CN102949353B - oxaliplatin lyophilized pharmaceutical composition for injection and - Google Patents
oxaliplatin lyophilized pharmaceutical composition for injection and Download PDFInfo
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- CN102949353B CN102949353B CN201210423175.4A CN201210423175A CN102949353B CN 102949353 B CN102949353 B CN 102949353B CN 201210423175 A CN201210423175 A CN 201210423175A CN 102949353 B CN102949353 B CN 102949353B
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Abstract
Preparation of an oxaliplatin lyophilized pharmaceutical composition for injection. The invention relates to a preparation method of the oxaliplatin lyophilized powder injection. The method comprises the following steps: 1) recrystallization of oxaliplatin: using isopropyl alcohol and acetonitrile to recrystallize oxaliplatin, so as to obtain an oxaliplatin crystalline powder; and 2) preparation of the oxaliplatin lyophilized powder injection: adding a proper amount of lactose and water for injection into the oxaliplatin crystalline powder.
Description
Technical field:
The present invention relates to field of pharmaceutical preparations, particularly a kind of preparation of preparation of antitumor drug oxaliplatin.
Background technology:
Oxaliplatin, chemistry (1R, 2R)-(1,2-cyclohexane diamine-N, N') [ethanedioic acid (2-)-O, O'] network platinum by name.Its structural formula is:
Oxaliplatin belongs to the platinum analog derivative, and its central pt atom is surrounded by an oxalic acid and 1.2-diamino cyclohexane extraction, is transoid conformation, is a stereoisomer.As other platinum analog derivatives, oxaliplatin acts on DNA by producing the alkanisation conjugate, forms in chain and interchain linkage, thereby suppresses the synthetic of DNA and copy.Oxaliplatin is combined with DNA rapidly, needs at most 15 minutes, and the phase when being divided into two of cisplatin and DNA, the delay phase comprising after 48 hours.After administration one hour, by measuring leukocytic adduct, can show its existence in human body.DNA in reproduction process is synthetic, and the separation of DNA, RNA and cell protein is synthetic all suppressed thereafter, some cell line to cisplatin resistance, and oxaliplatin treatment is effective.
Indication: be applicable to the knot after fluorouracil is treated unsuccessfully, the patient that rectal cancer shifts, fluorouracil is used alone or in combination.
Usage and dosage: when medication alone or in combination, recommended dose, for to press 130mg/m2 of body surface area, adds infusion 2-6 hour in 250～500ml, 5 % glucose solutions.While not having main toxicity to occur, (21 days) administration in every 3 weeks 1 time.Adjust dosage with safety, especially neurologic safety is foundation.
The preparation of the oxaliplatin gone on the market mainly contains freezing-dried powder injection, and its adjuvant is lactose.The character of product is the loose block of white or off-white color or powder.
The patent that Chinese patent relates to oxaliplatin formulations has:
Oxaliplatin freeze-dried powder and preparation method thereof application number: 201210142677.X
High-optical-purity is trans-dextrorotation oxaliplatin freeze-dried powder and preparation method thereof application number: and 201210178848.4
A kind of oxaliplatin crystalline compounds and lyophilized injectable powder application number thereof: 201210147684.9
A kind of oxaliplatin medicament composition and preparation method thereof application number: 200910304674.X
A kind of preparation method application number of take the lyophilized injectable powder that high solids content mannitol is adjuvant: 200710191485.7
A kind of oxaliplatin freeze-dried powder and preparation method thereof application number: 200710191484.2
Oxaliplatin for Injection lyophilized injectable powder and preparation method thereof application number: 200610165396.0
The nanometer suspension injection application number of oxaliplatin platinum phospholipid compound intravenously administrable: 200610084357.8
Oxaliplatin intravenous injection and preparation method thereof application number: 200510021947.1
The adjuvant used in these patents comprises lactose, mannitol, sucrose, glucose, citric acid etc.
By the research to above oxaliplatin injection needle injection, we find, use oxaliplatin injection needle injection prepared by above-mentioned adjuvant to there is unstability, in depositing for avoiding the medicine variable color to need low temperature storage, find after deliberation the oxalic acid in the oxaliplatin raw material, silver nitrate, the existence of the impurity such as two hydroxo oxaliplatins, two water diamidogen cyclohexane extraction platinum has affected the stability of oxaliplatin product, and this is because method in the preparation of existing oxaliplatin raw material determines.
The oxaliplatin injection needle injection is intravenous injection, higher to the purity requirement of its crude drug, and total impurities content should be less than 1% according to pharmacopeia, and wherein the content of each related impurities all should be less than 0.1%.But it is recrystallization solvent that prior art adopts water or ethanol, though after recrystallization, the content of oxaliplatin is greater than 99%, wherein the content of the related impurities of 1 unknown structure is greater than 0.2%.
