JP4536837B2 - Manufacturing method of sustained-release preparation - Google Patents

Description

また、サンドスタチン（USP4087390, 4093574, 4100117, 4253998）なども好適である。
上記の生理活性ペプチドの中でも、５-oxo-Pro−His−Trp−Ser−Tyr−DLeu−Leu−Arg−Pro−NH-C₂H₅（リュープレリン）またはその塩（特に、酢酸塩）が好適である。
【００１１】
本明細書中で使用される略号としては、
略号 名称
Ｎ(４Ｈ₂−furoyl）Ｇly ：Ｎ−テトラヒドロフロイルグリシン残基
ＮＡc ：Ｎ−アセチル基
Ｄ２Ｎal ：Ｄ−３−（２−ナフチル）アラニン残基
Ｄ４ＣlＰhe ：Ｄ−３−（４−クロロフェニル）アラニン残基
Ｄ３Ｐal ：Ｄ−３−（３−ピリジル）アラニン残基
ＮＭeＴyr ：Ｎ−メチルチロシン残基
Ａph（Ａtz） ：Ｎ−〔５'−（３'−アミノ−１'Ｈ−１'，２'，４ '−トリアゾリル）〕フェニルアラニン残基
ＮＭeＡph（Ａtz） ：Ｎ−メチル−〔５'−（３'−アミノ−１'Ｈ−１' ，２'，４'−トリアゾリル）〕フェニルアラニン 残基
ＤＬys（Ｎic） ：Ｄ−（ε−Ｎ−ニコチノイル）リシン残基
ＤＣit ：Ｄ−シトルリン残基
ＤＬys（AzaglyNic） ：Ｄ−（アザグリシルニコチノイル）リシン残基
ＤＬys（AzaglyFur） ：Ｄ−（アザグリシルフラニル）リシン残基
ＤhＡrg（Ｅt₂） ：Ｄ−（Ｎ,Ｎ'−ジエチル）ホモアルギニン残基
ＤＡph（Ａtz） ：Ｄ−Ｎ−〔５'−（３'−アミノ−１'Ｈ−１'，２'，４'−トリアゾリル）〕フェニルアラニン残基
ＤhＣi ：Ｄ−ホモシトルリン残基
Ｌys（Ｎisp） ：（ε−Ｎ−イソプロピル）リシン残基
hＡrg（Ｅt₂） ：（Ｎ,Ｎ'−ジエチル）ホモアルギニン残基
ＤＳer（tＢu） ：Ｄ−（Ｏ-t-ブチル）セリン残基
ＤＨis（ＩmBzl） ：Ｄ−（π−ベンジル）ヒスチジン残基
その他アミノ酸に関し、略号で表示する場合、ＩＵＰＡＣ−ＩＵＢコミッション・オブ・バイオケミカル・ノーメンクレーチュアー（Commission on Biochemical Nomenclature）(ヨーロピアン・ジャーナル・オブ・バイオケミストリー（European Journal of Biochemistry）第１３８巻、９〜３７頁（１９８４年））による略号あるいは該当分野における慣用略号に基づくものとし、また、アミノ酸に関して光学異性体がありうる場合は、特に明示しなければＬ体を示すものとする。
【００１２】
上記の徐放性製剤に用いられる徐放性基剤としては、生体内分解性ポリマーなどが好ましく、その具体例としては、例えば、α−ヒドロキシカルボン酸類（例、グリコール酸、乳酸、ヒドロキシ酪酸等）、ヒドロキシジカルボン酸類（例、リンゴ酸）、ヒドロキシトリカルボン酸（例、クエン酸）等の１種以上から合成され、遊離のカルボキシル基を有する重合体、共重合体、あるいはこれらの混合物、ポリ−α−シアノアクリル酸エステル、ポリアミノ酸（例、ポリ−γ−ベンジル−Ｌ−グルタミン酸等）、無水マレイン酸系共重合体（例、スチレン−マレイン酸共重合体等）等が挙げられる。
ポリマーにおける重合の形式は、ランダム、ブロック、グラフトのいずれでもよい。また、上記α−ヒドロキシカルボン酸類、ヒドロキシジカルボン酸類、ヒドロキシトリカルボン酸類が分子内に光学活性中心を有する場合、Ｄ−体、Ｌ−体およびＤＬ−体のいずれも用いることができる。これらの中でも乳酸−グリコール酸重合体、ポリ−α−シアノアクリル酸エステルが好ましい。さらに好ましくは、乳酸−グリコール酸重合体である。
【００１３】
生体内分解性ポリマーは、好ましくは（Ａ）グリコール酸と一般式
【化２】

（式中、Ｒは炭素数２から８のアルキル基を表す）で示されるヒドロキシカルボン酸との共重合体および（Ｂ）ポリ乳酸を混合した生体内分解性ポリマーまたは乳酸とグリコール酸との共重合体である。
【００１４】
一般式〔II〕中、Ｒで示される炭素数２から８の直鎖もしくは分枝状のアルキル基としては、例えば、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec−ブチル、tert−ブチル、ペンチル、イソペンチル、ネオペンチル、tert−ペンチル、１−エチルプロピル、ヘキシル、イソヘキシル、１,１−ジメチルブチル、２,２−ジメチルブチル、３,３−ジメチルブチル、２−エチルブチルなどが挙げられる。好ましくは、炭素数２から５の直鎖もしくは分枝状のアルキル基が用いられる。具体例としては、例えば、エチル、プロピル、イソプロピル、ブチル、イソブチルなどが挙げられる。特に好ましくは、Ｒはエチルである。
一般式〔II〕で示されるヒドロキシカルボン酸としては、例えば、２−ヒドロキシ酪酸、２−ヒドロキシ吉草酸、２−ヒドロキシ−３−メチル酪酸、２−ヒドロキシカプロン酸、２−ヒドロキシイソカプロン酸、２−ヒドロキシカプリン酸などが挙げられる。このうち特に、２−ヒドロキシ酪酸、２−ヒドロキシ吉草酸、２−ヒドロキシ−３−メチル酪酸、２−ヒドロキシカプロン酸が好ましい。一般式〔II〕で示されるヒドロキシカルボン酸は、特に好ましくは２-ヒドロキシ酪酸である。これらのヒドロキシカルボン酸はＤ−体、Ｌ−体およびＤ，Ｌ−体の何れでもよいが、Ｄ−体／Ｌ−体（モル％）が約７５／２５〜約２５／７５の範囲のものが好ましい。さらに好ましくは、Ｄ−体／Ｌ−体（モル％）が約６０／４０〜約４０／６０の範囲のヒドロキシカルボン酸である。特に好ましくは、Ｄ−体／Ｌ−体（モル％）が約５５／４５〜約４５／５５の範囲のヒドロキシカルボン酸である。
【００１５】
グリコール酸と一般式〔II〕で示されるヒドロキシカルボン酸との共重合体（以下、グリコール酸共重合体と略称する）において、共重合の形式は、ランダム，ブロック，グラフトの何れでもよい。好ましくは、ランダム共重合体である。
一般式〔II〕で示されるヒドロキシカルボン酸は、１種または２種以上適宜の割合で用いてもよい。
上記（Ａ）のグリコール酸共重合体におけるグリコール酸と一般式〔II〕で示されるヒドロキシカルボン酸との組成比は、グリコール酸が約１０〜約７５モル％、残りがヒドロキシカルボン酸である場合が好ましい。さらに好ましくは、グリコール酸が約２０〜約７５モル％、残りがヒドロキシカルボン酸である場合である。特に好ましくは、グリコール酸が約４０〜約７０モル％、残りがヒドロキシカルボン酸である場合である。これらグリコール酸共重合体は、重量平均分子量が約２,０００から約１００,０００のものが用いられる。好ましくは、重量平均分子量が約３,０００から約８０,０００の共重合体である。さらに好ましくは、重量平均分子量が約５,０００から約５０,０００の共重合体である。また、これらのグリコール酸共重合体の分散度（重量平均分子量／数平均分子量）は約１.２から約４.０が好ましい。特に好ましくは、分散度が約１.５から約３.５の共重合体である。
上記（Ａ）のグリコール酸共重合体は、公知の製造法、例えば、特開昭６１−２８５２１号公報に記載の方法に従って合成できる。
【００１６】
ポリ乳酸としては、Ｌ−体、Ｄ−体およびこれらの混合物の何れでもよいが、Ｄ−体／Ｌ−体（モル％）が約７５／２５〜約２０／８０の範囲のものが好ましい。さらに好ましくは、Ｄ−体／Ｌ−体（モル％）が約６０／４０〜約２５／７５の範囲のポリ乳酸である。特に好ましくは、Ｄ−体／Ｌ−体（モル％）が約５５／４５〜約２５／７５の範囲のポリ乳酸である。該ポリ乳酸は、重量平均分子量が約１,５００から約１００,０００の範囲のものが好ましい。さらに好ましくは、重量平均分子量が約２,０００から約８０,０００の範囲のポリ乳酸である。特に好ましくは、重量平均分子量が約３,０００から約５０,０００の範囲あるいは約１０，０００〜６０，０００（さらに好ましくは、約１５，０００〜約５０，０００）の範囲のポリ乳酸である。また、ポリ乳酸の分散度は約１.２から約４.０が好ましい。特に好ましくは、分散度が約１.５から約３.５の場合である。
ポリ乳酸の合成法については、乳酸の二量体であるラクタイドを開環重合する方法と乳酸を脱水重縮合する方法が知られている。
【００１７】
本発明の製剤基剤におけるグリコール酸共重合体（Ａ）とポリ乳酸（Ｂ）は、例えば（Ａ）／（Ｂ）で表わされる混合比（重量％）が約１０／９０〜約９０／１０の範囲で使用される。好ましくは、混合比（重量％）が約２０／８０〜約８０／２０の範囲である。さらに好ましくは、約３０／７０〜約７０／３０の範囲である。
（Ａ），（Ｂ）のうち何れかの成分が多すぎると、（Ａ）もしくは（Ｂ）成分を単独で使用した場合とほとんど同じ薬物放出パターンを有する製剤しか得られず、混合基剤による放出後期の直線的な放出パターンが期待できない。グリコール酸共重合体およびポリ乳酸の分解・消失速度は分子量あるいは組成によって大きく変化するが、一般的にはグリコール酸共重合体の分解・消失速度の方が速いため、混合するポリ乳酸の分子量を大きくする、あるいは（Ａ）／（Ｂ）で表わされる混合比を小さくすることによって放出期間を長くすることができる。逆に、混合するポリ乳酸の分子量を小さくする、あるいは（Ａ）／（Ｂ）で表わされる混合比を大きくすることによって放出期間を短くすることもできる。さらに、一般式〔II〕で示されるヒドロキシカルボン酸の種類や割合を変化させることにより、放出期間を調節することもできる。
【００１８】
生体内分解性ポリマーとしてポリ乳酸または乳酸−グリコール酸共重合体（以下、単に乳酸−グリコール酸重合体と称す。）を用いる場合、その乳酸／グリコール酸組成比（モル％）は１００／０〜４０／６０が好ましく、１００／０〜４５／５５がさらに好ましく、とりわけ１００／０〜５０／５０が好ましい。
上記の乳酸−グリコール酸重合体の重量平均分子量は３,０００〜１００,０００が好ましく、さらに５,０００〜８０,０００が特に好ましい。また、乳酸−グリコール酸重合体の分散度（重量平均分子量／数平均分子量）は約１.２〜約４.０が好ましく、さらに約１.５〜約３.５が特に好ましい。
乳酸−グリコール酸重合体の分解・消失速度は組成あるいは分子量によって大きく変化するが、一般的にはグリコール酸分率が低いほど分解・消失が遅いため、グリコール酸分率を低くするかあるいは分子量を大きくすることによって放出期間を長くすることができる。逆に、グリコール酸分率を高くするかあるいは分子量を小さくすることによって放出期間を短くすることもできる。長期間（例えば、１〜６カ月、好ましくは１〜４カ月）型徐放性製剤（固形）とするには、上記の組成比および重量平均分子量の範囲の乳酸−グリコール酸重合体が好ましい。上記の組成比および重量平均分子量の範囲の乳酸−グリコール酸重合体よりも分解が早い乳酸−グリコール酸重合体を選択すると初期バーストの抑制が困難であり、逆に上記の組成比および重量平均分子量の範囲の乳酸−グリコール酸重合体よりも分解が遅い乳酸−グリコール酸重合体を選択すると有効量の薬物が放出されない期間を生じやすい。
【００１９】
本明細書における重量平均分子量、数平均分子量および分散度とは、重量平均分子量が１２０,０００、５２,０００、２２,０００、９,２００、５,０５０、２,９５０、１,０５０、５８０、１６２の９種類のポリスチレンを基準物質としてゲルパーミエーションクロマトグラフィー（ＧＰＣ）で測定したポリスチレン換算の分子量および算出した分散度をいう。測定は、ＧＰＣカラムＫＦ８０４Ｌ×２（昭和電工製）、ＲＩモニターＬ−３３００（日立製作所製）を使用、移動相としてクロロホルムを用いる。また、生体内分解性ポリマーをアセトン−メタノール混合溶媒に溶解し、フェノールフタレインを指示薬としてこの溶液をアルコール性水酸化カリウム溶液でカルボキシル基を滴定して末端基定量による数平均分子量を算出する。以下これを末端基定量による数平均分子量と表記する。
末端基定量による数平均分子量が絶対値であるのに対してＧＰＣ測定による数平均分子量は分析あるいは解析条件（例えば、移動相の種類、カラムの種類、基準物質、スライス幅の選択、ベースラインの選択等）によって変動する相対値であるため、一義的な数値化は困難であるが、例えば乳酸とグリコール酸から無触媒脱水重縮合法で合成され、末端に遊離のカルボキシル基を有する重合体では、ＧＰＣ測定による数平均分子量と末端基定量による数平均分子量とがほぼ一致する。この乳酸−グリコール酸重合体の場合にほぼ一致するとは、末端基定量による数平均分子量がＧＰＣ測定による数平均分子量の約０.５〜約２倍の範囲内であることをいい、好ましくは約０.７〜約１.５倍の範囲内であることをいう。
【００２０】
乳酸−グリコール酸重合体は、乳酸とグリコール酸からの無触媒脱水重縮合（特開昭６１−２８５２１号）あるいはラクタイドとグリコライド等の環状体からの触媒を用いた開環重合（Encyclopedic Handbook of Biomaterials and Bioengineering PartA：Materials, Volume 2, Marcel Dekker, Inc. 1995年）で製造できる。
開環重合で合成される重合体はカルボキシル基を有しない重合体であるが、該重合体を化学的に処理して末端を遊離のカルボキシル基にした重合体（ジャーナル オブ コントロールド リリーズ（J. Controlled Release），４１巻、２４９−２５７頁、１９９６年）を用いることもできる。
上記の末端に遊離のカルボキシル基を有する乳酸−グリコール酸重合体は公知の製造法（例えば無触媒脱水重縮合法、特開昭６１−２８５２１号公報参照）で問題なく製造でき、さらには末端に特定されない遊離のカルボキシル基を有する重合体は公知の製造法（例えば、ＷＯ９４／１５５８７号公報参照）で製造できる。
