation. As other additives, for example, excipients, disintegrants, binders, lubricants, pH adjusters, inorganic salts, solvents and the like may be applied.
Examples of the excipient include sugars such as lactose, maltose, mannitol, sucrose, erythritol, sorbitol, fucose, xylitol, fructose, inositol, and starch.
Examples of the disintegrant include carmellose, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate, carmellose calcium, croscarmellose sodium and the like.
Examples of the binder include hydroxypropyl cellulose, pipromerose, polyvinyl alcohol, polyvinylpyrrolidone and the like.
Examples of the lubricant include magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, and sucrose fatty acid ester.
Examples of the pH adjuster include hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, malic acid, mesylic acid, tosylic acid, besilic acid and the like. A buffer agent containing these acidic additives as a main component and containing an alkali metal salt, an alkaline earth metal salt, and an ammonium salt may be used.
Examples of inorganic salts include calcium chloride, sodium chloride, calcium oxide, magnesium sulfate and the like.
The solvent is usually a single solvent such as water, physiological saline, 5% dextrose or mannitol aqueous solution, a water-soluble organic solvent (for example, glycerol, ethanol, dimethylsulfoxide, N-methylpyrrolidone, polyethylene glycol, cremophore, etc.) or a single solvent thereof. Mixed solvent), polyethylene glycols (for example, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 4000, etc.).
These additives can be used without particular limitation as long as the purity is acceptable for pharmaceutical preparation applications. Only one of these additives may be used, or a mixture thereof may be used. It is optionally used when preparing the pharmaceutical composition or pharmaceutical preparation.
本発明の医薬組成物は、該医薬組成物を含む医薬品として製造することができる。
この医薬品としての製剤形は、錠剤、分散錠、チュアブル錠、発泡錠、トローチ剤、ドロップ剤、硬カプセル剤、軟カプセル剤、顆粒剤、散剤、丸剤、ドライシロップ剤、浸剤・煎剤、舐剤、シロップ剤、ドリンク剤、懸濁剤、口腔内崩壊錠、ゼリー剤、等の内用剤、坐剤、パップ剤、プラスター剤、軟膏剤、クリーム剤、ムース剤液、液剤、点眼剤、エアゾール剤、噴霧剤等の外用剤が挙げることができる。これらの製剤形に限定されるものではないが、適用する好ましい製剤形として挙げることができる。
また、本発明の医薬組成物を注射剤として用いる場合、水性注射剤、非水性注射剤、懸濁性注射剤、乳濁性注射剤、用時溶解又は懸濁して用いる製剤形として、皮内注射、皮下注射、筋肉内注射、静脈内注射、中心静脈内注射、動脈内注射、脊髄腔内注射等が挙げられる。これらに限定されるものではないが、適用する好ましい製剤形、投与経路として挙げることができる。
The pharmaceutical composition of the present invention can be produced as a pharmaceutical product containing the pharmaceutical composition.
The formulation forms of this drug are tablets, dispersion tablets, chewable tablets, effervescent tablets, troches, drops, hard capsules, soft capsules, granules, powders, pills, dry syrups, soaking agents / decoctions, licking agents. , Syrups, drinks, suspensions, orally disintegrating tablets, jelly, etc., suppositories, paps, plasters, ointments, creams, mousse solutions, liquids, eye drops, aerosols Examples include external preparations such as agents and sprays. Although not limited to these formulation forms, it can be mentioned as a preferred formulation form to be applied.
When the pharmaceutical composition of the present invention is used as an injection, it is used intradermally as an aqueous injection, a non-aqueous injection, a suspension injection, an emulsion injection, or a formulation used by dissolving or suspending at the time of use. Examples thereof include injection, subcutaneous injection, intramuscular injection, intravenous injection, central intravenous injection, intraarterial injection, and intraspinal injection. Although not limited to these, it can be mentioned as a preferable formulation form and administration route to be applied.
