CN1224386C - Fumagucin injection against cancers and its preparing method - Google Patents
Fumagucin injection against cancers and its preparing method Download PDFInfo
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- CN1224386C CN1224386C CN 03111183 CN03111183A CN1224386C CN 1224386 C CN1224386 C CN 1224386C CN 03111183 CN03111183 CN 03111183 CN 03111183 A CN03111183 A CN 03111183A CN 1224386 C CN1224386 C CN 1224386C
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Abstract
The present invention relates to a fumagucin injection and a preparation method thereof. 1, 2-propanediol is used as a solvent, wherein the solvent contains 10 to 20% of fumagucin and 0.1 to 0.3% of citric acid. The preparation method comprises: liquid is prepared under an aseptic condition; liquid is filtered in an aseptic mode; the liquid is subpackaged, and the fumagucin injection is formed. The preparation process of the present invention is simple, and the operability is strong. The fumagucin injection has good reproducibility, and is basically consistent with the requirements for mass production.
Description
Technical field
The invention belongs to a kind of pharmaceutical preparation and preparation method for the treatment of cancer, relate in particular to a kind of TNP-470 injection that is used for the treatment of cancer and preparation method thereof.
Background technology
At present, the chemotherapeutic of using clinically belongs to the cell toxicant class basically.Though this class medicine can kill and wound cancerous cell in a large number, toxic and side effects is big, and drug resistance is arranged, the metastasis weak effect.Based on a large amount of in recent years research, it is found that the chemical compound of many inhibition angiogenesis, and in external and body, obtained gratifying result in the experiment.Nineteen ninety, propagation and the inductive neovascularity of in-vivo tumour that discoveries such as the Ingber of Harvard Medical School and Folkman: the secretions of Aspergillus fumigatus (Aspergillus Fumigatus)---Amebacilin (Fumagillin) suppresses the extracorporeal blood vessel endotheliocyte generate.Though Amebacilin can suppress the growth of mouse tumor, also cause the serious decline of mice body weight simultaneously.The military field chemical company of Japan (Takeda Chemical Industriels) has carried out a series of structure of modification to Amebacilin, finally filter out TNP-470 from many Fumagillin derivants, its another name is O-(chloroacetylcarbamoyl) fumagillol (TNP-470).Describe the chemical constitution and the character of TNP-470 among the Japan Patent 63-219287 in detail.Subsequently people such as Shigeo Yanai reported adopt triglyceride be solvent the TNP-470 vein with the injection type (Int.J.Pharm. (1995), 123 (2), 237-45).People are to its research of carrying out a large amount of cytobiologies, pharmacodynamics, pharmacokinetics and clinical observation, facts have proved that TNP-470 is by suppressing the novel remedies for cancer that the tumor neovascularity generates the low toxicity that suppresses tumor proliferation, efficient, metastasis.
Summary of the invention
It is simple to the purpose of this invention is to provide a kind of preparation process, workable, favorable reproducibility, and what meet big production requirement substantially is used for the treatment of TNP-470 injection of cancer and preparation method thereof.
According to the TNP-470 injection that is used for the treatment of cancer of the present invention, it is characterized in that it is with 1, the 2-propylene glycol is a solvent, wherein contains TNP-470 10-20%.
Another characteristics of the present invention are that it also contains citric acid 0.1-0.3%.
Its preparation method is, aseptic dosing, used vessel, container, pipeline, equipment etc. must be sterilized routinely, drying, take by weighing TNP-470 or Ma Jixin and citric acid by recipe quantity and put in the Agitation Tank, add 1 of recipe quantity, 2-propylene glycol under the room temperature, stir, dissolving makes the abundant mixing of medicinal liquid, and medicinal liquid at first passes through G through decompression
3After filter bulb filters,, detect intermediate, be filled in the 2ml ampoule, fill nitrogen, seal, lamp inspection, check, packing again by 0.22 μ F type microporous filter membrane aseptic filtration.
