JP2000086501A - Liposome formulation of human calcitonin - Google Patents

Liposome formulation of human calcitonin

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JP2000086501A
JP2000086501A JP10257356A JP25735698A JP2000086501A JP 2000086501 A JP2000086501 A JP 2000086501A JP 10257356 A JP10257356 A JP 10257356A JP 25735698 A JP25735698 A JP 25735698A JP 2000086501 A JP2000086501 A JP 2000086501A
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human calcitonin
formulation
liposome
administration
liposomes
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Hirotaka Nagasaki
Junichi Okada
純一 岡田
博隆 長崎
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Sankyo Co Ltd
三共株式会社
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Abstract

PROBLEM TO BE SOLVED: To obtain a liposome formulation having excellent preserving stability and high enclosing percentage of human calcitonin by dispersing liposome containing human calcitonin in an aqueous solution having a specific pH.
SOLUTION: This formulation is obtained by dispersing liposome preferably containing 5-35 mol% of lipid (e.g. phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, phosphatidic acid, cardiolipin, dicetylphosphoric acid or the like) containing human calcitonin and having a negative charge and 40-60 mol% of cholesterol in an aqueous solution having pH 5-10. In the formulation, an amount of the lipid constituting liposome is preferably used as 10-100 wt. times of human calcitonin. The objective formulation is usable as an injection formulation for subcutaneous administration or intramuscular administration, parenteral formulation for intrarectal administration, rhinenchysis administration, etc., or for peroral administration, etc. A human calcitonin concentration in the formulation is preferably 0.01-10 mg /mL.
COPYRIGHT: (C)2000,JPO

Description

【発明の詳細な説明】 DETAILED DESCRIPTION OF THE INVENTION

【0001】 [0001]

【発明の属する技術分野】本発明は、ヒトカルシトニンの保存安定性を良好にし、高いヒトカルシトニン封入率を有するリポソーム製剤に関するものである。 The present invention relates to is to improve the storage stability of human calcitonin, the present invention relates to a liposome preparation having a high human calcitonin encapsulation rate.

【0002】 [0002]

【従来の技術】カルシトニンは、破骨細胞による骨吸収を抑える働きをもつホルモンであり、骨粗鬆症の治療薬として利用されている(白木正孝、ホルモンと臨床、38 BACKGROUND OF THE INVENTION calcitonin is a hormone that has a function to suppress the bone resorption by osteoclasts, it has been used as a therapeutic drug for osteoporosis (Shiraki Masataka, hormones and the clinical, 38
巻、547-554頁、1990参照)。 , Pp. 547-554, see 1990). このホルモンは32アミノ酸残基からなるポリペプチドであり、サケ、ウナギ、ブタ、ヒト型等といった様々な種由来のものが用いられているが、それぞれ互いに構造が一部異なるため、薬理活性の強さや物理化学的性質が異なる(ヨーロピアン・ジャーナル・オブ・バイオケミストリー: Eur. J.Bioche This hormone is a polypeptide consisting of 32 amino acid residues, salmon, eel, porcine, have been used those derived from various species such as human and the like, differ structures each other part, strong pharmacological activity Saya physicochemical properties are different from each other (European journal of Biochemistry:. Eur J.Bioche
m., 221巻, 1117-1125頁, 1994年参照)。 m., 221, pp. 1117-1125, see 1994).

