JP2662842B2 - Parathyroid hormone stabilizing composition - Google Patents
Parathyroid hormone stabilizing compositionInfo
- Publication number
- JP2662842B2 JP2662842B2 JP4313381A JP31338192A JP2662842B2 JP 2662842 B2 JP2662842 B2 JP 2662842B2 JP 4313381 A JP4313381 A JP 4313381A JP 31338192 A JP31338192 A JP 31338192A JP 2662842 B2 JP2662842 B2 JP 2662842B2
- Authority
- JP
- Japan
- Prior art keywords
- pth
- freeze
- parathyroid hormone
- disaccharide
- monosaccharide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Description
【発明の詳細な説明】DETAILED DESCRIPTION OF THE INVENTION
【０００１】[0001]
【産業上の利用分野】本発明は、パラサイロイドホルモ
ン（Ｐａｒａｔｈｙｒｏｉｄ Ｈｏｒｍｏｎｅ；ＰＴ
Ｈ）の安定化法およびパラサイロイドホルモンを有効成
分とする医薬組成物に関する。BACKGROUND OF THE INVENTION The present invention relates to a parathyroid hormone (PT).
The present invention relates to a method for stabilizing H) and a pharmaceutical composition containing a parathyroid hormone as an active ingredient.
【０００２】[0002]
【従来の技術】ＰＴＨは、カルシトニン類やビタミンＤ
類とともに、血中カルシウム濃度の調節に関与するホル
モンであり、副甲状腺機能低下症の診断薬として用いら
れている。微量のＰＴＨを、用時溶解型凍結乾燥製剤と
して製剤化する場合、マンニトール等の糖類あるいはゼ
ラチン等の高分子物質を安定化剤として配合する方法
が、一般的に用いられている（特開昭６３−６０９４０
号公報、特開平２−１１１号公報）。2. Description of the Related Art PTH is composed of calcitonins and vitamin D.
Along with other hormones, they are hormones involved in the regulation of blood calcium levels and are used as diagnostics for hypoparathyroidism. When a small amount of PTH is formulated as a freeze-dried preparation at the time of use, a method in which a saccharide such as mannitol or a polymer substance such as gelatin is blended as a stabilizer is generally used (Japanese Patent Application Laid-open No. 63-60940
JP, JP-A-2-111).
【０００３】[0003]
【発明が解決しようとする課題】ペプチド、蛋白質等の
用時溶解型凍結乾燥剤の安定化剤としては、マンニトー
ルが最も繁用されているが、マンニトールをＰＴＨの用
時溶解型凍結乾燥製剤の安定化剤として使用したとき、
その安定化効果については、充分に満足し難い。また、
ゼラチン等の高分子物質の場合は、安定化効果は高い
が、免疫学的な安全性に問題がある場合が多い。Mannitol is most frequently used as a stabilizer for a freeze-dried freeze-dried preparation such as peptides and proteins, but mannitol is used as a stabilizer for freeze-dried freeze-dried preparations of PTH. When used as a stabilizer,
Its stabilizing effect is not fully satisfactory. Also,
In the case of a high molecular substance such as gelatin, the stabilizing effect is high, but there are many problems in immunological safety.
【０００４】[0004]
【課題を解決するための手段】このような問題点を解決
すべく、安全で安定な製剤処方を得るため、種々研究を
続けた結果、意外にも、単糖類または二糖類に一定量の
塩化ナトリウムを配合して凍結乾燥することにより、糖
単独の場合より凍結乾燥製剤の安定性が著しく向上する
ことを見出した。この結果、ＰＴＨの凍結乾燥製剤の安
定化剤として単糖類または二糖類と塩化ナトリウムを併
用することにより、安全でしかも熱安定性に優れたＰＴ
Ｈの凍結乾燥製剤を調製することが可能となった。In order to solve such problems, various studies were conducted to obtain a safe and stable pharmaceutical formulation. As a result, surprisingly, a certain amount of chloride was added to a monosaccharide or disaccharide. It has been found that the stability of a freeze-dried preparation is significantly improved by adding sodium and freeze-drying as compared with the case of using only sugar. As a result, by using a monosaccharide or disaccharide in combination with sodium chloride as a stabilizer of a freeze-dried preparation of PTH, a safe and heat-stable PT can be obtained.
It became possible to prepare a lyophilized formulation of H.
