CN102151243B - Paclitaxel injection and preparation method thereof - Google Patents

Abstract

The invention belongs to the technical field of medicine, and particularly relates to a paclitaxel injection and a preparation method thereof. The invention provides a paclitaxel injection having stable quality and low toxicity. The paclitaxel injection provided by the invention contains paclitaxel, polyglycol 15-hydroxystearate, anhydrous alcohol and one or more of citric acid, hydrochloric acid, tartaric acid and malic acid. The preferable formula of the paclitaxel injection comprises 5.4-6.6mg/ml paclitaxel, 5-80(V/V) polyglycol 15-hydroxystearate, 20-95%(V/V) anhydrous alcohol and 0.005-0.02%(mg/ml) citric acid.

Description

A kind of paclitaxel injection and preparation method thereof

Technical field

The invention belongs to medical technical field, particularly, the present invention relates generally to a kind of paclitaxel injection, and the present invention provides its preparation method simultaneously.

Background technology

Paclitaxel (Paolitaxel, trade name Taxol)) be isolated Diterpenoids from bulbus with unique texture from taxaceae platymiscium yewtree, its skeleton is named as taxane (taxane).Extremely pay attention to clinically due to its unique pharmacological action and curative effect.On December 29th, 1992, and U.S. FDA official approval paclitaxel is as the novel anti-tumor medicine listing for the treatment of advanced ovarian cancer, and the chief Bai Luode of American Cancer Society (Brode) is described as paclitaxel the topmost anti-cancer agent of finding over nearly 15 years.After this people are at its pharmacology action, and the research of the aspect such as medicine source makes great progress.Present this product clinical a line and second line treatment for ovarian cancer and breast carcinoma and NSCLC.Head and neck cancer, the esophageal carcinoma, spermocytoma, recurrence Fei Hejin lymphomas etc.

Paclitaxel is a kind of medicine of antitumaous effect mechanism uniqueness, be that this product is a kind of novel class microtubule medicine, can promote the microtubule dimer to be assembled into microtubule, then by stoping microtubule depolymerization to make microtubule stable. this kind stability action can suppress microtubule net normal gravity and learn restructuring.The microtubule net to be reassembled as cell life cycle and cell division function institute essential.The antitumaous effect mechanism of paclitaxel is mainly to make the mitosis of tumor cell stop and make apoptosis of tumor cells by suppressing the depolymerization of microtubule net, causes at last death of neoplastic cells.It is reported paclitaxel except the resisting mitosis effect is arranged, also have the antitumor action of activating macrophage mediation ^[1]

Studies show that, paclitaxel injection in vivo, external obvious antitumor action is arranged all, and antitumor spectra is wide, belongs to cell toxicant class PTS.Be used for clinically the treatment of kinds cancer.

Mention in present numerous patent and adopt polyoxyethylene castor oil and dehydrated alcohol (1: 1) preparation paclitaxel injection, but because can causing in-vivo tissue amine, polyoxyethylene castor oil itself discharges, after administration number minute, cause the part patient anaphylaxiss such as drug eruption, rapid breathing, bronchospasm to occur.Present clinical use is reacted for Polyglucan, and the oral dexamethasone 20mg respectively front 12 hours of paclitaxel treatment and 6 hours treats intramuscular injection in front 30 minutes～60 minutes or oral diphenhydramine 50mg, quiet notes cimetidine 300mg or ranitidine 500mg.Make so whole process very inconvenient and need careful monitoring medication process.And the paclitaxel injection of the HS15 production of mentioning in the use this patent can be avoided above problem just.

Summary of the invention

The present invention seeks to overcome the prior art deficiency, a kind of steady quality and hypotoxic paclitaxel injection are provided.

The invention provides a kind of preparation method of paclitaxel injection, the paclitaxel injection that adopts the method to produce has solved the toxicity problem that present paclitaxel injection exists in clinical practice.

Paclitaxel injection of the present invention contains one or more in paclitaxel, HS15, dehydrated alcohol and citric acid, hydrochloric acid, tartaric acid and malic acid.

Paclitaxel injection of the present invention, optimizing prescriptions is: contain content of taxol 5.4-6.6mg/ml, HS15 content is 5～80 (V/V), and dehydrated alcohol content is 20～95% (V/V), and citric acid content is 0.005%～0.02% (mg/ml).

Paclitaxel injection of the present invention, best prescription is: containing content of taxol is 6mg/ml, and HS15 content is 50% (V/V), and dehydrated alcohol is 50% (V/V), and citric acid is 0.015%.

The invention described above paclitaxel injection, citric acid wherein can replace with hydrochloric acid.

The invention described above paclitaxel injection, citric acid wherein can replace with tartaric acid.

The invention described above paclitaxel injection, citric acid wherein can replace with malic acid.

The invention provides a kind of preparation method of paclitaxel injection, wherein comprise following preparation process:

Embodiment one:

1. get the paclitaxel of appropriate anhydrous alcohol solution recipe quantity, get solution A;

2. the HS15 of getting recipe quantity adds in mentioned solution, gets solution B;

3. prepare 1% anhydrous citric acid alcoholic solution, the mentioned solution pH regulator between 3.0-5.0, is got solution C;

4. add ethanol solution to the full dose of preparing liquid in mentioned solution, stir evenly, get solution D;

5. get solution D, conventional method is filtered, fill, and sterilization, packing namely gets paclitaxel injection of the present invention.

