JPH0466202B2 - - Google Patents
Info
- Publication number
- JPH0466202B2 JPH0466202B2 JP19026084A JP19026084A JPH0466202B2 JP H0466202 B2 JPH0466202 B2 JP H0466202B2 JP 19026084 A JP19026084 A JP 19026084A JP 19026084 A JP19026084 A JP 19026084A JP H0466202 B2 JPH0466202 B2 JP H0466202B2
- Authority
- JP
- Japan
- Prior art keywords
- aqueous solution
- concentration
- freeze
- temperature
- drug
- 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
Links
- 239000003814 drug Substances 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 20
- 239000007864 aqueous solution Substances 0.000 claims description 19
- 229940079593 drug Drugs 0.000 claims description 16
- 239000013078 crystal Substances 0.000 claims description 15
- 230000005496 eutectics Effects 0.000 claims description 14
- 238000004108 freeze drying Methods 0.000 claims description 6
- 238000001556 precipitation Methods 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 238000007710 freezing Methods 0.000 claims description 3
- 230000008014 freezing Effects 0.000 claims description 3
- 238000001035 drying Methods 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 7
- 238000007796 conventional method Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 229960003408 cefazolin sodium Drugs 0.000 description 4
- FLKYBGKDCCEQQM-WYUVZMMLSA-M cefazolin sodium Chemical compound [Na+].S1C(C)=NN=C1SCC1=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 FLKYBGKDCCEQQM-WYUVZMMLSA-M 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000002542 deteriorative effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012931 lyophilized formulation Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000003186 pharmaceutical solution Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
Landscapes
- Drying Of Solid Materials (AREA)
- Medicinal Preparation (AREA)
Description
【発明の詳細な説明】
産業上の利用分野：
この発明は、医薬品の凍結乾燥方法の改良に関
するものであり、注射剤等の凍結乾燥製剤の製造
に利用される。DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application: The present invention relates to an improvement in a method for freeze-drying pharmaceuticals, and is used in the production of freeze-dried preparations such as injections.
従来技術：
医薬品の凍結乾燥製剤は、異物の混入を回避で
きる点において品質的に優れた製剤であり、特に
注射剤の一剤型として多用されている。そして、
従来、この種の製剤は、水との共晶体析出濃度よ
り低い濃度の水溶液を凍結乾燥することにより製
造されていた。Prior Art: Freeze-dried pharmaceutical preparations are excellent quality preparations in that they can avoid contamination with foreign substances, and are often used particularly as single-dose forms of injections. and,
Conventionally, this type of preparation has been produced by freeze-drying an aqueous solution having a concentration lower than the eutectic precipitation concentration with water.
解決すべき問題点：
従来の凍結乾燥法では、水との共晶体析出濃度
より低い濃度の水溶液を冷却していたため、まず
氷が析出して水溶液中の医薬品の濃度が次第に高
められていた。そして、その濃度が水との共晶体
析出濃度に達すれば該共晶体が析出するものと考
えられるが、実際には凍結条件が動的な過程（非
平衡過程）であるため共晶体が析出せず、水溶液
は高濃度化され、ついには高粘度化されて、医薬
品の結晶が析出しないで溶液状態のまま固化され
て、いわゆるエントロピー凍結体が生成してい
た。この凍結体中の水分は昇華し難いため、乾燥
に長時間を要し効率的でなかつた。しかも、乾燥
を完全ならしめるためには、通常の乾燥工程に比
べてより高温でより低圧の過酷な条件を必要と
し、そのためゴム栓中の昇華性物質まで昇華され
て医薬品に付着し、凍結乾燥製剤の品質を低下さ
せるという問題もあつた。Problems to be solved: In the conventional freeze-drying method, an aqueous solution with a concentration lower than the eutectic precipitation concentration with water was cooled, so ice first precipitated and the concentration of the drug in the aqueous solution gradually increased. It is thought that the eutectic will precipitate when its concentration reaches the eutectic precipitation concentration with water, but in reality, the eutectic does not precipitate because the freezing conditions are a dynamic process (non-equilibrium process). First, the aqueous solution becomes highly concentrated, and eventually becomes highly viscous, and the drug crystals do not precipitate and solidify in the solution state, producing what is called an entropic frozen substance. Since the water in this frozen body is difficult to sublimate, drying takes a long time and is not efficient. Moreover, to ensure complete drying, harsh conditions such as higher temperatures and lower pressures are required compared to normal drying processes, and as a result, even the sublimable substances in the rubber stopper sublimate and adhere to the drug, resulting in freeze-drying. There was also the problem of deteriorating the quality of the preparation.
