JP2739482B2 - Method for producing stable calcitonin injection - Google Patents
Method for producing stable calcitonin injectionInfo
- Publication number
- JP2739482B2 JP2739482B2 JP63201750A JP20175088A JP2739482B2 JP 2739482 B2 JP2739482 B2 JP 2739482B2 JP 63201750 A JP63201750 A JP 63201750A JP 20175088 A JP20175088 A JP 20175088A JP 2739482 B2 JP2739482 B2 JP 2739482B2
- Authority
- JP
- Japan
- Prior art keywords
- calcitonin
- injection
- producing stable
- lysine
- stable
- 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
Links
- 102000055006 Calcitonin Human genes 0.000 title claims description 14
- 108060001064 Calcitonin Proteins 0.000 title claims description 14
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 title claims description 14
- 229960004015 calcitonin Drugs 0.000 title claims description 14
- 238000002347 injection Methods 0.000 title claims description 14
- 239000007924 injection Substances 0.000 title claims description 14
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- 150000001413 amino acids Chemical class 0.000 claims description 4
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000004472 Lysine Substances 0.000 description 6
- 239000003708 ampul Substances 0.000 description 5
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 4
- 235000018977 lysine Nutrition 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- KSIYPKPZIBBUFR-LJNLPFSOSA-N CSCC[C@H](NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1)C(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(N)=O Chemical compound CSCC[C@H](NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1)C(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(N)=O KSIYPKPZIBBUFR-LJNLPFSOSA-N 0.000 description 3
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 3
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 3
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 229960003104 ornithine Drugs 0.000 description 3
- 235000019766 L-Lysine Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 210000001685 thyroid gland Anatomy 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 1
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 230000003913 calcium metabolism Effects 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940045662 porcine thyroid Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
【発明の詳細な説明】 「産業上の利用分野」 本発明は安定なカルシトニン注射液を製造する方法に
関するものである。The present invention relates to a method for producing a stable calcitonin injection solution.
カルシトニンは哺乳動物の甲状腺に存在するカルシウ
ム代謝に重要な役割をもつホルモンであり、高カルシウ
ム血症や骨粗しょう症の治療薬として広く利用されてい
る。Calcitonin is a hormone present in the thyroid gland of mammals and plays an important role in calcium metabolism, and is widely used as a therapeutic drug for hypercalcemia and osteoporosis.
「従来の技術」 カルシトニンは酸性水溶液中では比較的安定であるこ
とは知られているが、長期安定性を必要とする医薬品に
あっては凍結乾燥粉末として供せねばならない。注射薬
として用時溶解して用いねばならない。"Prior art" Calcitonin is known to be relatively stable in aqueous acidic solutions, but it must be provided as a lyophilized powder for pharmaceuticals requiring long-term stability. It must be dissolved as an injection before use.
「発明が解決しようとする課題」 注射薬として用いる時は溶解して用いねばならない。
また、注射残液についても冷暗所に保存するという煩ら
わしさがある 「課題を解決するための手段」 カルシトニンに、安定化剤として塩基性アミノ酸を加
えることにより上記のような不便さを解決し、医薬品と
して安全に使用しうる安定なカルシトニン注射液をうる
ことを目的とする。"Problem to be solved by the invention" When used as an injection, it must be dissolved before use.
In addition, there is the inconvenience of storing the injection residual solution in a cool and dark place. "Means for solving the problem" To solve the above inconvenience by adding a basic amino acid as a stabilizer to calcitonin. Another object of the present invention is to provide a stable calcitonin injection which can be safely used as a pharmaceutical.
本発明に用いるカルシトニンはブタ甲状腺より製した
もので、その製造方法、純度等の制限を受けるものでな
く現在医薬品として用いられている凍結乾燥品もこの対
象となる。The calcitonin used in the present invention is produced from porcine thyroid gland, and is not limited by the production method, purity, etc., and includes freeze-dried products currently used as pharmaceuticals.
ここに使用しうる塩基性アミノ酸としてはリジン、ア
ルギニン、ヒスチジン等が含まれるがリジン及びオルニ
チンの効果が特に大きく、その作用はＤ体、Ｌ体で変わ
らない。The basic amino acids that can be used here include lysine, arginine, histidine and the like, but the effects of lysine and ornithine are particularly large, and the effects are the same in the D-form and the L-form.
カルシトニン注射液中への添加量は0.5％以上の濃度
で安定性効果が現われるが実用上１〜２％が望ましい。Although the stability effect appears at a concentration of 0.5% or more in the calcitonin injection solution, 1-2% is desirable in practical use.
「作用」 以下にアミノ酸、糖類、その他化合物のカルシトニン
注射液に対する安定化作用を実験例によって示す。"Effects" The stabilizing effects of amino acids, saccharides and other compounds on calcitonin injection are shown below by experimental examples.