In above-mentioned preparation method step, step 5. in, citric acid solution is regulated pH value preferably to 3.5-4.5.

Implement two:

1. get the paclitaxel of appropriate anhydrous alcohol solution recipe quantity, get solution A;

2. the HS15 of getting recipe quantity adds in mentioned solution, gets solution B;

3. prepare 1% hydrochloric acid ethanol solution, the mentioned solution pH regulator between 3.0-5.0, is got solution C;

4. add ethanol solution to the full dose of preparing liquid in mentioned solution, stir evenly, get solution D;

5. get solution D, conventional method is filtered, fill, and sterilization, packing namely gets paclitaxel injection of the present invention.

In above-mentioned preparation method step, step 5. in, citric acid solution is regulated pH value preferably to 3.5-4.5.

Implement three:

1. get the paclitaxel of appropriate anhydrous alcohol solution recipe quantity, get solution A;

2. the HS15 of getting recipe quantity adds in mentioned solution, gets solution B;

3. prepare 1% tartaric acid ethanol solution, the mentioned solution pH regulator between 3.0-5.0, is got solution C;

4. add ethanol solution to the full dose of preparing liquid in mentioned solution, stir evenly, get solution D;

5. get solution D, conventional method is filtered, fill, and sterilization, packing namely gets paclitaxel injection of the present invention.

In above-mentioned preparation method step, step 5. in, citric acid solution is regulated pH value preferably to 3.5-4.5.

Implement four:

1. get the paclitaxel of appropriate anhydrous alcohol solution recipe quantity, get solution A;

2. the HS15 of getting recipe quantity adds in mentioned solution, gets solution B;

3. prepare 1% malic acid ethanol solution, the mentioned solution pH regulator between 3.0-5.0, is got solution C;

4. add ethanol solution to the full dose of preparing liquid in mentioned solution, stir evenly, get solution D;

5. get solution D, conventional method is filtered, fill, and sterilization, packing namely gets paclitaxel injection of the present invention.

In above-mentioned preparation method step, step 5. in, citric acid solution is regulated pH value preferably to 3.5-4.5.

Invention description:

The HS15 ester is recorded by " European Pharmacopoeia " latest edition at present.HS15 is a kind of nonionic solubilizer and emulsifying agent, is made by 12 hydroxy stearic acids reactions of the oxirane of 15 moles and 1 mole.Viscosity pole is low, but still intramuscular injection when 30% concentration.

In order to illustrate that paclitaxel injection of the present invention has good stability and safety, according to embodiment 1 preparation paclitaxel injection of the present invention, sterilising conditions is selected 115 ℃ of pressure sterilizing 30min, gets product one of the present invention.Place it in room temperature environment, during respectively at firm placement, place sample thief check in 3,6,12,24 months, observe its outward appearance and measure content of taxol and its related substances, result of the test is as follows:

Table 1 paclitaxel injection room temperature is investigated the stability test result

As can be seen from Table 1, paclitaxel injection of the present invention is after room temperature is deposited 24 months, and product content and related substance do not change than basic with depositing preliminary phase, illustrate that quality stability of the present invention is good.

Get 6 of the healthy new zealand rabbits of body weight 2.6-3.0kg, provided by the anti-Pharmaceutical Group company limited in Shandong, Shandong, the male and female dual-purpose is divided into two groups, i.e. medicine group and matched group at random.Rabbit is placed in holder, the left auricular vein instillation of medicine group rabbit product one 10ml/kg of the present invention, the left auricular vein instillation of matched group rabbit 0.9% normal saline 10ml/kg, drip velocity is 20/min, administration in morning every day 1 time, for three days on end.During instillation and after instiling, note observing the instillation position and have or not redness, hyperemia, the stimulation such as hemorrhage and downright bad.In the last administration after 24 hours, with sacrifice of animal, cut rabbit you put and fixedly send pathology to carry out histopathologic examination in 10% formalin from proximal part 1cm place, drop position.

Result of the test:

Perusal: the irritant reaction such as obvious redness, hyperemia, necrosis do not appear in instillation product of the present invention one rabbit ear position, with the rabbit ear no significant difference of the 0.9% sodium chloride injection group that instils.

Pathological examination: 0.9% sodium chloride injection matched group: sending specimen is rabbit ear tissue.The skin histology structure is normal, and epidermis is without thickening, and subcutaneous tissue has no the morphological changes such as hyperemia, edema.Auricular vein has no expansion, and vascular endothelial cell also has no and increases and the change such as arrangement disorder, and blood vessel wall is without thickening, in official jargon without changes such as mural thrombus and inflammatory cell infiltrations.

Product one administration group of the present invention: the same matched group of microscopy rabbit ear tectology, tube wall has no mural thrombus, and the significances such as inorganization degeneration or necrosis stimulate, without obviously pathomorphology change.