【0003】この中で、ヒト由来のカルシトニンは、ヒトに投与した時に副作用が小さいことが期待される一方、他に比べ水溶液中での安定性がきわめて低いという性質を持つ(ジャーナル・オブ・バイオロジカル・ケミストリー: J. Biol. Chem. 268巻, 6415-6422頁, 1993 [0003] In this, calcitonin derived from human, while side effects are small when administered to a human can be expected, stability in aqueous solutions than the other has the property that extremely low (Journal of Biotechnology logical chemistry:.. J. Biol Chem 268, pp. 6415-6422, 1993
年参照)。 Reference year). とりわけ、pH5以上の、特に中性又はアルカリ性の溶液中では速やかに繊維状の凝集塊を形成する。 Especially, the pH5 or higher, quickly form agglomerates fibrous, especially neutral or alkaline solution.
ヒトカルシトニンそのものの不安定性は、凍結乾燥法などにより固体化させることで解決することができる。 Instability of human calcitonin itself, can be solved by solidifying by freeze drying. そのような水溶液中で不安定な薬物は、一般的に、投与前に凍結乾燥粉末を水に溶解する用時溶解型製剤とすることが多い。 Unstable medicament in such aqueous solutions is generally often the use upon dissolution formulations the lyophilized powder is dissolved in water prior to administration. しかし、この方法は投与のたびに溶解操作を行わなければならず、取り扱いが繁雑である。 However, this method must be performed dissolved operation each time of administration, handling thereof is complicated. 水溶液中で不安定な薬物の水溶液中での保存安定性を向上させることができれば、溶液製剤化することで溶解操作が不要になり利便性が向上する。 If it is possible to improve the storage stability in an aqueous solution of labile drug in an aqueous solution, dissolved operation by the solution formulation improves the usability becomes unnecessary. また、用時溶解型の場合でもくり返し投与の際の保存期間が延長できるため、溶解操作の頻度を減らすことができるといったメリットが生まれる。 Further, since the storage period of time of repeated administration even at the time of use soluble forms can be extended, merit can reduce the frequency of dissolution operation is born.

【0004】前述のように、ヒトカルシトニンの水溶液製剤を長期間安定に保存させるためには、前述の特徴があるため溶液を酸性にしなければならなかった。 [0004] As described above, in order to save the aqueous formulation of human calcitonin stably for a long period of time had to acidified solution because of the characteristics described above. しかし、人体において酸性の水溶液を投与し難い部位があること、酸性中で溶解性あるいは安定性に乏しい添加物を使用できなくなるなどの問題点があった。 However, that there is a site where hardly administering an aqueous solution of acid in the human body, there is a problem, such as can not use the poor additive solubility or stability in acidic.

【0005】本発明者らは上記の問題点を克服するべく検討を重ねた結果、ヒトカルシトニンをリポソームに封入することにより、中性またはアルカリ性条件下におけるヒトカルシトニンの保存安定性が向上することを見出した。 [0005] The present inventors have result of repeated studies to overcome the problems described above, by enclosing the human calcitonin in liposomes, the storage stability of human calcitonin in neutral or alkaline conditions can be improved heading was.

【0006】ここで、「リポソーム」とは、リン脂質を主成分とした脂質二重膜で水相を内封した閉鎖小胞であり、「リポソームに封入する」とは、ある薬物を内部の水相または脂質膜中に取り込んだリポソームを製造することを指す。 [0006] Here, the "liposome" is a closed vesicle was Uchifu the aqueous phase with a lipid bilayer membrane in which the phospholipid as a main component, and "encapsulated in liposomes", certain drugs inside of It refers to the production of liposomes incorporating in the aqueous phase or lipid film.

【0007】リポソームの製造において最も重要な因子は薬物の封入率である。 [0007] The most important factor in the production of liposomes are encapsulation rate of the drug. 「封入率」とは、リポソーム製造時に仕込んだ薬物のうち、リポソームに封入される薬物の割合を指す。 The "inclusion rate" refers to all drugs were charged at the time of liposome preparation, refer to the percentage of drug encapsulated in a liposome. 封入率が高ければ、より少量の薬物で薬物封入リポソームを製造することが可能となるため、 Since the higher the encapsulation efficiency, it is possible to produce a drug-encapsulating liposomes a smaller amount of the drug,
製造コストを大幅に抑えることができる。 It is possible to suppress the production cost significantly. また同時に、 At the same time,
リポソーム当りの薬物量が増えることにもなるため、投与容積を減らしたり、高濃度の製剤を作ることができるなど、製剤的なメリットも生まれる。 Since also that the amount of drug per liposome increases, or decrease the dose volume and can be made a high concentration of the formulation, born also formulated benefits.

【0008】ところが、一般的にペプチド性薬物のリポソームへの封入率は低い。 [0008] However, generally encapsulating rate into liposomes peptidic drug is low.

