JP4402350B2 - Solid pharmaceutical composition and method for producing the same - Google Patents

Description

【００１１】
共重合体としては、ランダム共重合体、ブロック共重合体のいずれの形態でもよく、ランダム共重合体が好ましい。
本発明に用いる共重合体は、ＭＰＣとブチルメタクリレートとの構成モル比が３／７〜６／４である。ＭＰＣが２０モル％未満では得られる共重合体の水への溶解性が低くなり、６５モル％を超えると本発明の固形医薬品組成物の再溶解性が悪くなるので好ましくない。
本発明に用いる共重合体の重量平均分子量は、好ましくは１０００〜５００００００、注射剤においては代謝性向上の観点から、より好ましくは１００００〜１２００００である。
【００１２】
前記共重合体は、前記単量体を、公知の溶液重合、塊状重合、乳化重合、懸濁重合等の方法を用いて、必要に応じて重合系を不活性ガス、例えば、窒素、二酸化炭素、ヘリウムで置換し、通常重合温度０〜１００℃、重合時間１０分〜４８時間の条件でラジカル重合させる方法等により調製することができる。重合にあたっては重合開始剤を用いることができ、該重合開始剤としては、２，２’−アゾビス（２−アミジノプロパン）二塩酸塩、４，４’−アゾビス（４−シアノ吉草酸）、２，２’−アゾビス（２−（５−メチル−２−イミダゾリン−２−イル）プロパン）二塩酸塩、２，２’−アゾビス（２−（２−イミダゾリン−２−イル）プロパン）二塩酸塩、２，２’−アゾビスイソブチルアミド二水和物、過硫酸アンモニウム、過硫酸カリウム、過酸化ベンゾイル、ジイソプロピルペルオキシジカーボネート、ｔ−ブチルペルオキシ−２−エチルヘキサノエート、ｔ−ブチルペルオキシピバレート、ｔ−ブチルペルオキシジイソブチレート、過酸化ラウロイル、アゾビスイソブチロニトリル（以下ＡＩＢＮと略記する）、２，２’−アゾビス（２，４−ジメチルバレロニトリル）、ｔ−ブチルペルオキシネオデカノエート（商品名「パーブチルＮＤ」、日本油脂（株）製、以下Ｐ−ＮＤと略記する）又はこれらの混合物等が挙げられる。前記重合開始剤には各種レドックス系の促進剤を用いてもよい。重合開始剤の使用量は、単量体組成物１００重量部に対して０．０１〜５．０重量部が好ましい。共重合体の精製は、再沈澱法、透析法、限外濾過法など一般的な精製法により行うことができる。
【００１３】
本発明の固形医薬品組成物に含まれる薬剤は、２５℃で水に対して１０００ｐｐｍ以下の溶解度を有するもの、溶解度が１０ｍｇ／ｍｌ以下、かつエタノール又は、水とエタノールの混合溶媒に可溶な難水溶性の薬剤であり、たとえば以下のものが挙げられる。
【００１４】
鎮痛薬、抗アレルギー剤、抗真菌薬、抗炎症剤、抗不整脈剤、抗生物質、抗凝固薬、抗うつ薬、抗糖尿病薬、抗てんかん薬、抗高血圧薬、抗痛風薬、抗マラリア薬、抗偏頭痛薬、抗ムスカリン薬、抗腫瘍薬、抗原生動物薬、不安寛解剤、甲状腺薬、抗甲状腺薬、抗ウイルス薬、食欲抑制剤、ビスホスホネート、心臓変力薬、心臓血管系薬剤、コルチコステロイド、利尿剤、ドーパミン作動性薬、胃腸薬、止血剤、ヒスタミン受容体拮抗薬、催眠薬、免疫抑制薬、腎臓保護薬、脂質調節剤、筋弛緩薬、神経弛緩薬、向神経性薬、オピオイド作動薬及び拮抗薬、副交感神経作用剤、プロテアーゼ阻害剤、プロスタグランジン、鎮静薬、性ホルモン、刺激剤、交感神経作用剤、血管拡張薬及びキサンチンを包含する多様な既知タイプの薬剤から選択され得る。これらは２種類またはそれ以上の組み合わせを含んでもよい。
【００１５】
難水溶性の薬剤としては、たとえばパクリタキセル、アムホテリシン、シクロスポリン等があげられる。
【００１６】
本発明の固形医薬品組成物はその目的によって薬理学的に許容される担体を混合することが可能であり、また、必要に応じて、通常の防腐剤、抗酸化剤、着色剤、甘味剤、吸着剤、湿潤剤等の添加物を用いることもできる。
