CN1376468A - Freeze dried hydroxy camptothecin powder for injection and its preparing process - Google Patents
Freeze dried hydroxy camptothecin powder for injection and its preparing process Download PDFInfo
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- CN1376468A CN1376468A CN 02114913 CN02114913A CN1376468A CN 1376468 A CN1376468 A CN 1376468A CN 02114913 CN02114913 CN 02114913 CN 02114913 A CN02114913 A CN 02114913A CN 1376468 A CN1376468 A CN 1376468A
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Abstract
A freeze-dried hydroxy camptothecin powder injection for treating primary liver cancer, gastrointestinal cancer, vesical cancer, lung cancer, leukemia, etc is prepared from hydroxy camptothecin, aminoacetic acid, lactose, sodium hydroxide and the water for injection through preparing buffer liquid from sodium hydroxide, aminoacetic acid and the water for injection, dissolving hydroxy camptothecin in it to obtain solution A, dissolving lactose in the water for injection to obtain solution B, adding A and rest of aminoacetic acid to B, stirring, regulating pH value, adding water for injection, filtering loading in containers, freeze drying and sealing.
Description
Technical field
The present invention relates to hydroxy camptothecin anticancer drugs technology of preparing, specifically is a kind of freeze dried hydroxy camptothecin powder for injection and preparation method thereof.
Background technology
Hydroxy camptothecin is the natural plants alkali that extracts in the fruit of China endemic plant Fructus seu radix camptothecae acuminatae (Fructus Camptothecae Acuminatae) (Camptotheca acuminata Decsne), be China pharmacy expert through extremely hard and bitter effort, many units, multi-disciplinaryly go all out to cooperate in the exploitation of 1977 annual proper motions, the distinctive natural plants anticarcinogen of China succeeded in developing.As the effective ingredient of natural plants, camptothecines such as hydroxy camptothecin are the anticarcinogens that a unique up to now class acts on topoisomerase I (TOPO I).Camptothecine once was used for the treatment of multiple carcinoma in the seventies, because of toxic and side effects has limited its development and application greatly.Because Chinese scholar has been succeeded in developing the hydroxy camptothecin of high-efficiency low-toxicity and has been obtained significant curative effect clinically, recently the foreign scholar has found its inhibitory action to TOPO I, such medicine causes the attention of international tumor circle again, has now become a big focus of cancer therapy drug research.
Hydroxy camptothecin can suppress the normal function that topoisomerase I (TOPO I) engages the DNA chain rupture again, and further causes the dna single chain break, suppresses dna replication dna, and the interference cell cycle (suppresses the S phase, postpones G
2Phase), and make chromosomal DNA produce fracture, multiple effects such as degraded under the synergistic synthesis result of the multiple modulin of body, finally cause the death of carcinoma cell.
Hydroxy camptothecin shows good antineoplastic activity in animal experiment.Clinically gastrointestinal cancer, hepatocarcinoma, bladder cancer, tumor of head and neck, pulmonary carcinoma etc. there is better curative effect; Therefore its major side effects is bone marrow depression and digestive tract reaction, but obviously alleviates than the toxicity of camptothecine, receives an acclaim clinically and payes attention to.Hydroxy camptothecin is owing to have unique Anticancer Effect and Mechanism, be well suited for comprising that with other chemotherapeutic anticarcinogens such as anthracene nucleus class, etoposide and antimetabolite, alkanes carry out combined chemotherapy, also be fit to share with biological response modifier, radiotherapy etc., be with a wide range of applications clinically, once be listed in national essential drugs for a long time.In the world, the bright prospects of such medicine have also been seen by many countries, furnish a huge amount of money for to develop and study.
At present, commercially available hydroxy camptothecin (HCPT) preparation is the injection liquid drugs injection, though the hydroxy camptothecin aqueous injection has good curative effect to kinds of tumors clinically, stability is not good but owing to the restriction of dosage form, effect duration only is 1 year, in fact deposits promptly to begin in 8 months small amount of precipitate to occur, deepen the iso-metamorphism situation.And the aqueous injection quality standard all is a provincial standard, used quantitative approach is a uv detection method, it is qualified to be more than 5% purity, 15% impurity is arranged approximately, batch differences is big, and clinical practice shows that the content of toxic and side effects and impurity is proportionate, and causes certain influence so just for clinical drug safety and effectiveness.
Summary of the invention
The objective of the invention is to overcome the above-mentioned deficiency of prior art, a kind of freeze dried hydroxy camptothecin powder for injection that is used for the treatment of cancer and preparation method thereof is provided.