For overcoming the problem of impurity content, we use new recrystallization reagent to carry out remove impurity to oxaliplatin impurity, finally obtain a kind of high-quality oxaliplatin, its content is more than 99.5%, the oxaliplatin injection needle injection good stability prepared with this raw material, without cryopreservation, place for a long time also invariant color.
Summary of the invention:
The invention provides a kind of preparation method of oxaliplatin injection needle injection, the method comprises the following steps:
1) recrystallization of oxaliplatin, adopt isopropyl alcohol and acetonitrile 1:3(v/v) carry out recrystallization to purchasing available oxaliplatin, method is as follows: by the crude product oxaliplatin (purity 98.6%) of buying on market, isopropyl alcohol and acetonitrile 1:3(v/v by 30 times of amounts (w/v)) mixed solvent recrystallization 2 times, all use 1%(g/ml at every turn) active carbon boils, filters, cooling crystallization, filter, drying, obtain oxaliplatin crystalline powder (purity 99.6%);
2) preparation of oxaliplatin injection needle injection, method is as follows:
Get recipe quantity oxaliplatin and lactose and add 90% water for injection, heated and stirred is to dissolving (heating-up temperature remains on below 80 ℃) fully; Let cool to room temperature, with 0.1mol/L sodium hydroxide solution regulator solution pH value to 5.0-7.0, inject water and be dissolved to full dose, then use 0.22 μ m filter membrane aseptic filtration to clear and bright, the intermediate check, fill, lyophilizing, gland, lamp inspection, packing gets final product.
Above-mentioned preparation method of the present invention obtains through screening, and screening process is as follows:
The thick product of the commercially available oxaliplatin of table 1 is processed the content of impurity in rear each sample with different solvents
| Solvent | Impurity (%) |
| Water | 0.96 |
| Ethanol | 0.85 |
| Methanol | 0.84 |
| Isopropyl alcohol | 0.67 |
| Acetonitrile | 0.80 |
| Isopropyl alcohol and acetonitrile (1:1) | 0.73 |
| Isopropyl alcohol and acetonitrile (2:1) | 0.62 |
| Isopropyl alcohol and acetonitrile (3:1) | 0.46 |
| Isopropyl alcohol and acetonitrile (1:2) | 0.61 |
| Isopropyl alcohol and acetonitrile (1:3) | 0.75 |
Above result demonstration, isopropyl alcohol and acetonitrile (3:1) purification effect is best, and the product that the method obtains detects through HPLC, oxalic acid, silver nitrate, the content of two hydroxo oxaliplatins, four kinds of impurity of two water diamidogen cyclohexane extraction platinum all is less than 0.1%.
Study on the stability:
Purchase available preparation on preparation prepared by the method in the embodiment of the present invention and market and carry out accelerated stability contrast investigation, sample is placed in 40 ℃ of incubators, measure the content of oxaliplatin by the HPLC method, observe the color and luster of sample simultaneously, result is as follows:
Table 2
Long-term stable experiment
By test agent in three batches of Oxaliplatin for Injections, by intending the listing packing, three batches of Oxaliplatin for Injections that prepare by prior art of another preparation, put equally 25 ℃ ± 2 ℃, in the climatic chamber of RH60% ± 10%, respectively at sampling in 3,6,9,12,18,24 months, the character of sample for reference, acidity, clarity and color, visible foreign matters, related substance and content.0 month measurement result of measurement result and sample compares.Result shows: this product investigation in 12 months that keeps sample through for a long time, indices with 0 month and commercially availablely contrast relatively indifference of medicine, but sampling in the time of 24 months, sample size of the present invention is stable, change minimum, but prior art products content descend obviously, the color jaundice.Conclusion: Oxaliplatin for Injection three batch samples (20090501,20090502,20090503) were through accelerated test and long-term reserved sample observing 6 months, show that this product is stable under the room temperature preservation condition, according to tentative this product effect duration effect duration of listing medicine be 24 months.
The present invention also screens the formula of preparation, and the selection result is as follows:
Quantity of solvent is investigated
According to oxaliplatin national drug standards WS
1-(X-117)-2003Z, this product character is white or off-white color crystalline powder, slightly soluble in water.Therefore, in the situation that the oxaliplatin consumption is fixing, the optimum amount of water for injection (solvent) is investigated.According to result of the test, we determine that this product quantity of solvent 100ml/500mg is comparatively suitable, i.e. the 10ml/ bottle.Amount of excipient is determined
This product has selected lactose as this product excipient.Its consumption in prescription screens according to test.The result of the test demonstration, the clarity of character, solubility and the solution of lactose consumption freeze-dried products when 2.5%-4.5% and color are all good.Consider, with the low dosage person of choosing under texts, finally determine that the lactose consumption is 3.5%(w/v, g/ml).