問題点を解決するための手段：
この発明の発明者らは、乾燥工程で昇華される
水分が共晶体中の氷や医薬品結晶中の結晶水であ
れば乾燥が容易である点に着目し、鋭意研究の結
果、この発明を完成した。Means for solving the problem: The inventors of the present invention focused on the fact that drying is easy if the water sublimed in the drying process is ice in the eutectic or crystal water in the pharmaceutical crystal. As a result of intensive research, this invention was completed.
すなわち、この発明の方法では従来技術とは逆
に、凍結されるべき水溶液の濃度が共晶体析出濃
度よりも高いため、これを冷却するとまず医薬品
の結晶が析出して水溶液の濃度が従来法とは逆に
順次低下し、共晶体析出濃度に達したところで共
晶体が確実に析出する。したがつて、凍結体の乾
燥が極めて容易となり、従来法に比べてより短時
間に、かつより緩和な条件下に乾燥することがで
きる。 That is, in the method of this invention, contrary to the prior art, the concentration of the aqueous solution to be frozen is higher than the eutectic precipitation concentration, so when it is cooled, the pharmaceutical crystals first precipitate, and the concentration of the aqueous solution is lower than that of the conventional method. On the contrary, it gradually decreases, and when the eutectic precipitation concentration is reached, the eutectic is reliably precipitated. Therefore, it becomes extremely easy to dry the frozen body, and it can be dried in a shorter time and under milder conditions than in conventional methods.
この発明の方法は、まず医薬品の水溶液を調製
することにより行われる。 The method of this invention is carried out by first preparing an aqueous solution of the drug.
この発明の方法において用いられる医薬品は、
温度差により水溶液から析出する性質を有するも
のであればよく、特に限定されないが、この発明
の方法により得られるのが凍結乾燥製剤であると
いう点を考慮すれば注射用医薬品であるのが通例
であり、殊に注射用抗生物質にこの発明の方法を
適用するのが最も効果的である。このような注射
用抗生物質としては、例えばセフアゾリンナトリ
ウム、セフテゾールナトリウム等が挙げられる。 The pharmaceuticals used in the method of this invention are:
It is not particularly limited as long as it has the property of being precipitated from an aqueous solution due to a temperature difference, but considering that the method of this invention is a freeze-dried preparation, it is usually an injectable drug. In particular, it is most effective to apply the method of the present invention to injectable antibiotics. Examples of such injectable antibiotics include cefazolin sodium and ceftesol sodium.
これらの医薬品を溶解すべき水としては、この
発明の方法により得られる凍結乾燥製剤が注射剤
である場合には、注射用蒸留水が用いられる。 Distilled water for injection is used as the water in which these pharmaceuticals are to be dissolved, when the freeze-dried preparation obtained by the method of the present invention is an injection.
そして、水溶液中の医薬品の濃度の上限は、室
温で該医薬品が析出する濃度より低いことが必要
である。なぜならば、水溶液中の医薬品の濃度が
この上限値を越えると、水溶液ではなくて懸濁液
となり、個々のバイアル中への医薬品の充填量に
バラツキが生ずるからである。 The upper limit of the concentration of the drug in the aqueous solution needs to be lower than the concentration at which the drug precipitates at room temperature. This is because if the concentration of the drug in the aqueous solution exceeds this upper limit, the solution becomes a suspension rather than an aqueous solution, resulting in variations in the amount of the drug filled into individual vials.
また、水溶液中の医薬品の濃度の下限は、該医
薬品と水との共晶体の析出濃度より高いことが必
要であり、その理由は前述したところより明らか
である。 Further, the lower limit of the concentration of the drug in the aqueous solution needs to be higher than the precipitated concentration of the eutectic of the drug and water, and the reason for this is clear from the above.