The specific embodiment
Embodiment 1
Prescription component of the present invention and specification:
TNP-470 30g
1,2-propylene glycol 2000ml
Make 1000
Specification 30mg/2ml/ props up
Its preparation method is:
Aseptic dosing, used vessel, container, pipeline, equipment etc. must be sterilized routinely, drying, take by weighing TNP-470 or Ma Jixin puts in the Agitation Tank by recipe quantity, add 1 of recipe quantity under the room temperature, the 2-propylene glycol stirs, dissolving makes the abundant mixing of medicinal liquid, and medicinal liquid at first passes through G through decompression
3After filter bulb filters,, detect intermediate, be filled in the 2ml ampoule, fill nitrogen, seal, lamp inspection, check, packing again by 0.22 μ F type microporous filter membrane aseptic filtration.
Embodiment 2
Prescription component of the present invention and specification:
TNP-470 30g
Citric acid 4g
1,2-propylene glycol 2000ml
Make 1000
Specification 30mg/2ml/ props up
Its preparation method is:
Aseptic dosing, used vessel, container, pipeline. equipment etc. must be sterilized routinely, drying; Take by weighing TNP-470 and citric acid is put in the Agitation Tank by recipe quantity, add 1 of recipe quantity under the room temperature, the 2-propylene glycol stirs, and dissolving makes the abundant mixing of medicinal liquid; Medicinal liquid at first passes through G through decompression
3After filter bulb filters,, detect intermediate, be filled in the 2ml ampoule, fill nitrogen, seal, lamp inspection, check, packing again by 0.22 μ F type microporous filter membrane aseptic filtration.
The screening of prescription component
The injection of the embodiment of the invention 2 preparations, specification is propped up for containing TNP-470 30mg/2ml/, it be with pharmacopeia record 1, the 2-propylene glycol is the small-volume injection of solvent, again it is transferred to during clinical practice in 250ml5% glucose injection or 0.9% sodium chloride injection, for intravenous drip.
Dosage, dosage form, specification and administering mode deterministic process according to the embodiment of the invention 2 are as follows:
1, determining of non-water-soluble matchmaker's small-volume injection unstable under the condition that mineral acid, alkali exist because insoluble substantially in this medicine water, but thereby the non-water-soluble matchmaker of selection injection become inevitable.And adopt non-water-soluble matchmaker to prepare small-volume injection, than adopting other method medicine to be handled to make the preparation cost more much lower, and easy to operate, controllability is strong, thereby is more suitable for big production requirement.
2, through prescription screening and preliminarily stabilised test, 1, the 2-propylene glycol is functional to medicine dissolution, the more important thing is when medicine is transferred in 250ml5% glucose injection or 0.9% sodium chloride injection, since 1, the existence of 2-propylene glycol, and medicine is separated out precipitation no longer again, solution is clear and bright, meets the clinical application requirement.
3, medicine is responsive especially to heat, thus process using aseptic filtration packing, with 1, the small-volume injection of 2-propylene glycol preparation, through boiling 15 minutes and 30 minutes, medicine decomposes serious.Because 1, the 2-propylene glycol is difficult for microbiological contamination and breed bacteria, thereby can operate by aseptic filtration and realize industrialization.
4, of short duration half-life (about 0.5 hour), for keeping effective dose and certain drug treating time, should be with intravenous drip for well.
The screening of prescription component:
TNP-470 is not dissolved in water substantially, to hot and mineral acid, alkali sensitivity.Therefore, can only consider to prepare non-water-soluble matchmaker's small-volume injection, during clinical practice again capacity be transferred in 250ml5% glucose injection or 0.9% sodium chloride injection intravenous drip.
Concrete screening process is as follows:
1, the medicine dissolution performance is investigated
Get 95% ethanol, 1,2-propylene glycol, glycerol, Triglycerol Caprylate-Caprate TCC, PEG400, each 10ml of benzyl benzoate add the about 150mg of TNP-470 respectively, observe the dissolved situation of TNP-470 in HZQ-C air bath agitator.It is as follows to observe whole dissolution times under the room temperature:
95% ethanol 1 ' 15 "
PEG400 6 ' 28 "
1,2-propylene glycol 17 ' 36 "
Glycerol 24 ' 19 "
Benzyl benzoate 43 ' 41 "
1 hour not molten finishing of Triglycerol Caprylate-Caprate TCC
Conclusion: except that Triglycerol Caprylate-Caprate TCC, all applicable to the optimum solvent of this medicine.