また、開環重合後の化学的処理によって末端を遊離のカルボキシル基にした乳酸−グリコール酸重合体は、例えばベーリンガー エンゲルハイム（Boehringer Ingelheim KG）から市販されているものを用いてもよい。
【００２１】
本発明の製造法に用いられる徐放性製剤の懸濁液としては、上記した徐放性製剤を下記の懸濁液に用いられる溶媒に添加して調製する。徐放性製剤の懸濁液は、通常、ＭＣの場合、ＭＣとして、約１ｍｇ〜約３０００ｍｇ／ｍｌ、好ましくは約５ｍｇ〜約１０００ｍｇ／ｍｌに調製する。
該懸濁液としては更に凝集防止剤、例えば、水溶性糖類〔例、マンニトール，ラクトース，ブドウ糖，デンプン類（例、コーンスターチ等）〕、アミノ糖（例、グリシン，アラニン等）、タンパク質（例、ゼラチン，フィブリン，コラーゲン等）、無機塩（例、塩化ナトリウム，臭化ナトリウム，炭酸カリウム等）などを添加したものであっていてもよい。凝集防止剤としては、特に、Ｄ−マンニトールなどのマンニトールが好適である。
懸濁液に用いられる溶媒としては、例えば、注射用水（例、蒸留法や超濾過法などにより製造される水など）、ＵＦ水、ＲＯ水、イオン交換水、揮発性溶媒（例、エタノール、アセトンなど）、ポリエチレンングリコール、植物油、鉱物油、またはそれらの混合溶媒などが挙げられ、特に、注射用水などが好適である。また、懸濁安定化剤として、界面活性剤、増粘剤、ｐＨ調整剤などを添加することができる。界面活性剤としては、例えば、ポリソルベート類（例、ポリソルベート８０，ポリソルベート２０，ポリソルベート２０等）、プルロニック類（例、プルロニックＦ６８（一般名ポリオキシエチレンン〔１６０〕ポリオキシプロピレン〔３０〕グリコール）等）、ポリオキシエチレン硬化ヒマシ油類（例、ポリオキシエチレン硬化ヒマシ油５０、ポリオキシエチレン硬化ヒマシ油６０等）などが用いられる。増粘剤としては、例えば、カルボキシメチルセルロース類、（例、ＣＭＣ−Ｋ，ＣＭＣ−Ｎａ等）、ポリビニルピロリドン（ＰＶＰ）などが用いられる。ｐＨ調整剤としては、例えば、塩酸、水酸化ナトリウム、酢酸、乳酸、水酸化アンモニウム、炭酸ナトリウム、炭酸水素ナトリウムなどが用いられる。
【００２２】
本発明の製造法に用いられる凍結乾燥用容器は、通常、ＭＣ等の徐放性製剤の凍結乾燥に用いられる容器であれば何れのものであってもよく、例えば、凍結乾燥用トレーなどが用いられる。また、該容器としては、金属（好ましくは、ステンンレス（ＳＵＳ３１６，３０４等））製、ガラス製、陶器製のものが用いられる。更に本発明の製造法に用いられる凍結乾燥用容器としては、平板状のものも包含される。
該凍結乾燥容器の大きさは、凍結乾燥の規模に応じて、適宜選択することができる。具体的には、例えば、▲１▼横が約５ｍｍ〜約１０，０００ｍｍ、縦が約５ｍｍ〜約１０，０００ｍｍ、深さが約０．１ｍｍ〜約５００ｍｍのもの、好ましくは、▲２▼横が約５ｍｍ〜約７，０００ｍｍ、縦が約５ｍｍ〜約７，０００ｍｍ、深さが約１ｍｍ〜約１００ｍｍのもの、より好ましくは、▲３▼横が約５ｍｍ〜約５００ｍｍ、縦が約５ｍｍ〜約３００ｍｍ、深さが約５ｍｍ〜約１００ｍｍのものが用いられる。横、縦および深さの比率は特に限定されないが、通常、深さ１に対して横約１〜約２０、縦約１〜約１０、好ましくは、深さ１に対して横約１〜約１０、縦約１〜約６である。
容器の容量は、例えば、約１０ｍｌ〜約１００，０００ｍｌ、好ましくは、約１００ｍｌ〜約５，０００ｍｌ、特に好ましくは約３，０００ｍｌである。
該凍結乾燥用容器は、凍結乾燥時の吸引のために、容器の一部に空洞が施されているが、通常は天板を有しない凍結乾燥用容器が用いられる。
該凍結乾燥用容器の被覆に用いられる撥水性基材としては、例えば、フッ化エチレン樹脂（例、四フッ化エチレン樹脂、三フッ化エチレン樹脂、二フッ化エチレン樹脂）、フッ化ビニリデン樹脂、六フッ化プロピレン・四フッ化エチレン共重合体樹脂、変性フッ素樹脂、四フッ化エチレンとパーフロロアルコキシエチレンの共重合体樹脂、四フッ化エチレンとエチレンの共重合体樹脂などが挙げられ、なかでも、フッ化エチレン樹脂（例、四フッ化エチレン樹脂、三フッ化エチレン樹脂、二フッ化エチレン樹脂）が好ましく、テフロン（商品名）が好適である。
凍結乾燥用容器を撥水性基材で被覆（コート）する方法としては、自体公知あるいはそれに準じる方法が用いられるが、具体的には、メッキ法、蒸着法などが用いられる。
本発明の製造法で得られる固形徐放性製剤としては、本発明で用いられる徐放性製剤を本発明の製造法（凍結乾燥法）に付して得られる徐放性製剤であればいかなるものであっていてもよく、粉末状の徐放性製剤（例えば、ＭＣ末など）の他、自体公知の方法に準じて種々の形状に成型された（例えば、ペレット状、ニードル状など）徐放性製剤をも含有する。
【００２３】
以下に、本発明の製造法を具体的に詳細を説明する。
（１）内面の一部または全部が氷層で被覆された凍結乾燥用容器中で徐放性製剤を凍結乾燥することを特徴とする固形徐放性製剤の製造法について
氷層を作製するための水としては、例えば、注射用水（例、蒸留水など）、イオン交換水などが用いられる。
氷層で被覆する部分は凍結乾燥用容器の内面の一部または全部であるが、例えば、容器の内面のうち底面のみ、底面および側面の全部、底面の一部のみ、または底面および側面の一部のみであってもよい。また、容器の外面に氷層が形成されていてもよい。
凍結乾燥用容器中における氷層の厚さは、使用する容器の大きさ、徐放性製剤（徐放性製剤の懸濁液）の容量、凍結乾燥温度などに応じて、適宜選択することができるが、例えば、通常、容器の深さの約１／１０００〜約４／５、好ましくは約１／５００〜約１／５、より好ましくは約１／１００〜約１／１０、特に好ましくは約１／１０であって、約０．０１ｍｍ以上が好適である。より具体的には、約０．０１ｍｍ〜約４００ｍｍ、好ましくは約０．０１ｍｍ〜約２００ｍｍ、より好ましくは約０．０１ｍｍ〜約３０ｍｍ、さらに好ましくは約０．１ｍｍ〜約３０ｍｍ、特に好ましくは約０．１ｍｍ〜約１０ｍｍ、最も好ましくは約１ｍｍである。
氷層はトレーに水を注ぎ、通常約−８０℃〜約０℃、好ましくは約−５０℃〜約０℃で作製する。
【００２４】
凍結乾燥用容器中に氷層を形成させた後、徐放性製剤（徐放性製剤の懸濁液）を容器中に分注させ、凍結させることにより徐放性製剤（徐放性製剤の懸濁液）の凍結層を形成させる。
徐放性製剤の懸濁液は、通常、ＭＣの場合、ＭＣとして、約１ｍｇ〜約３０００ｍｇ／ｍｌ、好ましくは約５ｍｇ〜約１０００ｍｇ／ｍｌに調製する。
徐放性製剤（徐放性製剤の懸濁液）の容量は、使用する容器の大きさ、凍結乾燥温度などに応じて、適宜選択することができるが、通常、徐放性製剤の懸濁液の凍結層の厚さが、容器の深さの約１／１０００〜約４／５、好ましくは約１／５００〜約１／５、より好ましくは約１／１００〜約１／１０、特に好ましくは約１／１０である。また、容器１００ｍｌに対して、徐放性製剤の懸濁液の容量を約０．１ｍｌ〜約９９．９ｍｌ、好ましくは約１ｍｌ〜約９０ｍｌ、さらに好ましくは約１ｍｌ〜約４０ｍｌとすることもできる。さらに、氷層が容器の底から約１ｍｍの場合、徐放性製剤の懸濁液の凍結層を約１〜１０倍、好ましくは約１〜５倍とすることもできる。
例えば、容器として、横が約５ｍｍ〜約７，０００ｍｍ、縦が約５ｍｍ〜約７，０００ｍｍ、深さが約１ｍｍ〜１００ｍｍのものを用いる場合、氷層の厚さは通常約０．０１ｍｍ〜約３０ｍｍ、好ましくは約０．１ｍｍ〜約３０ｍｍ、より好ましくは約０．１ｍｍ〜１０ｍｍ、特に好ましくは約１ｍｍの厚さとする。一方、徐放性製剤の懸濁液の凍結層は、例えば、底面の氷層から約１ｍｍ〜約２０ｍｍ、好ましくは約２ｍｍ〜約１０ｍｍ、好ましくは約４ｍｍとする。
徐放性製剤（徐放性製剤の懸濁液）の凍結層は、予め約−１０℃〜約２０℃、好ましくは約０℃〜５℃に冷却しておいた徐放性製剤（徐放性製剤の懸濁液）を氷層の上に分注した後、通常約−８０℃〜約０℃、好ましくは約−５０℃〜約０℃で作製する。
このようにして、凍結乾燥容器中に氷層と徐放性製剤（徐放性製剤の懸濁液）の凍結層の２層を作製する。
凍結乾燥は自体公知の方法を用いて行うことができ、例えば、前記のＭＣまたはマイクロスフィアを開示した公開公報などに従って行うことができる。
好ましい凍結乾燥の方法としては、例えば、減圧下、凍結乾燥用容器の温度（棚温）が０℃以下（好ましくは、−４０℃〜０℃、より好ましくは、−２０℃〜０℃、さらに好ましくは、−１０℃〜０℃）で凍結乾燥容器内の氷結水分の昇華を完了させることを特徴とする方法など、具体的には、減圧下、棚温を０℃以下（好ましくは、−４０℃〜０℃、より好ましくは、−２０℃〜０℃、さらに好ましくは、−１０℃〜０℃）で保ち、凍結乾燥容器内の氷結水分の昇華を完了させることを特徴とする方法などがあげられる。
ここで、凍結乾燥用容器の温度（棚温）とは被凍結乾燥物を保持する容器またはその容器が接触している棚の温度のことを意味する。また、氷結水分とは氷結した自由水のことを意味する。
棚温を０℃以下（好ましくは、−４０℃〜０℃、より好ましくは、−２０℃〜０℃、さらに好ましくは、−１０℃〜０℃）で保つ場合には、約０．１時間以上、好ましくは約１時間〜５００時間、さらに好ましくは約５時間〜１００時間棚温を０℃以下に保ち、凍結乾燥容器内の氷結水分の昇華を完了させる。
上記の方法により凍結乾燥を行うことにより、氷結水分の昇華が０℃以下、即ち氷の融解しない低温（共晶点、融点以下の温度）で行われる結果、氷の融解および昇華速度が抑制されるために▲１▼凍結乾燥ケーキの崩れが防止され、▲２▼ＭＣ末の凍結乾燥容器外への飛散などが防止され、▲３▼さらにＭＣ末の高収量が確保され、▲４▼一定の品質のＭＣ末が製造できる。
【００２５】
（２）内面の一部または全部が撥水性基材で被覆された凍結乾燥用容器中で徐放性製剤（徐放性製剤の懸濁液）を凍結乾燥することを特徴とする固形徐放性製剤の製造法について
撥水性基材で被覆する部分は凍結乾燥用容器の内面の一部または全部であるが、例えば、容器の内面のうち底面のみ、底面および側面の全部、底面の一部のみ、または底面および側面の一部のみであってもよい。また、容器の外面も撥水性基材で被覆されていてもよい。
徐放性製剤（徐放性製剤の懸濁液）を容器中に分注させ、凍結させることにより徐放性製剤（徐放性製剤の懸濁液）の凍結層を形成させる。
徐放性製剤の懸濁液は、通常、ＭＣの場合、ＭＣとして、約１ｍｇ〜約３０００ｍｇ／ｍｌ、好ましくは約１ｍｇ〜約３００ｍｇ／ｍｌに調製する。
凍結乾燥用容器中における徐放性製剤（徐放性製剤の懸濁液）の容量、使用する容器の大きさ、凍結乾燥温度などに応じて、適宜選択することができるが、例えば、通常、徐放性製剤の懸濁液の凍結層の厚さが、容器の深さの約１／１０００〜約４／５、好ましくは約１／５００〜約１／５、より好ましくは約１／１００〜約１／１０、特に好ましくは約１／１０である。また、容器１００ｍｌに対して、徐放性製剤の懸濁液の容量を約０．１ｍｌ〜約９９．９ｍｌ、好ましくは約１ｍｌ〜約９０ｍｌ、さらに好ましくは約１ｍｌ〜約４０ｍｌとすることもできる。さらに、氷層が容器の底から約１ｍｍの場合、徐放性製剤の懸濁液の凍結層を約１〜１０倍、好ましくは約１〜５倍とすることもできる。
例えば、容器として、横が約５ｍｍ〜約７，０００ｍｍ、縦が約５ｍｍ〜約７，０００ｍｍ、深さが約１ｍｍ〜１００ｍｍのものを用いる場合、氷層の厚さは通常約０．０１ｍｍ〜約３０ｍｍ、好ましくは約０．１ｍｍ〜約３０ｍｍ、より好ましくは約０．１ｍｍ〜１０ｍｍ、特に好ましくは約１ｍｍの厚さとする。一方、徐放性製剤の懸濁液の凍結層は、例えば、底面の氷層から約１ｍｍ〜約２０ｍｍ、好ましくは約２ｍｍ〜約１０ｍｍ、好ましくは約４ｍｍとする。
徐放性製剤（徐放性製剤の懸濁液）の凍結層は、予め約−１０℃〜約２０℃、好ましくは約０℃〜５℃に冷却しておいた徐放性製剤（徐放性製剤の懸濁液）を氷層の上に分注した後、通常約−８０℃〜約０℃、好ましくは約−５０℃〜約０℃で作製する。
このようにして、凍結乾燥容器中に徐放性製剤（徐放性製剤の懸濁液）の凍結層を作製する。
凍結乾燥は上記の製造法（１）と同様にして行うことができる。
【００２６】
（３）撥水性基材で内面が被覆され、かつその内面の一部または全部が氷層で被覆された凍結乾燥用容器中で徐放性製剤（徐放性製剤の懸濁液）を凍結乾燥することを特徴とする固形徐放性製剤の製造法について
本法は、上記の製造法（１）における凍結乾燥用容器の代わりに、撥水性基材で内面が被覆された凍結乾燥用容器を用いる以外は、製造法（１）と同様にして実施することができる。
本法の場合、凍結乾燥用容器の内面のうち、少なくとも徐放性製剤（徐放性製剤の懸濁液）が接する部分全てが撥水性基材で被覆されていることが望ましい。
【００２７】
本発明の製造法は、次のような利点を有している。
（１）ＭＣ末がトレーに付着しないので、回収時にスクレーパーを使用して掻き取る必要がない。
（２）スクレーパーを使用して掻き取りを行う必要がないため、回収時に環境に暴露させる時間が短くなり、微生物などの混入の危険性がない。また、ＭＣは水分コントロールが必要な製剤であるため、環境暴露時間が短いことにより、理化学的な安定性の観点からも危険性が少ない。
（３）スクレーパーを使用した掻き取り操作が不要なため、トレーとスクレーパーの擦れに起因する異物発生・混入の危険性がない。
（４）ＭＣ末とトレーとの付着が少ないため、ＭＣ末の回収率が高い。
（５）さらに、上記のより好ましい凍結乾燥方法を適用することにより、より高収量で一定の品質のＭＣ末を回収することができることができる。
【００２８】
