CN102988285A - Docetaxel injection composition and preparation method thereof - Google Patents
Docetaxel injection composition and preparation method thereofDownload PDFInfo
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- CN102988285A CN102988285ACN2012105387030ACN201210538703ACN102988285ACN 102988285 ACN102988285 ACN 102988285ACN 2012105387030 ACN2012105387030 ACN 2012105387030ACN 201210538703 ACN201210538703 ACN 201210538703ACN 102988285 ACN102988285 ACN 102988285A
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Abstract
Description
Technical field
The present invention relates to a kind of field of pharmaceutical preparations, particularly a kind of safe, stable docetaxel injection composition and method of making the same.
Background technology
Docetaxel (English name Docetaxel), chemical name is: [2aR-[2a α, 4 β, 4a β, 6 β, 9 α, (α R ', β S '), 11 α, 12 α, 12a α, 12b α)]-β-[[(1,1-dimethyl ethyoxyl) carbonyl] amino]-alpha-carbonyl benzenpropanoic acid [12b-acetyl oxygen-12-benzoxy-2a, 3,4,4a, 5,6,9,10,11,12,12a, 12b-ten dihydros-4,6,11-trihydroxy-4a, 8,13,13-tetramethyl-5-oxo-7,11-methylene-1H-ring pentaene in the last of the ten Heavenly stems is [3,4] benzo [1,2-b] oxa-fourth ring-9-yl also] ester.Chemical structural formula:
Docetaxel is the taxanes antineoplastic agent, plays antitumor action by interference cell mitosis and the necessary microtubule network of inerphosei cells function.Docetaxel can with free tubulin binding, promote that tubulin is assembled into stable microtubule, suppress simultaneously its depolymerization, caused losing the fixing of the generation of microtubule fasolculus of normal function and microtubule, thereby suppressed the mitosis of cell.
Concrete indication is as follows:
Breast carcinoma
1. be applicable to the treatment of local late period or metastatic breast cancer.
2. docetaxel associating Herceptin is used for the metastatic breast cancer patient's of HER2 Overexpression treatment, and this type of patient did not accept the metastatic cancer chemotherapy in advance.
3. docetaxel associating amycin and ring phosphamidon copy chemotherapy for patient with breast cancer's postoperative of the lymph node positive.
Nonsmall-cell lung cancer
Be applicable to the treatment of local late period or transitivity non-small cell carcinoma, even failed take cisplatin as main chemotherapy.
Carcinoma of prostate
Docetaxel associating prednisone or meticortelone are used for the treatment of the hormone refractory metastatic prostate cancer.
The morning of this drug development, in U.S.'s listing, entered China in 1996, at present in the listing of many countries as far back as 1992.Because degraded is fast when entering body-internal-circulation, dosage is larger during use, and side effect is more.
But owing in the docetaxel indissoluble water, must add the solubilizing agent polyoxyethylene sorbitan monoleate, satisfy the requirement of clinical administration.Domestic listing docetaxel injection needed in temperature (2 ~ 8 ℃) storage, 24 months effect duration.Product transport, product store up and use very inconvenient.Polyoxyethylene sorbitan monoleate is as often freeing haemolysis and irritated untoward reaction in the clinical use procedure of insoluble drug solubilizing agent, bring unsafe hidden danger for clinical use, Solutol HS15 (Solutol HS15) is a kind of solubilizing agent by BASF AG's research and development, the standard that meets modern solubilizing agent, and by the injectable drug checking, this product is incorporated in the Deutscher Arzneibucs.
The present invention finds by research: with a certain amount of Solutol HS15 as solubilizing agent and stabilizing agent, substitute polyoxyethylene sorbitan monoleate, thereby the product chemical stability is significantly increased, reduce the generation of the untoward reaction of polyoxyethylene sorbitan monoleate, strong guarantee clinical safety, and can extend to 36 months from original 24 months in conventional temperature (2 ~ 25 ℃) lower storage period, product quality still meets the national drug standards, and (the empirical tests sterilization F that adopted first the rotary water bath sterilization in docetaxel injection preparation technology0Value is greater than 12, for excessively killing method), increase substantially the clinical drug safety in utilization.