2, small-volume injection is transferred in the infusion solutions, and admixture is investigated
Because TNP-470 is insoluble substantially in water, when entering in a large amount of transfusions, may separate out precipitation or separate out oil droplet with non-water-soluble matchmaker's solution state, do not reach the clinical application requirement.Therefore, can insoluble or insoluble drug be made non-water-soluble matchmaker's preparation to water, form clear and bright solution with infusion solutions in use, is the precondition of making non-water-soluble matchmaker's preparation.Concrete test method is: get each two parts of five kinds of solution under the above-mentioned solubility property investigation project, every part of each 2ml is transferred to respectively in 250ml5% glucose injection, 0.9% sodium chloride injection, and observed result is as follows after the jolting:
95% ethanol medicinal liquid 2ml → 5% glucose injection is separated out white precipitate
PEG400 medicinal liquid 2ml → 5% glucose injection is separated out white precipitate
1, the 2-propylene glycol medicinal liquid 2ml → clear and bright solution of 5% glucose injection
The glycerol medicinal liquid 2ml → clear and bright solution of 5% glucose injection
Benzyl benzoate medicinal liquid 2ml → 5% glucose injection is separated out white precipitate also
Produce the Shan pearl
95% ethanol medicinal liquid 2ml → 0.9% sodium chloride injection is separated out white precipitate
PEG400 medicinal liquid 2ml → 0.9% sodium chloride injection is separated out white precipitate
1,2-propylene glycol medicinal liquid 2ml → clear and bright solution of 0.9% sodium chloride injection
The glycerol medicinal liquid 2ml → clear and bright solution of 0.9% sodium chloride injection
Benzyl benzoate medicinal liquid 2ml → 0.9% sodium chloride injection is separated out white precipitate
And generation oil droplet
In sum, have only 1,2-propylene glycol and glycerol can tentatively satisfy the requirement of this preparation; But because glycerol viscosity is big, in the production packing and use in shift and all exist big difficultly, so can only select 1 for use, the 2-propylene glycol is the research that solvent carries out process aspect.
3, the investigation of TNP-470 injection stability in infusion solutions
1) assay:
The TNP-470 injection (990701) of embodiment 2 preparations is quantitatively joined respectively in 5% glucose injection and 0.9% sodium chloride injection, carry out assay by quality standard (draft), indicating content in 5% glucose injection is 98.3%, indicating content in 0.9% sodium chloride injection is 98.2%, conforms to substantially with the assay result 98.2% of 990701 batches of preparations.Illustrate that this product can use fully in above-mentioned two kinds of transfusions.
2) study on the stability
The TNP-470 injection (990701) of getting the embodiment of the invention 2 preparations joins respectively in 5% glucose injection and 0.9% sodium chloride injection, detects at 0,1,2,3,4,5 hour respectively, the results are shown in Table:
The research of preparation method:
1, the investigation of sterilising temp and time
With 1, it is to contain the injection that TNP-470 30mg/2ml/ props up that the 2-propylene glycol is made embodiment 1 specification with TNP-470, boils in water, takes out two groups of samples at 15 minutes and 30 minutes respectively, checks through thin layer chromatography.The result shows, sample in boiling water 15 minutes and 30 minutes, all hydrolysis of TNP-470.
Because TNP-470 is to thermally labile, during high temperature, its side chain very easily ruptures.So in its preparation process, must avoid the autoclaving sterilization, should adopt aseptic filtration packing under the room temperature.
2, selection of stabilizers
The TNP-470 injection of embodiment 2 preparation, with 1, the 2-propylene glycol is the sample of solvent preparation, 1 of every hydrochloric acid that adds 0.1mol/L respectively, 1 of the sodium hydroxide of 0.1mol/L, the citric acid of 4mg; The triethanolamine of 4mg.Sample at room temperature place 10 days TNP-470 injection (990409) with embodiment 2 preparation keep sample compare and in 80 ℃ of water-baths, place 30 ', result, TNP-470 are in the presence of citric acid, stability is than slightly improve of no citric acid existence.All unstable in inorganic acid alkali and triethanolamine.To keep sample again and place 30 minutes in 80 ℃ of water-baths with the sample that adds citric acid, the result proves that also adding citric acid will stablize, but all cannot handle by high temperature sterilize.