本発明の医薬組成物を用いた医薬品は、疾患の治療に適用することができる。適用できる疾患としては、例えば、心臓、肺、複合心肺、肝臓、腎臓、膵臓、皮膚、角膜等の移植における拒絶反応の抑制、例えば、関節炎、リウマチ疾患、全身性エリテマトーデス、多軟骨炎、硬皮症、ウェゲナー肉芽腫、皮膚筋炎、慢性活動性肝炎、重症筋無力症、乾癬、スティーブン− ジョンソン症候群、特発性スプルー、自己免疫炎症性大腸炎、内分泌性眼病、グレーブス病、結節炎、多発性硬化症、原発性胆汁性肝炎、若年性糖尿病(Ｉ型糖尿病)、ブドウ膜炎、乾燥性角結膜炎、春季角結膜炎、間質性肺線維症、乾癬性関節炎、糸球体腎炎、若年性皮膚筋炎等の自己免疫疾患及び炎症性疾患、喘息、例えば乳癌、腎癌、神経内分泌腫瘍、リンパ増殖性疾患、Ｂ細胞リンパ腺癌、結節性硬化症、増殖性皮膚疾患等の癌や過増殖性疾患等が挙げられる。これらの疾患に限定されるものではないが、適用する好ましい疾患として挙げることができる。 A drug using the pharmaceutical composition of the present invention can be applied to the treatment of a disease. Applicable diseases include, for example, suppression of rejection in transplantation of heart, lung, compound cardiopulmonary, liver, kidney, pancreas, skin, corneum, etc., for example, arthritis, rheumatic disease, systemic erythematosus, polychondritis, cirrhosis. Disease, Wegener's granulomas, dermatitis, chronic active hepatitis, severe myasthenia, psoriasis, Stephen-Johnson syndrome, idiopathic sprue, autoimmune inflammatory colitis, endocrine eye disease, Graves' disease, nodular inflammation, polysclerosis Disease, primary biliary hepatitis, juvenile diabetes (type I diabetes), vegetitis, keratoconjunctivitis sicca, keratoconjunctivitis spring, interstitial pulmonary fibrosis, psoriatic arthritis, glomerular nephritis, juvenile dermatitis, etc. Autoimmune diseases and inflammatory diseases, asthma, such as breast cancer, renal cancer, neuroendocrine tumor, lymphoproliferative disorder, B-cell lymphadenopathy, nodular sclerosis, proliferative skin disease and other cancers and hyperproliferative disorders. Can be mentioned. Although not limited to these diseases, it can be mentioned as a preferable disease to be applied.
本発明の医薬組成物を用いた医薬品の投与量は、患者の性別、年齢、生理的状態、病態等により当然変更されうるが、例えば成人１日当たり、ラパマイシン又はその誘導体として０．０１〜１００ｍｇ／ｍ２（体表面積）を投与する。この投与量に限定されるものではないが、適用する好ましい投与量として挙げることができる。 The dose of the drug using the pharmaceutical composition of the present invention can be naturally changed depending on the sex, age, physiological condition, pathological condition, etc. of the patient, but for example, 0.01 to 100 mg / day as rapamycin or a derivative thereof per day for an adult. Administer m 2 (body surface area). Although not limited to this dose, it can be mentioned as a preferred dose to be applied.
以下、本発明を実施例により更に説明する。ただし、本発明がこれらの実施例に限定されるものではない。
なお、本試験例における液体クロマトグラフィー（ＨＰＬＣ）を用いた分析においては、以下の条件にて測定した。
測定カラム：Zorbax Eclipse XDB-C18, Rapid resolution HT, 100mm × 4.6mm, 1.8μm
検出器：紫外吸光光度計（測定波長 278nm）
カラム温度
移動相A： 0.1%ギ酸，移動相B：メタノール/アセトニトリル = 50/50
移動相の濃度勾配：
時間(分) ； 0, 5, 17, 22, 24, 25, 28
移動相A(vol%)； 46, 46, 25, 10, 10, 46, 46
移動相B(vol%)； 64, 64, 75, 90, 90, 64, 64
流量：1.5 mL/min
注入量：10μL
Hereinafter, the present invention will be further described with reference to Examples. However, the present invention is not limited to these examples.
In the analysis using liquid chromatography (HPLC) in this test example, the measurement was performed under the following conditions.
Measurement column: Zorbax Eclipse XDB-C18, Rapid resolution HT, 100mm x 4.6mm, 1.8μm
Detector: Ultraviolet absorptiometer (measurement wavelength 278 nm)
Column temperature mobile phase A: 0.1% formic acid, mobile phase B: methanol / acetonitrile = 50/50
Mobile phase concentration gradient:
Hours (minutes); 0, 5, 17, 22, 24, 25, 28
Mobile phase A (vol%); 46, 46, 25, 10, 10, 46, 46
Mobile phase B (vol%); 64, 64, 75, 90, 90, 64, 64
Flow rate: 1.5 mL / min
Injection volume: 10 μL
［実施例１］
試験管にエベロリムス １５０ｍｇを秤量し、ジブチルヒドロキシトルエン（ＢＨＴ、ＭＥＲＣＫ社製）無水エタノール 溶液（３０ｍｇ／ｍＬ）１０μＬ及び無水エタノール ７５０μＬを加えた後、超音波を５分間照射し、エベロリムスの溶解を確認した。その後、この混合溶液中にヒプロメロース（ＴＣ−５ Ｅ Ｔｙｐｅ、信越化学社製）１５０ｍｇを加え超音波を５分間照射した。この混合溶液を、無水乳糖（Ｓｕｐｅｒ Ｔａｂ（登録商標） ２１ ＡＮ、 ＤＦＥ Ｐｈａｒｍａ社製）１３５０ｍｇを乳鉢に秤量したところへパスツールピペットにて滴下し、乳棒を用いて撹拌した。この粉体をナスフラスコに移し、エバポレーターにて３時間減圧乾燥して実施例１に係る医薬組成物を調製した。なお、乳糖の２５℃における臨界相対湿度は９５％以上である。
[Example 1]
Weigh 150 mg of everolimus into a test tube, add 10 μL of dibutylhydroxytoluene (BHT, manufactured by MERCK) absolute ethanol solution (30 mg / mL) and 750 μL of anhydrous ethanol, and then irradiate with ultrasonic waves for 5 minutes to confirm the dissolution of everolimus. did. Then, 150 mg of hypromellose (TC-5 E Type, manufactured by Shin-Etsu Chemical Co., Ltd.) was added to this mixed solution, and ultrasonic waves were irradiated for 5 minutes. 1350 mg of anhydrous lactose (Super Tab (registered trademark) 21 AN, manufactured by DFE Pharma) was added dropwise to a mortar and pestle, and the mixture was stirred with a pestle. This powder was transferred to an eggplant flask and dried under reduced pressure for 3 hours on an evaporator to prepare the pharmaceutical composition according to Example 1. The critical relative humidity of lactose at 25 ° C. is 95% or more.