本発明の製造法を用いて、徐放性製剤（徐放性製剤の懸濁液）を凍結乾燥した後、必要であれば、減圧下、徐放性製剤同士が融着しない条件内で加温して徐放性製剤中の水分および有機溶媒の除去を行ってもよい。この場合、好ましくは毎分約１０〜約２０℃の昇温速度の条件下で示差走査熱量計で求めた生体内分解性ポリマーの中間点ガラス転移温度よりも若干高い温度で加温する。より好ましくは生体内分解性ポリマーの中間点ガラス転移温度からこれより約３０℃高い温度範囲内で加温する。とりわけ、生体内分解性ポリマーとして乳酸−グリコール酸重合体を用いる場合には、その中間点ガラス転移温度以上中間点ガラス転移温度より２０℃高い温度範囲、好ましくは、中間点ガラス転移温度以上中間点ガラス転移温度より１０℃高い温度範囲で加温する。
加温時間は徐放性製剤の量などによって異なるものの、一般的には徐放性製剤自体が所定の温度に達した後、約１２時間〜約１６８時間が好ましく、さらに約４８時間〜約１２０時間が好ましい。特に、約４８時間〜約９６時間が好ましい。
加温方法は、徐放性製剤の集合が均一に加温できる方法であれば特に限定されない。
該加温乾燥方法の好ましい具体例として、例えば、恒温槽、流動槽、移動槽あるいはキルン中で加温乾燥する方法、マイクロ波で加温乾燥する方法などが用いられる。このなかで恒温槽中で加温乾燥する方法が好ましい。
【００２９】
上記のようにして得られる徐放性製剤の凍結乾燥品（固形）は、そのままあるいはこれを原料物質として種々の剤形に製剤化し、経口又は非経口で投与することができる。具体的には筋肉内、皮下、臓器などへの注射剤または埋め込み剤、鼻腔、直腸、子宮などへの経粘膜剤、経口剤〔例、カプセル剤（例、硬カプセル剤、軟カプセル剤等）、顆粒剤、散剤等の固形製剤、シロップ剤、乳剤、懸濁剤等の液剤等〕などとして投与することができる。
例えば、徐放性製剤（固形）を注射剤とするには、これらを分散剤（例、ツイーン（Tween）８０、ＨＣＯ−６０等の界面活性剤、ヒアルロン酸ナトリウム、カルボキシメチルセルロース、アルギン酸ナトリウム等の多糖類など）、保存剤（例、メチルパラベン、プロピルパラベンなど）、等張化剤（例、塩化ナトリウム、マンニトール、ソルビトール、ブドウ糖、プロリンなど）等と共に水性懸濁剤とするか、ゴマ油、コーン油などの植物油と共に分散して油性懸濁剤として実際に使用できる徐放性注射剤とする。
徐放性製剤（固形）の粒子径は、懸濁注射剤として使用する場合にはその分散度、通針性を満足する範囲であればよく、例えば、平均粒子径として約０.１〜３００μmの範囲が挙げられる。好ましくは、約１〜１５０μm の範囲の平均粒子径である。さらに好ましくは、約２〜１００μm の範囲の平均粒子径である。
徐放性製剤（固形）を無菌製剤にするには、製造全工程を無菌にする方法、ガンマ線で滅菌する方法、防腐剤を添加する方法等が挙げられるが、特に限定されない。
【００３０】
上記徐放性製剤（固形）は、低毒性であるので、ヒトまたは哺乳動物（例、サル、牛、豚、犬、ネコ、マウス、ラット、ウサギ等）に対して安全に用いることができる。
徐放性製剤（固形）の活性成分としての投与量は、主薬である生理活性ペプチドの種類と含量、剤形、生理活性ペプチド放出の持続時間、対象疾病、対象動物、投与方法などによって種々異なるが、生理活性ペプチドの有効量であればよい。主薬である生理活性ペプチドの１回当たりの投与量としては、例えば、徐放性製剤（固形）が１カ月製剤である場合、好ましくは、成人１人（体重５０Ｋｇとして）当たり約０.００１mg〜１００mg／kg体重の範囲から適宜選ぶことができる。さらに好ましくは約０.００５mg〜５０mg／kg体重の範囲から、特に好ましくは約０.０１mg〜１０mg／kg体重の範囲から適宜選ぶことができる。
より具体的には、前述の一般式〔Ｉａ〕で表わされるＬＨ−ＲＨアンタゴニストまたは一般式〔Ｉｂ〕で表わされるＬＨ−ＲＨアゴニストを生理活性ペプチドとして用いる場合、例えば、前立腺癌，前立腺肥大症，子宮内膜症，子宮筋腫，子宮線維腫，思春期早発症，乳癌，膀胱癌，子宮頸部癌，慢性リンパ性白血病，慢性骨髄性白血病，大腸癌，胃炎，ホジキン病，悪性黒色腫，移転，多発性骨髄腫，非ホジキン性リンパ腫，非小細胞肺癌，卵巣癌，消化性潰瘍，全身性真菌感染症，小細胞肺癌，心弁膜症，乳腺症，多嚢胞性卵巣，不妊，慢性無排卵症，婦人における適性排卵誘発，ざそう（アクネ），無月経（例、続発性無月経），卵巣および乳房の嚢胞性疾患（多嚢胞性卵巣を含む），婦人科系の癌、卵巣性高アンドロゲン血症および多毛症，胸腺幼若化を介したＴ細胞産生によるＡＩＤＳ，男性性犯罪者の治療のための男性避妊等のホルモン依存性疾患の治療・予防剤、避妊，月経前症候群（ＰＭＳ）の症状軽減のための薬剤、体外受精（ＩＶＦ）用剤などとして、特に、前立腺癌，前立腺肥大症，子宮内膜症，子宮筋腫，子宮線維腫，思春期早発症などの治療・予防剤や避妊薬として使用することができる。
該生理活性ペプチドの投与量は、その剤形、所望の薬物放出持続時間、対象疾病、対象動物などによって種々異なるが、薬物の有効量であればよい。薬物の１回当たりの投与量としては、例えば徐放性製剤（固形）が１カ月製剤である場合、好ましくは、成人１人当たり約０.００１mg〜約１０mg／kg体重の範囲から適宜選ぶことができる。さらに好ましくは、約０.００５mg〜約５mg／kg体重の範囲から適宜選ぶことができる。
１回当たりの徐放性製剤（固形）の投与量は成人１人当たり好ましくは、約０.００５mg〜５０mg／kg体重の範囲から適宜選ぶことができる。さらに好ましくは約０.０１mg〜３０mg／kg体重の範囲から適宜選ぶことができる。投与回数は、数週間に１回、１か月に１回、あるいは数か月に１回等、主薬である生理活性ペプチドの種類と含量、剤形、生理活性ペプチド放出の持続時間、対象疾病、対象動物などによって適宜選ぶことができる。
【００３１】
【発明の実施の形態】
以下に、実施例および参考例に基づいて本発明をより詳細に説明するが、本発明はこれらにより限定されるものではなく、また本発明の範囲を逸脱しない範囲で変化させてもよい。
【００３２】
【実施例】
参考例１ 徐放性ＭＣ（１カ月製剤）懸濁液の調製
ゼラチン２.４ｇ、酢酸リュープロレリン１５.２ｇを蒸留水１５.０ｇに加温しながら溶解した。この溶液に、別で調製した乳酸・グリコール酸共重合体（以下、ＰＬＧＡと略記）〔乳酸／グリコール酸＝７５／２５（モル％）、重量平均分子量：１０５００〕のジクロロメタン溶液３２１ｇ（内、ＰＬＧＡ １２１ｇ）を添加し、ミニミキサーで２分間撹拌乳化（回転数：１００００rpm）した。これを、予め溶解しておいた０.１％ポリビニールアルコール（ＰＶＡ）水溶液２５L に加えて再び乳化した。このＷ／Ｏ／Ｗエマルションを軽く撹拌しながら約３時間ほど脱溶媒した。得られたＭＣを７５μm の篩を通して荒い粒子を除去した後、遠心分離によって分離した。これを蒸留水で洗浄し、遊離の薬物、ＰＶＡを除去した後、少量の蒸留水とともに２５０μm および９０μmの篩で湿式篩過した。これに、１８.４ｇのＤ−マンニトールを加え溶解し、ＭＣの懸濁液とした。スケールに応じて、各原料の使用量を増減できる。
【００３３】
参考例２ 徐放性ＭＣ（３カ月製剤）懸濁液の調製
酢酸リュープロレリン１０.８ｇを蒸留水１２.５ｇに加温しながら溶解した。この溶液に、別で調製した乳酸重合体（以下、ＰＬＡと略記）〔重量平均分子量：１６０００〕のジクロロメタン溶液２５６ｇ（内、ＰＬＡ ９６ｇ）を添加し、ミニミキサーで２分間撹拌乳化（回転数：１００００rpm）した。これを、あらかじめ溶解しておいた０.１％ポリビニールアルコール（ＰＶＡ）水溶液２５Lに加えて再び乳化した。このＷ／Ｏ／Ｗエマルションを軽く撹拌しながら約３時間ほど脱溶媒した。得られたＭＣを７５μm の篩を通して荒い粒子を除去した後、遠心分離によって分離した。これを蒸留水で洗浄し、遊離の薬物、ＰＶＡを除去した後、少量の蒸留水とともに２５０μm および９０μmの篩で湿式篩過した。これに、１６.３ｇのＤ−マンニトールを加え溶解し、ＭＣの懸濁液とした。スケールに応じて、各原料の使用量を増減できる。
【００３４】
実施例１
凍結乾燥用トレー（横２００ｍｍ、縦１００ｍｍ、深さ２０ｍｍ）に、注射用水を用いて予め約１ｍｍの厚さの氷層をー３０℃で形成させた。このときトレーの内側壁にも氷層を形成させた（アイスライニング）。予め約５℃に冷却しておいた上記参考例１で得たＭＣ懸濁液８０ｍｌを、氷層を形成してなる凍結乾燥用トレー上に添加し、約−３０℃で十分凍結させた後、常法に従って凍結乾燥を行った。
一方、これとは別に、氷層を形成させない凍結乾燥用トレー上に該ＭＣ懸濁液８０ｍｌを添加し、約−３０℃で十分凍結させた後、常法に従って凍結乾燥を行った。
凍結乾燥後、それぞれのトレーを逆さにして、トレーからの凍結乾燥品のはく離・回収状況を観察した。
氷層を形成してなる凍結乾燥用トレーを用いた場合、凍結乾燥品をトレーから容易に回収することができ、トレーの表面にはＭＣ末の付着を認めなかった。一方、氷層を形成させない凍結乾燥用トレーを用いた場合、凍結乾燥品はトレーからはく離しなかった。また、ＭＣ末をスクレーパーで回収した後も、トレーにＭＣ末の付着を認めた。
【００３５】
実施例２
表面に撥水性の高分子であるテフロン（商品名）をコートした凍結乾燥用トレー（横２００ｍｍ、縦１００ｍｍ、深さ２０ｍｍ）に、予め約５℃に冷却しておいた上記参考例１で得たＭＣ懸濁液８０ｍｌを添加し、約−３０℃で十分凍結させた後、常法に従って凍結乾燥を行った。
一方、これとは別に、表面に撥水性処理を施していない凍結乾燥用トレー上に該ＭＣ懸濁液８０ｍｌを添加し、約−３０℃で十分凍結させた後、常法に従って凍結乾燥を行った。
凍結乾燥後、それぞれのトレーを逆さにして、トレーからの凍結乾燥品のはく離・回収状況を観察した。
表面に撥水性処理を施した凍結乾燥用トレーを用いた場合、凍結乾燥品をトレーから容易に回収することができ、トレーの表面にはＭＣ末の付着を認めなかった。一方、表面に撥水性処理を施していない凍結乾燥用トレーを用いた場合、凍結乾燥標品はトレーからはく離しなかった。また、ＭＣ末をスクレーパーで回収した後も、トレーにＭＣ末の付着を認めた。
【００３６】
実施例３
実施例２と同様のテフロンをコートした凍結乾燥用トレー（横２００ｍｍ、縦１００ｍｍ、深さ２０ｍｍ）に、注射用水を用いて予め約１ｍｍの厚さの氷層をー３０℃で形成させた。このときトレーの内側壁にも氷層を形成させた（アイスライニング）。予め約５℃に冷却しておいた上記参考例１で得たＭＣ懸濁液８０ｍｌを添加し、約−３０℃で十分凍結させた後、常法に従って凍結乾燥を行った。
一方、これとは別に、氷層を形成させておらず、かつ表面に撥水性処理を施していない凍結乾燥用トレー上に該ＭＣ懸濁液８０ｍｌを添加し、約−３０℃で十分凍結させた後、常法に従って凍結乾燥を行った。
凍結乾燥後、それぞれのトレーを逆さにして、トレーからの凍結乾燥品のはく離・回収状況を観察した。
表面に撥水性処理を施し、かつ氷層を形成させた凍結乾燥用トレーを用いた場合、凍結乾燥品をトレーから容易に回収することができ、トレーの表面にはＭＣ末の付着を認めなかった。一方、氷層を形成させておらず、かつ表面に撥水性処理を施していない凍結乾燥用トレーを用いた場合、凍結乾燥品はトレーからはく離しなかった。また、ＭＣ末をスクレーパーで回収した後も、トレーにＭＣ末の付着を認めた。
【００３７】
実施例４
〔表１〕に示す凍結乾燥用トレーの大きさと氷層の厚さとを組み合わせても、実施例１〜３と同様の結果が得られる。
【表１】

【００３８】
実施例５
酢酸リュープロレリン１５．１ｇを蒸留水１５．０ｇに加温しながら（７０℃〜８０℃）溶解した。この溶液に、別で調製した乳酸・グリコール酸共重合体（ＰＬＧＡ）[乳酸／グリコール酸＝７５／２５（モル％）、重量平均分子量：１０５００]のジクロロメタン溶液３２３．６ｇ（内、ＰＬＧＡ１２３．９ｇ）（２５〜３５℃にコントロールした）を添加し、混合物温度を４０℃以下にコントロールして、ミニミキサーで２分間攪拌乳化（回転数：１００００ｒｐｍ）した。
これを１８〜１９℃に冷却し、予め溶解しておいた０．１％ポリビニルアルコール（ＰＶＡ）（１８〜１９℃）水溶液２５Ｌに加え再び乳化した。このＷ／Ｏ／Ｗエマルションを軽く攪拌しながら約３時間ほど脱溶媒した。得られたＭＣを７５μｍの篩を通して粗い粒子を除去した後、少量の蒸留水とともに９０μｍの篩で湿式篩過した。これに、１８．４ｇのＤ−マンニトールを加え溶解し、ＭＣの懸濁液とした。
予め凍結乾燥用トレー（横１７０ｍｍ、縦２６０ｍｍ、深さ４０ｍｍ）に、注射用蒸留水で約２ｍｍの厚さの氷層を−３０℃で形成させたトレーに、上記ＭＣ懸濁液約４００ｍｌを添加し、約−３０℃で十分凍結させた後、常法または後述の実施例７に従って凍結乾燥を行う。
本方法により製造された凍結乾燥品は、それぞれのトレーからの凍結乾燥品のはく離・回収が容易であり、また、トレー表面にＭＣ末の付着は認められない。
【００３９】
実施例６
酢酸リュープロレリン１５．１ｇを蒸留水１３．０ｇに加温しながら（７０℃〜８０℃）溶解した。この溶液に、別で調製した乳酸・グリコール酸共重合体（ＰＬＧＡ）[乳酸／グリコール酸＝７５／２５（モル％）、重量平均分子量：１０５００]のジクロロメタン溶液３２３．６ｇ（内、ＰＬＧＡ１２３．６ｇ）（２５〜３５℃にコントロールした）を添加し、混合物温度を４０℃以下にコントロールして、ミニミキサーで２分間攪拌乳化（回転数：１００００ｒｐｍ）した。
これを１８〜１９℃に冷却し、予め溶解しておいた０．１％ポリビニルアルコール（ＰＶＡ）水溶液（１８〜１９℃）２５Ｌに加え再び乳化した。このＷ／Ｏ／Ｗエマルションを軽く攪拌しながら約３時間ほど脱溶媒した。得られたＭＣを７５μｍの篩を通して粗い粒子を除去した後、少量の蒸留水とともに９０μｍの篩で湿式篩過した。これに、１８．４ｇのＤ−マンニトールを加え溶解し、ＭＣの懸濁液とした。
予め凍結乾燥用トレー（横１７０ｍｍ、縦２６０ｍｍ、深さ４０ｍｍ）に、注射用蒸留水で約２ｍｍの厚さの氷層を−３０℃で形成させたトレーに、上記ＭＣ懸濁液約４００ｍｌを添加し、約−３０℃で十分凍結させた後、常法または後述の実施例７に従って凍結乾燥を行う。