実験例 種々の安定化剤とブタカルシトニン（40国際単位/m
l）を含む溶液を１規定塩酸でpH3.5にしたのち、無菌ろ
過して5mlアンプルに1mlずつ分注したのち、熔閉した。
室温放置における経時的残存活性を測定すると表１の如
くになる。なお測定方法は英国薬局方に従って行なっ
た。Experimental example Various stabilizers and porcine calcitonin (40 international units / m
The solution containing l) was adjusted to pH 3.5 with 1N hydrochloric acid, sterile-filtered, dispensed in 1 ml portions into 5 ml ampules, and then sealed.
Table 1 shows the residual activity over time at room temperature. The measurement was performed according to the British Pharmacopoeia.
表１から明らかなようにリジンとオルニチンのみが12
ケ月後にも活性の低下が認められなかった。 As is clear from Table 1, only lysine and ornithine contained 12
No activity decrease was observed even after months.
実験例に示す如く、カルシトニン注射液中に特にリジ
ン及びオルニチンを添加することによって１年以上安定
に保つことができることが理解されるが、医薬品添加物
として用いることを考慮するとＬ−リジンの使用が最も
適切と思われる。As shown in the experimental examples, it is understood that the addition of lysine and ornithine in the calcitonin injection solution can keep the stability more than one year. However, considering the use as a pharmaceutical additive, the use of L-lysine is not considered. Seems most appropriate.
「実施例」 実施例１ Ｌ−リジン2gとブタカルシトニン4,000国際単位を含
む水溶液100mlを１規定塩酸でpH3.5とし、無菌ろ過す
る。ろ過後5mlアンプルに1mlずつ分注して熔閉する。"Examples" Example 1 100 ml of an aqueous solution containing 2 g of L-lysine and 4,000 international units of porcine calcitonin is adjusted to pH 3.5 with 1N hydrochloric acid and sterile filtered. After filtration, 1 ml is dispensed into 5 ml ampules and sealed.
実施例２ Ｄ−リジン5g、ベンジルアルコール1gとブタカルシト
ニン4,000国際単位を含む水溶液100mlを１規定塩酸でpH
3.5とし、無菌ろ過する。ろ過後5mlアンプルに1mlずつ
分注して熔閉する。Example 2 100 ml of an aqueous solution containing 5 g of D-lysine, 1 g of benzyl alcohol and 4,000 international units of porcine calcitonin was adjusted to pH with 1N hydrochloric acid.
Set to 3.5 and filter aseptically. After filtration, 1 ml is dispensed into 5 ml ampules and sealed.
「発明の効果」 本発明はこのようにして成るから、従来は凍結乾燥粉
末としたカルシトニンを注射剤として用時溶解して用い
ねばならなかったことや、注射残液を冷暗所に保存する
ことを要した不便さを解消し、アンプルに熔閉した安定
なカルシトニン注射液を用時にアンプルをカットして直
ちに注射できる。[Effects of the Invention] Since the present invention is constructed in this way, it is necessary to dissolve calcitonin, which was conventionally freeze-dried powder, as an injection before use, and to store the injection residual solution in a cool and dark place. The required inconvenience is eliminated, and the ampoule can be injected immediately after cutting the ampoule into a stable calcitonin injection solution that has been sealed.
Claims (1)
際し、塩基性アミノ酸を加えることを特徴とする安定な
カルシトニン注射液の製造方法1. A method for producing a stable calcitonin injection, which comprises adding a basic amino acid when preparing an injection containing calcitonin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63201750A JP2739482B2 (en) | 1988-08-11 | 1988-08-11 | Method for producing stable calcitonin injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63201750A JP2739482B2 (en) | 1988-08-11 | 1988-08-11 | Method for producing stable calcitonin injection |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0249735A JPH0249735A (en) | 1990-02-20 |
| JP2739482B2 true JP2739482B2 (en) | 1998-04-15 |
Family
ID=16446319
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63201750A Expired - Lifetime JP2739482B2 (en) | 1988-08-11 | 1988-08-11 | Method for producing stable calcitonin injection |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2739482B2 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0643339B2 (en) * | 1990-05-25 | 1994-06-08 | 旭化成工業株式会社 | Method for stabilizing calcitonin aqueous solution composition |
| JPH078807B2 (en) * | 1990-09-11 | 1995-02-01 | 旭化成工業株式会社 | Elcatonin composition |
| DE19538687A1 (en) * | 1995-10-17 | 1997-04-24 | Boehringer Mannheim Gmbh | Stable pharmaceutical dosage forms containing parathyroid hormone |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61118325A (en) * | 1984-11-12 | 1986-06-05 | Yamanouchi Pharmaceut Co Ltd | Calcitonin drug through nose containing basic and/or neutral amino acid |
-
1988
- 1988-08-11 JP JP63201750A patent/JP2739482B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0249735A (en) | 1990-02-20 |
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