3, charge into noble gas
To contain 1 of 0.2% citric acid, the 2-propylene glycol is a solvent, the injection of preparation embodiment 2, charge into respectively nitrogen, carbon dioxide gas and not filling with inert gas investigate, sample was put into 80 ℃ of water-baths after 30 minutes, carried out the thin layer chromatography check.
The result: three kinds of samples are all responsive to heat.Charge into noble gas and tentatively confirm not have significant difference, but for for the purpose of safe, employing inflated with nitrogen method increases stability of formulation in the technology with filling with inert gas not.
In sum, by the screening of prescription component, the research of preparation method, by the injection that the prescription component screens and preparation method makes, because of adopting non-water-soluble matchmaker, it can satisfy that each step of preparation process requires and the requirement during clinical practice, has solved preferably in application, not separate out to precipitate and the time enough state that keeps relative stability in infusion solutions is arranged, and product steady quality at normal temperatures.
Claims (4)
1, a kind of TNP-470 injection that is used for the treatment of cancer is characterized in that being made up of TNP-470 30g and solvent 1,2-propylene glycol 2000ml.
2, a kind of TNP-470 injection that is used for the treatment of cancer is characterized in that being made up of TNP-470 30g, citric acid 4g and solvent 1,2-propylene glycol 2000ml.
3, the preparation method that is used for the treatment of the TNP-470 injection of cancer according to claim 1, it is characterized in that aseptic dosing, used vessel, container, pipeline, equipment are all sterilized routinely, drying, take by weighing TNP-470 30g, put in the Agitation Tank, add 1 under the room temperature, 2-propylene glycol 2000ml, stir, dissolving makes the abundant mixing of medicinal liquid, and medicinal liquid is at first after decompression is filtered by the G3 filter bulb, again by 0.22 μ F type microporous filter membrane aseptic filtration, detect intermediate, be filled in the 2ml ampoule, fill nitrogen, seal, lamp inspection, check, packing.
4, the preparation method that is used for the treatment of the TNP-470 injection of cancer according to claim 2, it is characterized in that aseptic dosing, used vessel, container, pipeline, equipment are all sterilized routinely, drying, take by weighing TNP-470 30g, citric acid 4g puts in the Agitation Tank, adds 1 under the room temperature, 2-propylene glycol 2000ml, stir, dissolving makes the abundant mixing of medicinal liquid, and medicinal liquid is at first after decompression is filtered by the G3 filter bulb, again by 0.22 μ F type microporous filter membrane aseptic filtration, detect intermediate, be filled in the 2ml ampoule, fill nitrogen, seal, lamp inspection, check, packing.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03111183 CN1224386C (en) | 2003-03-14 | 2003-03-14 | Fumagucin injection against cancers and its preparing method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03111183 CN1224386C (en) | 2003-03-14 | 2003-03-14 | Fumagucin injection against cancers and its preparing method |
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| Publication Number | Publication Date |
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| CN1530099A CN1530099A (en) | 2004-09-22 |
| CN1224386C true CN1224386C (en) | 2005-10-26 |
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| CN 03111183 Expired - Fee Related CN1224386C (en) | 2003-03-14 | 2003-03-14 | Fumagucin injection against cancers and its preparing method |
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Owner name: TIANMING MEDICINE SCIENCE DEVELOPMENT CO., LTD., Free format text: FORMER OWNER: YOU HAIMING Effective date: 20081114 |
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Effective date of registration: 20081114 Address after: A biological incubator building, Nanshan District hi tech, Guangdong, Shenzhen 2-315, China Patentee after: Shenzhen Tianming medical science and Technology Development Co Ltd Address before: Guangdong city of Shenzhen Province Overseas Chinese town square brigade Qi Yun Ge 21C Patentee before: You Haiming |
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