【０００５】すなわち、本発明の目的は、ＰＴＨを有効
成分とし、有効量の単糖類または二糖類および塩化ナト
リウムを含有することを特徴とする凍結乾燥医薬組成物
を提供することである。That is, an object of the present invention is to provide a lyophilized pharmaceutical composition comprising PTH as an active ingredient and containing an effective amount of a monosaccharide or disaccharide and sodium chloride.
【０００６】また、本発明の目的は、ＰＴＨと有効量の
単糖類または二糖類および塩化ナトリウムを水性媒体に
溶解した後、凍結乾燥することを特徴とするＰＴＨの安
定化法を提供することである。Another object of the present invention is to provide a method for stabilizing PTH, comprising dissolving PTH, an effective amount of a monosaccharide or disaccharide and sodium chloride in an aqueous medium, and freeze-drying the resultant. is there.
【０００７】まず、本発明の有効成分であるＰＴＨと
は、血清カルシウム上昇作用を有する分子量約４，００
０から１０，０００のペプチド類であって、３４〜８４
個のアミノ酸配列を有し、天然型ＰＴＨまたはその生物
学的に活性な類似体が知られている。例えばヒト−ＰＴ
Ｈ（ｈ−ＰＴＨ）（１−８４）〔Ｂｉｏｃｈｅｍｉｓｔ
ｒｙ １７， ５７２３ （１９７８）〕、ｈ−ＰＴＨ
（１−３８）〔特開昭５７−８１４４８号公報〕、ｈ−
ＰＴＨ（１−３４）〔Ｈｏｐｐｅ Ｓｅｙｌｅｒ’ｓ
Ｚ． Ｐｈｙｓｉｏｌ． Ｃｈｅｍ． ， ３５５，
４１５ （１９７４）〕、ｈ−ＰＴＨ（１−３４）ＮＨ
２ 〔特開昭５８−９６０５２号公報〕、〔Ｎｌｅ
８，１８〕ｈ−ＰＴＨ（１−３４）、〔Ｎｌ
ｅ８，１８，Ｔｙｒ３４〕ｈ−ＰＴＨ（１−３４）〔特
開昭５５−１１３７５３ 号公報〕、〔Ｎｌ
ｅ８，１８〕ｈ−ＰＴＨ（１−３４）ＮＨ２ 〔特開昭
６１−２４５９８号公報〕、〔Ｎｌｅ８，１８，Ｔｙｒ
３４〕ｈ−ＰＴＨ（１−３４）ＮＨ２ 〔特開昭６０−
２４９９６号公報〕、ラット−ＰＴＨ（１−８４）
〔Ｊ． Ｂｉｏｌ． Ｃｈｅｍ．， ２５９（５），
３３２０ （１９８４） 〕、ラット−ＰＴＨ（１−３
４）〔Ｅｎｄｏｃｒｉｎｏｌ．， １１７（３）， １
２３０ （１９８５）〕、ウシ−ＰＴＨ（１−８４）
〔Ａｍ． Ｊ． Ｍｅｄ．， ５０， ６３９（１９７
１） 〕、ウシ−ＰＴＨ（１−３４）、ウシ−ＰＴＨ
（１−３４）ＮＨ２〔Ｐｔｈｏｂｉｏｌｏｇｙ ａｎｎ
ｕａｌ １１， ５３ （１９８１）〕等が挙げられ、
好適には分子量約４，４００の３４個のアミノ酸配列を
有するｈ−ＰＴＨ（１−３４）である。First, PTH, which is an active ingredient of the present invention, has a molecular weight of about 4,000 having a serum calcium increasing effect.
0 to 10,000 peptides, 34 to 84
Naturally occurring PTH or a biologically active analog thereof having a single amino acid sequence is known. For example, human-PT
H (h-PTH) (1-84) [Biochemist
ry 17, 5723 (1978)], h-PTH
(1-38) [JP-A-57-81448], h-
PTH (1-34) [Hoppe Seyler's
Z. Physiol. Chem. , 355,
415 (1974)], h-PTH (1-34) NH
2 [JP-A-58-96052], [Nle
8,18 ] h-PTH (1-34), [Nl
e 8,18 , Tyr 34 ] h-PTH (1-34) [Japanese Patent Application Laid-Open No. 55-113753], [Nl
e 8, 18] h-PTH (1-34) NH 2 [JP 61-24598 JP], [Nle 8, 18, Tyr
34 ] h-PTH (1-34) NH 2 [JP-A-60-
No. 24996], rat-PTH (1-84)
[J. Biol. Chem. , 259 (5),
3320 (1984)], rat-PTH (1-3
4) [Endocrinol. , 117 (3), 1
230 (1985)], bovine-PTH (1-84)
[Am. J. Med. , 50, 639 (197
1)], bovine-PTH (1-34), bovine-PTH
(1-34) NH2 [Pthobiology ann
ual 11, 53 (1981)].
