JPS63174928A - Pharmaceutical for injection - Google Patents
Pharmaceutical for injectionInfo
- Publication number
- JPS63174928A JPS63174928A JP686987A JP686987A JPS63174928A JP S63174928 A JPS63174928 A JP S63174928A JP 686987 A JP686987 A JP 686987A JP 686987 A JP686987 A JP 686987A JP S63174928 A JPS63174928 A JP S63174928A
- Authority
- JP
- Japan
- Prior art keywords
- aspoxicillin
- trihydrate
- injection
- pharmaceutical
- basic substance
- 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.)
- Granted
Links
- 238000002347 injection Methods 0.000 title abstract description 17
- 239000007924 injection Substances 0.000 title abstract description 17
- 150000004684 trihydrates Chemical class 0.000 claims abstract description 23
- 239000000126 substance Substances 0.000 claims abstract description 18
- 238000002360 preparation method Methods 0.000 claims description 23
- 239000013078 crystal Substances 0.000 abstract description 10
- 239000000243 solution Substances 0.000 abstract description 10
- 239000000843 powder Substances 0.000 abstract description 6
- 241000894006 Bacteria Species 0.000 abstract description 2
- 230000002378 acidificating effect Effects 0.000 abstract description 2
- 239000003125 aqueous solvent Substances 0.000 abstract description 2
- 238000007796 conventional method Methods 0.000 abstract description 2
- 150000003839 salts Chemical class 0.000 abstract description 2
- BHELIUBJHYAEDK-OAIUPTLZSA-N Aspoxicillin Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3[C@H](C(C)(C)S[C@@H]32)C(O)=O)=O)NC(=O)[C@H](N)CC(=O)NC)=CC=C(O)C=C1 BHELIUBJHYAEDK-OAIUPTLZSA-N 0.000 abstract 6
- 229960000202 aspoxicillin Drugs 0.000 abstract 6
- 230000000845 anti-microbial effect Effects 0.000 abstract 2
- 230000001747 exhibiting effect Effects 0.000 abstract 2
- 238000002156 mixing Methods 0.000 abstract 1
- 238000004321 preservation Methods 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- 150000008064 anhydrides Chemical class 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 239000007972 injectable composition Substances 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 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
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
Abstract
Description
【発明の詳細な説明】 〔技術分野〕 本発明は注射用製剤に関する。[Detailed description of the invention] 〔Technical field〕 The present invention relates to injectable formulations.
アスボキシシリン〔化学名： （２Ｓ、ＳＲ，６Ｒ）
−６−（（２Ｒ） −２−（（２Ｒ） −２−アミノ−
３−（Ｎ−メチルカルバモイル）プロピオンアミド）−
２−（ｐ−ヒドロキシフェニル）アセタミド）−３，３
−ジメチル−７−オキソ−４−チア−１−アザビシクロ
（３，２，０）へブタン−２−カルボン酸〕はダラム陽
性菌及び陰性菌のいずれに対しても強い抗菌活性を有す
る優れた医薬化合物であり（特公昭５４−４３５１９号
）、粗製のアスポキシシリン含有水溶液を非極性多孔質
吸着樹脂で精製後凍結乾燥すれば、高純度の粉末として
得られることが知られている（特開昭５６−４０６８６
号）。Asboxicillin [Chemical name: (2S, SR, 6R)
-6-((2R) -2-((2R) -2-amino-
3-(N-methylcarbamoyl)propionamide)-
2-(p-hydroxyphenyl)acetamide)-3,3
-Dimethyl-7-oxo-4-thia-1-azabicyclo(3,2,0)hebutane-2-carboxylic acid] is an excellent drug that has strong antibacterial activity against both Durham-positive and -negative bacteria. It is known that a highly pure powder can be obtained by purifying a crude aqueous solution containing aspoxycillin with a non-polar porous adsorption resin and then freeze-drying it (Japanese Patent Publication No. 54-43519). -40686
issue).
しかし、上記特開昭５６−４０６８６号記載の方法で得
られるアスポキシシリンは無晶形無水物であり、吸湿性
を有し、防湿、遮光等を施さない条件下では保存時に十
分安定とは言い難いものであった。However, aspoxycillin obtained by the method described in JP-A No. 56-40686 is an amorphous anhydride, has hygroscopic properties, and is not sufficiently stable during storage without moisture protection or light shielding. Met.