賦形剤としては、例えば、乳糖、白糖、Ｄ−マンニトール、デンプン、コーンスターチ、結晶セルロース、軽質無水ケイ酸等が挙げられる。滑沢剤としては、例えば、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、コロイドシリカ等が挙げられる。結合剤としては、例えば、結晶セルロース、白糖、Ｄ−マンニトール、デキストリン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、デンプン、ショ糖、ゼラチン、メチルセルロース、カルボキシメチルセルロースナトリウム等が挙げられる。崩壊剤としては、例えば、デンプン、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム、Ｌ−ヒドロキシプロピルセルロース等が挙げられる。抗酸化剤としては、例えば、亜硫酸塩、アスコルビン酸、α−トコフェロール等が挙げられる。
【００１７】
本発明の固形医薬品組成物は、以下の方法で製造するのが好ましい。
本発明で特定する共重合体の水溶液と、上記薬剤を、エタノール又は、水とエタノールの混合溶媒に溶解させた薬剤溶液とを、混合した後、混合溶媒を取り除くことにより固形医薬品組成物を得る。ここでいう溶解とは可溶化、ミセル化など実質的に溶解している状態を含む。
混合時の温度は混合する薬剤の安定性を考慮して４℃以下でも可能であるが、室温（２０〜２５℃）での混合が好ましい。
上記共重合体水溶液と薬剤溶液とを混合した際の水とエタノールとの混合比は、重量比で２０／８０〜９５／５とすることが好ましく、３０／７０〜９０／１０とすることがさらに好ましい。
本発明の固形医薬品組成物における医薬品の含有量は、製剤の形態によって相違するが、通常、製剤全体に対して０．０１〜９０重量％、好ましくは０．１〜５０重量％、さらに好ましくは０．５〜２０重量％である。
【００１８】
本発明の固形医薬品組成物の形態は、固体であればよいが、その中でもフィルム状または粉末状とすることが、取り扱いなどの点で好ましい。
本発明の固形医薬品組成物のうちフィルム状組成物の厚さは０．００３〜５ｍｍ、好ましくは０．０１〜１ｍｍである。０．００３ｍｍ未満ではフィルムの剛性が落ちるため扱いにくくなり、５ｍｍを超えると再溶解性能が落ちる傾向がある。
粉末状組成物の粒径は特に既定されるものではなくその用法によって異なる。たとえば経肺吸入剤として使用する場合はできるだけ細かい粒子とすることが好ましい。
混合溶媒を取り除く方法は、フィルム状組成物ではキャスト法、凍結乾燥法などがあり、粉末状組成物ではフィルム化と同様の方法を用いて固形物を得た後、粉砕する方法、あるいはスプレードライ法などがある。
ここで、溶解する溶媒が水の含有量として９５重量％を超える場合、溶媒を取り除く際に時間がかかるため好ましくない。さらに、この場合、本発明の固形医薬品組成物中に水が残る可能性があり、薬剤の安定性や組成物そのものの安定性を低下させる点で好ましくない。また、溶解する溶媒が水の含有量として２０重量％未満の場合、固形医薬品組成物の再溶解性が著しく低下するので好ましくない。
本発明の固形医薬品組成物は固形物のまま貼付剤や経肺吸入剤、経口剤として使用することができ、また、カプセルに封入することもできる。さらに、使用前に水に再溶解してドリンク剤や注射剤としても使用可能である。
【００１９】
【実施例】
以下、本発明について具体的に説明する。
疎水性単量体としてブチルメタクリレート（以下ＢＭＡと略記する）を用い、特許文献４記載の方法によりＭＰＣのモル比が３０％、５０％および８０％であるランダム共重合体を製造した（以後それぞれＰＭＢ３７、ＰＭＢ５５およびＰＭＢ８２と略記する）。
【００２０】
実施例１
５ｍｇのパクリタキセルを１００μｌのエタノールに溶解し、パクリタキセル溶液とした。１００ｍｇのＰＭＢ３７を１ｍｌの蒸留水に溶解し、ＰＭＢ３７水溶液とした。パクリタキセル溶液１００μｌとＰＭＢ３７水溶液９００μｌとを混合し、７０℃に加温した。得られた透明溶液を７０℃にて風乾後、７０℃で２時間真空乾燥を行い、パクリタキセル含有固形物を得た。固形物を粉砕することにより粉末化した。この粉末を水に再溶解し、目視にて判断したところ無色透明なパクリタキセル水溶液が得られた。
実施例２
実施例１と同様の操作でＰＭＢ５５を用いてパクリタキセルの粉末化組成物を得た。この粉末を水に再溶解し、目視にて判断したところ無色透明なパクリタキセル水溶液が得られた。
【００２１】
実施例３
実施例１と同様にしてパクリタキセル溶液１００μｌとＰＭＢ３７水溶液９００μｌとを混合し、７０℃に加温した。得られた透明溶液をガラスプレート上に広げ、４０℃で２４時間放置し、溶媒を蒸発させることにより厚みが１００μｍのパクリタキセル含有フィルムを作成した。パクリタキセルの濃度をＨＰＬＣにて測定したところ１ｍｇ／ｃｍ²であった。このフィルムを水に再溶解し、目視にて判断したところ無色透明なパクリタキセル水溶液が得られた。