Preferably, it is h-PTH (1-34) having a molecular weight of about 4,400 and having 34 amino acid sequences.
【０００８】本発明において、単糖類としては、例えば
マンニトール、グルコース、ソルビトール、イノシトー
ル等が挙げられ、特にマンニトールが好ましい。また、
二糖類としては、例えばシュクロース、マルトース、ラ
クトース、トレハロース等が挙げられ、またこれらの糖
類は、単独または２種以上を併用して用いてもよく、さ
らにシュクロース、マルトース、ラクトースが特に好ま
しい。上記糖類の添加量は、ＰＴＨ１重量に対し、１重
量以上が好ましく、さらに好ましくは５０から１０００
重量添加すればよい。In the present invention, examples of the monosaccharide include mannitol, glucose, sorbitol, inositol and the like, and mannitol is particularly preferred. Also,
Examples of the disaccharide include sucrose, maltose, lactose, trehalose and the like. These saccharides may be used alone or in combination of two or more, and sucrose, maltose and lactose are particularly preferred. The amount of the saccharide to be added is preferably not less than 1 weight, more preferably from 50 to 1000, based on 1 weight of PTH.
What is necessary is just to add by weight.
【０００９】塩化ナトリウムの添加量は、糖類に対し多
い程ＰＴＨ類が安定であるが、糖類の２０％重量以上に
なると、凍結乾燥後のケーキに収縮が見られ、安定性も
低下する傾向にあるから、通常は糖類１重量に対し、１
／１０００重量から１／５重量、好ましくは１／１００
から１／１０重量添加すればよい。水性媒体としては、
例えば注射用蒸留水、生理食塩液や緩衝液が例示され
る。さらに上記の水性溶媒は毒性を示さない限り水溶性
有機溶媒、例えば少量のエタノール等を含んでいてもよ
い。The more sodium chloride is added to the saccharide, the more stable the PTH is. However, when the amount of saccharide exceeds 20% by weight, the freeze-dried cake shrinks and the stability tends to decrease. Therefore, usually, 1 weight per 1 saccharide
/ 1000 weight to 1/5 weight, preferably 1/100
May be added to 1/10 weight. As an aqueous medium,
For example, distilled water for injection, physiological saline and buffer are exemplified. Further, the above aqueous solvent may contain a water-soluble organic solvent, for example, a small amount of ethanol or the like, as long as it does not show toxicity.
【００１０】本発明の凍結乾燥医薬組成物を製造するに
は、例えば上記の組成のＰＴＨ、単糖類または二糖類お
よび塩化ナトリウムを、必要に応じて適宜公知のｐＨ調
製剤、等張化剤、安定化剤、増量剤、防腐剤等を混合
し、上記の水性媒体に溶解して無菌濾過し、常法に基づ
いて凍結乾燥すればよい。この凍結乾燥には、通常用い
られている条件下で、トレー凍結乾燥、スプレー凍結乾
燥、バイアル凍結乾燥などの公知の凍結乾燥法が採用で
きる。このようにして得られる組成物において、例えば
注射用凍結乾燥製剤において、１製剤当たり、例えば１
μｇ〜１５０ｐｇのＰＴＨ）好適にはｈ−（１−３４）
ＰＴＨを含有するものとして製剤設計してもよい。In order to produce the lyophilized pharmaceutical composition of the present invention, for example, PTH, a monosaccharide or a disaccharide and sodium chloride having the above-mentioned composition can be added, if necessary, to a known pH adjusting agent, an isotonic agent, A stabilizer, a bulking agent, a preservative, and the like may be mixed, dissolved in the above aqueous medium, sterile-filtered, and freeze-dried according to a conventional method. Known freeze-drying methods such as tray freeze-drying, spray freeze-drying, and vial freeze-drying can be employed for the freeze-drying under the conditions generally used. In the composition thus obtained, for example, in a freeze-dried preparation for injection, for example, 1
μg to 150 pg of PTH) preferably h- (1-34)
The formulation may be designed to contain PTH.