本方法により製造された凍結乾燥品は、それぞれのトレーからの凍結乾燥品のはく離・回収が容易であり、また、トレー表面にＭＣ末の付着は認められない。
【００４０】
実施例７ 徐放性ＭＣ（１ヶ月製剤）懸濁液への適用
凍結乾燥用トレー（横１７０ｍｍ、縦２６０ｍｍ、深さ４０ｍｍ）に注射用水を用いて予め約２ｍｍの厚さの氷層を−３０℃で形成させた。このときトレーの内側壁にも氷層を形成させた（アイスライニング）。予め約５℃に冷却しておいた上記参考例１で得たＭＣ懸濁液２００ｍＬを、氷層を形成している凍結乾燥用トレー上に添加し、約−３０℃で十分凍結させた後、以下に示す方法で凍結乾燥を行った。
懸濁液を約−３０℃で凍結後、２０℃／ｈｒで棚温度を−５℃まで上昇させ、約２０時間温度を保持した。その後、更に棚温度を２０℃／ｈｒで５１℃まで上昇させ、約４８時間保持した。
凍結乾燥後、凍結乾燥品の状態、およびトレーからのはく離・回収状況を観察した。
凍結乾燥品には崩れ・飛散を認めなかった。また凍結乾燥品をトレーから容易に回収することができ、トレー表面にはＭＣ末の付着を認めなかった。
【００４１】
実施例８ 徐放性ＭＣ（３ヶ月製剤）懸濁液への適用
凍結乾燥用トレー（横１７０ｍｍ、縦２６０ｍｍ、深さ４０ｍｍ）に注射用水を用いて予め約２ｍｍの厚さの氷層を−３０℃で形成させる。このときトレーの内側壁にも氷層を形成させる（アイスライニング）。予め約５℃に冷却しておいた上記参考例２で得たＭＣ懸濁液２００ｍＬを、氷層を形成している凍結乾燥用トレー上に添加し、約−３０℃で十分凍結させた後、以下に示す方法で凍結乾燥を行う。
懸濁液を約−３０℃で凍結後、２０℃／ｈｒで棚温度を−５℃まで上昇させ、約２０時間温度を保持する。その後、更に棚温度を２０℃／ｈｒで５０℃まで上昇させ、約４８時間保持する。
凍結乾燥品には崩れ・飛散を認めず、凍結乾燥品をトレーから容易に回収することができ、トレー表面にはＭＣ末の付着を認めない凍結乾燥方法ができる。
【００４２】
【発明の効果】
本発明の製造法によれば、凍結乾燥用容器と固形徐放性製剤との付着がなくなり、掻き取り操作をすることなく、固形徐放性製剤を回収することができるので、固形徐放性製剤の回収率が著しく向上する。また、固形徐放性製剤の環境暴露時間が短くなるため、無菌性維持も向上する。さらに、減圧下、凍結乾燥用容器の温度が０℃以下で凍結乾燥容器内の氷結水分の昇華を完了させることを特徴とする凍結乾燥方法を適用することにより、凍結乾燥ケーキの崩れ、飛散を防止し、より高収量で一定の品質のＭＣ末を回収することができることができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing a solid sustained-release preparation that allows a sustained-release preparation such as microspheres to be easily recovered without being exposed to the environment for a long time.
[0002]
[Prior art]
After the micro-capsule (microsphere) powder (hereinafter sometimes abbreviated as MC powder) is produced by the underwater drying method or the like, the micro-capsule (microsphere) (hereinafter sometimes abbreviated as MC) is manufactured. After separating, concentrating and recovering MC, the MC suspension obtained as a suspension together with the solvent described later is produced by dehydration and drying by freeze drying. At this time, mannitol or the like may be added to and dissolved in the suspension. Also, usually, after the MC suspension is dispensed into a tray, the MC suspension is frozen and lyophilized.
However, conventionally, after the freeze-drying, the MC powder has to be peeled and collected from the tray aseptically by hand using a scraper, and thus has the following drawbacks.
(1) MC powder adheres to the tray and must be scraped off using a scraper during recovery.
(2) Since scraping is performed manually and relatively long time is required for recovery, the time for exposure to the environment becomes long, and there is always a risk of contamination with microorganisms from the viewpoint of sterility assurance. In addition, since MC is a preparation that requires moisture control, long exposure time to the environment is dangerous from the viewpoint of physicochemical stability.
(3) Since the use of a scraper is indispensable in the scraping operation, there is a risk of foreign matter generation and contamination due to rubbing between the tray and the scraper.
(4) Since there is adhesion of the MC powder and the tray, the MC powder remains in the tray even after collection by the scraper, and there are MC powder that cannot be collected.
[0003]
[Problems to be solved by the invention]
Therefore, solid sustained-release preparations that can be recovered easily and in high yield after freeze-drying, and that have a short environmental exposure time and reduced risk of foreign matter generation and contamination The development of the manufacturing method of was desired.
[0004]
[Means for Solving the Problems]
As a result of intensive studies to solve the above problems, the present inventors have unexpectedly shortened the time by forming an ice layer on the tray in advance or coating the inner surface of the tray with a water-repellent substrate. In addition, it was found that MC powder after lyophilization can be recovered easily and simply. Furthermore, under reduced pressure, when the temperature of the freeze-drying container is 0 ° C. or less and completes the sublimation of the frozen moisture in the freeze-dried container, the freeze-dried cake is prevented from collapsing and scattering, resulting in higher yield and constant quality. It was also found that MC powder can be recovered. As a result of further research based on these findings, the present inventors have completed the present invention.
That is, the present invention
(1) A method for producing a solid sustained-release preparation, which comprises freeze-drying a sustained-release preparation in a freeze-drying container in which part or all of the inner surface is coated with an ice layer or a water-repellent substrate.
(2) The sustained-release preparation is freeze-dried in a freeze-drying container in which a part or all of the inner surface is coated with a water-repellent substrate and a part or all of the inner surface is coated with an ice layer. A method for producing a solid sustained-release preparation,
(3) The manufacturing method according to item (1) or (2), wherein the inner surface is only the bottom surface;
(4) The production method according to item (1) or (2), wherein the freeze-drying container is a tray;
(5) The manufacturing method according to item (1) or (2), wherein the thickness of the ice layer is about 0.01 mm to 30 mm,
(6) The water-repellent base material is tetrafluoroethylene resin, ethylene trifluoride resin, ethylene difluoride resin, vinylidene fluoride resin, hexafluoropropylene / tetrafluoroethylene copolymer resin, modified fluororesin, The production method according to item (1) or (2), which is a copolymer resin of tetrafluoroethylene and perfluoroalkoxyethylene, or a copolymer resin of tetrafluoroethylene and ethylene,
(7) The production method according to any one of items (1) to (6), wherein the sustained-release preparation is a microsphere;
(8) Providing the manufacturing method according to item (1) or (2), wherein the sublimation of icing water in the freeze-dried container is completed under reduced pressure when the temperature of the freeze-dried container is 0 ° C. or lower. To do.