実施例４
実施例３と同様にＰＭＢ５５を用いてパクリタキセルのフィルム化組成物を得た。このフィルムを水に再溶解し、目視にて判断したところ無色透明なパクリタキセル水溶液が得られた。
【００２２】
比較例１
１ｍｇのパクリタキセルを１００μｌのエタノールに溶解し、パクリタキセル溶液とした。これと５０ｍｇ／ｍｌの濃度のＰＭＢ８２水溶液９００μｌを混合した。得られた溶液を７０℃にて風乾後、７０℃で２時間真空乾燥を行い、パクリタキセル含有固形物を得た。固形物を粉砕することにより粉末化した。この粉末を水に再溶解したところ、パクリタキセルの沈殿が認められた。
比較例２
比較例１と同様にして１００μｌのパクリタキセル溶液とＰＭＢ８２水溶液９００μｌを混合した。得られた溶液をガラスプレート上に広げ、４０℃で２４時間放置し、溶媒を蒸発させることにより厚みが１００μｍのパクリタキセル含有フィルムを作成した。このフィルムを水に再溶解したところ、パクリタキセルの沈殿が認められた。
【００２３】
【発明の効果】
本発明の固形医薬品組成物は、再溶解性が良好である。特に難溶性の薬剤を固形化でき、再溶解性の良好な固形医薬品組成物を得ることができる。形状も、任意の形状を得ることができ、医薬品の貯蔵安定性および運搬性の向上、易飲性の向上を図ることが可能になる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a solidified pharmaceutical composition and a method for producing the same, and more particularly relates to a solid pharmaceutical composition excellent in re-solubility, transportability and ease of handling during drug administration, and a method for producing the same.
[0002]
[Prior art]
Conventionally, when a poorly soluble drug is powdered, there is almost no technique for solving the problem of good re-solubility at the time of administration. For example, a powder formulation composed of cyclosporine, a surfactant, and an organic solvent-soluble substance that is solid at room temperature has been proposed (Patent Document 1), but the re-solubility at the time of administration is not satisfactory. In addition to certain surfactants, it was necessary to include ingredients for powdering. In particular, regarding a film-formulated preparation, a dosage form composed of a film-forming agent, a gel-forming agent, and a filler has been proposed (Patent Document 2). However, in order to form a film, it is essential to add various auxiliary agents. Therefore, the operation is complicated, and further, this method has a fatal defect that a film of a hardly soluble drug cannot be formed.