Freeze dried hydroxy camptothecin powder for injection of the present invention, form by following raw material:
Hydroxy camptothecin 1.5-6.0g, glycine 0.5-15.0g,
Lactose 30.0-720.0g, sodium hydroxide 2.0-20.0g,
Water for injection adds to 1500-6000ml, makes 1000 altogether.
A kind of preparation method of freeze dried hydroxy camptothecin powder for injection is characterized in that taking following steps:
A, by above-mentioned preparation prescription batching, get the glycine of sodium hydroxide, 60-80% recipe quantity and the water for injection of 50-300ml and produce buffer, buffer is alkalescence, and pH is 7.5-10.5, wherein naoh concentration is 0.2%-2.0% (W/L), and glycine concentration is 0.1-3.0mol/L;
B, the hydroxy camptothecin raw material of recipe quantity is added in the described buffer, 1. stirring and dissolving gets solution;
C, lactose is put into the material-compound tank that 50-300ml water for injection is housed, water temperature is 15-50 ℃, and 2. stirring and dissolving gets solution;
D, with solution 1. with the glycine surplus pour into solution 2. in, stir, regulator solution pH to 8.0-11.0 adds the injection water to recipe quantity, measures liquor strength, by the filter membrane filtration sterilization to receiver, packing, the freeze dryer lyophilizing use in half tamponade, tamponade is packed.
This freeze dried hydroxy camptothecin powder for injection reasonable recipe, preparation is loose porous and solubility is good, and moisture is low, the purity height, meet national standard, be applicable to the treatment of malignant tumor such as primary hepatocarcinoma, gastrointestinal cancer, bladder cancer, tumor of head and neck, pulmonary carcinoma, leukemia clinically.
Its production overall process sterile working adopts the micropore filtering film degerming, cold drying, and product is not destroyed; Vacuum or noble gas are filled, and are difficult for oxidation takes place, and period of storage is long, and stability such as is improved at advantage, thereby have prolonged the effect duration of this medicine, are convenient to store, transportation and sale, also are convenient to guarantee the quality of product.
Description of drawings
Fig. 1 is preparation technology's flow chart of the present invention:
Fig. 2 is embodiment 1 a medicinal liquid freeze temperature curve chart;
Fig. 3 is embodiment 2 medicinal liquid freeze temperature curve charts;
Fig. 4 is embodiment 3 medicinal liquid freeze temperature curve charts.
The specific embodiment
Describe in detail below in conjunction with embodiment.
1000 freeze-dried powder prescriptions of embodiment 1:2mg/vial specification are:
Hydroxy camptothecin 1.8g, glycine 2.2g,
Lactose 45.0g, sodium hydroxide 10.0g,
Water for injection adds to 2100ml, makes 1000 altogether.
Wherein, hydroxy camptothecin is a principal agent, requires to feed intake respectively according to two kinds of production specifications (2mg/ props up, and 5mg/ props up).
Lactose is an excipient, as the skeleton support section of hydroxycamptothecin for injection freeze-dried powder.According to bibliographical information and in conjunction with the practical experience of my other antitumor lyophilized formulations of company, test by the simulation actual production, determined the ratio of principal agent and lactose: for the product of 2mg specification and 5mg specification, employing 1: the ratio of 20-120.
Buffer solution is made into by glycine and sodium hydroxide etc., and the alkaline environment when the principal agent dissolving is provided dissolves raw material.Adding glycine is in order to guarantee that raw material can dissolve and be unlikely to because of alkalescence is too high structure to be destroyed under alkali condition.Through test of many times, we find with the solute effect and the shock-absorbing capacity of the formulated buffer of the glycine solution of 0.2%-2.0% (W/L) sodium hydroxide solution and 0.1-3.0mol/L better, most preferred embodiment glycine concentration is 1mol/L, naoh concentration is 1% (W/L), the volume ratio of the two is 22: 2-20, buffer capacity is stronger.Another of glycine act as the pH value readjustment of solution, behind the material dissolution, adjusts pH value in the 8.0-11.0 scope, filtration then, packing and lyophilizing.
Water for injection is as the solvent of dissolving raw material.Charging quantity according to liquor strength and every medicine adds an amount of.Lactose adopts New Zealand's lactose company limited to produce product, meets British Pharmacopoeia (1993 editions) 1994 enlarged edition quality standards.Sodium hydroxide meets GB-629-81 (AR) quality standard.Glycine meets " 95 editions quality standards of Chinese pharmacopoeia.
The preparation technology such as the flow process of preparation are shown in Figure 1.