【0009】 [0009]

【発明が解決しようとする課題】本発明者らは、封入率の高いヒトカルシトニン封入リポソームを製造するために検討を重ねた結果、リポソーム構成脂質組成および製法を工夫することにより封入率が飛躍的に向上することを見出し、本発明を完成した。 The present inventors have found 0005] As a result of intensive studies in order to manufacture a highly encapsulation ratio human calcitonin liposome encapsulating dramatically encapsulation ratio by devising the liposome structure lipid composition and method It found that the improvement in, and completed the present invention.

【0010】 [0010]

【課題を解決するための手段】本発明は、(1)ヒトカルシトニンを含有するリポソームをpH5以上10以下の水溶液に分散したリポソーム製剤、(2)5乃至35モル%の負電荷を有する脂質および40乃至60モル%のコレステロールを構成成分とすることを特徴とする(1)記載のリポソーム製剤、(3)リポソーム製造工程において凍結融解処理を行うことにより得られる(2)記載のリポソーム製剤。 Means for Solving the Problems The present invention provides (1) a lipid having liposome formulation dispersed liposomes containing human calcitonin to an aqueous solution of pH5 to 10, (2) 5 to 35 mol% of negatively charged and characterized by a 40 to 60 mol% of cholesterol components (1) liposomal formulation according, (3) liposome formulation of the obtained (2), wherein by performing the freeze-thaw process in liposome manufacturing process. (4)負電荷を有する脂質が、ホスファチジルグリセロール、ホスファチジルセリン、ホスファチジルイノシトール、ホスファチジン酸、カルジオリピン及びジセチルリン酸からなる群より選択される1種又は2種以上の脂質であることを特徴とする、(2)又は(3) (4) a lipid having a negative charge, and wherein the phosphatidyl glycerol, phosphatidyl serine, phosphatidyl inositol, phosphatidic acid, one or more lipids selected from the group consisting of cardiolipin and dicetyl phosphate, ( 2) or (3)
記載のリポソーム製剤、に関する。 Liposome formulations described relates.

【0011】 [0011]

【発明の実施の形態】本発明のリポソームは構成成分として、5乃至35モル%の負電荷を有する脂質および40乃至 As Liposomes component of the present invention DETAILED DESCRIPTION OF THE INVENTION, lipids and 40 to have a negative charge of 5 to 35 mol%
60モル%のコレステロールを含む。 Containing 60 mol% of cholesterol. 負電荷を有する脂質として、好適には、ホスファチジルグリセロール、ホスファチジルセリン、ホスファチジルイノシトール、ホスファチジン酸、カルジオリピン、ジセチルリン酸などを挙げることができ、これらを単独または組み合わせて用いることができる。 As a lipid having a negative charge, preferably, phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, phosphatidic acid, cardiolipin, and the like can be illustrated dicetyl phosphate may be used alone or in combination.

【0012】その他のリポソーム構成成分として、例えば、卵黄レシチン、大豆レシチン、ホスファチジルコリン、ホスファチジルエタノールアミン、リゾフォスファチジルコリン、スフィンゴミエリンなどの天然由来もしくは合成によって得られるリン脂質などを必要に応じて使用することができる。 [0012] Other liposomal constituents, for example, egg yolk lecithin, soybean lecithin, phosphatidylcholine, phosphatidylethanolamine, lysophosphatidylcholine, used as needed, such as phospholipids obtained by naturally occurring or synthetic, such as sphingomyelin can do.

【0013】以上の脂質を用いてヒトカルシトニンを封入したリポソームを製造するが、その製造方法は、例えば、機械的分散法、薄膜法、逆相蒸発法、エタノール注入法、エーテル注入法、脱水−再水和法など公知の方法を挙げることができる(DDラシック、リポソームス: [0013] The above Lipid using manufacturing liposomes encapsulating human calcitonin, its production method, for example, a mechanical dispersion method, a thin film method, reverse phase evaporation method, ethanol injection method, ether injection method, dehydrated - mention may be made of a known method such as re-hydration method (DD Classic, liposomes S:
フロムフィジックス・ツー・アプリケーション/DDLa From Physics-to-application / DDLa
sic, Liposomes: from physics to application, Elsev sic, Liposomes: from physics to application, Elsev
ier Science Publishers, 1993年参照)。 ier Science Publishers, see 1993).