On the other hand, there have been various reports on solubilizers for poorly soluble drugs. Recently, oral or injectable compositions containing a copolymer having a lipid-like structure have improved the solubility of poorly soluble substances. It is disclosed that the absorbability is improved (Patent Document 3), and tablets are also mentioned as the dosage form. However, re-solubility in water is not always satisfactory, and no mention is made regarding film formation. Further, it has been disclosed that a copolymer of a hydrophilic monomer having a lipid-like structure and a hydrophobic monomer has a particularly high solubilizing ability (Patent Document 4). It is not clear whether the solubility is satisfactory.
[0003]
[Patent Document 1]
Japanese Patent No. 2536876, pages 1 to 5 [Patent Document 2]
Japanese Patent Application Laid-Open No. 7-100186, pages 1 to 10 [Patent Document 3]
JP-A-2002-80402, pages 1 to 19 [Patent Document 4]
JP-A-10-109029, pages 1-14
[Problems to be solved by the invention]
An object of the present invention is to provide a solid pharmaceutical composition having improved re-solubility upon administration, particularly a powdered and filmed solid pharmaceutical composition and a method for producing the same.
By achieving the above object, it becomes possible to improve the storage stability and transportability of pharmaceuticals and the ease of drinking.
[0005]
[Means for Solving the Problems]
As a result of intensive studies in view of the above problems, the present inventors have found that the molar ratio of MPC in the copolymer of 2-methacryloyloxyethyl phosphorylcholine (hereinafter abbreviated as MPC) and a hydrophobic monomer is completely unsaturated. It has been found that 20 to 65 mol% of monomers can dissolve a drug alone, not only can be easily solidified without adding an auxiliary agent, but also improve re-solubility upon administration. Was completed.
[0006]
That is, the gist of the present invention is as follows.
(1) The structural unit based on 2-methacryloyloxyethyl phosphorylcholine (I) and the structural unit based on butyl methacrylate (II) and based on 2-methacryloyloxyethyl phosphorylcholine (I) and the structural unit based on butyl methacrylate (II) is a copolymer aqueous solution having a compositional molar ratio of 3/7 to 6/4, and a solubility in water at 25 ° C. of 10 mg / ml or less, and can be used in ethanol or a mixed solvent of water and ethanol. A solid pharmaceutical composition in which a soluble drug is mixed with ethanol or a drug solution obtained by dissolving water and ethanol in a mixed solvent, and the solvent is removed to obtain a solid product.
(2) The said solid pharmaceutical composition whose mixing ratio of water and ethanol at the time of mixing the said copolymer aqueous solution and the said chemical | medical solution is 20 / 80-95 / 5 on a weight basis .
(3) The said solid pharmaceutical composition whose shape of a solid substance is a film form.
(4) The said solid pharmaceutical composition whose shape of a solid substance is a powder form.
(5) The said solid pharmaceutical composition whose thickness of a film is 0.003-5 mm.
(6) A method for producing the above-mentioned solid pharmaceutical composition, which has a structural unit (I) based on 2-methacryloyloxyethyl phosphorylcholine and a structural unit (II) based on butyl methacrylate , and includes 2-methacryloyloxyethyl phosphorylcholine. The aqueous solution of copolymer having a structural molar ratio of the structural unit (I) based on butyl methacrylate and the structural unit (II) based on butyl methacrylate is 3/7 to 6/4, and the solubility in water at 25 ° C. is 10 mg / ml or less. In addition, a drug soluble in ethanol or a mixed solvent of water and ethanol is mixed with a drug solution dissolved in ethanol or a mixed solvent of water and ethanol, and the mixing ratio of water and ethanol at this time is adjusted. after the 20 / 80-95 / 5, by weight, method of manufacturing the solid pharmaceutical composition, characterized in that to remove the mixed solvent.