A, press embodiment 1 preparation prescription batching, get the glycine of sodium hydroxide 10.0g, 1.32g (recipe quantity is 2.2g) and the water for injection of 100ml and produce buffer, buffer is alkalescence, and pH is 7.5-10.5, wherein glycine concentration is 1mol/L, and naoh concentration is 1% (W/L).
B, hydroxy camptothecin 1.8g is added in the described buffer, 1. stirring and dissolving gets solution;
C, lactose 45.0g is put into the material-compound tank that 100ml water for injection is housed, water temperature is 15 ℃, and 2. stirring and dissolving gets solution;
D, with solution 1. with glycine surplus 0.88g pour into solution 2. in, stir, regulator solution pH to 9.0-10.5 adds water for injection surplus 1900ml (recipe quantity 2100ml), measures liquor strength, by the filter membrane filtration sterilization to receiver, packing (1000), the freeze dryer lyophilizing is used in half tamponade, tamponade, packing.
The degerming measure: medicinal liquid adopts PULL company's disposable filtering film (0.22 μ m, diameter are 300mm, hydrophilic) filtration sterilization; Plug etc. adopt the sterilization of vacuum and steam sterilization cabinet, dry (121 ℃, 30min); The sterilization of production labor utensil employing dry heat sterilization cabinet (180 ℃, 2hr); Material-compound tank, equipment such as receiver, injection water pot, freeze dryer and pipeline adopt online sterilization;
This example adopts general freeze dryer lyophilizing, and the medicinal liquid freeze-drying curve is seen Fig. 2.
Temperature descending section temperature low spot :-55 ℃ keep in the 7HR lyophilizing this moment casings not evacuation
The section that heats up heating rate: 20 ℃/HR vacuum is 40～50 μ mHg
The high point of the section temperature that heats up: 20 ℃ of vacuums are 40～50 μ mHg
The high some retention time of temperature: 10HR vacuum is 40～50 μ mHg
The freeze dryer condenser temperature requires to below-40 ℃ in the whole dry run.After finishing drying, the vacuum requirement is 20～50 μ mHg in the freeze drying box.(option) requires vacuum to keep 7 hours down at temperature descending section temperature low spot-55 ℃ for-20 μ mHg. medicinal liquids when product fills nitrogen, the high point of section temperature kept 10 hours down for 20 ℃ heating up.
1000 freeze-dried powder prescriptions of embodiment 2:2mg/vial specification are:
Hydroxy camptothecin 2.0g, glycine 4.0g,
Lactose 100.0g, sodium hydroxide 10.0g,
Water for injection adds to 2500ml, makes 1000 altogether.
Its preparation process is as follows:
A ', press embodiment 2 preparation prescriptions batchings, get the glycine of sodium hydroxide 10g, 3g (recipe quantity is 4.0g) and the water for injection of 100ml and produce buffer, buffer is alkalescence, and pH is 8.5-10.0, wherein glycine concentration is 1mol/L, and naoh concentration is 1% (W/L).
B ', hydroxy camptothecin 2.0g is added in the described buffer, 1. stirring and dissolving gets solution;
C ', lactose 100.0g is put into the material-compound tank that 200ml water for injection is housed, water temperature is 20 ℃, and 2. stirring and dissolving gets solution;
D ', with solution 1. with glycine surplus 1.0g pour into solution 2. in, stir, regulator solution pH to 9.0-11.0 adds water for injection surplus 2200ml (recipe quantity 2500ml), measure liquor strength, by the filter membrane filtration sterilization to receiver, packing (1000), half tamponade, use the freeze dryer lyophilizing, fill nitrogen, tamponade, packing.
This routine medicinal liquid freeze-drying curve as shown in Figure 3.
Temperature descending section temperature low spot :-55 ℃ keep in the 7HR lyophilizing this moment casings not evacuation
A first intensification section heating rate: 20 ℃/HR vacuum is 40～50 μ mHg
The high point of the first intensification section temperature: 20 ℃ keep the 7HR vacuums is 40～50 μ mHg
A second intensification section heating rate: 20 ℃/HR vacuum is 40～50 μ mHg
The high point of the second intensification section temperature: 60 ℃ keep the 7HR vacuums is 40～50 μ mHg
Before the tamponade operation in preparation inflated with nitrogen, require when product fills nitrogen vacuum for freeze dryer condenser temperature requirement in the-whole dry run of 20inHg. for below-40 ℃.After finishing drying, the vacuum requirement is 20～50 μ mHg in the freeze drying box.Medicinal liquid kept 7 hours down at temperature descending section temperature low spot-55 ℃, kept 7 hours down for 20 ℃ at the first high point of section temperature that heats up, and kept 7 hours down for 60 ℃ at the second high point of section temperature that heats up.