［比較例１］
試験管にエベロリムス １５０ｍｇを秤量し、ジブチルヒドロキシトルエン（ＢＨＴ、ＭＥＲＣＫ社製）無水エタノール 溶液（３０ｍｇ／ｍＬ）１０μＬ及び無水エタノール ７５ｍＬを加えた後、ホモジナイザー（ＵＬＴＲＡ−ＴＵＲＲＡＸ（登録商標） Ｔ２５ ｄｉｇｉｔａｌ、ＩＫＡ社製）を用い１０，０００ｒｐｍにて１分間撹拌し、エベロリムスの溶解を確認した。この混合溶液中にヒプロメロース（ＴＣ−５ Ｅ Ｔｙｐｅ、信越化学社製）１３５０ｍｇ及び無水乳糖（Ｓｕｐｅｒ Ｔａｂ（登録商標） ２１ ＡＮ、 ＤＦＥ Ｐｈａｒｍａ社製）１５０ｍｇを添加し、ホモジナイザー（ＵＬＴＲＡ−ＴＵＲＲＡＸ（登録商標） Ｔ２５ ｄｉｇｉｔａｌ、ＩＫＡ社製）を用い１０，０００ｒｐｍにてさらに６０分間撹拌した。この混合液をスプレードライヤー（Ｍｉｎｉ Ｓｐｒａｙ Ｄｒｙｅｒ Ｂ−２９０、ＢＵＣＨＩ社製）にて噴霧乾燥し比較例１に係る医薬組成物を調製した。
[Comparative Example 1]
Weigh 150 mg of Eberolimus into a test tube, add 10 μL of dibutylhydroxytoluene (BHT, manufactured by MERCK) absolute ethanol solution (30 mg / mL) and 75 mL of absolute ethanol, and then homogenizer (ULTRA-TURRAX® T25 digital, IKA). The dissolution of Eberolimus was confirmed by stirring at 10,000 rpm for 1 minute using (manufactured by the same company). Hypromellose (TC-5 E Type, manufactured by Shin-Etsu Chemical Co., Ltd.) 1350 mg and anhydrous lactose (Super Tab (registered trademark) 21 AN, DFE Pharma) 150 mg were added to this mixed solution, and a homogenizer (ULTRA-TURRAX (registered trademark)) was added. ) T25 digital, manufactured by IKA), and the mixture was further stirred at 10,000 rpm for 60 minutes. This mixed solution was spray-dried with a spray dryer (Mini Spray Dryer B-290, manufactured by BUCHI) to prepare a pharmaceutical composition according to Comparative Example 1.
［比較例２］
試験管にエベロリムス １５０ｍｇを秤量し、ジブチルヒドロキシトルエン（ＢＨＴ、ＭＥＲＣＫ社製）無水エタノール 溶液（３０ｍｇ／ｍＬ）１０μＬ及び無水エタノール ７５０μＬを加えた後、超音波を５分間照射しエベロリムスの溶解を確認した。この混合溶液をヒプロメロース（ＴＣ−５ Ｅ Ｔｙｐｅ、信越化学社製）１５００ｍｇを乳鉢に秤量したところへパスツールピペットにて滴下し、乳棒を用いて撹拌した。この粉体をナスフラスコに移し、エバポレーターにて３時間減圧乾燥して比較例２に係る医薬組成物を調製した。
[Comparative Example 2]
150 mg of everolimus was weighed in a test tube, 10 μL of dibutylhydroxytoluene (BHT, manufactured by MERCK) absolute ethanol solution (30 mg / mL) and 750 μL of anhydrous ethanol were added, and then ultrasonic waves were applied for 5 minutes to confirm the dissolution of everolimus. .. This mixed solution was added dropwise with a Pasteur pipette to a place where 1500 mg of hypromellose (TC-5 E Type, manufactured by Shin-Etsu Chemical Co., Ltd.) was weighed in a mortar, and the mixture was stirred using a pestle. This powder was transferred to an eggplant flask and dried under reduced pressure for 3 hours on an evaporator to prepare a pharmaceutical composition according to Comparative Example 2.