[0007]
DETAILED DESCRIPTION OF THE INVENTION
The copolymer used in the present invention has a structural unit (I) based on MPC and a structural unit (II) based on butyl methacrylate .
MPC is represented by the following formula (1).
[0008]
[Chemical 1]

[0011]
The co-polymer, a random copolymer, may be in any form of a block copolymer, a random copolymer is preferable.
The copolymer used in the present invention has a constituent molar ratio of MPC and butyl methacrylate of 3/7 to 6/4. If the MPC is less than 20 mol%, the solubility of the resulting copolymer in water will be low, and if it exceeds 65 mol%, the resolubility of the solid pharmaceutical composition of the present invention will deteriorate, such being undesirable.
The weight average molecular weight of the copolymer used in the present invention is preferably 1000 to 5000000, and more preferably 10,000 to 120,000 for injections from the viewpoint of improving metabolic properties.
[0012]
In the copolymer, the monomer is converted into an inert gas, for example, nitrogen, carbon dioxide, if necessary using a known solution polymerization, bulk polymerization, emulsion polymerization, suspension polymerization or the like. It can be prepared by a method such as substitution with helium and radical polymerization under conditions of a polymerization temperature of 0 to 100 ° C. and a polymerization time of 10 minutes to 48 hours. In the polymerization, a polymerization initiator can be used. Examples of the polymerization initiator include 2,2′-azobis (2-amidinopropane) dihydrochloride, 4,4′-azobis (4-cyanovaleric acid), 2 , 2′-azobis (2- (5-methyl-2-imidazolin-2-yl) propane) dihydrochloride, 2,2′-azobis (2- (2-imidazolin-2-yl) propane) dihydrochloride 2,2′-azobisisobutyramide dihydrate, ammonium persulfate, potassium persulfate, benzoyl peroxide, diisopropyl peroxydicarbonate, t-butylperoxy-2-ethylhexanoate, t-butylperoxypivalate, t-butylperoxydiisobutyrate, lauroyl peroxide, azobisisobutyronitrile (hereinafter abbreviated as AIBN), 2,2′-azobis (2,4 Dimethylvaleronitrile), t-butyl peroxyneodecanoate (trade name "Perbutyl ND", manufactured by NOF Corp., P-ND abbreviated) or mixtures thereof or less. Various redox accelerators may be used as the polymerization initiator. As for the usage-amount of a polymerization initiator, 0.01-5.0 weight part is preferable with respect to 100 weight part of monomer compositions. The copolymer can be purified by a general purification method such as a reprecipitation method, a dialysis method, or an ultrafiltration method.
[0013]
Drug agent contained in the solid pharmaceutical compositions of the present invention are those having 1000ppm or less solubility in water at 25 ° C., solubility 10mg / ml or less, and ethanol or soluble in a mixed solvent of water and ethanol a poorly water-soluble drug, e.g., include the following.
[0014]
Analgesic, antiallergic, antifungal, antiinflammatory, antiarrhythmic, antibiotic, anticoagulant, antidepressant, antidiabetic, antiepileptic, antihypertensive, antigout, antimalarial, Antimigraine, Antimuscarinic, Antitumor, Antiprotozoal, Anxiolytic, Thyroid, Antithyroid, Antiviral, Appetite suppressant, Bisphosphonate, Cardioinotropic, Cardiovascular, Corti Costeroids, diuretics, dopaminergic drugs, gastrointestinal drugs, hemostatic agents, histamine receptor antagonists, hypnotics, immunosuppressive drugs, kidney protective drugs, lipid regulators, muscle relaxants, neuroleptic drugs, neuroactive drugs From a variety of known types of drugs, including opioid agonists and antagonists, parasympathomimetics, protease inhibitors, prostaglandins, sedatives, sex hormones, stimulants, sympathomimetics, vasodilators and xanthines Choice It can be. These may include two or more combinations.
[0015]
Examples of poorly water-soluble drugs include paclitaxel, amphotericin, cyclosporine and the like.