【００１１】[0011]
【実施例】以下に本発明を実施例を挙げてさらに詳細に
説明する。The present invention will be described in more detail with reference to the following examples.
【００１２】[0012]
【実施例１】ｈ−ＰＴＨ（１−３４）（旭化成工業社
製）２．１６ｍｇとマンニトール３００ｍｇおよび塩化
ナトリウム３０ｍｇをとり、無菌蒸留水３０ｍｌを加え
溶解させた。無菌濾過後、ガラスバイアルに０．５ｍｌ
ずつ分注し、凍結乾燥を行い窒素置換後、打栓、巻き締
めし、用時溶解型乾燥製剤を得た（本発明品１）。Example 1 2.16 mg of h-PTH (1-34) (manufactured by Asahi Kasei Corporation), 300 mg of mannitol and 30 mg of sodium chloride were dissolved in 30 ml of sterile distilled water. After aseptic filtration, 0.5 ml in a glass vial
After dispensing, freeze-drying and purging with nitrogen, stoppering and squeezing were performed to obtain a dry-use dry preparation (Product 1 of the present invention).
【００１３】[0013]
【実施例２】実施例１において、マンニトールの代わり
に次表の糖類を使用し、塩化ナトリウムを下記表１の量
を用いて、同様に処理し、各凍結乾燥製剤を得た。Example 2 In Example 1, saccharides shown in the following table were used in place of mannitol, and sodium chloride was treated in the same manner using the amounts shown in Table 1 below to obtain freeze-dried preparations.
【００１４】[0014]
【表１】 [Table 1]
【００１５】[0015]
【実施例３】ウシＰＴＨ（１−３４）（シグマ社製）
０．３ｍｇとマンニトール２４０ｍｇおよび塩化ナトリ
ウム２４ｍｇをとり、無菌蒸留水１２ｍｌを加え溶解さ
せた。無菌濾過後ガラスアンプルに０．５ｍｌずつ分注
し、凍結乾燥後熔閉して用時溶解型製剤を得た。Example 3 Bovine PTH (1-34) (manufactured by Sigma)
0.3 mg, 240 mg of mannitol and 24 mg of sodium chloride were taken and dissolved by adding 12 ml of sterile distilled water. After aseptic filtration, 0.5 ml was dispensed into glass ampules, freeze-dried and sealed to obtain a ready-to-use formulation.
【００１６】[0016]
【実施例４】ラットＰＴＨ（１−３４）（旭化成工業社
製）０．２ｍｇとトレハロース１６０ｍｇおよび塩化ナ
トリウム１０ｍｇをとり、無菌蒸留水８ｍｌを加え溶解
させた。次にガラスアンプルに０．１ｍｌずつ分注し、
凍結乾燥後熔閉し、含量測定用標準品を得た。Example 4 0.2 mg of rat PTH (1-34) (manufactured by Asahi Kasei Corporation), 160 mg of trehalose and 10 mg of sodium chloride were dissolved in 8 ml of sterile distilled water. Next, 0.1ml is dispensed into glass ampules,
After freeze-drying and sealing, a standard product for content measurement was obtained.
【００１７】[0017]
【実施例５】〔Ｎｌｅ8,18〕−ｈ−ＰＴＨ（１−３４）
（旭化成工業社製）０．６ｍｇとトレハロース１６０ｍ
ｇおよび塩化ナトリウム２４ｍｇをとり、無菌蒸留水２
４ｍｌを加え溶解させた。無菌濾過後、ガラスバイアル
に０．５ｍｌずつ分注し、凍結乾燥後、打栓、巻き締め
し、用時溶解型乾燥製剤を得た。Embodiment 5 [Nle 8,18 ] -h-PTH (1-34)
0.6 mg (manufactured by Asahi Kasei Kogyo) and trehalose 160 m
g and 24 mg of sodium chloride.
4 ml was added and dissolved. After aseptic filtration, 0.5 ml was dispensed into a glass vial, freeze-dried, stoppered and rolled up to obtain a dry formulation ready for use.