[0005]
Furthermore, the present invention provides
(9) The manufacturing method according to item (1) or (2), wherein the thickness of the ice layer is about 1/1000 to about 4/5 of the depth of the container,
(10) The production method according to (1) or (2), wherein the thickness of the frozen layer of the suspension of the sustained-release preparation is 1/1000 to about 4/5 of the depth of the container,
(11) The container has a width of about 5 mm to about 7,000 mm, a length of about 5 mm to about 7,000 mm, a depth of about 1 mm to 100 mm, and an ice layer of about 0.01 mm to about 30 mm. ) Or the manufacturing method according to item (2),
(12) The production method according to any one of items (1) to (11), wherein the sustained-release preparation is a sustained-release preparation containing a physiologically active peptide,
(13) The production method according to any one of items (1) to (11), wherein the sustained-release preparation is a sustained-release preparation containing a physiologically active peptide and a biodegradable polymer;
(14) The production method according to item (12) or (13), wherein the physiologically active peptide is an LH-RH agonist or LH-RH antagonist;
(15) The bioactive peptide is 5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH-C₂H_Five(Leuprorelin) or a salt thereof, the production method according to item (12) or (13),
(16) The bioactive peptide is 5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH-C₂H_Five(12) or (13), the production method of (leuprorelin) acetate,
(17) The production method according to item (13), wherein the biodegradable polymer is an α-hydroxycarboxylic acid polymer;
(18) The production method according to item (17), wherein the α-hydroxycarboxylic acid polymer is a lactic acid-glycolic acid polymer;
(19) The production method according to item (18), wherein the composition ratio of lactic acid to glycolic acid is about 100/0 to about 40/60 (mol%);
(20) The production method according to item (18), wherein the polymer has a weight average molecular weight of about 3,000 to about 100,000.
(21) The production method according to item (13), wherein the biodegradable polymer is polylactic acid, and
(22) The process according to item (21), wherein the polylactic acid has a weight average molecular weight of about 10,000 to about 60,000.
[0006]
Examples of sustained-release preparations used in the production method of the present invention include microspheres. The microspheres referred to in the present invention include microcapsules, microparticles and the like. Specifically, JP-A-60-10056, JP-A-62-201816, JP-A-02-124814, JP-A-04-321622, JP-A-05-112468, JP-A-05-05. -194200, JP-A-06-293636, JP-A-06-145046, JP-A-06-192068, JP-A 08-169818, JP-A 09-132524, JP-A 09-212417. The microspheres or microcapsules described in Japanese Patent Application Laid-Open No. 09-2221418 and the like are used.
[0007]
As the drug contained in the sustained-release preparation, a physiologically active peptide is preferable. For example, the molecular weight is about 300 to about 40,000, preferably the molecular weight is about 400 to about 30,000, and more preferably the molecular weight is about 500 to 500. About 20,000 physiologically active peptides are used.
As such a bioactive peptide, for example, a basic acid capable of forming a salt with a weak acid having a pKa of 4.0 or more (eg, carbonic acid, bicarbonate, boric acid, lower alkane monocarboxylic acid having 1 to 3 carbon atoms, etc.). It preferably has a group. Moreover, it may have a free or salt-form acidic group in addition to the basic group.
A typical activity of the physiologically active peptide is hormonal action. The physiologically active peptide may be a natural product, a synthetic product, a semi-synthetic product, a genetic engineering product, or an analog and / or derivative thereof. The mechanism of action of these bioactive peptides may be either agonistic or antagonistic.
Examples of the physiologically active peptide include luteinizing hormone releasing hormone (also referred to as LH-RH or gonadotropin releasing hormone, Gn-RH), insulin, somatostatin, somatostatin derivative (eg, sandstatin; USP 4,087,390, 4,093,574) , 4,100,117 and 4,253,998), growth hormone (GH), growth hormone releasing hormone (GH-RH), prolactin, erythropoietin (EPO), corticosteroid (ACTH), ACTH derivatives (eg, evilatide), melanocyte stimulating hormone ( MSH), thyroid hormone releasing hormone ((pyr) Glu-His-ProNH₂TRH), salts and derivatives thereof (JP-A-50-121273, JP-A-52-116465), thyroid stimulating hormone (TSH), luteinizing hormone (LH), follicle stimulating hormone (FSH), vasopressin , Vasopressin derivatives (eg, desmopressin), oxytocin, calcitonin, glucagon, gastrin, secretin, punkreozymine, cholecystokinin, angiotensin, human placental lactogen, human chorionic gonadotropin (HCG), enkephalin, enkephalin derivative (eg, USP4 , 277,394, EP-31567), endorphins, kyotorphins, interferons (eg, interferon-α, β, γ), interleukins (eg, various types of interleukins 1 to 12), tuftsin, thymopoietin, thymosin, thymos Murine, thymic factor (THF), blood thymic factor (FTS) and its derivatives (USP 4,229,438), tumor necrosis factor (TNF), colony-inducing factor (eg, CSF, GCSF, GMCSF, MCSF), motilin, Dynorphin, bombesin, neurotensin, cerulein, bradykinin, atrial natriuretic factor, nerve growth factor (NGF), cell growth factor (eg, EGF, TGF-β, PDGF, acidic FGF, basic FGF), neurotrophic factor (Eg, NT-3, NT-4, CNTF, GDNF, BDNF), peptides having endothelin antagonistic activity and analogs (derivatives) thereof (EP-436189, EP-457195, EP-496452, JP-A-3-94692) No. 1, JP-A-3-130299), insulin receptor, insulin-like growth factor (IGF) -1 receptor -IHC-2 receptor, transferrin receptor, epidermal growth factor, rhodencity lipoprotein (LDL) receptor, macrophage scavenger receptor, GLUT-4 transporter, growth hormone receptor, MHC having activity to inhibit leptin receptor internalization Peptides derived from α1 domain of major histocompatibility class I antigen complex (Proceedings of the National Academy of Sciences of the United State of America) 91, 9086-9090 (1994); 94, 11692-11697 (1997)) and its analogs (derivatives), and fragments or derivatives of these fragments.
[0008]
When the physiologically active peptide is a salt, pharmacologically enjoyable salts and the like can be mentioned. For example, when the physiologically active peptide has a basic group such as an amino group in the molecule, the basic group and an inorganic acid (eg, hydrochloric acid, sulfuric acid, nitric acid, boric acid, etc.), an organic acid (eg, carbonic acid, heavy acid, etc.) And salts with carbonic acid, succinic acid, acetic acid, propionic acid, trifluoroacetic acid, etc.). In addition, when the physiologically active peptide has an acidic group such as a carboxyl group in the molecule, an inorganic base (eg, an alkali metal such as sodium or potassium, an alkaline earth metal such as calcium or magnesium) or an organic base (eg, triethylamine) And salts with organic amines such as basic amino acids such as arginine). In addition, the physiologically active peptide may form a metal complex compound (eg, copper complex, zinc complex, etc.).
Preferable specific examples of the physiologically active peptide used in the present invention include, for example, LH-RH such as prostate cancer, prostatic hypertrophy, endometriosis, uterine fibroid, uterine fibroma, precocious puberty, breast cancer, etc. LH-RH analogs effective for hormone-induced diseases and contraceptives and salts thereof, growth hormone and hormone-dependent diseases induced thereby, digestive system diseases such as peptic ulcer, etc. Effective somatostatin derivatives and salts thereof.
Specific examples of the LH-RH analogs or salts thereof include, for example, Treatment with GnRH analogs: Controversies and perspectives [The Parthenon Publishing Group Ltd. .) Issued 1996], and the peptides described in JP-T-3-503165, JP-A-3-101695, JP-A-7-97334, and JP-A-8-259460.
[0009]
Specific examples of the physiologically active peptide (LH-RH antagonist) having LH-RH antagonistic activity include, for example, the general formula [Ia]
X-D2Nal-D4ClPhe-D3Pal-Ser-A-B-Leu-C-Pro-DAlaNH₂
[Wherein X is N (4H₂-Furoyl) Gly or NAc, A is a residue selected from NMeTyr, Tyr, Aph (Atz), NMeAph (Atz), B is DLys (Nic), DCit, DLys (AzaglyNic), DLys (AzaglyFur), DhArg (Et₂), DAph (Atz), and DhCi, C represents Lys (Nisp), Arg, hArg (Et₂And the like, or a salt thereof.
These peptides can be produced by the methods described in the above-mentioned literatures or publications or a method analogous thereto.
Specific examples of the physiologically active peptide (LH-RH agonist) having LH-RH agonistic action include, for example, the general formula [Ib]
5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z
[Wherein Y is a residue selected from DLeu, DAla, DTrp, DSer (tBu), D2Nal, DHis (ImBzl), Z is NH—C₂H_FiveOr Gly-NH₂Or a salt thereof. Among them, Y is DLeu and Z is NH-C.₂H_FiveA peptide or a salt thereof is preferred. These peptides can be produced by the methods described in the above-mentioned literatures or publications or a method analogous thereto.
[0010]
Specific examples of somatostatin derivatives or salts thereof include, for example, Proc. Natl. Acad. Sci. USA, Vol. 93, pages 12513-12518 (1996) or the literature. It is described in the cited literature.
[Chemical 1]

Sandstatin (USP 4087390, 4093574, 4100117, 4253998) and the like are also suitable.
Among the above physiologically active peptides, 5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH-C₂H_Five(Leuprelin) or a salt thereof (particularly acetate) is preferred.
[0011]
Abbreviations used in this specification include:
Abbreviation Name
N (4H₂-Furoyl) Gly: N-tetrahydrofuroylglycine residue
NAc: N-acetyl group
D2Nal: D-3- (2-naphthyl) alanine residue
D4ClPhe: D-3- (4-chlorophenyl) alanine residue
D3Pal: D-3- (3-pyridyl) alanine residue
NMeTyr: N-methyltyrosine residue
Aph (Atz): N- [5 ′-(3′-amino-1′H-1 ′, 2 ′, 4′-triazolyl)] phenylalanine residue
NMeAph (Atz): N-methyl- [5 ′-(3′-amino-1′H-1 ′, 2 ′, 4′-triazolyl)] phenylalanine residue
DLys (Nic): D- (ε-N-nicotinoyl) lysine residue
DCit: D-citrulline residue
DLys (AzaglyNic): D- (azaglycylnicotinoyl) lysine residue
DLys (AzaglyFur): D- (azaglycylfuranyl) lysine residue
DhArg (Et₂: D- (N, N′-diethyl) homoarginine residue
DAph (Atz): DN- [5 ′-(3′-amino-1′H-1 ′, 2 ′, 4′-triazolyl)] phenylalanine residue
DhCi: D-homocitrulline residue
Lys (Nisp): (ε-N-isopropyl) lysine residue
hArg (Et₂: (N, N′-diethyl) homoarginine residue
DSer (tBu): D- (Ot-butyl) serine residue
DHis (ImBzl): D- (π-benzyl) histidine residue
Regarding other amino acids, when indicated by abbreviations, IUPAC-IUB Commission of Biochemical Nomenclature (European Journal of Biochemistry, Vol. 138), 9-37 (1984)) or based on conventional abbreviations in the relevant field, and when there is an optical isomer with respect to amino acids, L form is shown unless otherwise specified.
[0012]
The sustained-release base used in the above-mentioned sustained-release preparation is preferably a biodegradable polymer, and specific examples thereof include α-hydroxycarboxylic acids (eg, glycolic acid, lactic acid, hydroxybutyric acid, etc.). ), Hydroxydicarboxylic acids (eg, malic acid), hydroxytricarboxylic acids (eg, citric acid) and the like, polymers having free carboxyl groups, copolymers, or mixtures thereof, poly- Examples include α-cyanoacrylic acid esters, polyamino acids (eg, poly-γ-benzyl-L-glutamic acid and the like), maleic anhydride copolymers (eg, styrene-maleic acid copolymer and the like), and the like.
The type of polymerization in the polymer may be random, block or graft. When the α-hydroxycarboxylic acids, hydroxydicarboxylic acids, and hydroxytricarboxylic acids have an optically active center in the molecule, any of D-form, L-form and DL-form can be used. Among these, lactic acid-glycolic acid polymer and poly-α-cyanoacrylic acid ester are preferable. More preferred is a lactic acid-glycolic acid polymer.
[0013]
The biodegradable polymer is preferably (A) glycolic acid and a general formula
[Chemical 2]

(Wherein R represents an alkyl group having 2 to 8 carbon atoms) and (B) a biodegradable polymer obtained by mixing polylactic acid or a copolymer of lactic acid and glycolic acid. It is a polymer.
[0014]
In the general formula [II], examples of the linear or branched alkyl group having 2 to 8 carbon atoms represented by R include ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl. , Isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like. Preferably, a linear or branched alkyl group having 2 to 5 carbon atoms is used. Specific examples include ethyl, propyl, isopropyl, butyl, isobutyl and the like. Particularly preferably R is ethyl.
Examples of the hydroxycarboxylic acid represented by the general formula [II] include 2-hydroxybutyric acid, 2-hydroxyvaleric acid, 2-hydroxy-3-methylbutyric acid, 2-hydroxycaproic acid, 2-hydroxyisocaproic acid, 2 -Hydroxycapric acid and the like. Of these, 2-hydroxybutyric acid, 2-hydroxyvaleric acid, 2-hydroxy-3-methylbutyric acid, and 2-hydroxycaproic acid are particularly preferable. The hydroxycarboxylic acid represented by the general formula [II] is particularly preferably 2-hydroxybutyric acid. These hydroxycarboxylic acids may be any of D-form, L-form and D, L-form, and those having D-form / L-form (mol%) in the range of about 75/25 to about 25/75. Is preferred. More preferably, it is a hydroxycarboxylic acid having a D-form / L-form (mol%) in the range of about 60/40 to about 40/60. Particularly preferred is a hydroxycarboxylic acid having a D-form / L-form (mol%) in the range of about 55/45 to about 45/55.