In order to overcome the shortcoming of existing commercially available prod, obtain safer, stable docetaxel injection prescription and preparation method, we have carried out conscientiously research to docetaxel injection prescription and preparation method.Adopt the single factor design method, the use of the used solubilizing agent of docetaxel injection and stabilizing agent Solutol HS15 (Solutol HS15) has been carried out investigating (and with commercial preparation prescription contrast).By the character to product, pH value and docetaxel degradation rate are evaluation index with the docetaxel injection of different solubilizing agent ratios preparation, and preferred solubilizing agent ratio is prepared the preparation that can achieve the above object, thereby finished the present invention.
Summary of the invention
The object of the present invention is to provide a kind of steady quality, safe and reliable docetaxel injection.
Below the present invention is described in detail.
Docetaxel injection provided by the invention is take docetaxel as active component, and dehydrated alcohol is that solvent, Solutol HS15 are solubilizing agent and stabilizing agent, are prepared from as pH adjusting agent with anhydrous citric acid.
For this reason, the invention provides a kind of docetaxel injection compositions, it is composed as follows:
Its concentration range of principal agent docetaxel is 20 ~ 60mg/ml;
The proportion of principal agent and solvent dehydrated alcohol is 1:1 ~ 1:50(g/ml)
The ratio of principal agent and Solutol HS15, its proportion are 1:1 ~ 1:50(g/ml);
The pH adjusting agent anhydrous citric acid is 3 to 4.5 with the scope of its regulator solution pH;
Most preferred docetaxel that injecta composition, its prescription is composed as follows:
Its concentration of principal agent docetaxel is 20mg/ml or 40mg/ml;
The proportion of principal agent and solvent dehydrated alcohol is respectively 1:25(g/ml);
The proportion of principal agent and Solutol HS15 is respectively 1:25(g/ml);
The pH adjusting agent anhydrous citric acid is 3.7 with the scope of its regulator solution pH.
Another object of the present invention is to provide the preparation method of docetaxel injection, comprises the steps:
(a) it is for subsequent use to take by weighing respectively docetaxel, dehydrated alcohol (injection), the Solutol HS15 (injection) of recipe quantity;
(b) docetaxel is added in the dehydrated alcohol (injection), then in airtight container, be stirred to whole dissolvings;
(c) Solutol HS15 is heated 50-60 ℃ of dissolving, join in the dehydrated alcohol of the pastille for preparing mix homogeneously;
(d) regulate pH value to 3.7 with the citric acid soln for preparing in advance, fill the nitrogen fill to the 7ml cillin bottle, half tamponade;
(e) place in the freeze dryer, remove ethanol;
(f) sample behind the Zha Gai is put in the rotary water bath formula sterilizing cabinet, adopted and excessively to kill the method sterilization, sterilising conditions is selected from 121 ℃ of lower sterilizations 12 minutes, a kind of in 126 ℃ of lower sterilizations 4 minutes.After sterilization, namely get docetaxel and penetrate liquid.
Wherein, the citric acid soln of regulating in the pH value with citric acid soln is in advance preparation, can be mixed with the solution of 0.5-2N concentration, with conventional method citric acid soln is joined in the drug solution, and the pH value of regulator solution stops to add to suitable making.
Also can calculate the addition of anhydrous citric acid according to equivalent calculation, directly and the pH that obtains of medicine and solvent be gained.
Composition and engineering method of the present invention obtains through screening, and screening process is as follows:
The screening of prescription: according to (trade name: taxotere) description is determined this product write out a prescription each supplementary material and amount ranges thereof according to the product that gone on the market.Wherein solubilizer polyethylene glycol stearate 15 equal-volumes are substituted polyoxyethylene sorbitan monoleate.
The screening of technique: mainly done following two kinds of technical studies
1, the investigation of material dissolution stirring frequency, time:
Take by weighing docetaxel and the dehydrated alcohol of recipe quantity, the raw material docetaxel is joined in the dehydrated alcohol, take mixing time, material dissolution situation as evaluation criteria, concrete outcome sees the following form.