【００１８】[0018]
【実施例６】ｈ−ＰＴＨ（１−８４）（シグマ社製）
０．１５ｍｇとトレハロース１００ｍｇおよび塩化ナト
リウム１０ｍｇをとり、無菌蒸留水１０ｍｌを加え溶解
させた。次にガラスアンプルに０．２ｍｌずつ分注し、
凍結乾燥後熔閉し、生物活性測定用標準品を得た。Embodiment 6 h-PTH (1-84) (manufactured by Sigma)
0.15 mg, 100 mg of trehalose and 10 mg of sodium chloride were taken and dissolved in 10 ml of sterile distilled water. Next, 0.2ml is dispensed into glass ampules,
After freeze-drying and sealing, a standard product for measuring biological activity was obtained.
【００１９】[0019]
【実施例７】ｈ−ＰＴＨ（１−３４）（旭化成工業社
製）０．５４ｍｇとグルコース７５ｍｇおよび塩化ナト
リウム７．５ｍｇをとり、無菌蒸留水１５ｍｌを加え溶
解させた。無菌濾過後、ガラスアンプルに１ｍｌずつ分
注し、凍結乾燥後打栓、巻き締めし、用時溶解型乾燥製
剤を得た。EXAMPLE 7 0.54 mg of h-PTH (1-34) (manufactured by Asahi Kasei Corporation), 75 mg of glucose and 7.5 mg of sodium chloride were dissolved in 15 ml of sterile distilled water. After aseptic filtration, 1 ml was dispensed into glass ampoules, freeze-dried, stoppered and tightly wound to obtain a dry formulation ready for use.
【００２０】[0020]
【実施例８】ｈ−ＰＴＨ（１−３４）（旭化成工業社
製）１．０８ｍｇとソルビトール３００ｍｇおよび塩化
ナトリウム１５ｍｇをとり、無菌蒸留水１５ｍｌを加え
溶解させた。無菌濾過後、ガラスアンプルに０．５ｍｌ
ずつ分注し、凍結乾燥後打栓、巻き締めし、用時溶解型
乾燥製剤を得た。Example 8 1.08 mg of h-PTH (1-34) (manufactured by Asahi Kasei Corporation), 300 mg of sorbitol and 15 mg of sodium chloride were dissolved in 15 ml of sterile distilled water. After sterile filtration, add 0.5 ml to glass ampoule
The solution was dispensed, freeze-dried, stoppered and tightly wound to obtain a dry-use dried preparation.
【００２１】[0021]
【実施例９】ｈ−ＰＴＨ（１−３４）（旭化成工業社
製）１．０８ｍｇとイノシトール３００ｍｇおよび塩化
ナトリウム３０ｍｇをとり、無菌蒸留水１５ｍｌを加え
溶解させた。無菌濾過後、ガラスアンプルに０．５ｍｌ
ずつ分注し、凍結乾燥後打栓、巻き締めし、用時溶解型
乾燥製剤を得た。Example 9 1.08 mg of h-PTH (1-34) (manufactured by Asahi Kasei Corporation), 300 mg of inositol and 30 mg of sodium chloride were dissolved in 15 ml of sterile distilled water. After sterile filtration, add 0.5 ml to glass ampoule
The solution was dispensed, freeze-dried, stoppered and tightly wound to obtain a dry-use dried preparation.
【００２２】[0022]
【実施例１０】 ＰＴＨ安定性試験 〔対象製剤〕前述の実施例１および実施例２で得た本発
明品１〜９、および下記の通り製剤化された対照品１〜
７の各々を、安定性試験の対象製剤とした。[Example 10] PTH stability test [Target formulations] Products 1 to 9 of the present invention obtained in Examples 1 and 2 described above and Controls 1 to 1 formulated as described below
Each of 7 was used as a target formulation for the stability test.