［比較例３］
試験管にヒプロメロース（ＴＣ−５ Ｅ Ｔｙｐｅ、信越化学社製）７５ｍｇを秤量し、水 ３００μＬを加えヒプロメロースを溶解させた。この溶液をエベロリムス １５０ｍｇと無水乳糖（Ｓｕｐｅｒ Ｔａｂ（登録商標） ２１ ＡＮ、 ＤＦＥ Ｐｈａｒｍａ社製）１４２５ｍｇを乳鉢に秤量し乳棒で撹拌し混合したところへ、パスツールピペットにて滴下し乳棒を用いて撹拌した。さらに、ジブチルヒドロキシトルエン（ＢＨＴ、ＭＥＲＣＫ社製）無水エタノール 溶液（３０ｍｇ／ｍＬ）１０μＬを加え、乳棒を用いて撹拌した。この粉体をナスフラスコに移し、エバポレーターにて３時間減圧乾燥して比較例３に係る医薬組成物を調製した。
[Comparative Example 3]
75 mg of hypromellose (TC-5 E Type, manufactured by Shin-Etsu Chemical Co., Ltd.) was weighed in a test tube, and 300 μL of water was added to dissolve hypromellose. 150 mg of Eberolimus and 1425 mg of anhydrous lactose (Super Tab (registered trademark) 21 AN, manufactured by DFE Pharma) were weighed in a pestle, stirred with a pestle, and then added dropwise with a pastur pipette and stirred with a pestle. did. Further, 10 μL of an absolute ethanol solution (30 mg / mL) of dibutylhydroxytoluene (BHT, manufactured by MERCK) was added, and the mixture was stirred using a pestle. This powder was transferred to an eggplant flask and dried under reduced pressure for 3 hours on an evaporator to prepare a pharmaceutical composition according to Comparative Example 3.
［比較例４］
乳鉢にエベロリムス １５０ｍｇ、無水乳糖（Ｓｕｐｅｒ Ｔａｂ（登録商標） ２１ ＡＮ、 ＤＦＥ Ｐｈａｒｍａ社製）１５０ｍｇ、ヒプロメロース（ＴＣ−５ Ｅ Ｔｙｐｅ、信越化学社製）１３５０ｍｇ及びジブチルヒドロキシトルエン（ＢＨＴ、ＭＥＲＣＫ社製）０．３ｍｇを秤量し、乳棒にて撹拌した。この混合紛体を単発打錠機にて成形後、粉砕して比較例４に係る医薬組成物を調製した。
[Comparative Example 4]
Everolimus 150 mg, anhydrous lactose (Super Tab® 21 AN, manufactured by DFE Pharma) 150 mg, hypromellose (TC-5 E Type, manufactured by Shin-Etsu Chemical Co., Ltd.) 1350 mg and dibutylhydroxytoluene (BHT, manufactured by MERCK) 0 in a mortar. .3 mg was weighed and stirred with a pestle. This mixed powder was molded by a single-shot tableting machine and then pulverized to prepare a pharmaceutical composition according to Comparative Example 4.
［試験例１]
実施例１及び比較例１〜４の方法で得られた医薬組成物約１ｇ及びエベロリムス原薬 １００ｍｇをそれぞれ褐色サンプル瓶に採取し蓋をしないで、遮光下６０℃／飽和塩化コバルト水溶液（相対湿度約４９％）にて調湿したデシケータ内に保存した。
保存試験１０日後及び１４日後のエベロリムスの残存量を液体クロマトグラフィー（ＨＰＬＣ）にて測定し、各時点におけるエベロリムスの残存率を算出した。なお残存率は以下の式に従い算出した。結果を表１に示した。
エベロリムス残存率（％）＝（各時点におけるＨＰＬＣ測定エベロリムスピーク面積／粉体秤量値）／（保存前（イニシャル）におけるＨＰＬＣ測定エベロリムスピーク面積／粉体秤量値）×１００
[Test Example 1]
Approximately 1 g of the pharmaceutical composition obtained by the methods of Example 1 and Comparative Examples 1 to 4 and 100 mg of everolimus drug substance were collected in a brown sample bottle, respectively, without a lid, and at 60 ° C./saturated cobalt chloride aqueous solution (relative humidity). It was stored in a desiccator whose humidity was adjusted at about 49%).