The investigation of material dissolution stirring frequency, time
Experiment conclusion: by different stirring frequency are investigated and the material dissolution situation, so we determine final stirring frequency
1200～1500rpm, mixing time 15min.
2, except ethanol optimization screening:
This product has added dehydrated alcohol as solvent in process for preparation, docetaxel is unstable in ethanol, and impurity obviously increases, and enters and may have a negative impact to health in the body.Therefore this technique is removed ethanol, and for removing ethanol in the finished product, we have carried out corresponding craft screening.
In order to guarantee gnotobasis, so that drug safety, we select freeze dryer as the equipment except ethanol, control the residual quantity of ethanol by control the temperature inside the box and pumpdown time.The below adopts different the temperature inside the box, pumpdown time, investigates as foundation with alcohol residue.
Except the ethanol the selection result
Conclusion: show by experiment temperature at 35 ℃, the pumpdown time can be removed ethanol more than 21 hours, shortens the pumpdown time when removing ethanol satisfying, and makes things convenient for suitability for industrialized production.
The docetaxel injection of technical solution of the present invention preparation is compared with existing commercially available docetaxel injection product, can place 2-25 ℃ of preservation, can significantly strengthen its safety and stability.
Below further specify beneficial effect of the present invention by test data:
The test of test example 1 sterilization stability
Docetaxel injection sample to embodiment 1, embodiment 2 and comparative example 1 preparation is estimated, and investigates preparation character, pH value and docetaxel degradation rate.The results are shown in Table 1.
The stability of the different prescription of table 1 docetaxel injection
| Detect index | Embodiment 1 | Embodiment 2 | Comparative example 1 |
| Character | The white oily liquids | The white oily liquids | The white oily liquids |
| PH value | 3.71 | 3.52 | 3.6 |
| Degradation rate | 6.2% | 6.5% | 15.6% |
By as seen from Table 1, the sample of the more commercially available formula preparation of docetaxel injection of the present invention's preparation is at aspects such as safety and stabilities, performance better.
The test of test example 2 storage-stables
The docetaxel injection preparation of embodiment 1, embodiment 2 and comparative example 1 preparation was preserved 24 months under temperature (2 ~ 25 ℃), take content, total impurities as investigating index, carried out long-time stability and investigate test.The results are shown in Table 2.
Table 2 different prescription docetaxel injection long-time stability under 2 ~ 25 ℃ of holding conditions
| Minute | Embodiment 1 | Embodiment 2 | Comparative example 1 |
| 0 month | 6..2% | 6.5% | 15.6% |
| March | 6..8% | 7.0% | 16.7% |
| June | 7.0% | 7.1% | 19.5% |
| JIUYUE | 7.2% | 7.4% | 22.5% |
| December | 7.8% | 8.0% | 25.2% |
| 18 months | 8.0% | 8.2% | 28.3% |
| 24 months | 8.5% | 8.6% | 36.4% |
| 36 months | 9.0% | 9.1% | 39.2% |
| 36 months content of drug | 91.0% | 90.9% | 60.8% |
By as seen from Table 2, the sample of the more commercially available formula preparation of docetaxel injection of the present invention's preparation can be 2 ~ 25 ℃ of lower storages of conventional refrigeration temperature 36 months, and product quality still meets the national drug standards.
What wherein comparative example 1 adopted is the preparation method of traditional injection, and prescription derives from Sanofi-Aventis drugmaker should the product description.Method is as follows:
20g docetaxel, dehydrated alcohol are added in the container, are stirred well to dissolving, add 0.1% needle-use activated carbon (w/v), absorption was stirred 5 minutes; 0.45um filter membrane decarburization.Add polyoxyethylene sorbitan monoleate 540g, mixed 10 minutes, add anhydrous citric acid and regulate pH value to 3.4-4.1, standardize solution 1000ml stirred 10 minutes.Fill, except ethanol, the button plug rolls lid.
The invention effect
As mentioned above, can provide high-quality docetaxel injection by the present invention.Injection of the present invention can be the lower storage of conventional refrigeration temperature (2 ~ 25 ℃) 36 months, and product quality still meets the national drug standards.