Heating-up temperature is investigated
Therefore known according to the oxaliplatin physicochemical property, this product is slightly soluble in water, in the ingredients process, in order to guarantee crude drug, dissolves fast, adopts heating for dissolving and investigate the heating for dissolving temperature while being 50 ℃ and 80 ℃ the impact on product quality.By writing out a prescription respectively preparating liquid letting cool to room temperature, adjust pH to 6.0 with the 0.1mol/L sodium hydroxide solution, inject water and be dissolved to full dose, then use 0.22 μ m filter membrane aseptic filtration, fill, lyophilizing.Sample after lyophilizing has been carried out checking contrast.Result shows: this product preparation heating-up temperature when ingredients is 50 ℃ and 80 ℃, the equal no significant difference of the clarity of the character of sample, visible foreign matters, acidity, solution and color, related substance and content after lyophilization, the equal conformance with standard regulation of quality.Illustrate that the oxaliplatin raw material is more stable to ratio of specific heat.In order to guarantee product quality, thus determine this product when ingredients heating and temperature control below 80 ℃.
The pH value scope is investigated
According to Oxaliplatin for Injection import standard pH value scope, be (4.0 ~ 7.0), by prescription preparating liquid, the sample liquid (4.00 ~ 7.00) that is adjusted to different pH value with sodium hydroxide solution and the hydrochloric acid solution of 0.1mol/L, filtration, fill, lyophilizing.Sample after lyophilizing is accelerated to investigate (40 ± 2 ℃).According to result of the test and with reference to the Oxaliplatin for Injection WS1-(X-090 that goes on the market)-2003 quality standards, determine that this product pH value scope is between 5.0～7.0.
Active carbon is investigated
In the injection preparation process, generally need to add a certain amount of active carbon to adsorb impurity, decolouring, remove endotoxin etc., so my company is while being studied this product production technology, also whether active carbon added and how many additions has carried out comparative study.Result of the test shows: whether active carbon adds character, clarity and color, visible foreign matters and other related substance item etc. to this product not make significant difference, so this product does not add active carbon while producing.Refer to data 8.
Determining of lyophilizing program
Sample is put in household freezer, after pre-freeze to temperature is-45 ℃ of left and right, then kept freezing about 3 hours; Evacuation afterwards, and be warming up to 0 ℃ with 1 ℃/h of left and right, for making moisture in goods, reduce, be rapidly heated to 40 ℃ with 5 ℃/hs of left and right, then be incubated more than 6 hours, to eliminate moisture, get final product.
The hemolytic test:
This laboratory observation Oxaliplatin for Injection have or not haemolysis.
Experimentation:
Prepare 2% red cell suspension:
Get a Sanguis Leporis seu oryctolagi 10ml, put into the conical beaker jolting 10min that cleaning fills glass bead, after removing Fibrinogen, add 10 times of amount normal saline (0.9%), shake up, with the centrifugal 15min of 2000r/min, abandoning supernatant, the precipitation erythrocyte, then use the normal saline cyclic washing to till the supernatant redfree, measure blood cell, with normal saline, be configured to 2% red cell suspension.
Method of testing:
Get 7 of clean tube, be numbered, No. 1-5 pipe is test sample pipe, No. 6 negative control tube, No. 7 positive control tube.Add successively 2% red cell suspension and normal saline by table 4 proportional quantity, after mixing, place 30min in 37 ℃ ± 0.5 ℃ water bath with thermostatic control, then add respectively not commensurability Oxaliplatin for Injection, the 6th pipe does not add medicinal liquid and adds normal saline and do the negative control pipe, the 7th pipe does not also add medicinal liquid, normal saline changes adding distil water, does the positive control pipe, after each test tube all shakes up, put in 37 ℃ ± 0.5 ℃ water bath with thermostatic control, start to observe put into rear 15min, 30min, 45min, 1h, 2h, 3h, 4h has or not haemolysis to occur.
Experimental result shows: Oxaliplatin for Injection joins 15min, 30min after 2% rabbit erythrocyte suspension, 45min, 1h, 2h, 3h, 4h and the transparent and flocculent deposit of red cell suspension all do not occur, shows that this batch of preparation do not have haemolysis and erythroagglutination.
Vascular stimulation tests:
This laboratory observation the Oxaliplatin for Injection auricular vein injection impact on family's rabbit ear blood vessel.