The residual amount of everolimus after 10 days and 14 days of the storage test was measured by liquid chromatography (HPLC), and the residual rate of everolimus at each time point was calculated. The survival rate was calculated according to the following formula. The results are shown in Table 1.
Everolimus residual rate (%) = (HPLC measurement everolimus peak area / powder weighing value at each time point) / (HPLC measurement before storage (initial) everolimus peak area / powder weighing value) × 100
［表１］
エベロリムス原薬は、遮光下６０℃／飽和塩化コバルト水溶液（相対湿度約４９％）保存条件で、酸化等の分解反応が急速に進む物性であった。このような事情から、現在流通しているエベロリムス製剤（アフィニトール（登録商標）錠及びサーティカン（登録商標）錠）は、エベロリムスにヒプロメロース、乳糖及びジブチルヒドロキシトルエン（ＢＨＴ）を処方した医薬組成物として製造している。
比較例１は、特許文献１（特表平１１−５０９２２３号公報）に記載の医薬組成物を模して調製した組成物である。また、比較例２は、特許文献４（国際公開ＷＯ２０１３／０２２２０１号）に記載のエベロリムスの安定性を考慮した医薬組成物である。
The everolimus drug substance had the physical characteristics that the decomposition reaction such as oxidation proceeded rapidly under the storage condition of 60 ° C./saturated cobalt chloride aqueous solution (relative humidity about 49%) under shading. Under these circumstances, everolimus preparations (Affinitol (registered trademark) tablets and Certican (registered trademark) tablets) currently on the market are used as pharmaceutical compositions in which everolimus is formulated with hypromerose, lactose and dibutylhydroxytoluene (BHT). Manufacture.
Comparative Example 1 is a composition prepared by imitating the pharmaceutical composition described in Patent Document 1 (Japanese Patent Laid-Open No. 11-509223). Further, Comparative Example 2 is a pharmaceutical composition in consideration of the stability of everolimus described in Patent Document 4 (International Publication WO2013 / 022201).
実施例１は、公知の医薬組成物と比較してエベロリムスの酸化等を抑制して、高い安定性を奏することが示された。このことは、エベロリムスの安定性は、添加剤の処方組成のみならず、その調製方法に大きく影響を受けることを示すものである。すなわち、エベロリムス溶液を乳糖に添加する方法により調製された医薬組成物が、エベロリムスの安定性向上をもたらすことが明らかとなった。すなわち、本発明に係る実施例１の医薬組成物は、遮光下６０℃で飽和塩化コバルト溶液により相対湿度約４９％調湿した保存条件において、１４日後に有効成分であるエベロリムスが８０％以上で含有する安定性を有することが示された。
したがって、本発明に係る実施例１は、薬効発現に基づく有効成分含量が担保され、また分解物に起因すると懸念される副作用の発現を防止することができる。本発明によってエベロリムス等の有効成分の安定性が高く、さらに安全性が高い医薬製剤を提供することができることが示された。
Example 1 was shown to exhibit high stability by suppressing the oxidation of everolimus as compared with known pharmaceutical compositions. This indicates that the stability of everolimus is greatly influenced not only by the formulation composition of the additive but also by the preparation method thereof. That is, it was clarified that the pharmaceutical composition prepared by the method of adding the everolimus solution to lactose brings about the improvement of the stability of everolimus. That is, the pharmaceutical composition of Example 1 according to the present invention contains 80% or more of everolimus, which is an active ingredient, after 14 days under storage conditions in which the relative humidity is adjusted to about 49% with a saturated cobalt chloride solution at 60 ° C. under light shielding. It has been shown to have stability to contain.
Therefore, in Example 1 according to the present invention, the content of the active ingredient based on the manifestation of the medicinal effect can be ensured, and the occurrence of side effects that may be caused by the decomposed product can be prevented. It has been shown that the present invention can provide a pharmaceutical preparation having high stability and safety of an active ingredient such as everolimus.