【0014】ヒトカルシトニンを封入させるためのリポソーム構成脂質は、重量でヒトカルシトニンの10倍乃至 [0014] Liposomes constituent lipids for encapsulated human calcitonin, or 10 times the human calcitonin by weight
100倍量用いるのが好適である。 It is preferable to use 100 times.

【0015】上記の方法で製造したリポソームの分散液中には、封入されなかった一部のヒトカルシトニンがリポソーム外に残っているが、このリポソーム分散液を凍結融解処理することにより、さらに封入率を向上させることができる。 [0015] The dispersion of liposomes prepared by the above method, a part of human calcitonin unencapsulated remains outside the liposomes, by freeze-thawing the liposomal dispersion further encapsulation efficiency it is possible to improve the. 凍結融解処理とは、リポソーム分散液を液体窒素などで急速に凍結したのち40 oC前後で融解する手法である(DD Lasic, Liposomes: from physics Freeze-thaw treatment is a technique in which a liposome dispersion is melted at 40 oC before and after After rapidly frozen such as in liquid nitrogen (DD Lasic, Liposomes: from physics
to application, Elsevier Science Publishers, 1993 to application, Elsevier Science Publishers, 1993
参照)。 reference).

【0016】カルシトニン封入リポソームとリポソームに封入されずに分散液中に残ったヒトカルシトニンとは、ゲル濾過法や超遠心処理などの方法によって分離することができる。 The remaining human calcitonin and the dispersion without being encapsulated calcitonin encapsulated liposome and liposome, can be separated by methods such as gel filtration or ultracentrifugation.

【0017】リポソームに封入されたヒトカルシトニンは、ヒトカルシトニン単独では凝集してしまうような中性あるいはアルカリ性の溶液中でも安定に保存されるため、中性あるいはアルカリ性に調節した水溶液中に分散することができる。 [0017] Human calcitonin encapsulated in a liposome, because the human calcitonin alone is stably stored even neutral or alkaline solutions such as tend to aggregate, to be dispersed in an aqueous solution adjusted to neutral or alkaline it can.

【0018】このリポソーム製剤中には、中性あるいはアルカリ性を調節する成分の他に、必要に応じて製剤学的に許容できる添加物、例えば、塩化ナトリウム、ブドウ糖などの等張化剤、塩化ベンゼトニウム、塩化ベンザルコニウムなどの防腐剤などを配合することができる。 [0018] In this liposomal formulation, to the other components that adjust the neutral or alkaline, pharmaceutically acceptable additives as needed, for example, sodium chloride, isotonic agents such as glucose, benzethonium chloride , it can be blended such as preservatives, such as benzalkonium chloride.
本発明のヒトカルシトニン封入リポソーム製剤は、皮下投与、筋肉内投与用などの注射製剤や、直腸投与、点鼻投与用などの非経口製剤や、経口製剤などに用いることができる。 Human calcitonin-encapsulated liposome preparation of the present invention, subcutaneous administration, or injection preparations such as for intramuscular administration, rectal administration, or parenteral formulations, such as for nasal administration can be used such as the oral formulations.

【0019】製剤中のヒトカルシトニン濃度は、投与経路および投与回数によって異なるが、0.01乃至10 mg/mL [0019] Human calcitonin concentration in the formulation varies depending upon the route of administration and frequency of administration, 0.01 to 10 mg / mL
とするのが好適である。 It is preferable to the.

【0020】 [0020]