またこのアスポキシシリンは水溶液から弱酸性下に晶析
させれば経時安定性にすぐれ、結晶の嵩密度が小さく、
帯電性も少ないなど医薬製剤原料として極めて優れた特
性を有する新規３水和物結晶として得られる（特願昭６
１−２２６４２３号）が、このアスポキシシリン・３水
和物は水に対する溶解度が小さく （２，８ｇ／１００
−水、０℃）、そのままでは注射用製剤として用い難い
。すなわち、注射用製剤においては保存安定性の面から
保存時は固体とし、投与時に溶液とすることが望ましい
が、アス゛ボキシシリン・３水和物は前述の如く溶解度
が小さくこのままで患者に投与しようとすれば多量の溶
媒を必要とすることとなり、投与に長時間を要したり、
或いは被投与患者に必要以上の負担を与えることが避け
られない。In addition, this aspoxycillin has excellent stability over time when crystallized from an aqueous solution under mild acidity, and the bulk density of the crystals is small.
It is obtained as a new trihydrate crystal that has extremely excellent properties as a raw material for pharmaceutical preparations, such as low chargeability (patent application filed in 1983).
1-226423), but this aspoxycillin trihydrate has low solubility in water (2.8 g/100
- water, 0°C), it is difficult to use it as an injection preparation as it is. In other words, from the standpoint of storage stability, it is desirable for injectable preparations to be in a solid state during storage and in a solution form during administration, but asiboxicillin trihydrate has low solubility as mentioned above, making it difficult to administer it to patients as is. If the drug requires a large amount of solvent, administration may take a long time,
Alternatively, it is unavoidable to place an unnecessary burden on the recipient patient.
本発明はアスボキシシリン・３水和物と薬理的に許容し
得る塩基性物質を含有する注射用製剤に関する。上記製
剤は水に対する低溶解度のゆえに注射用製剤として利用
し難かったアスボキシシリン・３水和物を注射用製剤と
して利用し得ることに成功したものであって、例えばア
スポキシシリン・３水和物１モルに対し塩基性物質を約
０．４〜１モル用いるときはアスボキシシリンを約５〜
３０Ｗ／Ｖχ含有する溶液を容易に調製することができ
る。また塩基性物質量を適宜調節することによって所望
量のアスポキシシリンを含有する溶液とすることができ
るという優れた特徴を有する。The present invention relates to an injectable preparation containing asboxicillin trihydrate and a pharmacologically acceptable basic substance. The above formulation has succeeded in using asboxycillin trihydrate, which was difficult to use as an injectable formulation due to its low solubility in water, as an injectable formulation. On the other hand, when using about 0.4 to 1 mole of a basic substance, about 5 to 1 mole of asboxycillin is used.
A solution containing 30 W/Vχ can be easily prepared. Furthermore, it has the excellent feature that a solution containing a desired amount of aspoxycillin can be obtained by appropriately adjusting the amount of basic substance.
本発明の注射用製剤においてアスボキシシリン・３水和
物と共に用いられる薬理的に許容し得る塩基性物質（以
下、単に塩基性物質と云う）としては、例えば炭酸カリ
ウム、炭酸ナトリウムなどの炭酸アルカリ金属塩、リジ
ン、アルギニン、オルニチンなどの塩基性アミノ酸、ト
リスヒドロキシメチルアミノメタンなどがあげられる。Examples of the pharmacologically acceptable basic substances (hereinafter simply referred to as basic substances) used together with asboxicillin trihydrate in the injectable preparation of the present invention include alkali metal carbonates such as potassium carbonate and sodium carbonate. , basic amino acids such as lysine, arginine, ornithine, and trishydroxymethylaminomethane.
本発明の注射用製剤においてアスボキシシリン・３水和
物と塩基性物質の比率は、アスボキシシリン・３水和物
１モルに対し塩基性物質が約０．４〜１モル、とりわけ
約０．６〜０．９モルであるのが好ましく、約０．７〜
０．９モルであるのが最も好ましい。In the injectable preparation of the present invention, the ratio of asboxicillin trihydrate to basic substance is about 0.4 to 1 mol, particularly about 0.6 to 0. .9 mol is preferred, and about 0.7 to .9 mol.
Most preferably it is 0.9 mole.
本発明の注射用製剤はアスボキシシリン・３水和物およ
び塩基性物質をそれぞれ結晶ないし粉末状で一緒に製剤
化して単一製剤としたものであってもよく、またアスボ
キシシリン・３水和物および塩基性物質をそれぞれ別個
に製剤化したユニット製剤であってもよい。The injectable preparation of the present invention may be a single preparation by formulating asboxicillin trihydrate and a basic substance together in crystal or powder form, or asboxicillin trihydrate and a basic substance. It may also be a unit preparation in which each substance is formulated separately.
