薬品部第一室 研究業績　2001.6-2002.5

誌上発表

The Study of the Applicability of Content Uniformity and Weight Variation Test - The State of Commercial Tablets and Capsules in Japan -
Katori, N., Aoyagi, N., Kojima, S.:
Chem. Pharm. Bull.，.49，1412-1419（2001）

This study intends to determine the rational criteria (e.g., threshold value) for applying the weight variation test and to investigate the adequacy of the acceptance value for existing commercial products in Japan. The studied products were 489 lots (3 lots3163 products) of compressed tablets (plain, film-coated, sugar-coated) and 42 lots (3 lots314 products) of hard capsules marketed in Japan. Product-specific intra-lot relative standard deviation of content (RSDD ), weight (RSD_W ) and concentration (RSD_C ) were calculated. A good correlation was found between RSD_D and RSD_C but not between RSD_D and RSD_W . These findings indicate that 1) it is difficult to rationally set the threshold level for weight variation, especially regarding the dosage forms except for plain tablets, 2) the application of weight variation tests should, in principle, be decided on the mixing homogeneity that is RSDC . 3) Most (99.6%) of the tablets and all the capsules investigated met the requirement of content uniformity test of JP13.

Keywords: content uniformity; mixing homogeneity; Japanese Pharmacopoeia; International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)

Maintenance of quaternary structure in the frozen state stabilizes lactate dehydrogenase during freeze-drying
Anchordoquy, TJ.*, Izutsu, KI., Randolph, TW.*1, Carpenter, JF.*:
Arch. Biochem. Biophys., 390, 35-41 (2001)

Polymers often fail to inhibit protein unfolding during lyophilization because steric hindrance prevents effective hydrogen bonding of the polymer to the protein's surface. However, in certain cases, polymers have been shown to stabilize multimeric enzymes during lyophilization. Here we test the hypothesis that this protection is due to inhibition of dissociation into subunits during freezing using mixtures of lactate dehydrogenase isozymes that form electrophoretically distinguishable hybrid tetramers during reversible dissociation. We examined hybridization and recovery of catalytic activity during freeze-thawing and freeze-drying in the presence of polymers (dextran, Ficoll, and polyethylene glycol), sugars, and surfactants. The surfactants did not protect LDH during freeze-thawing or freeze-drying. Polymers and sugars prevented dissociation of LDH during the freezing step of lyophilization, resulting in greater recovery of enzyme activity after lyophilization and rehydration. This beneficial effect was observed even in systems that do not form glassy solids during freezing and drying. We suggest that stabilization during drying results in part from greater inherent stability of the assembled holoenzyme relative to that of the dissociated monomers. Polymers inhibit freezing-induced dissociation thermodynamically because they are preferentially excluded from the surface of proteins, which increases the free energy of dissociation and denaturation.

Key words: freeze-drying, protein formulation, stabilization
*1 Center for Pharmaceutical Biotechnology, University of Colorado

各種タンパク質と二糖類の凍結溶液中における混合性
伊豆津健一(Izutsu, Ken-ichi)，小嶋茂雄(Kojima, Shigeo)：
低温生物工学会誌，47, 106-108 (2001)

Miscibility of proteins and saccharides (monosaccharides to oligosaccharides) in aqueous frozen solutions was studied through thermal analysis to model freeze-dried protein formulations. Thermal transitions (glass transition temperature of maximally freeze-concentrated solutions: Tg's) of the frozen solutions showed varied solute miscibility depending on the combinations and concentration ratios. Many protein and saccharide combinations were freeze-concentrated into amorphous mixture phase in protein-rich to moderately saccharide-rich concentration ratios, whereas saccharide phase appeared besides the mixture phase above certain saccharide/protein concentration ratios. Some saccharide-rich combinations separated into individual phases in the freeze-concentrates.

Key words: phase separation, freeze-drying, protein formulation

綜説

薬局方製剤試験の国際調和の動向
Aoyagi, N.(Aoyagi, Nobuo; 青柳伸男):
医薬品研究,、32 (11), 699〜708

薬局方製剤試験の国際調和の課題である溶出試験、崩壊試験、含量均一性試験、質量偏差試験、不溶性微粒子試験、注射剤の排出可能容量試験について、これまでの進捗状況と抱える問題点を紹介した。また、含量均一性試験、質量偏差試験は現在の日局の試験法が最適な標準試験法として認知され、採用される方向にあるが、それを例にとり、医薬品の品質向上を目指し、国際調和を良い方向に進展させるには、基礎となる科学的データが重要な役割を果たすことを示した。

Keywords: International harmonization, pharmacopoeia, dissolution test, content uniformity

単行本

我が国の生物学的同等性試験と国際調和、DDS研究の進歩
青柳伸男，
静岡DDS研究会編、 バイオメディカルリサーチプレス、東京（2001）pp.63-69。

日本薬局方技術情報 2001
青柳伸男,
日本公定書協会編，じほう，東京（2001），pp235〜239.

日本薬局方技術情報 2001
香取典子,
日本公定書協会編，じほう，東京（2001），pp92〜97，pp 121〜124.

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学会発表

In vivo 吸収の変動を予測しうる溶出試験の構築：ニフェジピン製剤
青柳伸男、石井文由、緒方宏泰
日本薬学会第122年会（2002.3）

凍結溶液における各種タンパク質と糖類の相分離と高次構造安定化作用
伊豆津健一、青柳伸男、小嶋茂雄
日本薬学会第122年会（2002.3）

In vitro 溶出試験におけるラグ時間とヒト血中濃度との関連性の検討
三原潔、臺綾子、石井文由、青柳伸男、緒方宏泰
日本薬学会第122年会（2002.3）

各種タンパク質と二糖類の凍結溶液中における混合性
伊豆津　健一, 小嶋　茂雄：
低温生物工学会第４7年会 (2001.6)

Miscibility of proteins and saccharides in frozen solutions.
Izutsu, K., Aoyagi, N., Kojima, S.:
American Association of Pharmaceutical Scientists Pharmaceutics and Drug Delivery Conference (2002.4)

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講演

Dissolution testing - relation with drug absorption
N.Aoyagi:
EUFEPS World Conference on Drug Absorption and Drug Delivery (2001.6)

我が国の生物学的同等性試験と国際調和
青柳伸男
第10回 DDSカンフェランス(2001.6)

含量均一性試験と質量偏差試験の適用_我が国における市販の錠剤およびカプセルについて_
香取典子、青柳伸男、小嶋茂雄
平成13年度標準処方研究会　(2000.10)

品質管理の新しい考え方：スキップ・工程内試験、パラメトリックリリース
青柳伸男、
平成１３年度東北三県合同医薬品等製造管理者・責任技術者等講習会(2001.11)

溶出試験の変動要因と信頼性
青柳伸男
平成１３年度日本薬剤師会試験検査センター技術講習会(2001.11)