[0015]
In the copolymer of glycolic acid and hydroxycarboxylic acid represented by the general formula [II] (hereinafter abbreviated as glycolic acid copolymer), the copolymerization may be random, block or graft. A random copolymer is preferable.
The hydroxycarboxylic acid represented by the general formula [II] may be used alone or in an appropriate ratio.
The composition ratio of glycolic acid to the hydroxycarboxylic acid represented by the general formula [II] in the glycolic acid copolymer of (A) is about 10 to about 75 mol% of glycolic acid and the rest is hydroxycarboxylic acid Is preferred. More preferably, the glycolic acid is about 20 to about 75 mol% and the remainder is hydroxycarboxylic acid. Particularly preferred is when the glycolic acid is about 40 to about 70 mol% and the remainder is hydroxycarboxylic acid. These glycolic acid copolymers have a weight average molecular weight of about 2,000 to about 100,000. Preferably, the copolymer has a weight average molecular weight of about 3,000 to about 80,000. More preferred is a copolymer having a weight average molecular weight of about 5,000 to about 50,000. Further, the dispersity (weight average molecular weight / number average molecular weight) of these glycolic acid copolymers is preferably about 1.2 to about 4.0. Particularly preferred is a copolymer having a dispersity of about 1.5 to about 3.5.
The glycolic acid copolymer (A) can be synthesized according to a known production method, for example, the method described in JP-A No. 61-28521.
[0016]
The polylactic acid may be any of L-form, D-form and a mixture thereof, but preferably has a D-form / L-form (mol%) in the range of about 75/25 to about 20/80. More preferred is polylactic acid having a D-form / L-form (mol%) in the range of about 60/40 to about 25/75. Particularly preferred is polylactic acid having a D-form / L-form (mol%) in the range of about 55/45 to about 25/75. The polylactic acid preferably has a weight average molecular weight in the range of about 1,500 to about 100,000. More preferably, the polylactic acid has a weight average molecular weight in the range of about 2,000 to about 80,000. Particularly preferred is a polylactic acid having a weight average molecular weight in the range of about 3,000 to about 50,000, or in the range of about 10,000 to 60,000 (more preferably about 15,000 to about 50,000). . Also, the polylactic acid has a dispersity of preferably about 1.2 to about 4.0. Particularly preferred is a degree of dispersion of from about 1.5 to about 3.5.
As a method for synthesizing polylactic acid, a method of ring-opening polymerization of lactide which is a dimer of lactic acid and a method of dehydrating polycondensation of lactic acid are known.
[0017]
The glycolic acid copolymer (A) and polylactic acid (B) in the preparation base of the present invention have a mixing ratio (% by weight) represented by, for example, (A) / (B) of about 10/90 to about 90/10. Used in the range of Preferably, the mixing ratio (wt%) is in the range of about 20/80 to about 80/20. More preferably, it is in the range of about 30/70 to about 70/30.
When either component (A) or (B) is too much, only a preparation having almost the same drug release pattern as that obtained when the component (A) or (B) is used alone can be obtained. A linear release pattern in the late release cannot be expected. The degradation / disappearance rate of glycolic acid copolymer and polylactic acid varies greatly depending on the molecular weight or composition, but in general, the degradation / disappearance rate of glycolic acid copolymer is faster. The release period can be lengthened by increasing or decreasing the mixing ratio represented by (A) / (B). Conversely, the release period can be shortened by reducing the molecular weight of the polylactic acid to be mixed or by increasing the mixing ratio represented by (A) / (B). Furthermore, the release period can be adjusted by changing the type and ratio of the hydroxycarboxylic acid represented by the general formula [II].
[0018]
When polylactic acid or a lactic acid-glycolic acid copolymer (hereinafter simply referred to as lactic acid-glycolic acid polymer) is used as the biodegradable polymer, the lactic acid / glycolic acid composition ratio (mol%) is 100/0 to 40/60 is preferable, 100/0 to 45/55 is more preferable, and 100/0 to 50/50 is particularly preferable.
The weight average molecular weight of the lactic acid-glycolic acid polymer is preferably from 3,000 to 100,000, more preferably from 5,000 to 80,000. Further, the dispersity (weight average molecular weight / number average molecular weight) of the lactic acid-glycolic acid polymer is preferably about 1.2 to about 4.0, more preferably about 1.5 to about 3.5.
The degradation / disappearance rate of the lactic acid-glycolic acid polymer varies greatly depending on the composition or molecular weight. Generally, the lower the glycolic acid fraction, the slower the degradation / disappearance, so the lower the glycolic acid fraction or the lower the molecular weight. Increasing the length can lengthen the release period. Conversely, the release period can be shortened by increasing the glycolic acid fraction or decreasing the molecular weight. In order to obtain a long-term (for example, 1 to 6 months, preferably 1 to 4 months) sustained-release preparation (solid), a lactic acid-glycolic acid polymer having the above composition ratio and weight average molecular weight is preferable. When a lactic acid-glycolic acid polymer that decomposes faster than a lactic acid-glycolic acid polymer in the range of the above composition ratio and weight average molecular weight is selected, it is difficult to suppress the initial burst, and conversely, the above composition ratio and weight average molecular weight When a lactic acid-glycolic acid polymer that is slower in degradation than a lactic acid-glycolic acid polymer in the range is selected, a period during which an effective amount of drug is not released is likely to occur.
[0019]
In the present specification, the weight average molecular weight, number average molecular weight, and dispersity are weight average molecular weights of 120,000, 52,000, 22,000, 9,200, 5,050, 2,950, 1,050, 580. , 162 molecular weight in terms of polystyrene measured by gel permeation chromatography (GPC) using nine types of polystyrene of 162 as a reference substance, and calculated dispersity. The measurement uses GPC column KF804L × 2 (manufactured by Showa Denko), RI monitor L-3300 (manufactured by Hitachi, Ltd.), and chloroform as the mobile phase. In addition, a biodegradable polymer is dissolved in an acetone-methanol mixed solvent, and this solution is titrated with an alcoholic potassium hydroxide solution using phenolphthalein as an indicator to calculate the number average molecular weight by end group determination. Hereinafter, this is expressed as a number average molecular weight determined by terminal group determination.
The number average molecular weight by end group quantification is an absolute value, whereas the number average molecular weight by GPC measurement is analyzed or analyzed under conditions such as selection of mobile phase type, column type, reference material, slice width, baseline Since it is a relative value that varies depending on the selection, etc., it is difficult to make a unique numerical value. For example, a polymer synthesized from lactic acid and glycolic acid by a non-catalytic dehydration polycondensation method and having a free carboxyl group at the terminal The number average molecular weight determined by GPC measurement and the number average molecular weight determined by terminal group determination are almost the same. In the case of this lactic acid-glycolic acid polymer, almost the same means that the number average molecular weight determined by terminal group determination is in the range of about 0.5 to about 2 times the number average molecular weight determined by GPC measurement, preferably about It is in the range of 0.7 to about 1.5 times.
[0020]
Lactic acid-glycolic acid polymer is a non-catalytic dehydration polycondensation from lactic acid and glycolic acid (Japanese Patent Laid-Open No. 61-28521) or ring-opening polymerization using a catalyst from a cyclic compound such as lactide and glycolide (Encyclopedic Handbook of Biomaterials and Bioengineering Part A: Materials, Volume 2, Marcel Dekker, Inc. 1995).
A polymer synthesized by ring-opening polymerization is a polymer having no carboxyl group, but the polymer is chemically treated to a terminal carboxyl group (Journal of Control Release (J. Controlled Release), 41, 249-257, 1996) can also be used.
The above-mentioned lactic acid-glycolic acid polymer having a free carboxyl group can be produced without any problem by a known production method (for example, non-catalytic dehydration polycondensation method, see JP-A No. 61-28521). A polymer having a free carboxyl group that is not specified can be produced by a known production method (see, for example, WO94 / 15587).
In addition, as the lactic acid-glycolic acid polymer having a terminal carboxyl group formed by a chemical treatment after the ring-opening polymerization, for example, those commercially available from Boehringer Ingelheim KG may be used.
[0021]
As a suspension of the sustained-release preparation used in the production method of the present invention, the above-mentioned sustained-release preparation is added to a solvent used for the following suspension. In the case of MC, the suspension of the sustained-release preparation is usually prepared as about 1 mg to about 3000 mg / ml, preferably about 5 mg to about 1000 mg / ml as MC.
The suspension further includes an aggregation inhibitor such as a water-soluble saccharide [eg, mannitol, lactose, glucose, starches (eg, corn starch, etc.)], amino sugar (eg, glycine, alanine, etc.), protein (eg, Gelatin, fibrin, collagen, etc.), inorganic salts (eg, sodium chloride, sodium bromide, potassium carbonate, etc.) and the like may be added. As the aggregation preventing agent, mannitol such as D-mannitol is particularly suitable.
Examples of the solvent used for the suspension include water for injection (eg, water produced by a distillation method, ultrafiltration method, etc.), UF water, RO water, ion-exchanged water, volatile solvent (eg, ethanol, Acetone), polyethylene glycol, vegetable oil, mineral oil, or a mixed solvent thereof. Water for injection is particularly preferable. Moreover, surfactant, a thickener, a pH adjuster etc. can be added as a suspension stabilizer. Examples of the surfactant include polysorbates (eg, polysorbate 80, polysorbate 20, polysorbate 20, etc.), pluronics (eg, pluronic F68 (generic name polyoxyethylene [160] polyoxypropylene [30] glycol), etc. ), Polyoxyethylene hydrogenated castor oil (eg, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, etc.), and the like are used. As the thickener, for example, carboxymethylcelluloses (eg, CMC-K, CMC-Na, etc.), polyvinylpyrrolidone (PVP), etc. are used. Examples of the pH adjuster include hydrochloric acid, sodium hydroxide, acetic acid, lactic acid, ammonium hydroxide, sodium carbonate, sodium bicarbonate, and the like.
[0022]
The container for freeze-drying used in the production method of the present invention may be any container as long as it is generally used for freeze-drying sustained-release preparations such as MC, such as a freeze-drying tray. Used. Further, as the container, one made of metal (preferably stainless steel (SUS316, 304, etc.)), glass or earthenware is used. Furthermore, as a freeze-drying container used in the production method of the present invention, a flat plate is also included.
The size of the freeze-drying container can be appropriately selected according to the scale of freeze-drying. Specifically, for example, (1) the width is about 5 mm to about 10,000 mm, the length is about 5 mm to about 10,000 mm, and the depth is about 0.1 mm to about 500 mm, preferably (2) width Of about 5 mm to about 7,000 mm, length of about 5 mm to about 7,000 mm, depth of about 1 mm to about 100 mm, more preferably (3) about 5 mm to about 500 mm in width and about 5 mm in length One having a depth of about 300 mm and a depth of about 5 mm to about 100 mm is used. The ratio of the width, the length and the depth is not particularly limited, but is usually about 1 to about 20 in the width to the depth 1, about 1 to about 10 in the length, preferably about 1 to about the width for the depth 1. 10, about 1 to about 6 in length.
The volume of the container is, for example, about 10 ml to about 100,000 ml, preferably about 100 ml to about 5,000 ml, particularly preferably about 3,000 ml.
The freeze-drying container has a cavity formed in a part of the container for suction during freeze-drying, but a freeze-drying container having no top plate is usually used.
Examples of the water-repellent substrate used for coating the freeze-drying container include, for example, a fluorinated ethylene resin (eg, ethylene tetrafluoride resin, ethylene trifluoride resin, ethylene difluoride resin), vinylidene fluoride resin, Examples include hexafluoropropylene / tetrafluoroethylene copolymer resin, modified fluororesin, copolymer resin of tetrafluoroethylene and perfluoroalkoxyethylene, and copolymer resin of ethylene tetrafluoride and ethylene. However, fluorinated ethylene resins (eg, tetrafluoroethylene resin, trifluoroethylene resin, difluoroethylene resin) are preferable, and Teflon (trade name) is preferable.
As a method of coating (coating) the freeze-drying container with a water-repellent substrate, a method known per se or a method analogous thereto is used, and specifically, a plating method, a vapor deposition method, or the like is used.
The solid sustained-release preparation obtained by the production method of the present invention may be any sustained-release preparation obtained by subjecting the sustained-release preparation used in the present invention to the production method (lyophilization method) of the present invention. In addition to powdery sustained-release preparations (eg, MC powder), various shapes (eg, pellets, needles, etc.) that have been molded into various shapes according to methods known per se Also contains a releasable formulation.
[0023]
The production method of the present invention will be specifically described below in detail.
(1) A method for producing a solid sustained-release preparation characterized by freeze-drying a sustained-release preparation in a freeze-drying container in which part or all of the inner surface is covered with an ice layer
As water for producing the ice layer, for example, water for injection (eg, distilled water), ion-exchanged water or the like is used.
The portion covered with the ice layer is a part or the whole of the inner surface of the freeze-drying container. For example, only the bottom surface, the entire bottom surface and the side surface, the entire bottom surface, or the bottom surface and the side surface of the inner surface of the container. It may be only part. An ice layer may be formed on the outer surface of the container.
The thickness of the ice layer in the freeze-drying container may be appropriately selected according to the size of the container used, the volume of the sustained-release preparation (sustained-release preparation suspension), the freeze-drying temperature, and the like. For example, it is usually about 1/1000 to about 4/5, preferably about 1/500 to about 1/5, more preferably about 1/100 to about 1/10, particularly preferably about the depth of the container. It is about 1/10, and about 0.01 mm or more is preferable. More specifically, about 0.01 mm to about 400 mm, preferably about 0.01 mm to about 200 mm, more preferably about 0.01 mm to about 30 mm, still more preferably about 0.1 mm to about 30 mm, particularly preferably about 0.1 mm to about 10 mm, most preferably about 1 mm.