【００２３】〔対照品の調製〕 （１） ｈ−ＰＴＨ（１−３４）（旭化成工業社製）
２．１６ｍｇと塩化ナトリウム３０ｍｇをとり、無菌蒸
留水３０ｍｌを加え溶解させた。無菌濾過後、ガラスバ
イアルに０．５ｍｌずつ分注し、凍結乾燥を行い窒素置
換後、打栓、巻き締めし、用時溶解型凍結乾燥製剤を得
た（対照品１）。 （２） ｈ−ＰＴＨ（１−３４）（旭化成工業社製）
２．１６ｍｇとマンニトール３００ｍｇをとり、以下同
様に処理し、用時溶解型凍結乾燥製剤を得た（対照品
２）。 （３） ｈ−ＰＴＨ（１−３４）（旭化成工業社製）
２．１６ｍｇとシュクロース３００ｍｇをとり、以下同
様に処理し、用時溶解型凍結乾燥製剤を得た（対照品
３）。 （４） ｈ−ＰＴＨ（１−３４）（旭化成工業社製）
２．１６ｍｇとマルトース３００ｍｇをとり、以下同様
に処理し、用時溶解型凍結乾燥製剤を得た（対照品
４）。 （５） ｈ−ＰＴＨ（１−３４）（旭化成工業社製）
２．１６ｍｇとラクトース３００ｍｇをとり、以下同様
に処理し、用時溶解型凍結乾燥製剤を得た（対照品
５）。 （６） ｈ−ＰＴＨ（１−３４）（旭化成工業社製）
２．１６ｍｇとシュクロース６００ｍｇをとり、以下同
様に処理し、用時溶解型凍結乾燥製剤を得た（対照品
６）。 （７） ｈ−ＰＴＨ（１−３４）（旭化成工業社製）
２．１６ｍｇとマンニトール６００ｍｇをとり、以下同
様に処理し、用時溶解型凍結乾燥製剤を得た（対照品
７）。[Preparation of Control Product] (1) h-PTH (1-34) (manufactured by Asahi Kasei Corporation)
2.16 mg and 30 mg of sodium chloride were taken and dissolved in 30 ml of sterile distilled water. After aseptic filtration, 0.5 ml was dispensed into a glass vial, freeze-dried, replaced with nitrogen, stoppered and tightly wound to obtain a freeze-dried preparation for use when used (control product 1). (2) h-PTH (1-34) (manufactured by Asahi Kasei Corporation)
2.16 mg and 300 mg of mannitol were taken and treated in the same manner to obtain a freeze-dried preparation at the time of use (Control product 2). (3) h-PTH (1-34) (manufactured by Asahi Kasei Corporation)
2.16 mg and 300 mg of sucrose were taken and treated in the same manner as described above to obtain a freeze-dried preparation ready for use (Control 3). (4) h-PTH (1-34) (manufactured by Asahi Kasei Corporation)
2.16 mg and maltose (300 mg) were taken and treated in the same manner to obtain a freeze-dried preparation for use at the time of use (Control product 4). (5) h-PTH (1-34) (manufactured by Asahi Kasei Corporation)
2.16 mg and lactose (300 mg) were taken and treated in the same manner to obtain a freeze-dried preparation for use at the time of use (Control product 5). (6) h-PTH (1-34) (manufactured by Asahi Kasei Corporation)
2.16 mg and 600 mg of sucrose were taken and treated in the same manner as described below to obtain a freeze-dried preparation at the time of use (Control product 6). (7) h-PTH (1-34) (manufactured by Asahi Kasei Corporation)
2.16 mg and 600 mg of mannitol were taken and treated in the same manner as described above to obtain a freeze-dried preparation for use at the time of use (control product 7).
【００２４】〔試験方法〕前述の実施例１および実施例
２で得た本発明品１〜９および対照品１〜７の各々を４
０℃に保存し、経時的にサンプリングを行い、次の条件
による高速液体クロマトグラフィー（ＨＰＬＣ）を用い
てＰＴＨ含量を測定した。 ＨＰＬＣ測定条件 カラム：ＹＭＣ ＡＭ−３０３ ＯＤＳ Ｓ−５ １２
０Å（ＹＭＣ社製）内径４．６×２５０ｍｍ 移動相：０．１％ＴＦＡ：アセトニトリル＝７３：２７
〜６８：３２（１７分） 流速：１．０ｍｌ／分 検出：ＵＶ ２８０ｎｍ[Test method] Each of the products 1 to 9 of the present invention and the control products 1 to 7 obtained in the above Examples 1 and 2
It was stored at 0 ° C., sampled with time, and the PTH content was measured using high performance liquid chromatography (HPLC) under the following conditions. HPLC measurement conditions Column: YMC AM-303 ODS S-5 12
0Å (manufactured by YMC) Inner diameter 4.6 × 250 mm Mobile phase: 0.1% TFA: acetonitrile = 73: 27
-68: 32 (17 min) Flow rate: 1.0 ml / min Detection: UV 280 nm
【００２５】〔結果〕各試料の組成と４０℃、３ヶ月間
保存のＰＴＨ残存率を表２に示した。[Results] Table 2 shows the composition of each sample and the residual ratio of PTH stored at 40 ° C. for 3 months.