[0016]
The solid pharmaceutical composition of the present invention can be mixed with a pharmacologically acceptable carrier depending on the purpose, and if necessary, a conventional preservative, antioxidant, coloring agent, sweetener, Additives such as adsorbents and wetting agents can also be used.
Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, and the like. Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, and the like. Examples of the antioxidant include sulfite, ascorbic acid, α-tocopherol and the like.
[0017]
The solid pharmaceutical composition of the present invention is preferably produced by the following method.
After mixing the aqueous solution of the copolymer specified in the present invention and the drug solution obtained by dissolving the drug in ethanol or a mixed solvent of water and ethanol , the mixed solvent is removed to obtain a solid pharmaceutical composition. obtain. The dissolution here includes a substantially dissolved state such as solubilization and micellization.
The temperature during mixing are possible in light of the stability of the drug mixing even 4 ° C. or less, arbitrary preferable is mixing at room temperature (20-25 ° C.).
The mixing ratio of water and ethanol when the copolymer aqueous solution and the drug solution are mixed is preferably 20/80 to 95/5, and preferably 30/70 to 90/10 in weight ratio. Further preferred.
The content of the pharmaceutical in the solid pharmaceutical composition of the present invention varies depending on the form of the preparation, but is usually 0.01 to 90% by weight, preferably 0.1 to 50% by weight, more preferably, based on the whole preparation. 0.5 to 20% by weight.
[0018]
The solid pharmaceutical composition of the present invention may be in the form of a solid, but among them, a film or powder is preferable in terms of handling.
Of the solid pharmaceutical composition of the present invention, the film-like composition has a thickness of 0.003 to 5 mm, preferably 0.01 to 1 mm. If the thickness is less than 0.003 mm, the rigidity of the film is lowered, so that it is difficult to handle. If the thickness exceeds 5 mm, the remelting performance tends to be lowered.
The particle size of the powdery composition is not particularly defined and varies depending on its usage. For example, when used as a pulmonary inhaler, it is preferable to make the particles as fine as possible.
Methods for removing the mixed solvent include a casting method and a freeze-drying method for film-like compositions, and a powder-like composition is obtained by using a method similar to film formation and then pulverizing or spray-drying. There are laws.
Here, when the solvent to be dissolved exceeds 95% by weight as the water content, it takes time to remove the solvent, which is not preferable. Furthermore, in this case, water may remain in the solid pharmaceutical composition of the present invention, which is not preferable in terms of reducing the stability of the drug and the stability of the composition itself. Moreover, when the solvent to melt | dissolve is less than 20 weight% as content of water, since the resolubility of a solid pharmaceutical composition falls remarkably, it is unpreferable.
The solid pharmaceutical composition of the present invention can be used as a patch, a pulmonary inhalation agent or an oral preparation as it is in a solid state, and can also be encapsulated. Furthermore, it can be redissolved in water before use and used as a drink or injection.
[0019]
【Example】
Hereinafter, the present invention will be specifically described.
Using butyl methacrylate (hereinafter abbreviated as BMA) as a hydrophobic monomer, random copolymers having a MPC molar ratio of 30%, 50% and 80% were produced by the method described in Patent Document 4 (hereinafter, respectively) Abbreviated as PMB37, PMB55 and PMB82).
[0020]
Example 1
5 mg of paclitaxel was dissolved in 100 μl of ethanol to obtain a paclitaxel solution. 100 mg of PMB37 was dissolved in 1 ml of distilled water to obtain a PMB37 aqueous solution. 100 μl of paclitaxel solution and 900 μl of PMB37 aqueous solution were mixed and heated to 70 ° C. The obtained transparent solution was air-dried at 70 ° C. and then vacuum-dried at 70 ° C. for 2 hours to obtain a paclitaxel-containing solid. The solid was pulverized by grinding. When this powder was redissolved in water and visually judged, a colorless and transparent paclitaxel aqueous solution was obtained.
Example 2
A paclitaxel powdered composition was obtained using PMB55 in the same manner as in Example 1. When this powder was redissolved in water and visually judged, a colorless and transparent paclitaxel aqueous solution was obtained.