1000 freeze-dried powder prescriptions of embodiment 3:5mg/vial specification are composed as follows:
Hydroxy camptothecin 5.0g, glycine 8.0g,
Lactose 300.0g, sodium hydroxide 10.0g,
Water for injection adds to 4000ml, makes 1000 altogether.
Its preparation process is as follows:
A ", press embodiment 3 preparation prescriptions batchings; get the glycine of sodium hydroxide 10g, 5.6g (recipe quantity is 8.0g) and the water for injection of 300ml and produce buffer, buffer is alkalescence, and pH is 7.5-10.5; wherein glycine concentration is 1mol/L, and naoh concentration is 1% (W/L).
B ", hydroxy camptothecin 5.0g is added in the described buffer, 1. stirring and dissolving gets solution;
C ", lactose 300.0g is put into the material-compound tank that 300ml water for injection is housed, water temperature is 25 ℃, 2. stirring and dissolving gets solution;
D ", with solution 1. with glycine surplus 2.4g pour into solution 2. in; stir; regulator solution pH to 8.0-10.0, add water for injection surplus 3400ml (recipe quantity 4000ml), measure liquor strength; by the filter membrane filtration sterilization to receiver; packing (1000), half tamponade use the freeze dryer lyophilizing; tamponade, packs.
Embodiment 3 medicinal liquid freeze-drying curves as shown in Figure 4.
Temperature descending section temperature low spot :-55 ℃ keep in the 7HR lyophilizing this moment casings not evacuation
A first intensification section heating rate: 15 ℃/HR vacuum is 40～50 μ mHg
The high point of the first intensification section temperature: 5 ℃ keep the 7HR vacuums is 40～50 μ mHg
A second intensification section heating rate: 20 ℃/HR vacuum is 40～50 μ mHg
The high point of the second intensification section temperature: 30 ℃ keep the 7HR vacuums is 40～50 μ mHg
The 3rd an intensification section heating rate: 10 ℃/HR vacuum is 40～50 μ mHg
The high point of the 3rd intensification section temperature: 50 ℃ keep the 7HR vacuums is 40～50 μ mHg
Product also can select to fill nitrogen, require when filling nitrogen vacuum for freeze dryer condenser temperature requirement in the-whole dry run of 20inHg. for below-40 ℃.After finishing drying, the vacuum requirement is 20～50 μ mHg in the freeze drying box.This routine medicinal liquid kept 7 hours down at temperature descending section temperature low spot-55 ℃, kept 7 hours down for 5 ℃ at the first high point of section temperature that heats up, and kept 7 hours down for 30 ℃ at the second high point of section temperature that heats up, and kept 7 hours down for 50 ℃ at the 3rd high point of section temperature that heats up.
This method adopts general freeze-dry process, and according to product characteristics, the important technological parameters of its freeze-drying curve temperature descending section, heat up section, temperature hold section is as follows:
Temperature descending section temperature low spot :-30～-70 ℃ keep in the 2-10HR lyophilizing this moment casings not evacuation
Heating rate: 5-45 ℃/HR vacuum of the section that heats up is 20～200 μ mHg
The high point of the section temperature that heats up: 0-70 ℃ of vacuum is 20～200 μ mHg
It is 20～200 μ mHg that the high point of temperature keeps section time: 1-25HR (sectional carries out) vacuum
The freeze dryer condenser temperature requires to below-40 ℃ in the whole dry run.After finishing drying, the vacuum requirement is 0～200 μ mHg in the freeze drying box.Requiring vacuum when product fills nitrogen (option) is-50～10inHg.In freeze-drying process, medicinal liquid kept 2-10 hour down temperature descending section temperature low spot-30～-70 ℃, kept 1-25HR hour down for 0-70 ℃ at the high point of section temperature that heats up, and can divide the multistage lyophilizing at the freeze-drying process herb liquid.
Guangdong Provincial Medicines Checkout station's check of this freeze dried hydroxy camptothecin powder, survey report is as follows:
Touchstone: National Drug Administration's standard (trying) WS-046 (X-036)-2001 (1). (2)
Submitted sample quantity: 50 of 2mg specifications; 50 of 5mg specifications.
Inspection item: character, discriminating, basicity, moisture, related substance, uniformity of dosage units, unusual toxin, pyrogen, aseptic, the clarity of solution, clarity, assay.
Assay: (qualified) up to specification.
Check conclusion: hydroxycamptothecin for injection meets national standard.