これらの製剤は常法により製することができ、例えば単
一製剤の場合はアスボキシシリン・３水和物および塩基
性物質をそれぞれ結晶又は粉末で混合し、この混合物を
バイアル等に充填し締栓することにより単一製剤とする
ことが出来る。またユニット製剤の場合は、アスポキシ
シリン・３水和物および塩基性物質をそれぞれ結晶また
は粉末でそれぞれ別個にバイアル等に充填するか或いは
アスボキシシリン・３水和物は結晶または粉末としてバ
イアル等に充填し、塩基性物質は水溶液としてバイアル
等に充填し、ついで締栓して各成分の製剤を一組とする
ことによりユニット製剤とすることが出来る。These preparations can be manufactured by conventional methods; for example, in the case of a single preparation, asboxicillin trihydrate and a basic substance are mixed in the form of crystals or powder, and this mixture is filled into a vial, etc., and the cap is closed. This allows for a single preparation. In the case of a unit preparation, aspoxycillin trihydrate and the basic substance are each filled as crystals or powder into vials separately, or aspoxycillin trihydrate is filled as crystals or powder into vials, etc. A basic substance can be made into a unit preparation by filling a vial or the like as an aqueous solution and then sealing the vial to form a set of preparations for each component.
かくして得られる本発明の注射用製剤は、前記の通り速
やかに溶解して高濃度のアスボキシシリン溶液となり、
また塩基性物質量を適宜調節することによって所望量の
アスボキシシリンを含有する溶液とすることができ、し
かも良好な保存安定性を有するという優れた特徴を存す
る。The injectable preparation of the present invention thus obtained dissolves rapidly to form a highly concentrated asboxicillin solution as described above,
Further, by appropriately adjusting the amount of basic substance, a solution containing a desired amount of asboxycillin can be obtained, and it has excellent characteristics such as good storage stability.
なお、アスボキシシリン・３水和物結晶は例えばアスポ
キシシリン又はその塩を水性溶媒（水、含水低級アルカ
ノール、含水低級アルカノン等）から弱酸性条件下（ｐ
Ｈ３〜６）で晶析させることにより製することができる
。In addition, asboxycillin trihydrate crystals can be obtained by, for example, aspoxycillin or a salt thereof in an aqueous solvent (water, water-containing lower alkanol, water-containing lower alkanone, etc.) under weakly acidic conditions (p
It can be produced by crystallizing with H3-6).
以下、本発明を実施例により更に詳細に説明する。Hereinafter, the present invention will be explained in more detail with reference to Examples.
実施例１
アスボキシシリン・３水和物をアスボキシシリン無水物
に換算して１００重量部と炭酸ナトリウム１７重量部（
アスボキシシリンに対し０．７９モル比）を混合し、こ
の混合物を１バイアル当たりアスボキシシリン無水物に
換算して１ｇとなるように１０１１１１のバイアルに充
填し、締栓することにより注射用製剤を得る。Example 1 100 parts by weight of asboxycillin trihydrate and 17 parts by weight of sodium carbonate (converted to asboxycillin anhydride)
(0.79 molar ratio to asboxicillin), and this mixture is filled into 101111 vials so that each vial contains 1 g in terms of asboxicillin anhydride, and the injection preparations are obtained by sealing the vials.
この注射用製剤に注射用蒸溜水５ ｍｌを加えたときバ
イアルの内容物はすみやかに溶解し、２０Ｗ／Ｖ％のア
スボキシシリンを含有する澄明な注射液（ｐＨ約７．５
）となる。When 5 ml of distilled water for injection was added to this injection preparation, the contents of the vial were rapidly dissolved, resulting in a clear injection solution (pH approximately 7.5) containing 20 W/V% asboxicilin.
).
実施例２
アスポキシシリン・３水和物をアスポキシシリン無水物
に換算して１００重量部とアルギニン２１゜３重量部（
アスボキシシリンに対し０．６モル比）を混合し、この
混合物を１バイアル当たりアスボキシシリン無水物に換
算して１ｇとなるように２５ｍ１のバイアルに充填し、
締栓することにより注肘用製剤を得る。Example 2 100 parts by weight of aspoxycillin trihydrate converted to aspoxycillin anhydride and 21°3 parts by weight of arginine (
0.6 molar ratio to asboxycillin), and this mixture was filled into 25 ml vials so that each vial contained 1 g in terms of asboxycillin anhydride.
A preparation for elbow injection is obtained by tightening the stopper.