The ice layer is prepared by pouring water into a tray and usually at about -80 ° C to about 0 ° C, preferably about -50 ° C to about 0 ° C.
[0024]
After an ice layer is formed in a freeze-drying container, a sustained-release preparation (sustained-release preparation suspension) is dispensed into the container and frozen to obtain a sustained-release preparation (sustained-release preparation). A frozen layer of the suspension is formed.
In the case of MC, the suspension of the sustained-release preparation is usually prepared as about 1 mg to about 3000 mg / ml, preferably about 5 mg to about 1000 mg / ml as MC.
The volume of the sustained-release preparation (sustained-release preparation suspension) can be appropriately selected according to the size of the container used, the lyophilization temperature, etc. The thickness of the frozen layer of the liquid is about 1/1000 to about 4/5, preferably about 1/500 to about 1/5, more preferably about 1/100 to about 1/10 of the depth of the container, especially Preferably it is about 1/10. The volume of the sustained-release preparation suspension can be about 0.1 ml to about 99.9 ml, preferably about 1 ml to about 90 ml, more preferably about 1 ml to about 40 ml with respect to 100 ml of the container. . Further, when the ice layer is about 1 mm from the bottom of the container, the frozen layer of the sustained-release preparation suspension can be about 1 to 10 times, preferably about 1 to 5 times.
For example, when a container having a width of about 5 mm to about 7,000 mm, a length of about 5 mm to about 7,000 mm, and a depth of about 1 mm to 100 mm is used, the thickness of the ice layer is usually about 0.01 mm to about The thickness is about 30 mm, preferably about 0.1 mm to about 30 mm, more preferably about 0.1 mm to 10 mm, and particularly preferably about 1 mm. On the other hand, the frozen layer of the suspension of the sustained-release preparation is, for example, about 1 mm to about 20 mm, preferably about 2 mm to about 10 mm, preferably about 4 mm from the bottom ice layer.
The frozen layer of the sustained-release preparation (sustained-release preparation suspension) has been previously cooled to about −10 ° C. to about 20 ° C., preferably about 0 ° C. to 5 ° C. The suspension is prepared at about -80 ° C to about 0 ° C, preferably about -50 ° C to about 0 ° C.
In this manner, two layers of an ice layer and a frozen layer of a sustained-release preparation (sustained-release preparation suspension) are prepared in a freeze-dried container.
Freeze-drying can be performed using a method known per se, for example, according to the above-mentioned publications that disclose MC or microspheres.
As a preferred freeze-drying method, for example, the temperature (shelf temperature) of the freeze-drying container is 0 ° C. or less (preferably −40 ° C. to 0 ° C., more preferably −20 ° C. to 0 ° C. Preferably, the method is characterized in that the sublimation of frozen moisture in the freeze-dried container is completed at −10 ° C. to 0 ° C., specifically, the shelf temperature is 0 ° C. or lower under reduced pressure (preferably − 40 ° C. to 0 ° C., more preferably −20 ° C. to 0 ° C., more preferably −10 ° C. to 0 ° C.), and the sublimation of the frozen water in the freeze-dried container is completed. Can be given.
Here, the temperature (shelf temperature) of the freeze-drying container means the temperature of the container holding the object to be freeze-dried or the shelf in contact with the container. Freezing water means free water that has frozen.
When the shelf temperature is kept at 0 ° C. or lower (preferably −40 ° C. to 0 ° C., more preferably −20 ° C. to 0 ° C., and still more preferably −10 ° C. to 0 ° C.), about 0.1 hour As described above, preferably the shelf temperature is kept at 0 ° C. or lower for about 1 hour to 500 hours, more preferably about 5 hours to 100 hours, and the sublimation of the frozen moisture in the freeze-dried container is completed.
As a result of freeze-drying by the above method, sublimation of freezing moisture is performed at 0 ° C. or less, that is, at a low temperature at which the ice does not melt (eutectic point, temperature below the melting point). Therefore, (1) the freeze-dried cake is prevented from collapsing, (2) MC powder is prevented from scattering outside the freeze-dried container, (3) high yield of MC powder is secured, and (4) constant. MC powder of quality can be manufactured.
[0025]
(2) A solid sustained release characterized by freeze-drying a sustained-release preparation (suspension-release preparation suspension) in a freeze-drying container in which part or all of the inner surface is coated with a water-repellent substrate. The manufacturing method
The part covered with the water-repellent substrate is a part or all of the inner surface of the freeze-drying container. For example, only the bottom surface, all of the bottom surface and side surfaces, only part of the bottom surface, or only the bottom surface and side surfaces It may be only a part of. Further, the outer surface of the container may be covered with a water-repellent substrate.
The sustained-release preparation (sustained-release preparation suspension) is dispensed into a container and frozen to form a frozen layer of the sustained-release preparation (sustained-release preparation suspension).
In the case of MC, the suspension of the sustained-release preparation is usually prepared as about 1 mg to about 3000 mg / ml, preferably about 1 mg to about 300 mg / ml as MC.
Depending on the volume of the sustained release preparation (sustained release preparation suspension) in the container for freeze drying, the size of the container to be used, the freeze drying temperature, etc., it can be appropriately selected. The thickness of the frozen layer of the suspension of sustained release preparation is about 1/1000 to about 4/5, preferably about 1/500 to about 1/5, more preferably about 1/100 of the depth of the container. To about 1/10, particularly preferably about 1/10. The volume of the sustained-release preparation suspension can be about 0.1 ml to about 99.9 ml, preferably about 1 ml to about 90 ml, more preferably about 1 ml to about 40 ml with respect to 100 ml of the container. . Further, when the ice layer is about 1 mm from the bottom of the container, the frozen layer of the sustained-release preparation suspension can be about 1 to 10 times, preferably about 1 to 5 times.
For example, when a container having a width of about 5 mm to about 7,000 mm, a length of about 5 mm to about 7,000 mm, and a depth of about 1 mm to 100 mm is used, the thickness of the ice layer is usually about 0.01 mm to about The thickness is about 30 mm, preferably about 0.1 mm to about 30 mm, more preferably about 0.1 mm to 10 mm, and particularly preferably about 1 mm. On the other hand, the frozen layer of the suspension of the sustained-release preparation is, for example, about 1 mm to about 20 mm, preferably about 2 mm to about 10 mm, preferably about 4 mm from the bottom ice layer.
The frozen layer of the sustained-release preparation (sustained-release preparation suspension) has been previously cooled to about −10 ° C. to about 20 ° C., preferably about 0 ° C. to 5 ° C. The suspension is prepared at about -80 ° C to about 0 ° C, preferably about -50 ° C to about 0 ° C.
In this way, a frozen layer of a sustained release preparation (sustained release preparation suspension) is prepared in a freeze-dried container.
Freeze-drying can be performed in the same manner as in the above production method (1).
[0026]
(3) Freezing a sustained release preparation (sustained release preparation suspension) in a freeze-drying container, the inner surface of which is coated with a water-repellent substrate and part or all of the inner surface is covered with an ice layer. About manufacturing method of solid sustained-release preparation characterized by drying
This method is carried out in the same manner as in the production method (1) except that a freeze-drying vessel whose inner surface is coated with a water-repellent substrate is used instead of the freeze-drying vessel in the production method (1). be able to.
In the case of this method, it is desirable that at least all of the inner surface of the freeze-drying container that is in contact with the sustained-release preparation (sustained-release preparation suspension) is coated with a water-repellent substrate.
[0027]
The production method of the present invention has the following advantages.
(1) Since the MC powder does not adhere to the tray, there is no need to scrape it off using a scraper during recovery.
(2) Since it is not necessary to scrape off using a scraper, the exposure time to the environment during collection is shortened, and there is no risk of contamination with microorganisms. In addition, since MC is a preparation that requires moisture control, the environmental exposure time is short, so that there is little risk from the viewpoint of physicochemical stability.
(3) Since no scraping operation using a scraper is required, there is no risk of foreign matter generation or mixing due to friction between the tray and the scraper.
(4) Since there is little adhesion between the MC powder and the tray, the recovery rate of the MC powder is high.
(5) Furthermore, by applying the more preferable freeze-drying method described above, it is possible to recover MC powder with higher yield and constant quality.
[0028]
After freeze-drying the sustained-release preparation (sustained-release preparation suspension) using the production method of the present invention, if necessary, it is added under conditions where the sustained-release preparations are not fused under reduced pressure. The water and the organic solvent in the sustained-release preparation may be removed by heating. In this case, the heating is preferably performed at a temperature slightly higher than the midpoint glass transition temperature of the biodegradable polymer obtained by a differential scanning calorimeter under a temperature rising rate of about 10 to about 20 ° C. per minute. More preferably, the biodegradable polymer is heated within a temperature range about 30 ° C. higher than the midpoint glass transition temperature of the biodegradable polymer. In particular, when a lactic acid-glycolic acid polymer is used as the biodegradable polymer, a temperature range higher than the midpoint glass transition temperature and 20 ° C. higher than the midpoint glass transition temperature, preferably the midpoint above the midpoint glass transition temperature. Heat in a temperature range 10 ° C higher than the glass transition temperature.
Although the heating time varies depending on the amount of the sustained-release preparation and the like, generally, about 12 hours to about 168 hours are preferable after the sustained-release preparation itself reaches a predetermined temperature, and further about 48 hours to about 120 hours. Time is preferred. In particular, about 48 hours to about 96 hours are preferable.
The heating method is not particularly limited as long as the assembly of sustained-release preparations can be uniformly heated.
Preferable specific examples of the heating and drying method include, for example, a method of heating and drying in a thermostatic bath, a fluidized bath, a moving tank or a kiln, a method of heating and drying with a microwave, and the like. Among these, the method of heating and drying in a thermostatic bath is preferable.
[0029]
The lyophilized product (solid) of the sustained release preparation obtained as described above can be formulated as it is or as a raw material into various dosage forms and administered orally or parenterally. Specifically, intramuscular, subcutaneous, organ injections or implants, nasal cavity, rectal, uterine transmucosal agents, oral agents (eg, capsules (eg, hard capsules, soft capsules, etc.)) , Solid preparations such as granules and powders, liquids such as syrups, emulsions and suspensions, etc.].
For example, in order to use sustained-release preparations (solid) as injections, these can be used as dispersants (eg, surfactants such as Tween 80 and HCO-60, sodium hyaluronate, carboxymethyl cellulose, sodium alginate, etc. Polysaccharides), preservatives (eg, methylparaben, propylparaben, etc.), isotonic agents (eg, sodium chloride, mannitol, sorbitol, glucose, proline, etc.), etc. A sustained-release injection that can be used as an oily suspension by dispersing with vegetable oil.
When used as a suspension injection, the particle size of the sustained-release preparation (solid) may be in a range satisfying the degree of dispersion and needle penetration. For example, the average particle size is about 0.1 to 300 μm. Range. Preferably, the average particle size is in the range of about 1 to 150 μm. More preferably, the average particle size is in the range of about 2 to 100 μm.
In order to make a sustained-release preparation (solid) into a sterile preparation, there are a method of sterilizing the whole manufacturing process, a method of sterilizing with gamma rays, a method of adding a preservative, and the like.
[0030]
The sustained-release preparation (solid) has low toxicity and can be safely used for humans or mammals (eg, monkeys, cows, pigs, dogs, cats, mice, rats, rabbits, etc.).
The dose of the sustained-release preparation (solid) as an active ingredient varies depending on the type and content of the bioactive peptide as the main drug, the dosage form, the duration of release of the bioactive peptide, the target disease, the target animal, the administration method, etc. However, any effective amount of the physiologically active peptide may be used. For example, when the sustained-release preparation (solid) is a 1-month preparation, the dose of the physiologically active peptide as the active ingredient is preferably about 0.001 mg to 1 adult (with a body weight of 50 kg). It can be appropriately selected from the range of 100 mg / kg body weight. More preferably, it can be appropriately selected from the range of about 0.005 mg to 50 mg / kg body weight, particularly preferably from the range of about 0.01 mg to 10 mg / kg body weight.
More specifically, when the LH-RH antagonist represented by the general formula [Ia] or the LH-RH agonist represented by the general formula [Ib] is used as a bioactive peptide, for example, prostate cancer, prostatic hypertrophy, Endometriosis, uterine fibroid, uterine fibroma, precocious puberty, breast cancer, bladder cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, gastritis, Hodgkin's disease, malignant melanoma, relocation , Multiple myeloma, non-Hodgkin's lymphoma, non-small cell lung cancer, ovarian cancer, peptic ulcer, systemic fungal infection, small cell lung cancer, valvular disease, mastopathy, polycystic ovary, infertility, chronic anovulation Disease, induction of appropriate ovulation in women, acne, amenorrhea (eg, secondary amenorrhea), cystic diseases of the ovary and breast (including polycystic ovary), gynecological cancer, ovarian high Androgenemia and Treatment / prevention of hormone-dependent diseases such as male contraception for treatment of male offenders, contraception, premenstrual syndrome (PMS) symptom reduction As a drug for in vitro fertilization (IVF), especially as a treatment / prevention agent or contraceptive for prostate cancer, benign prostatic hyperplasia, endometriosis, uterine fibroids, uterine fibroma, precocious puberty, etc. Can be used.
The dose of the physiologically active peptide varies depending on the dosage form, desired drug release duration, target disease, target animal, etc., but may be an effective amount of the drug. For example, when the sustained-release preparation (solid) is a one-month preparation, the dose per drug is preferably selected from the range of about 0.001 mg to about 10 mg / kg body weight per adult. it can. More preferably, it can be appropriately selected from the range of about 0.005 mg to about 5 mg / kg body weight.