この発明の方法で用いられる医薬品の水溶液の
濃度は、上記の上限値と下限値の範囲内であれば
よいが、上限値に近い方が、凍結体から昇華させ
る水分量が少ないため、より好ましい。なお、上
記の上限濃度および下限濃度は個々の医薬品につ
いて常法によりそれぞれ求めることができる。 The concentration of the aqueous pharmaceutical solution used in the method of this invention may be within the range of the above upper and lower limits, but it is more preferable that it is closer to the upper limit because the amount of water sublimated from the frozen body is smaller. . In addition, the above-mentioned upper limit concentration and lower limit concentration can be determined for each drug by a conventional method.
このようにして調製された医薬品の水溶液は、
これを無菌過したのち、個々のバイアル中へ所
定量ずつ注入するのが好ましい。 The aqueous solution of pharmaceuticals prepared in this way is
After sterilization, it is preferable to inject predetermined amounts into individual vials.
医薬品の水溶液を充填したバイアルを、次いで
凍結乾燥機内に収容して氷点下まで冷却する。こ
の工程はいわゆる医薬品の晶析過程であり、医薬
品の結晶が析出すると共に、水の一部が氷結す
る。冷却温度は医薬品の種類によつても異なる
が、通常、約−10℃前後で充分である。 The vial filled with the aqueous solution of the drug is then placed in a freeze dryer and cooled to below freezing. This process is a so-called pharmaceutical crystallization process, in which pharmaceutical crystals are precipitated and a portion of the water freezes. The cooling temperature varies depending on the type of medicine, but usually around -10°C is sufficient.
冷却温度が目標点に達したならば、次いで氷が
融解し、かつ、結晶の一部が残存する温度すなわ
ち20℃付近まで昇温させ、その温度で維持する。
結晶の一部がバイアル底部に沈積したら、常法に
より−30℃付近まで冷却してバイアル中の内容物
を完全に凍結固化させる。この工程は、いわゆる
結晶成長と共晶体生成過程であり、最終的には医
薬品の結晶と氷から成る混合物が凍結体として得
られる。 Once the cooling temperature reaches the target point, the temperature is then raised to a temperature at which the ice melts and some of the crystals remain, that is, around 20°C, and maintained at that temperature.
Once a portion of the crystals have settled at the bottom of the vial, the contents in the vial are completely frozen and solidified by cooling to around -30°C using a conventional method. This process is a so-called crystal growth and eutectic formation process, and ultimately a frozen mixture of pharmaceutical crystals and ice is obtained.
このようにして得られる凍結体を次いで常法に
より加温、減圧下に乾燥する。この工程はいわゆ
る乾燥過程であり、共晶体中の氷が昇華させられ
ると共に、医薬品の結晶中に結晶水が含まれてい
る場合にはその結晶水も同時に昇華させられる。 The frozen product thus obtained is then heated and dried under reduced pressure in a conventional manner. This process is a so-called drying process, in which the ice in the eutectic is sublimated, and if crystal water of the drug is included, the crystal water is also sublimed at the same time.
乾燥工程が終了したならば、必要に応じてバイ
アル中の空気を窒素置換したのち密栓して、凍結
乾燥製剤が得られる。 When the drying process is completed, the air in the vial is replaced with nitrogen if necessary, and the vial is tightly capped to obtain a lyophilized preparation.
発明の作用効果：
この発明の方法によれば、昇華させられるべき
水分は、共晶体中の氷および医薬品の結晶中の結
晶水のみであり、従来法に比して容易に昇華させ
得るため、短時間で乾燥工程を終了することがで
き、効率的である。Effects of the invention: According to the method of the present invention, the only water to be sublimated is ice in the eutectic and crystal water in the pharmaceutical crystals, which can be sublimed more easily than in conventional methods. The drying process can be completed in a short time and is efficient.
その上、加温条件および減圧条件が従来法に比
べて緩和であるため、ゴム栓中の昇華性物質が昇
華して医薬品に付着するという品質面での陥も克
服される。 Furthermore, since the heating conditions and depressurization conditions are milder than those of conventional methods, the quality problem of sublimable substances in the rubber stopper sublimating and adhering to pharmaceuticals can also be overcome.