この注射用製剤に注射用蒸溜水２９ｍ１を加えたときバ
イアルの内容物はすみやかに溶解し、５−／Ｖ％のアス
ボキシシリンを含有する澄明な注射液（ｐＨ約７．０）
となる。When 29 ml of distilled water for injection was added to this injection preparation, the contents of the vial were rapidly dissolved, resulting in a clear injection solution containing 5-/V% asboxicillin (pH approximately 7.0).
becomes.
実施例３
アスポキシシリン・３水和物をアスポキシシリン無水物
としてＩｇ、炭酸ナトリウム１９３ｍｇをそれぞれ別個
の１０ ｍｌバイアルに充填し、締栓することにより注
射用製剤を得る。Example 3 Aspoxycillin trihydrate is used as aspoxycillin anhydride, Ig and 193 mg of sodium carbonate are filled into separate 10 ml vials, and the vials are capped to obtain an injectable preparation.
炭酸ナトリウムのバイアルに注射用蒸溜水５ｍｌを加え
て炭酸ナトリウム水溶液を得、この水溶液をアスボキシ
シリン・３水和物のバイアルに加えたとき、アスポキシ
シリン・３水和物はすみやかに溶解し、２０Ｗ／Ｖ％の
アスボキシシリンを含有する澄明な注射液（ｐＨ約７．
６）となる。5 ml of distilled water for injection was added to a vial of sodium carbonate to obtain an aqueous sodium carbonate solution, and when this aqueous solution was added to a vial of asboxycillin trihydrate, aspoxycillin trihydrate was rapidly dissolved and the concentration was 20 W/V. % asboxicilin (pH approximately 7.0%).
6).
実施例４〜５
実施例１において炭酸ナトリウム１７重量部にかえて、
下記表に示す量の塩基性物質を用い、以下実施例１と同
様に実施することによりアスボキシシリンの注射用製剤
を得る。Examples 4-5 In Example 1, instead of 17 parts by weight of sodium carbonate,
An injectable preparation of asboxicillin is obtained by carrying out the following procedure in the same manner as in Example 1 using the basic substance in the amount shown in the table below.
これらの注射用製剤に注射用蒸溜水５ ｍｌを加えたと
きバイアルの内容物はすみやかに溶解し、同表に示す濃
度のアスボキシシリンを含有する澄明な注射液となる。When 5 ml of distilled water for injection was added to these injection preparations, the contents of the vial were rapidly dissolved to form a clear injection solution containing asboxicillin at the concentration shown in the table.
表
参考例
アスボキシシリンの無晶形無水物１０ｇに水５０ ｍ
ｌを加え、４０℃に加温し溶解後希塩酸でｐＨ４，０に
調整する。３０℃１時間ＰＡ拌後５°Ｃ迄冷却し析出す
る結晶を濾過、水洗後乾燥することにより、白色のアス
ボキシシリン・３水和物８ｇを得る。Table reference example 10 g of amorphous anhydride of asboxicillin and 50 m of water
1, heated to 40°C, dissolved, and adjusted to pH 4.0 with dilute hydrochloric acid. After stirring under PA at 30°C for 1 hour, the mixture was cooled to 5°C, and the precipitated crystals were filtered, washed with water, and dried to obtain 8 g of white asboxycillin trihydrate.
水分値（ＫＦ）１０．０５％（３モル相当）含量（ＨＰ
ＬＣ）９９．７％
旋光度（α） ＝＋ １７９． ５ ’（Ｃ＝１．０．
水）粉末Ｘ線回折パターンMoisture value (KF) 10.05% (equivalent to 3 moles) Content (HP
LC) 99.7% Optical rotation (α) = + 179. 5' (C=1.0.
Water) Powder X-ray diffraction pattern
Claims (1)
性物質とからなる注射用製剤。An injectable preparation consisting of aspoxycillin trihydrate and a pharmacologically acceptable basic substance.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP686987A JPS63174928A (en) | 1987-01-14 | 1987-01-14 | Pharmaceutical for injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP686987A JPS63174928A (en) | 1987-01-14 | 1987-01-14 | Pharmaceutical for injection |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63174928A true JPS63174928A (en) | 1988-07-19 |
| JPH053848B2 JPH053848B2 (en) | 1993-01-18 |
Family
ID=11650239
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP686987A Granted JPS63174928A (en) | 1987-01-14 | 1987-01-14 | Pharmaceutical for injection |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63174928A (en) |
-
1987
- 1987-01-14 JP JP686987A patent/JPS63174928A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPH053848B2 (en) | 1993-01-18 |
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