［実施例２］
試験管にエベロリムス ３０ｍｇを秤量し、ジブチルヒドロキシトルエン（ＢＨＴ、ＭＥＲＣＫ社製）無水エタノール 溶液（６ｍｇ／ｍＬ）１０μＬ及び無水エタノール １２０μＬを加えた後、超音波を５分間照射し、エベロリムスの溶解を確認した。その後、この混合溶液中にヒプロメロース（ＴＣ−５ Ｅ Ｔｙｐｅ、信越化学社製）３０ｍｇを加え超音波を５分間照射した。この混合溶液を、トレハロース（林原社製）２７０ｍｇを乳鉢に秤量したところへパスツールピペットにて滴下し、乳棒を用いて撹拌した。この粉体をナスフラスコに移し、エバポレーターにて３時間減圧乾燥して実施例２に係る医薬組成物を調製した。なお、トレハロースの２５℃における臨界相対湿度は９５％以上である。
[Example 2]
Weigh 30 mg of everolimus into a test tube, add 10 μL of dibutylhydroxytoluene (BHT, manufactured by MERCK) absolute ethanol solution (6 mg / mL) and 120 μL of anhydrous ethanol, and then irradiate with ultrasonic waves for 5 minutes to confirm the dissolution of everolimus. did. Then, 30 mg of hypromellose (TC-5 E Type, manufactured by Shin-Etsu Chemical Co., Ltd.) was added to this mixed solution, and ultrasonic waves were irradiated for 5 minutes. This mixed solution was added dropwise with a Pasteur pipette to a place where 270 mg of trehalose (manufactured by Hayashibara Co., Ltd.) was weighed in a pestle, and the mixture was stirred using a pestle. This powder was transferred to an eggplant flask and dried under reduced pressure for 3 hours on an evaporator to prepare a pharmaceutical composition according to Example 2. The critical relative humidity of trehalose at 25 ° C. is 95% or more.
［実施例３］
試験管にエベロリムス ３０ｍｇを秤量し、ジブチルヒドロキシトルエン（ＢＨＴ、ＭＥＲＣＫ社製）無水エタノール 溶液（６ｍｇ／ｍＬ）１０μＬ及び無水エタノール １２０μＬを加えた後、超音波を５分間照射し、エベロリムスの溶解を確認した。その後、この混合溶液中にヒプロメロース（ＴＣ−５ Ｅ Ｔｙｐｅ、信越化学社製）３０ｍｇを加え超音波を５分間照射した。この混合溶液を、Ｄ−マンニトール（Ｒｏｑｕｅｔｔｅ Ｐｈａｒｍａ社製）２７０ｍｇを乳鉢に秤量したところへパスツールピペットにて滴下し、乳棒を用いて撹拌した。この粉体をナスフラスコに移し、エバポレーターにて３時間減圧乾燥して実施例３に係る医薬組成物を調製した。なお、マンニトールの２５℃における臨界相対湿度は９５％以上である。
[Example 3]
Weigh 30 mg of everolimus into a test tube, add 10 μL of dibutylhydroxytoluene (BHT, manufactured by MERCK) absolute ethanol solution (6 mg / mL) and 120 μL of anhydrous ethanol, and then irradiate with ultrasonic waves for 5 minutes to confirm the dissolution of everolimus. did. Then, 30 mg of hypromellose (TC-5 E Type, manufactured by Shin-Etsu Chemical Co., Ltd.) was added to this mixed solution, and ultrasonic waves were irradiated for 5 minutes. This mixed solution was added dropwise to a place where 270 mg of D-mannitol (manufactured by Roquette Pharma) was weighed in a mortar with a Pasteur pipette, and the mixture was stirred using a pestle. This powder was transferred to an eggplant flask and dried under reduced pressure for 3 hours on an evaporator to prepare a pharmaceutical composition according to Example 3. The critical relative humidity of mannitol at 25 ° C. is 95% or more.
［比較例５］
試験管にエベロリムス ３０ｍｇを秤量し、ジブチルヒドロキシトルエン（ＢＨＴ、ＭＥＲＣＫ社製）無水エタノール 溶液（６ｍｇ／ｍＬ）１０μＬ及び無水エタノール １２０μＬを加えた後、超音波を５分間照射し、エベロリムスの溶解を確認した。その後、この混合溶液中にヒプロメロース（ＴＣ−５ Ｅ Ｔｙｐｅ、信越化学社製）３０ｍｇを加え超音波を５分間照射した。この混合溶液を、ソルビトール（メルクジャパン社製）２７０ｍｇを乳鉢に秤量したところへパスツールピペットにて滴下し、乳棒を用いて撹拌した。この粉体をナスフラスコに移し、エバポレーターにて３時間減圧乾燥して比較例５に係る医薬組成物を調製した。なお、ソルビトールの２５℃における臨界相対湿度は約７０％である。
[Comparative Example 5]
Weigh 30 mg of everolimus into a test tube, add 10 μL of dibutylhydroxytoluene (BHT, manufactured by MERCK) absolute ethanol solution (6 mg / mL) and 120 μL of anhydrous ethanol, and then irradiate with ultrasonic waves for 5 minutes to confirm the dissolution of everolimus. did. Then, 30 mg of hypromellose (TC-5 E Type, manufactured by Shin-Etsu Chemical Co., Ltd.) was added to this mixed solution, and ultrasonic waves were irradiated for 5 minutes. This mixed solution was added dropwise with a Pasteur pipette to a place where 270 mg of sorbitol (manufactured by Merck Japan) was weighed in a pestle, and the mixture was stirred using a pestle. This powder was transferred to an eggplant flask and dried under reduced pressure for 3 hours on an evaporator to prepare a pharmaceutical composition according to Comparative Example 5. The critical relative humidity of sorbitol at 25 ° C. is about 70%.