【実施例】以下、実験例及び比較例によって本発明をさらに詳細に説明する。 EXAMPLES Hereinafter, a more detailed description of the experimental examples and comparative examples present invention. 実施例1モル比4/1/5のジミリストイルホスファチジルコリン(DM Dimyristoyl phosphatidylcholine Example 1 molar ratio 4/1/5 (DM
PC、日本油脂(株)製)/ジミリストイルホスファチジルグリセロール(DMPG、日本油脂(株)製)/コレステロール(Chol、東京化成(株)製)からなる脂質混合物80mg PC, manufactured by NOF Corp.) / dimyristoyl phosphatidyl glycerol (DMPG, manufactured by NOF Corporation) / cholesterol lipid mixture consisting of (Chol, Tokyo Kasei Co., Ltd.) 80 mg
を、ナスフラスコ中にて10 mLのクロロホルムで溶解し、ロータリーエバポレーターにて溶媒を留去して薄膜を調製した。 It was dissolved in 10 mL of chloroform at in an eggplant-shaped flask, to prepare a thin film by removing the solvent by a rotary evaporator. そこに3 mg/mL ヒトカルシトニン(ペプチド研究所(株)製)を溶解させた0.001 N塩酸を1 mL加え脂質を水和させた。 The 3 mg / mL 0.001 N hydrochloric acid was dissolved human calcitonin (manufactured by Peptide Institute Inc.) was hydrated 1 mL added lipids therein. その後プローブ型ソニケーター処理によりリポソームを形成させたのち、液体窒素による凍結、40 oC水浴による解凍を3回繰り返し、ヒトカルシトニン封入リポソームを調製した。 After allowed then form liposomes by the probe type sonicator process, frozen with liquid nitrogen, repeated 3 times thaw by 40 oC water bath, to prepare human calcitonin-containing liposome.

【0021】上記の方法で得られたカルシトニン封入リポソーム分散液を超遠心処理(140,000g ( 20 min)し、 [0021] The calcitonin-containing liposome dispersion obtained by the above method and ultracentrifugation (140,000g (20 min),
リポソームを沈降させ未封入のヒトカルシトニンと分離した。 Separated from the unencapsulated human calcitonin precipitated liposomes. リポソーム画分および上澄中のヒトカルシトニンを定量したところ、ヒトカルシトニンのリポソームへの封入率は99%であった。 Quantitative determination of human calcitonin liposome fraction and in supernatant, encapsulation ratio in liposomes of human calcitonin was 99%.

【0022】リポソーム中のヒトカルシトニンの定量法は、以下の通りである。 [0022] The method for the determination of human calcitonin in the liposome is as follows.

【0023】リポソームを含む分散液100μLに9mg/mL N [0023] dispersion 100μL containing liposomes 9 mg / mL N
aClを含む0.01N塩酸900μLを加え、2mLのクロロホルム/ It added 0.01N hydrochloric acid 900μL containing NaCl, 2 mL of chloroform /
メタノール(1/1)を加え振とうし脂質を溶解させた。 Shi shaking added methanol (1/1) was dissolved lipids. その後遠心し水相と有機溶媒相を分離させ、水相中のヒトカルシトニンを以下に示す条件でHPLC定量した。 Then centrifuged to separate the aqueous phase and organic solvent phase, the human calcitonin in the aqueous phase was determined by HPLC under the following conditions. カラム:ODP-50 6D(昭和電工(株)製) サイズ:内径 6.0 mm、長さ 150 mm 移動相:蒸留水/アセトニトリル/トリフルオロ酢酸(70/3 Column: ODP-50 6D (manufactured by Showa Denko KK) Size: inner diameter 6.0 mm, 150 mm length Mobile phase: distilled water / acetonitrile / trifluoroacetic acid (70/3
0/0.05) 検出波長:225 nm 流速:1.5 mL/min 保持時間:約6.1min 実施例2モル比2/1/3のDMPC/DMPG/Cholからなるヒトカルシトニン封入リポソームを実施例1と同じ方法で調製したところ、封入率は99%であった。 0 / 0.05) Detection wavelength: 225 nm flow rate: 1.5 mL / min Retention time: about 6.1min Example 2 molar ratio 2/1/3 DMPC / DMPG / same way human calcitonin-containing liposome of Example 1 consisting of Chol in was prepared, encapsulation efficiency was 99%. 実施例3モル比1/2/3のDMPC/DMPG/Cholからなるヒトカルシトニン封入リポソームを実施例1と同じ方法で調製したところ、封入率は100%であった。 Was prepared human calcitonin encapsulated liposomes composed of DMPC / DMPG / Chol Example 3 molar ratio 1/2/3 in the same manner as in Example 1, encapsulation rate was 100%. 実施例4モル比4/1/5のDMPC/ジセチルホスフェート(DP、シグマ社製)/Cholからなるヒトカルシトニン封入リポソームを実施例1と同じ方法で調製したところ、封入率は96% DMPC / dicetyl phosphate of Example 4 molar ratio 4/1/5 (DP, Sigma) was human calcitonin encapsulated liposomes composed of / Chol were prepared in the same manner as in Example 1, encapsulation rate 96%
であった。 Met. 実施例5モル比4/1/5のDMPC/ホスファチジルイノシトール(PI、 DMPC / phosphatidylinositol (PI Example 5 molar ratio 4/1/5,
シグマ社製)/Cholからなるヒトカルシトニン封入リポソームを実施例1と同じ方法で調製したところ、封入率は100%であった。 Was human calcitonin encapsulated liposomes composed of Sigma) / Chol were prepared in the same manner as in Example 1, encapsulation rate was 100%. 実施例6モル比4/1/5のDMPC/DMPG/Cholからなるヒトカルシトニン封入リポソームを実施例1と同じ方法で調製し、超遠心処理しリポソームを沈降させ、上澄を防腐剤として Human calcitonin encapsulated liposomes composed of DMPC / DMPG / Chol Example 6 molar ratio 4/1/5 was prepared in the same manner as in Example 1, ultracentrifugation and to precipitate the liposomes, the supernatant as a preservative
0.1 mg/mL塩化ベンゼトニウムを含む50 mMクエン酸緩衝液(pH6)または50 mMホウ酸緩衝液(pH9)に置換しリポソームを再分散させた。 It was redispersed substituted liposomes 50 mM citrate buffer containing 0.1 mg / mL benzethonium chloride (pH 6) or 50 mM borate buffer (pH 9).