【００２６】[0026]
【表２】 [Table 2]
【００２７】表２の結果よりわかるように、塩化ナトリ
ウム単独添加または糖類単独添加よりも、塩化ナトリウ
ムおよび糖類を併用した本発明品の方がいずれも安定で
あり、塩化ナトリウムおよび糖類の併用効果が認められ
た。ところが、糖類単独では、４０℃、３ヶ月後の安定
性が著しく低下した。また、塩化ナトリウム単独では、
凍結乾燥においてケーキが収縮し好ましくなく、かつ、
安定性も著しく低下した。As can be seen from the results in Table 2, the product of the present invention using sodium chloride and a saccharide together is more stable than adding sodium chloride alone or a saccharide alone, and the combined effect of sodium chloride and a saccharide is less. Admitted. However, the stability of the saccharides alone after 3 months at 40 ° C. was significantly reduced. Also, with sodium chloride alone,
The cake shrinks during lyophilization, which is undesirable, and
The stability was also significantly reduced.
【００２８】[0028]
【発明の効果】上記の通り、有効量の単糖類または二糖
類および塩化ナトリウムをＰＴＨの安定化剤として用い
ることにより、安定で安全性の高いＰＴＨ凍結乾燥製剤
を得ることが可能となった。As described above, by using an effective amount of a monosaccharide or disaccharide and sodium chloride as a stabilizer for PTH, a stable and highly safe freeze-dried PTH preparation can be obtained.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ａ６１Ｋ 9/14 Ｅ (72)発明者 大野 勝 静岡県田方郡大仁町三福632番地の１ 旭化成工業株式会社内 (72)発明者 榊原 秀夫 静岡県田方郡大仁町三福632番地の１ 旭化成工業株式会社内 (56)参考文献 特開 昭59−163313（ＪＰ，Ａ) 特開 昭63−60940（ＪＰ，Ａ) 特開 昭63−115821（ＪＰ，Ａ) 特開 平２−111（ＪＰ，Ａ) 特開 平２−22233（ＪＰ，Ａ) 特開 平４−247034（ＪＰ，Ａ) 特開 昭61−118325（ＪＰ，Ａ) 国際公開93／11785（ＷＯ，Ａ)──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. 6 Identification code Agency reference number FI Technical display location A61K 9/14 E (72) Inventor Masaru Ono 1 632 Mifuku, Oni-cho, Tata-gun, Shizuoka Prefecture Asahi Kasei Inside of Industrial Co., Ltd. (72) Inventor Hideo Sakakibara 1 of 632, Mifuku, Ohi-machi, Tatagata-gun, Shizuoka Pref. Asahi Kasei Kogyo Co., Ltd. (56) References JP-A-59-163313 (JP, A) JP-A-63-60940 (JP, A) JP-A-63-115821 (JP, A) JP-A-2-111 (JP, A) JP-A-2-22233 (JP, A) JP-A-4-247034 (JP, A) 61-118325 (JP, A) WO 93/11785 (WO, A)
Claims (8)
学的に活性な類似体を有効成分とし、有効量の単糖類ま
たは二糖類および塩化ナトリウムを含有することを特徴
とする凍結乾燥医薬組成物。1. Parathyroid hormone or an organism thereof
A biologically active analog as the active ingredient and an effective amount of monosaccharides or
Or a lyophilized pharmaceutical composition comprising a disaccharide and sodium chloride.
ルビトール、イノシトール、二糖類がシュクロース、マ
ルトース、ラクトース、トレハロースからなる群より選
ばれる請求項１記載の凍結乾燥医薬組成物。2. A monosaccharide mannitol, glucose, sorbitol, inositol, disaccharides sucrose, maltose, lactose, lyophilized pharmaceutical composition of claim 1 wherein is selected from the group consisting of trehalose.
（１−３４）である請求項１または２記載の凍結乾燥医
薬組成物。3. The method of claim 1, wherein the parathyroid hormone is human-PTH.
The freeze-dried physician according to claim 1 or 2, which is (1-34).
Drug composition .
（１−３４）であり、単糖類または二糖類がシュクロー
スである請求項１記載の凍結乾燥医薬組成物。4. The method according to claim 1, wherein the parathyroid hormone is human-PTH.
(1-34), wherein the monosaccharide or disaccharide is sucrose.
The lyophilized pharmaceutical composition according to claim 1, which is a lyophilized pharmaceutical composition .
学的に活性な類似体と有効量の単糖類または二糖類およ
び塩化ナトリウムを水性媒体に溶解した後、凍結乾燥す
ることを特徴とするパラサイロイドホルモンの安定化
法。5. A parathyroid hormone or an organism thereof.