Conclusion: intravenous drip product one of the present invention is without obviously vascular stimulation effect.

Get the Cavia porcellus body weight between 255-345g, provided by the anti-Pharmaceutical Group company limited in Shandong, Shandong, totally 18 of male and female dual-purposes are divided into negative control (0.9% sodium chloride injection) group, tested material group and positive control (5% ovalbumin normal saline) group, 6 every group.The corresponding Pharmaceutical 0.5ml/ of each animal every other day lumbar injection, continuous 3 times.Only get 3 corresponding medicinal liquid 1ml/ of Cavia porcellus intravenous injection injecting for the first time every group of rear 14 days and 21 day respectively, observe that in rear 15 minutes of injection, each Cavia porcellus has or not anaphylaxis.

The results are shown in following table:

Conclusion: the paclitaxel injection Hypersensitive tests result is negative.

Getting the New Zealand white rabbit body weight is between 3kg, and cardiac puncture blood sampling 10ml is provided by the anti-Pharmaceutical Group company limited in Shandong, Shandong, put into the triangular flask jolting 10 minutes that fills sterile glass beads, except defibrinating, make into defibrinated blood, add appropriate normal saline to graduated centrifuge tube, centrifugal with 3000 rev/mins, abandoning supernatant, cyclic washing 3-4 time, to centrifugal rear supernatant colourless till, the gained erythrocyte is made into 2% red blood cell suspension with normal saline, and test is used altogether.

Get 7, test tube, press table 1 proportioning and just love red cell suspension, normal saline or the distilled water as 2%, then add respectively not commensurability test sample, after shaking up, put 37 ℃ of water-baths, observe respectively each pipe and had or not haemolysis and hemagglutination at 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours.The results are shown in Table 2.

Table 1: paclitaxel injection hemolytic test application of sample table

Table 2: paclitaxel injection hemolytic test result

Conclusion: paclitaxel injection produced without haemolysis and hemagglutination within observing time, illustrated that paclitaxel injection hemolytic test result is negative.

The invention has the beneficial effects as follows by adopting HS15 to replace traditional polyoxyethylene castor oil, solved the toxic and side effects that the polyoxyethylene castor oil intravenous injection produces, increased the safety of clinical application.Do experiment with Canis familiaris L., above-mentioned two kinds of materials are given respectively the dosage of 100mg/kg, the histamine release situation is as follows:

Claims (3)

1. the preparation method of a paclitaxel injection is characterized in that comprising following preparation process:

1. get the paclitaxel of appropriate anhydrous alcohol solution recipe quantity, get solution A;

2. Polyethylene Glycol 15 hydroxystearic acids of getting recipe quantity add in mentioned solution, get solution B;

3. prepare 1% anhydrous citric acid alcoholic solution, the mentioned solution pH regulator between 3.5-4.5, is got solution C;

4. add ethanol solution to the full dose of preparing liquid in mentioned solution, stir evenly, get solution D;

5. get solution D, conventional method is filtered, fill, and sterilization, packing namely gets paclitaxel injection;

Described paclitaxel injection each component content is: paclitaxel 5.4～6.6mg/ml, Polyethylene Glycol 15 hydroxystearic acids 5～80 (V/V), dehydrated alcohol 20～95% (V/V), citric acid 0.005%～0.02% (mg/ml).

2. the preparation method of a paclitaxel injection is characterized in that comprising following preparation process:

1. get the paclitaxel of appropriate anhydrous alcohol solution recipe quantity, get solution A;

2. Polyethylene Glycol 15 hydroxystearic acids of getting recipe quantity add in mentioned solution, get solution B;

3. prepare 1% tartaric acid ethanol solution, the mentioned solution pH regulator between 3.5-4.5, is got solution C;

4. add ethanol solution to the full dose of preparing liquid in mentioned solution, stir evenly, get solution D;

5. get solution D, conventional method is filtered, fill, and sterilization, packing namely gets paclitaxel injection;

Described paclitaxel injection each component content is: paclitaxel 5.4～6.6mg/ml, Polyethylene Glycol 15 hydroxystearic acids 5～80 (V/V), dehydrated alcohol 20～95% (V/V), tartaric acid 0.005%～0.02% (mg/ml).

3. paclitaxel injection preparation method is characterized in that comprising following preparation process:

1. get the paclitaxel of appropriate anhydrous alcohol solution recipe quantity, get solution A;

2. Polyethylene Glycol 15 hydroxystearic acids of getting recipe quantity add in mentioned solution, get solution B;

3. prepare 1% malic acid ethanol solution, the mentioned solution pH regulator between 3.5-4.5, is got solution C;

4. add ethanol solution to the full dose of preparing liquid in mentioned solution, stir evenly, get solution D;

5. get solution D, conventional method is filtered, fill, and sterilization, packing namely gets paclitaxel injection;

Described paclitaxel injection each component content is: paclitaxel 5.4～6.6mg/ml, Polyethylene Glycol 15 hydroxystearic acids 5～80 (V/V), dehydrated alcohol 20～95% (V/V), malic acid 0.005%～0.02% (mg/ml).