Experimental technique: get 6 of rabbit, male, body weight 2.5-3.0kg, divide two groups, 3 every group.For the reagent group with constant flow pump to the slow injection injection oxaliplatin of the left ear auricular vein of rabbit 5ml/ only, within 10 minutes, injected, negative control group is with same administering mode intravenous injection 5% glucose solution, all every three days once, continuous four times, 48h before each administration and after last administration, 96h carries out perusal ear local vascular to the animal injection site and stimulates situation, after observing end, put to death 2 rabbit for every group, clip injection site ear, put into 10% formalin fixing, paraffin embedding, section, HE dyeing, observe blood vessel under light microscopic and have or not degeneration and tissue necrosis, remaining 1 rabbit was put to death afterwards in 14 days, clip injection site ear, put into 10% formalin fixing, paraffin embedding, section, HE dyeing, observe blood vessel under light microscopic and have or not degeneration and tissue necrosis.
Experimental result: do the cut sections for microscopic examination of rabbit ear vascular pathological after continuous four administrations, have no necrosis and degeneration.
Point out this batch of Oxaliplatin for Injection intravenous injection without obviously vascular stimulation reaction.
The specific embodiment:
Further illustrate by the following examples the present invention, but not as limitation of the present invention.
The preparation of oxaliplatin injection needle injection
1) recrystallization of oxaliplatin, adopt isopropyl alcohol and acetonitrile 1:3(v/v) carry out recrystallization to purchasing available oxaliplatin, method is as follows: by crude product oxaliplatin (purity 98.6%), isopropyl alcohol and acetonitrile 1:3(v/v by 30 times of amounts (w/v)) the mixed solvent heating for dissolving, adding subsequently 1%(g/ml) active carbon boils 1 hour, filtered while hot, solution cooling crystallization, obtain oxaliplatin crystallization (yield 95.8%, purity 99.6%);
2) preparation of oxaliplatin injection needle injection, method is as follows:
Get recipe quantity oxaliplatin and lactose and add 90% water for injection, heated and stirred is to dissolving (heating-up temperature remains on below 80 ℃) fully; Let cool to room temperature, with 0.1mol/L sodium hydroxide solution regulator solution pH value to 5.0-7.0, inject water and be dissolved to full dose, then use 0.22 μ m filter membrane aseptic filtration to clear and bright, the intermediate check, fill, lyophilizing, gland, lamp inspection, packing gets final product.
Claims (1)
1. the preparation method of an oxaliplatin injection needle injection, the method comprises the following steps:
1) recrystallization of oxaliplatin: adopt isopropyl alcohol and acetonitrile 3:1 to carry out recrystallization to purchasing available oxaliplatin, method is as follows: by the crude product oxaliplatin, with the mixed solvent recrystallization of the isopropyl alcohol of 30 times of amounts and acetonitrile 3:1 2 times, add subsequently 1% active carbon to boil 1 hour, filtered while hot, the solution cooling crystallization, filter, drying, obtain the oxaliplatin crystalline powder;
2) preparation of oxaliplatin injection needle injection:
Get oxaliplatin and lactose and add 90% water for injection, heated and stirred is to dissolving fully, and wherein heating-up temperature remains on below 80 ℃; Let cool to room temperature,, inject water and be settled to full dose to 5.0-7.0 with 0.1mol/L sodium hydroxide solution regulator solution pH value, then use 0.22 μ m filter membrane aseptic filtration to clear and bright, the intermediate check, fill, lyophilizing, gland, lamp inspection, packing gets final product.
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| CN104829653B (en) * | 2015-05-06 | 2016-03-23 | 山东罗欣药业集团股份有限公司 | A kind of oxaliplatin hydrate crystal and lyophilized injectable powder thereof |
| CN104945443A (en) * | 2015-07-23 | 2015-09-30 | 青岛蓝盛洋医药生物科技有限责任公司 | Drug, namely oxaliplatin compound, for treating cancer |
| CN105055324A (en) * | 2015-09-23 | 2015-11-18 | 青岛华之草医药科技有限公司 | Platinum anticancer oxaliplatin composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101289468A (en) * | 2008-05-19 | 2008-10-22 | 昆明贵金属研究所 | New oxaliplatin derivate |
| CN102643308A (en) * | 2012-05-11 | 2012-08-22 | 海南锦瑞制药股份有限公司 | Oxaliplatin crystal compound and freeze-dried powder injection |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101289468A (en) * | 2008-05-19 | 2008-10-22 | 昆明贵金属研究所 | New oxaliplatin derivate |
| CN102643308A (en) * | 2012-05-11 | 2012-08-22 | 海南锦瑞制药股份有限公司 | Oxaliplatin crystal compound and freeze-dried powder injection |
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