【0024】このヒトカルシトニン封入リポソーム分散液を25 oC恒温室内に経時保存し、一定期間後、リポソーム分散液中の残存ヒトカルシトニンを定量したところ、リポソームに封入したヒトカルシトニンは2週間後p [0024] The human calcitonin encapsulated liposome dispersion was stored over time in 25 oC thermostatic chamber, after a certain period of time, was quantified the residual human calcitonin liposome dispersion, human calcitonin encapsulated in the liposomes after 2 weeks p
H6では約80%、pH9では約100%残存した。 In H6 about 80%, remained in pH9 about 100%.

【0025】リポソーム分散液中のヒトカルシトニンの定量法は、以下の通りである。 [0025] The method for the determination of human calcitonin of liposomal dispersion, are as follows.

【0026】リポソーム分散液を生理食塩水で適宜希釈して、1%ポリエチレングリコールモノオクチルフェニルエーテル(東京化成(株)製)でリポソームを破壊した。 [0026] The liposome dispersion was appropriately diluted with saline, and disrupted liposomes with 1% polyethylene glycol mono octyl phenyl ether (manufactured by Tokyo Kasei Co.). 孔径0.2μmのフィルター(ミリポアディメクス13、 Having a pore size of 0.2μm filter (Millipore di Mex 13,
ミリポア社製)にて濾過しヒトカルシトニン凝集体を除いた後、実施例1に示したHPLC条件でヒトカルシトニンを定量した。 After removing the filtered human calcitonin aggregates at Millipore) and quantified human calcitonin by HPLC conditions described in Example 1. 比較例1 DMPCのみからなるヒトカルシトニン封入リポソームを実施例1と同じ方法で調製したところ、ヒトカルシトニンはリポソームに封入されなかった。 Human calcitonin encapsulated liposomes composed of only Comparative Example 1 DMPC was prepared in the same manner as in Example 1, human calcitonin was encapsulated in liposomes. 比較例2モル比1/1のDMPC/Cholからなるヒトカルシトニン封入リポソームを実施例1と同じ方法で調製したところ、封入率は実施例1に比べ低い16%であった。 When a human calcitonin encapsulated liposomes composed of DMPC / Chol of Comparative Example 2 molar ratio of 1/1 was prepared in the same manner as in Example 1, encapsulation rate was 16% lower than in Example 1. 比較例3モル比で4/1のDMPC/DMPGからなるヒトカルシトニン封入リポソームを、実施例1と同じ方法で調製したところ、 When a human calcitonin encapsulated liposomes in Comparative Example 3 molar ratio consists 4/1 of DMPC / DMPG, were prepared in the same manner as in Example 1,
封入率は実施例1に比べ低い77%であった。 Encapsulation efficiency was 77% lower than in Example 1. 比較例4リポソームに封入していないヒトカルシトニンの中性、 Neutral human calcitonin which is not enclosed in Comparative Example 4 Liposomes,
アルカリ性条件下での保存安定性を実施例6に示した方法で調べたところ、ヒトカルシトニンはpH6では6日後に約10%に減少し、pH9では1日後に約10%に減少した。 Was examined by the method shown the storage stability in alkaline conditions in Example 6, human calcitonin is reduced to approximately 10% after 6 days at pH 6, it was reduced about 10% after 1 day in pH 9. これは、リポソームに封入されたヒトカルシトニンに比べ低い安定性であった。 This was less stable than human calcitonin encapsulated in liposomes. 比較例5リポソームに封入していないヒトカルシトニンに、実施例4と同じ脂質組成のヒトカルシトニンを封入していない空リポソームを加えた分散液について、実施例6に示した方法で、中性、アルカリ性条件下での保存安定性を調べたところ、リポソーム外のヒトカルシトニンはpH6 Human calcitonin which is not enclosed in Comparative Example 5 Liposome, the dispersion liquid obtained by adding the empty liposomes without encapsulated human calcitonin having the same lipid composition as Example 4, by the method shown in Example 6, a neutral, alkaline Examination of the storage stability under the conditions, human calcitonin outside the liposomes pH6
では6日後に約30%に減少し、pH9では1日後に約10%に減少した。 In decreased to approximately 30% after 6 days, it decreased to about 10% after 1 day in pH 9. これは、リポソームに封入されたヒトカルシトニンに比べ低い安定性であった。 This was less stable than human calcitonin encapsulated in liposomes.