［比較例６］
試験管にエベロリムス ３０ｍｇを秤量し、ジブチルヒドロキシトルエン（ＢＨＴ、ＭＥＲＣＫ社製）無水エタノール 溶液（６ｍｇ／ｍＬ）１０μＬ及び無水エタノール １２０μＬを加えた後、超音波を５分間照射し、エベロリムスの溶解を確認した。その後、この混合溶液中にヒプロメロース（ＴＣ−５ Ｅ Ｔｙｐｅ、信越化学社製）３０ｍｇを加え超音波を５分間照射した。この混合溶液を、グルコース（サンエイ糖化社製）２７０ｍｇを乳鉢に秤量したところへパスツールピペットにて滴下し、乳棒を用いて撹拌した。この粉体をナスフラスコに移し、エバポレーターにて３時間減圧乾燥して比較例６に係る医薬組成物を調製した。なお、グルコースの２５℃における臨界相対湿度は約９０％である。
[Comparative Example 6]
Weigh 30 mg of everolimus into a test tube, add 10 μL of dibutylhydroxytoluene (BHT, manufactured by MERCK) absolute ethanol solution (6 mg / mL) and 120 μL of anhydrous ethanol, and then irradiate with ultrasonic waves for 5 minutes to confirm the dissolution of everolimus. did. Then, 30 mg of hypromellose (TC-5 E Type, manufactured by Shin-Etsu Chemical Co., Ltd.) was added to this mixed solution, and ultrasonic waves were irradiated for 5 minutes. This mixed solution was added dropwise with a Pasteur pipette to a place where 270 mg of glucose (manufactured by Sanei Saccharification Co., Ltd.) was weighed in a pestle, and the mixture was stirred using a pestle. This powder was transferred to an eggplant flask and dried under reduced pressure for 3 hours on an evaporator to prepare a pharmaceutical composition according to Comparative Example 6. The critical relative humidity of glucose at 25 ° C. is about 90%.
［比較例７］
試験管にエベロリムス ３０ｍｇを秤量し、ジブチルヒドロキシトルエン（ＢＨＴ、ＭＥＲＣＫ社製）無水エタノール 溶液（６ｍｇ／ｍＬ）１０μＬ及び無水エタノール １２０μＬを加えた後、超音波を５分間照射し、エベロリムスの溶解を確認した。この混合溶液をヒプロメロース（ＴＣ−５ Ｅ Ｔｙｐｅ、信越化学社製）３００ｍｇを乳鉢に秤量したところへ、パスツールピペットにて滴下し乳棒を用いて撹拌した。この粉体をナスフラスコに移し、エバポレーターにて３時間減圧乾燥して比較例７に係る医薬組成物を調製した。
[Comparative Example 7]
Weigh 30 mg of everolimus into a test tube, add 10 μL of dibutylhydroxytoluene (BHT, manufactured by MERCK) absolute ethanol solution (6 mg / mL) and 120 μL of anhydrous ethanol, and then irradiate with ultrasonic waves for 5 minutes to confirm the dissolution of everolimus. did. 300 mg of hypromellose (TC-5 E Type, manufactured by Shin-Etsu Chemical Co., Ltd.) was weighed in a mortar, and the mixed solution was added dropwise with a Pasteur pipette and stirred using a pestle. This powder was transferred to an eggplant flask and dried under reduced pressure for 3 hours on an evaporator to prepare a pharmaceutical composition according to Comparative Example 7.
［試験例２]
実施例２，３及び比較例５〜７の方法で得られた医薬組成物約２５０ｍｇをそれぞれ褐色サンプル瓶に採取し蓋をしないで、遮光下６０℃／飽和塩化コバルト水溶液（相対湿度約４９％）にて調湿したデシケータ内に保存した。
保存試験７日後及び１４日後のエベロリムスの残存量を液体クロマトグラフィー（ＨＰＬＣ）にて測定し、各時点におけるエベロリムスの残存率を算出した。なお残存率は以下の式に従い算出した。結果を表１に示した。
[Test Example 2]
Approximately 250 mg of the pharmaceutical composition obtained by the methods of Examples 2 and 3 and Comparative Examples 5 to 7 was collected in a brown sample bottle, and the temperature was 60 ° C./saturated cobalt chloride aqueous solution (relative humidity: about 49%) without a lid. ) Was stored in a humidity-controlled desiccator.
The residual amount of everolimus after 7 days and 14 days of the storage test was measured by liquid chromatography (HPLC), and the residual rate of everolimus at each time point was calculated. The survival rate was calculated according to the following formula. The results are shown in Table 1.