[0021]
Example 3
In the same manner as in Example 1, 100 μl of the paclitaxel solution and 900 μl of the PMB37 aqueous solution were mixed and heated to 70 ° C. The obtained transparent solution was spread on a glass plate, allowed to stand at 40 ° C. for 24 hours, and the solvent was evaporated to prepare a paclitaxel-containing film having a thickness of 100 μm. The concentration of paclitaxel was measured by HPLC and found to be 1 mg / cm ² . When this film was redissolved in water and judged visually, a colorless and transparent paclitaxel aqueous solution was obtained.
Example 4
A paclitaxel film-forming composition was obtained using PMB55 in the same manner as in Example 3. When this film was redissolved in water and judged visually, a colorless and transparent paclitaxel aqueous solution was obtained.
[0022]
Comparative Example 1
1 mg of paclitaxel was dissolved in 100 μl of ethanol to obtain a paclitaxel solution. This was mixed with 900 μl of an aqueous PMB82 solution having a concentration of 50 mg / ml. The obtained solution was air-dried at 70 ° C. and then vacuum-dried at 70 ° C. for 2 hours to obtain a paclitaxel-containing solid. The solid was pulverized by grinding. When this powder was redissolved in water, precipitation of paclitaxel was observed.
Comparative Example 2
In the same manner as in Comparative Example 1, 100 μl of paclitaxel solution and 900 μl of PMB82 aqueous solution were mixed. The obtained solution was spread on a glass plate, allowed to stand at 40 ° C. for 24 hours, and the solvent was evaporated to prepare a paclitaxel-containing film having a thickness of 100 μm. When this film was redissolved in water, precipitation of paclitaxel was observed.
[0023]
【The invention's effect】
The solid pharmaceutical composition of the present invention has good resolubility. In particular, a poorly soluble drug can be solidified, and a solid pharmaceutical composition with good resolubility can be obtained. As for the shape, an arbitrary shape can be obtained, and it becomes possible to improve the storage stability and transportability of pharmaceuticals and the ease of drinking.

Claims (6)

2-methacryloyloxyethyl phosphorylcholine to based constituent unit (I) and has the structural unit (II) based on butyl methacrylate, 2-methacryloyloxyethyl phosphorylcholine structural units based on choline (I) and based on butyl methacrylate constituent unit (II) A copolymer aqueous solution having a constitutional molar ratio of 3/7 to 6/4 ,
A drug solution having a solubility in water at 25 ° C. of 10 mg / ml or less and soluble in ethanol or a mixed solvent of water and ethanol, dissolved in ethanol or a mixed solvent of water and ethanol,
A solid pharmaceutical composition that is mixed to remove the solvent to form a solid . The solid pharmaceutical composition according to claim 1 , wherein a mixing ratio of water and ethanol when the aqueous copolymer solution and the drug solution are mixed is 20/80 to 95/5 on a weight basis . The solid pharmaceutical composition according to claim 1 or 2, wherein the solid is in the form of a film. Claim 1 or claim 2 solid pharmaceutical composition according the shape of the solid is in powder form.   The solid pharmaceutical composition according to claim 3, wherein the film has a thickness of 0.003 to 5 mm. A method for producing a solid pharmaceutical composition according to any one of claims 1 to 5,
2-methacryloyloxyethyl phosphorylcholine to based constituent unit (I) and has the structural unit (II) based on butyl methacrylate, 2-methacryloyloxyethyl phosphorylcholine structural units based on choline (I) and based on butyl methacrylate constituent unit (II) A copolymer aqueous solution having a constitutional molar ratio of 3/7 to 6/4 ,
A drug solution having a solubility in water at 25 ° C. of 10 mg / ml or less and soluble in ethanol or a mixed solvent of water and ethanol, dissolved in ethanol or a mixed solvent of water and ethanol,
A method for producing a solid pharmaceutical composition, wherein the mixture is mixed and the mixing ratio of water and ethanol is 20/80 to 95/5 on a weight basis, and then the mixed solvent is removed.