The dose of the sustained-release preparation (solid) per dose is preferably appropriately selected from the range of about 0.005 mg to 50 mg / kg body weight per adult. More preferably, it can be appropriately selected from the range of about 0.01 mg to 30 mg / kg body weight. The frequency of administration is once every few weeks, once every month, once every several months, etc., the type and content of the bioactive peptide as the main drug, dosage form, duration of bioactive peptide release, target disease Depending on the target animal, it can be selected as appropriate.
[0031]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described in more detail based on examples and reference examples. However, the present invention is not limited thereto, and may be changed without departing from the scope of the present invention.
[0032]
【Example】
Reference Example 1 Preparation of Sustained Release MC (1 Month Formulation) Suspension
2.4 g of gelatin and 15.2 g of leuprorelin acetate were dissolved in 15.0 g of distilled water while heating. Into this solution, 321 g of a lactic acid / glycolic acid copolymer (hereinafter abbreviated as PLGA) [lactic acid / glycolic acid = 75/25 (mol%), weight average molecular weight: 10500] dichloromethane solution prepared separately (including PLGA) 121 g) was added and emulsified with a minimixer for 2 minutes with stirring (rotation speed: 10,000 rpm). This was added to 25 L of a 0.1% aqueous solution of polyvinyl alcohol (PVA) previously dissolved and emulsified again. The W / O / W emulsion was desolvated for about 3 hours while stirring gently. The obtained MC was passed through a 75 μm sieve to remove coarse particles, and then separated by centrifugation. This was washed with distilled water to remove free drug and PVA, and then wet sieved with 250 μm and 90 μm sieves together with a small amount of distilled water. To this, 18.4 g of D-mannitol was added and dissolved to obtain a suspension of MC. The amount of each raw material used can be increased or decreased according to the scale.
[0033]
Reference Example 2 Preparation of Sustained Release MC (3-month Formulation) Suspension
10.8 g of leuprorelin acetate was dissolved in 12.5 g of distilled water while heating. To this solution, 256 g of a lactic acid polymer prepared separately (hereinafter abbreviated as PLA) [weight average molecular weight: 16000] in dichloromethane (of which PLA 96 g) was added and stirred and emulsified with a minimixer for 2 minutes (rotation speed: 10,000 rpm). This was added to 25 L of a 0.1% polyvinyl alcohol (PVA) aqueous solution previously dissolved and emulsified again. The W / O / W emulsion was desolvated for about 3 hours while stirring gently. The obtained MC was passed through a 75 μm sieve to remove coarse particles, and then separated by centrifugation. This was washed with distilled water to remove free drug and PVA, and then wet sieved with 250 μm and 90 μm sieves together with a small amount of distilled water. To this, 16.3 g of D-mannitol was added and dissolved to obtain a suspension of MC. The amount of each raw material used can be increased or decreased according to the scale.
[0034]
Example 1
An ice layer having a thickness of about 1 mm was formed in advance at −30 ° C. using water for injection on a freeze-drying tray (width 200 mm, length 100 mm, depth 20 mm). At this time, an ice layer was also formed on the inner wall of the tray (ice lining). 80 ml of the MC suspension obtained in Reference Example 1 previously cooled to about 5 ° C. was added onto a freeze-drying tray formed with an ice layer and sufficiently frozen at about −30 ° C. The lyophilization was performed according to a conventional method.
On the other hand, 80 ml of the MC suspension was added onto a freeze-drying tray that did not form an ice layer, and was sufficiently frozen at about −30 ° C., and then freeze-dried according to a conventional method.
After lyophilization, each tray was turned upside down, and the state of peeling / collecting of the lyophilized product from the tray was observed.
When a freeze-drying tray formed with an ice layer was used, the freeze-dried product could be easily recovered from the tray, and no adhesion of MC powder was observed on the surface of the tray. On the other hand, when a freeze-drying tray that does not form an ice layer was used, the freeze-dried product was not peeled off from the tray. Further, even after the MC powder was collected with a scraper, the adhesion of the MC powder was observed on the tray.
[0035]
Example 2
Obtained in Reference Example 1 above, which was previously cooled to about 5 ° C. on a freeze-drying tray (200 mm wide, 100 mm long, 20 mm deep) coated with Teflon (trade name) which is a water-repellent polymer on the surface. After adding 80 ml of the MC suspension and sufficiently freezing at about −30 ° C., lyophilization was performed according to a conventional method.
On the other hand, 80 ml of the MC suspension is added onto a freeze-drying tray whose surface has not been subjected to water repellency treatment, and sufficiently frozen at about −30 ° C., and then freeze-dried according to a conventional method. It was.
After lyophilization, each tray was turned upside down, and the state of peeling / collecting of the lyophilized product from the tray was observed.
When a freeze-drying tray having a water-repellent treatment on the surface was used, the freeze-dried product could be easily recovered from the tray, and no adhesion of MC powder was observed on the surface of the tray. On the other hand, when a freeze-drying tray whose surface was not subjected to water repellency treatment was used, the freeze-dried sample was not peeled off from the tray. Further, even after the MC powder was collected with a scraper, the adhesion of the MC powder was observed on the tray.
[0036]
Example 3
An ice layer having a thickness of about 1 mm was formed in advance at −30 ° C. using water for injection on a freeze-drying tray (200 mm wide, 100 mm long, 20 mm deep) coated with Teflon as in Example 2. At this time, an ice layer was also formed on the inner wall of the tray (ice lining). After adding 80 ml of the MC suspension obtained in Reference Example 1 previously cooled to about 5 ° C. and sufficiently frozen at about −30 ° C., lyophilization was performed according to a conventional method.
On the other hand, 80 ml of the MC suspension is added onto a freeze-drying tray on which no ice layer has been formed and the surface has not been subjected to water repellency treatment, and is sufficiently frozen at about −30 ° C. After that, lyophilization was performed according to a conventional method.
After lyophilization, each tray was turned upside down, and the state of peeling / collecting of the lyophilized product from the tray was observed.
When a freeze-dried tray with a water-repellent treatment on the surface and an ice layer formed is used, the freeze-dried product can be easily recovered from the tray, and no adhesion of MC powder is observed on the surface of the tray. It was. On the other hand, when a freeze-drying tray in which an ice layer was not formed and the surface was not subjected to water repellency treatment, the freeze-dried product was not peeled off from the tray. Further, even after the MC powder was collected with a scraper, the adhesion of the MC powder was observed on the tray.
[0037]
Example 4
Even when the size of the freeze-drying tray shown in [Table 1] and the thickness of the ice layer are combined, the same results as in Examples 1 to 3 can be obtained.
[Table 1]

[0038]
Example 5
15.1 g of leuprorelin acetate was dissolved in 15.0 g of distilled water while heating (70 ° C. to 80 ° C.). To this solution, 323.6 g of a dichloromethane solution of lactic acid / glycolic acid copolymer (PLGA) [lactic acid / glycolic acid = 75/25 (mol%), weight average molecular weight: 10500] prepared separately (including PLGA 123.9 g) ) (Controlled at 25 to 35 ° C.) was added, the temperature of the mixture was controlled to 40 ° C. or lower, and the mixture was stirred and emulsified with a minimixer (rotation speed: 10,000 rpm) for 2 minutes.
This was cooled to 18 to 19 ° C., added to 25 L of a 0.1% polyvinyl alcohol (PVA) (18 to 19 ° C.) aqueous solution previously dissolved, and emulsified again. The W / O / W emulsion was desolvated for about 3 hours while stirring gently. Coarse particles were removed from the obtained MC through a 75 μm sieve and then wet sieved with a 90 μm sieve together with a small amount of distilled water. To this, 18.4 g of D-mannitol was added and dissolved to obtain a suspension of MC.
About 400 ml of the above MC suspension was placed on a tray in which an ice layer having a thickness of about 2 mm was formed with distilled water for injection at −30 ° C. in advance on a freeze-drying tray (170 mm wide, 260 mm long, 40 mm deep). After adding and sufficiently freezing at about −30 ° C., lyophilization is performed according to a conventional method or Example 7 described later.
The freeze-dried product produced by this method is easy to peel and collect the freeze-dried product from each tray, and no adhesion of MC powder to the tray surface is observed.
[0039]
Example 6
15.1 g of leuprorelin acetate was dissolved in 13.0 g of distilled water while heating (70 ° C. to 80 ° C.). Into this solution, 323.6 g of a lactic acid / glycolic acid copolymer (PLGA) [lactic acid / glycolic acid = 75/25 (mol%), weight average molecular weight: 10500] prepared separately was added (including PLGA 123.6 g). ) (Controlled at 25 to 35 ° C.) was added, the temperature of the mixture was controlled to 40 ° C. or lower, and the mixture was stirred and emulsified with a minimixer (rotation speed: 10,000 rpm) for 2 minutes.
This was cooled to 18 to 19 ° C., added to 25 L of a 0.1% aqueous solution of polyvinyl alcohol (PVA) (18 to 19 ° C.) previously dissolved, and emulsified again. The W / O / W emulsion was desolvated for about 3 hours while stirring gently. The obtained MC was passed through a 75 μm sieve to remove coarse particles, and then wet sieved with a 90 μm sieve together with a small amount of distilled water. To this, 18.4 g of D-mannitol was added and dissolved to obtain a suspension of MC.
About 400 ml of the above MC suspension was placed on a tray in which an ice layer having a thickness of about 2 mm was formed with distilled water for injection at −30 ° C. in advance on a freeze-drying tray (170 mm wide, 260 mm long, 40 mm deep). After adding and sufficiently freezing at about −30 ° C., lyophilization is performed according to a conventional method or Example 7 described later.
The freeze-dried product produced by this method is easy to peel and collect the freeze-dried product from each tray, and no adhesion of MC powder to the tray surface is observed.
[0040]
Example 7 Application to Sustained Release MC (1 Month Formulation) Suspension
An ice layer having a thickness of about 2 mm was formed in advance at −30 ° C. using water for injection on a freeze-drying tray (170 mm wide, 260 mm long, 40 mm deep). At this time, an ice layer was also formed on the inner wall of the tray (ice lining). After 200 mL of the MC suspension obtained in Reference Example 1 previously cooled to about 5 ° C. was added to the freeze-drying tray forming the ice layer and sufficiently frozen at about −30 ° C. Then, lyophilization was performed by the following method.
After the suspension was frozen at about −30 ° C., the shelf temperature was increased to −5 ° C. at 20 ° C./hr, and the temperature was maintained for about 20 hours. Thereafter, the shelf temperature was further increased to 51 ° C. at 20 ° C./hr and held for about 48 hours.
After lyophilization, the condition of the lyophilized product and the state of peeling / collecting from the tray were observed.
The freeze-dried product did not collapse or scatter. Further, the freeze-dried product could be easily recovered from the tray, and no adhesion of MC powder was observed on the tray surface.
[0041]
Example 8 Application to Sustained Release MC (Three Month Formulation) Suspension
An ice layer having a thickness of about 2 mm is previously formed at −30 ° C. using water for injection on a freeze-drying tray (170 mm wide, 260 mm long, 40 mm deep). At this time, an ice layer is also formed on the inner wall of the tray (ice lining). After 200 mL of the MC suspension obtained in Reference Example 2 previously cooled to about 5 ° C. was added to the freeze-drying tray forming the ice layer and sufficiently frozen at about −30 ° C. Then, lyophilization is performed by the following method.
After freezing the suspension at about −30 ° C., the shelf temperature is increased to −5 ° C. at 20 ° C./hr and the temperature is maintained for about 20 hours. Thereafter, the shelf temperature is further increased to 50 ° C. at 20 ° C./hr and held for about 48 hours.
The freeze-dried product can be easily recovered from the tray without causing collapse or scattering, and a freeze-drying method can be performed in which no adhesion of MC powder is observed on the tray surface.
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【The invention's effect】
According to the production method of the present invention, since there is no adhesion between the freeze-drying container and the solid sustained-release preparation, and the solid sustained-release preparation can be recovered without scraping, The recovery rate of the preparation is significantly improved. In addition, the sterility maintenance is improved because the environmental exposure time of the solid sustained-release preparation is shortened. Furthermore, by applying a freeze-drying method characterized by completing the sublimation of frozen moisture in the freeze-dried container when the temperature of the freeze-dried container is 0 ° C. or less under reduced pressure, the freeze-dried cake may be crushed and scattered. It is possible to prevent and recover MC powder with higher yield and constant quality.

Claims (6)

A method for producing solid microspheres, characterized in that the microspheres are freeze-dried in a freeze-drying tray in which part or all of the inner surface is coated with an ice layer or water-repellent substrate having a thickness of 0.1 mm to 30 mm. The microspheres are freeze-dried in a freeze-drying tray in which a part or the whole of the inner surface is coated with a water-repellent substrate and a part or the whole of the inner surface is coated with an ice layer having a thickness of 0.1 mm to 30 mm. A method for producing solid microspheres.   The method according to claim 1 or 2, wherein the inner surface is only the bottom surface.   Water-repellent substrate is ethylene tetrafluoride resin, ethylene trifluoride resin, ethylene difluoride resin, vinylidene fluoride resin, hexafluoropropylene / tetrafluoroethylene copolymer resin, modified fluororesin, tetrafluoroethylene 3. The production method according to claim 1, which is a copolymer resin of ethylene and perfluoroalkoxyethylene, or a copolymer resin of ethylene tetrafluoride and ethylene. The manufacturing method in any one of Claims 1-4 whose microsphere is a microcapsule. The method according to claim 1 or 2, wherein the freeze-drying is such that the sublimation of the frozen moisture in the freeze-drying tray is completed when the temperature of the freeze-drying tray is 0 ° C or lower under reduced pressure.