［表２］
エベロリムス溶液を滴下する糖として、トレハロース及びマンニトールを用いた医薬組成物（実施例２及び３）も遮光下６０℃／飽和塩化コバルト水溶液（相対湿度約４９％）保存条件における１４日目のエベロリムス残存率は、共に８０％以上であった。一方、ソルビトール及びグルコースを用いた医薬組成物（比較例５及び６）、並びに水溶性セルロース誘導体であるヒロドキシプロピルメチルセルロース（ヒプロメロース）を用いた医薬組成物は、エベロリムスの分解は急速に進行し、１４日後には約３〜５割が分解した。比較例７はある程度のエベロリムスの安定性は確保されたものの、本試験保存条件下で該医薬組成物の黄変色が認められた。
以上の結果から、エベロリムス溶液を添加する糖類として、トレハロース及びマンニトールも適用できることが明らかとなった。これらは２５℃における相対臨界湿度が９５％以上の糖類であり、吸湿性の少ない糖類を用いることが重要であることが示唆された。
The pharmaceutical compositions (Examples 2 and 3) using trehalose and mannitol as the sugar to which the everolimus solution is added dropwise also remain everolimus on the 14th day under the storage condition of 60 ° C./saturated cobalt chloride aqueous solution (relative humidity about 49%) under shading. The rates were both over 80%. On the other hand, in the pharmaceutical compositions using sorbitol and glucose (Comparative Examples 5 and 6) and the pharmaceutical compositions using hirodoxypropylmethylcellulose (hypromellose), which is a water-soluble cellulose derivative, the decomposition of everolimus progresses rapidly. After 14 days, about 30 to 50% was decomposed. In Comparative Example 7, although the stability of everolimus was secured to some extent, yellowing of the pharmaceutical composition was observed under the storage conditions of this test.
From the above results, it was clarified that trehalose and mannitol can also be applied as sugars to which the everolimus solution is added. These are saccharides having a relative critical humidity of 95% or more at 25 ° C., suggesting that it is important to use saccharides having low hygroscopicity.
ラパマイシン又はその誘導体は酸化等の化学変化を受けやすい物性であり、医薬製剤として市場流通させるためには保存条件下における安定性を確保する必要がある。ラパマイシン又はその誘導体の化学的安定性において、ＢＨＴ等の抗酸化剤を含めた添加剤組成のみならず、その処方調製方法が大きく影響することが明らかとなった。すなわち、エベロリムス溶液を、２５℃における相対臨界湿度が９５％以上の糖類へ添加する方法により調製された医薬組成物が、エベロリムスの安定性向上をもたらすことが判った。
本発明に係る医薬組成物は、薬効発現に基づく有効成分含量が担保され、また分解物に起因すると懸念される副作用の発現を防止することができる。したがって、本発明によってエベロリムス等の有効成分の安定性が高く、さらに安全性が高い医薬製剤を提供することができることが示された。
Rapamycin or its derivative has physical characteristics that are susceptible to chemical changes such as oxidation, and it is necessary to ensure stability under storage conditions in order to market it as a pharmaceutical preparation. It has been clarified that not only the additive composition including an antioxidant such as BHT but also the formulation preparation method thereof have a great influence on the chemical stability of rapamycin or a derivative thereof. That is, it was found that a pharmaceutical composition prepared by adding an everolimus solution to a saccharide having a relative critical humidity of 95% or more at 25 ° C. brings about an improvement in the stability of everolimus.
In the pharmaceutical composition according to the present invention, the content of the active ingredient based on the manifestation of the medicinal effect is guaranteed, and the occurrence of side effects which may be caused by the decomposed product can be prevented. Therefore, it has been shown that the present invention can provide a pharmaceutical preparation having high stability and safety of an active ingredient such as everolimus.
Claims (4)
前記ラパマイシン誘導体は、エベロリムス又はテムシロリムスであり、
ラパマイシン又はその誘導体１質量部に対し、２５℃における臨界相対湿度が９５％以上の糖類を５〜５０質量部用いる、
医薬組成物の製造方法。 A medicament containing rapamycin or a derivative thereof, which comprises a step of adding a solution containing rapamycin or a derivative thereof to a saccharide in a solid state having a critical relative humidity of 95% or more at 25 ° C., and then removing a solvent of the solution. A method for producing a composition
The rapamycin derivative is everolimus or temsirolimus.
5 to 50 parts by mass of saccharides having a critical relative humidity of 95% or more at 25 ° C. are used with respect to 1 part by mass of rapamycin or a derivative thereof.
A method for producing a pharmaceutical composition.
The method for producing a pharmaceutical composition according to any one of claims 1 to 3, wherein the solution containing rapamycin or a derivative thereof contains a water-soluble cellulose derivative.
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