Histological active after a monosaccharide or disaccharide Oyo <br/> beauty sodium chloride analogs and effective amount dissolved in an aqueous medium, Stabilization para thyroid hormone, which comprises freeze-drying .
ルビトール、イノシトール、二糖類がシュクロース、マ
ルトース、ラクトース、トレハロースからなる群より選
ばれる請求項５記載の安定化法。6. The method according to claim 5, wherein the monosaccharide is mannitol, glucose, sorbitol, inositol, and the disaccharide is selected from the group consisting of sucrose, maltose, lactose, and trehalose.
（１−３４）である請求項５または６記載の安定化法。The method according to claim 5 or 6, wherein (1-34).
（１−３４）であり、単糖類または二糖類がシュクロー
スである請求項５記載の安定化法。 」 8. The method according to claim 8, wherein the parathyroid hormone is human-PTH.
(1-34), wherein the monosaccharide or disaccharide is sucrose.
6. The method according to claim 5, wherein "
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/244,758 US5563122A (en) | 1991-12-09 | 1992-12-08 | Stabilized parathyroid hormone composition |
| EP92924889A EP0619119B1 (en) | 1991-12-09 | 1992-12-08 | Stabilized parathyroid hormone composition |
| ES92924889T ES2129048T3 (en) | 1991-12-09 | 1992-12-08 | STABILIZED COMPOSITION OF PARATHYROID HORMONE. |
| DE69228828T DE69228828T2 (en) | 1991-12-09 | 1992-12-08 | STABILIZED PARATHORMONE COMPOSITION |
| KR1019940701972A KR0131678B1 (en) | 1991-12-09 | 1992-12-08 | Stabilized parathyroid hormone composition |
| PCT/JP1992/001599 WO1993011785A1 (en) | 1991-12-09 | 1992-12-08 | Stabilized parathyroid hormone composition |
| AU30950/92A AU3095092A (en) | 1991-12-09 | 1992-12-08 | Stabilized parathyroid hormone composition |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP35023691 | 1991-12-09 | ||
| JP3-350236 | 1991-12-09 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH05306235A JPH05306235A (en) | 1993-11-19 |
| JP2662842B2 true JP2662842B2 (en) | 1997-10-15 |
Family
ID=18409147
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4313381A Expired - Lifetime JP2662842B2 (en) | 1991-12-09 | 1992-11-24 | Parathyroid hormone stabilizing composition |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2662842B2 (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE9801495D0 (en) * | 1998-04-28 | 1998-04-28 | Astra Ab | Protein formulation |
| KR20080028942A (en) | 2005-07-20 | 2008-04-02 | 교와 메덱스 가부시키가이샤 | Method of stabilizing peptide contained in biosample |
| ES2843649T3 (en) | 2009-09-09 | 2021-07-20 | Asahi Kasei Pharma Corp | Therapeutic / prophylactic agent containing PTH for osteoporosis, characterized in that PTH is administered once a week in a unit dose of 200 units |
| CN103561757B (en) | 2011-06-07 | 2016-01-06 | 旭化成制药株式会社 | High-purity is containing PTH freeze-dried preparation and manufacture method thereof |
| JP6840951B2 (en) * | 2016-08-04 | 2021-03-10 | 昭和電工マテリアルズ株式会社 | Products for culturing, culturing vessels, and methods for producing culturing vessels |
| JP6637220B2 (en) * | 2017-09-22 | 2020-01-29 | 旭化成ファーマ株式会社 | Teriparatide-containing liquid pharmaceutical composition having excellent pharmacokinetics and / or safety |
| WO2019059302A1 (en) * | 2017-09-22 | 2019-03-28 | 旭化成ファーマ株式会社 | Teriparatide-containing liquid pharmaceutical composition having excellent stability |
| BR112020019711A2 (en) | 2018-04-16 | 2021-02-09 | Ioulia Tseti | pharmaceutical composition of dry powder for inhalation |
| WO2019220654A1 (en) * | 2018-05-17 | 2019-11-21 | 旭化成ファーマ株式会社 | Preparation having reduced n-formylpiperidine content and/or rarely undergoing collapse or shrinkage of lyophilized cake thereof |
-
1992
- 1992-11-24 JP JP4313381A patent/JP2662842B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH05306235A (en) | 1993-11-19 |
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