【0027】 [0027]

【発明の効果】以上の通り、本発明のヒトカルシトニンのリポソーム製剤は、高い封入率を有し、中性またはアルカリ性条件下でのヒトカルシトニンの保存安定性を向上させる効果を持つ。 As described above, according to the present invention, liposomal formulations of human calcitonin of the present invention has a high encapsulation rate has the effect of improving the storage stability of human calcitonin in neutral or alkaline conditions.

───────────────────────────────────────────────────── フロントページの続き Fターム(参考) 4C076 AA19 CC30 DD63 DD70 FF63 FF70 GG50 4C084 CA18 DB31 MA24 NA03 NA05 ZA311 ZA312 ZA971 ZA972 ZB221 ZB222 ZC031 ZC032 ────────────────────────────────────────────────── ─── front page of continued F-term (reference) 4C076 AA19 CC30 DD63 DD70 FF63 FF70 GG50 4C084 CA18 DB31 MA24 NA03 NA05 ZA311 ZA312 ZA971 ZA972 ZB221 ZB222 ZC031 ZC032

Claims (4)

    【特許請求の範囲】 [The claims]
  1. 【請求項1】ヒトカルシトニンを含有するリポソームをp The method according to claim 1 Liposomes containing human calcitonin p
    H5以上10以下の水溶液に分散したリポソーム製剤。 Dispersed liposomal formulation to an aqueous solution of H5 to 10.
  2. 【請求項2】5乃至35モル%の負電荷を有する脂質および4 Wherein 5 to lipids and 4 having a 35 mole percent negative charge
    0乃至60モル%のコレステロールを構成成分とすることを特徴とする請求項1記載のリポソーム製剤。 0 to liposome preparation according to claim 1, characterized in that the component 60 mol% cholesterol.
  3. 【請求項3】リポソーム製造工程において凍結融解処理を行うことにより得られる請求項2記載のリポソーム製剤。 3. A liposomal formulation of claim 2, wherein the obtained by performing the freeze-thaw process in liposome manufacturing process.
  4. 【請求項4】負電荷を有する脂質が、ホスファチジルグリセロール、ホスファチジルセリン、ホスファチジルイノシトール、ホスファチジン酸、カルジオリピン及びジセチルリン酸からなる群より選択される1種又は2種以上の脂質であることを特徴とする、請求項2又は3記載のリポソーム製剤。 Lipid having wherein negative charges, characterized in that phosphatidyl glycerol, phosphatidyl serine, phosphatidyl inositol, phosphatidic acid, one or more lipids selected from the group consisting of cardiolipin and dicetyl phosphate , claim 2 or 3 liposomal formulation according.
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