In sum, the invention provides a kind of new docetaxel injection prescription and preparation method, production process is simple, and cost is low, has distinct creativeness and practicality, in clinical use good application prospect will be arranged.
The specific embodiment
The present invention will be described in more detail by the following examples, but the present invention is not limited to this.
Embodiment 1
20g docetaxel, 500ml dehydrated alcohol are added in the container, fully stir (stirring frequency 1200～1500rpm, mixing time 15min) to dissolving, add 0.1% needle-use activated carbon (w/v), absorption was stirred 5 minutes; 0.45um filter membrane decarburization.Add the 500ml Solutol HS15, mixed 10 minutes.Add anhydrous citric acid and regulate pH value to 3.4-4.1, add dehydrated alcohol and be settled to 1000ml, stirred 10 minutes.Fill, except ethanol (as the equipment except ethanol, temperature is at 35 ℃ with freeze dryer, and the pumpdown time is more than 21 hours), the button plug rolls lid.To rotary water-bath sterilizing cabinet, at 126 ℃ of sterilizations 4 minutes (empirical tests sterilization F0Value is greater than 12, for excessively killing method) and get final product.
Embodiment 2
20g docetaxel, 500ml dehydrated alcohol are added in the container, fully stir (stirring frequency 1200～1500rpm, mixing time 15min) to dissolving, add 0.1% needle-use activated carbon (w/v), absorption was stirred 5 minutes; 0.45um filter membrane decarburization.Add Solutol HS15 250ml, mixed 10 minutes.Add anhydrous citric acid and regulate pH value to 3.4-4.1, add dehydrated alcohol and be settled to 1000ml, stirred 10 minutes.Fill, except ethanol (as the equipment except ethanol, temperature is at 35 ℃ with freeze dryer, and the pumpdown time is more than 21 hours), the button plug rolls lid.To rotary water-bath sterilizing cabinet, at 126 ℃ of sterilizations 4 minutes (empirical tests sterilization F0Value is greater than 12, for excessively killing method) and get final product.
Embodiment 3
40g docetaxel, 500ml dehydrated alcohol are added in the container, are stirred well to dissolving, add 0.1% needle-use activated carbon (w/v), absorption was stirred 5 minutes; 0.45um filter membrane decarburization.Add the 540ml Solutol HS15, mixed 10 minutes.Add anhydrous citric acid and regulate pH value to 3.4-4.1, add dehydrated alcohol and be settled to 1000ml, stirred 10 minutes.Fill, except ethanol, the button plug rolls lid.To rotary water-bath sterilizing cabinet, at 126 ℃ of sterilizations 4 minutes (empirical tests sterilization F0Value is greater than 12, for excessively killing method) and get final product.
Embodiment 4
40g docetaxel, 40ml dehydrated alcohol are added in the container, are stirred well to dissolving, add 0.1% needle-use activated carbon (w/v), absorption was stirred 5 minutes; 0.45um filter membrane decarburization.Add the 250ml Solutol HS15, mixed 10 minutes.Add anhydrous citric acid and regulate pH value to 3.4-4.1, add dehydrated alcohol and be settled to 1000ml, stirred 10 minutes.Fill, except ethanol, the button plug rolls lid.To rotary water-bath sterilizing cabinet, at 126 ℃ of sterilizations 4 minutes (empirical tests sterilization F0Value is greater than 12, for excessively killing method) and get final product.
Embodiment 5
20g docetaxel, 1000ml dehydrated alcohol are added in the container, are stirred well to dissolving, add 0.1% needle-use activated carbon (w/v), absorption was stirred 5 minutes; 0.45um filter membrane decarburization.Add the 500ml Solutol HS15, mixed 10 minutes.Add anhydrous citric acid and regulate pH value to 3.4-4.1, add dehydrated alcohol and be settled to 1000ml, stirred 10 minutes.Fill, except ethanol, the button plug rolls lid.To rotary water-bath sterilizing cabinet, at 121 ℃ of sterilizations 12 minutes (empirical tests sterilization F0Value is greater than 12, for excessively killing method) and get final product.