実施例：
次に、この発明の方法を実施例により具体的に
説明する。なお、実施例中の温度は凍結乾燥機内
の棚の温度を意味する。Examples: Next, the method of the present invention will be specifically explained using examples. In addition, the temperature in Examples means the temperature of the shelf in a freeze dryer.
実施例 １
セフアゾリンナトリウム（400ｇ力価）を注射
用蒸留水（1040ml）に溶解して、セフアゾリンナ
トリウムの28％水溶液を調製する。この水溶液を
3.3ml容量のバイアル400本に分注し、凍結乾燥機
内に収容する。次いで約１時間を要して−10℃付
近まで冷却したのち、約１時間を要して20℃付近
まで昇温させ、同温度で約１時間保持する。次い
で約２時間を要して−30℃付近まで冷却し、内容
物を凍結させたのち、約150mTorrの減圧下に約
３時間を要して13℃付近まで昇温させる。同温、
同圧下に約14時間乾燥を続けたのち、各バイアル
を密栓して、セフアゾリンナトリウム１ｇ力価を
含有する凍結乾燥製剤を得る。Example 1 A 28% aqueous solution of cefazolin sodium is prepared by dissolving cefazolin sodium (400 g strength) in distilled water for injection (1040 ml). This aqueous solution
Dispense into 400 vials with a capacity of 3.3 ml and store in a freeze dryer. Next, it takes about 1 hour to cool down to around -10°C, and then it takes about 1 hour to raise the temperature to around 20°C, and is maintained at the same temperature for about 1 hour. Next, it takes about 2 hours to cool down to around -30°C to freeze the contents, and then the temperature is raised to around 13°C over about 3 hours under reduced pressure of about 150 mTorr. Same temperature,
After continuing drying under the same pressure for about 14 hours, each vial is tightly stoppered to obtain a lyophilized formulation containing a titer of 1 g of cefazolin sodium.
Claims (1)
結乾燥方法において、該医薬品を、その室温晶析
濃度より低くかつ水との共晶体析出濃度より高い
濃度範囲の水溶液とし、該水溶液を氷点下まで冷
却して医薬品を晶析させ、次いで氷が融解しかつ
析出結晶が溶解しない温度範囲まで昇温させ、同
温度を維持したのち再び冷却して医薬品の結晶を
成長させると共に系全体を完全に凍結させたの
ち、再び昇温させて減圧下に乾燥することを特徴
とする医薬品の凍結乾燥方法。1. In a freeze-drying method for pharmaceuticals that involves crystallization from an aqueous solution by a temperature difference, the pharmaceutical is made into an aqueous solution with a concentration lower than its room temperature crystallization concentration and higher than the eutectic precipitation concentration with water, and the aqueous solution is cooled to below freezing. The drug was crystallized using the system, and then the temperature was raised to a temperature range where the ice melted and the precipitated crystals did not dissolve. After maintaining the same temperature, the system was cooled again to grow the drug crystals and completely freeze the entire system. A method for freeze-drying pharmaceuticals, which is then heated again and dried under reduced pressure.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19026084A JPS6168412A (en) | 1984-09-10 | 1984-09-10 | Freeze-drying of medicine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19026084A JPS6168412A (en) | 1984-09-10 | 1984-09-10 | Freeze-drying of medicine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6168412A JPS6168412A (en) | 1986-04-08 |
| JPH0466202B2 true JPH0466202B2 (en) | 1992-10-22 |
Family
ID=16255181
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP19026084A Granted JPS6168412A (en) | 1984-09-10 | 1984-09-10 | Freeze-drying of medicine |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6168412A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5044091B1 (en) * | 1989-04-18 | 1997-12-30 | Sankyo Co | Method of preparing a freeze-dried formulation of a drug |
| DE4327063A1 (en) | 1993-08-12 | 1995-02-16 | Kirsten Dr Westesen | Ubidecarenone particles with modified physicochemical properties |
| WO2002005787A1 (en) * | 2000-07-17 | 2002-01-24 | Takeda Chemical Industries, Ltd. | Production method for freeze-dried products |
-
1984
- 1984-09-10 JP JP19026084A patent/JPS6168412A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6168412A (en) | 1986-04-08 |
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