The animal experiment of this freeze dried hydroxy camptothecin powder for injection is reported as follows: 1. test name: hydroxycamptothecin for injection local toxicity and other safety testings 2. test units: Zhongshan Medical Univ.'s drug development center 3. pilot projects: local excitation test, hemolytic test, hypersensitive test 4. test methods:
1., local excitation test irritant reaction (some ocular administration), perusal, man of the histopathologic examination rabbit ear vascular stimulation by each structure part of rabbit eyes after the perusal administration irritant reaction of reacting (auricular vein drug administration by injection), perusal rabbit quadriceps femoris (administered intramuscular) is estimated.
2., hemolytic test has or not haemolysis and agglutination to estimate by observing medicine to the stripped erythrocyte of rabbit.
3., the Cavia porcellus anaphylaxis is estimated behind the hypersensitive test perusal intraperitoneal injection.5, conclusion:
Result of the test shows that hydroxycamptothecin for injection does not have haemolysis and agglutination to the equal nonirritant of rabbit vein injection, intramuscular injection and eye dripping to tame rabbit erythrocyte, and the Cavia porcellus drug administration by injection was not met quick reaction.
Claims (8)
1, a kind of freeze dried hydroxy camptothecin powder for injection is characterized in that being made up of following raw material:
Hydroxy camptothecin 1.5-6.0g, glycine 0.5-15.0g,
Lactose 30.0-720.0g, sodium hydroxide 2.0-20.0g,
Water for injection adds to 1500-6000ml, makes 1000 altogether.
2, a kind of preparation method of freeze dried hydroxy camptothecin powder for injection is characterized in that taking following steps:
A, by the described preparation prescription amount of claim 1 batching, the water for injection of getting the glycine of sodium hydroxide, 60-80% recipe quantity and 50-300ml is produced the buffer of alkalescence;
B, the hydroxy camptothecin raw material of recipe quantity is added in the described buffer, 1. stirring and dissolving gets solution;
C, lactose is put into the material-compound tank that 50-300ml water for injection is housed, water temperature is 15-50 ℃, and 2. stirring and dissolving gets solution;
D, with solution 1. with the glycine surplus pour into solution 2. in, stir, regulator solution pH to 8.0-11.0 adds the injection water to recipe quantity, measures liquor strength, by the filter membrane filtration sterilization to receiver, packing, the freeze dryer lyophilizing use in half tamponade, tamponade is packed.
3, according to the preparation method of the described freeze dried hydroxy camptothecin powder for injection of claim 2, it is characterized in that: before the tamponade operation in preparation inflated with nitrogen, require vacuum to be-20inHg when filling nitrogen.
4, according to the preparation method of the described freeze dried hydroxy camptothecin powder for injection of claim 2, it is characterized in that: described buffer is alkalescence, and pH is 7.5-10.5.
5, according to the preparation method of the described freeze dried hydroxy camptothecin powder for injection of claim 2, it is characterized in that: in freeze-drying process, medicinal liquid kept 2-10 hour down freeze-drying curve temperature descending section temperature low spot-30～-70 ℃, and the high point of section temperature kept 1-25HR hour down for 0-70 ℃ heating up.
6, according to the preparation method of the described freeze dried hydroxy camptothecin powder for injection of claim 5, it is characterized in that: divide the multistage lyophilizing at the freeze-drying process herb liquid.
7, according to the preparation method of the described freeze dried hydroxy camptothecin powder for injection of claim 2, it is characterized in that: described glycine concentration is 0.1-3.0mol/L, and naoh concentration is 0.2%-2.0% (W/L).
8, according to the preparation method of the described freeze dried hydroxy camptothecin powder for injection of claim 7, it is characterized in that: described glycine concentration is 1mol/L, and naoh concentration is 1% (W/L).
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1326525C (en) * | 2004-11-26 | 2007-07-18 | 复旦大学 | 10-hydroxy camptothecin long cyclic liposome and its freeze aried preparation |
| CN101244272B (en) * | 2005-04-06 | 2010-07-14 | 山东蓝金生物工程有限公司 | Anti-solid tumors pharmaceutical combination containing topological enzyme inhibitor |
-
2002
- 2002-03-01 CN CN 02114913 patent/CN1376468A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1326525C (en) * | 2004-11-26 | 2007-07-18 | 复旦大学 | 10-hydroxy camptothecin long cyclic liposome and its freeze aried preparation |
| CN101244272B (en) * | 2005-04-06 | 2010-07-14 | 山东蓝金生物工程有限公司 | Anti-solid tumors pharmaceutical combination containing topological enzyme inhibitor |
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