Embodiment 6
30g docetaxel, 200ml dehydrated alcohol are added in the container, are stirred well to dissolving, add 0.1% needle-use activated carbon (w/v), absorption was stirred 5 minutes; 0.45um filter membrane decarburization.Add the 250ml Solutol HS15, mixed 10 minutes.Add anhydrous citric acid and regulate pH value to 3.4-4.1, add dehydrated alcohol and be settled to 1000ml, stirred 10 minutes.Fill, except ethanol, the button plug rolls lid.To rotary water-bath sterilizing cabinet, at 121 ℃ of sterilizations 12 minutes (empirical tests sterilization F0Value is greater than 12, for excessively killing method) and get final product.
Embodiment 7
25g docetaxel, 100ml dehydrated alcohol are added in the container, are stirred well to dissolving, add 0.1% needle-use activated carbon (w/v), absorption was stirred 5 minutes; 0.45um filter membrane decarburization.Add the 250ml Solutol HS15, mixed 10 minutes.Add anhydrous citric acid and regulate pH value to 3.4-4.1, add dehydrated alcohol and be settled to 1000ml, stirred 10 minutes.Fill, except ethanol, the button plug rolls lid.To rotary water-bath sterilizing cabinet, at 121 ℃ of sterilizations 12 minutes (empirical tests sterilization F0Value is greater than 12, for excessively killing method) and get final product.
Embodiment 8
60g docetaxel, 300ml dehydrated alcohol are added in the container, fully stir (stirring frequency 1200～1500rpm, mixing time 15min) to dissolving, add 0.1% needle-use activated carbon (w/v), absorption was stirred 5 minutes; 0.45um filter membrane decarburization.Add the 500ml Solutol HS15, mixed 10 minutes.Add anhydrous citric acid and regulate pH value to 3.4-4.1, add dehydrated alcohol and be settled to 1000ml, stirred 10 minutes.Fill, except ethanol (as the equipment except ethanol, temperature is at 35 ℃ with freeze dryer, and the pumpdown time is more than 21 hours), the button plug rolls lid.To rotary water-bath sterilizing cabinet, at 126 ℃ of sterilizations 4 minutes (empirical tests sterilization F0Value is greater than 12, for excessively killing method) and get final product.
Claims (5)
1. docetaxel injection, it is characterized in that it is composed as follows: its concentration range of principal agent docetaxel is 20～60mg/ml; The proportion of principal agent and solvent dehydrated alcohol is 1:1～1:50, and the proportion of principal agent and solubilizer polyethylene glycol stearate 15 is 1:1～1:50, and the pH adjusting agent anhydrous citric acid is 3～4.5 with the scope of its regulator solution pH;
Its preparation method is as follows:
(a) it is for subsequent use to take by weighing respectively docetaxel, dehydrated alcohol, Solutol HS15;
(b) docetaxel is added in the dehydrated alcohol, then in airtight container, be stirred to whole dissolvings;
(c) Solutol HS15 is heated 50-60 ℃ of dissolving, join mix homogeneously in the dehydrated alcohol of the pastille for preparing;
(d) regulate pH value to 3.7 with citric acid soln, fill the nitrogen fill to the 7ml cillin bottle, half tamponade;
(e) place in the freeze dryer, remove ethanol;
(f) sample behind the Zha Gai is put in the rotary water bath formula sterilizing cabinet, the method sterilization is excessively killed in employing, and sterilising conditions is selected from 121 ℃ of lower sterilizations 12 minutes or 126 ℃ of lower sterilizations 4 minutes, namely gets docetaxel and penetrate liquid after sterilization.
2. injection according to claim 1 is characterized in that, it is composed as follows: its concentration range of principal agent docetaxel is 20mg/ml or 40mg/ml; The proportion of principal agent and solvent dehydrated alcohol is respectively 1:25; The proportion of principal agent and solubilizer polyethylene glycol stearate 15 is 1:25; The pH adjusting agent anhydrous citric acid, its concentration is 25mM;
Its preparation method is as follows:
(a) it is for subsequent use to take by weighing respectively docetaxel, dehydrated alcohol, Solutol HS15;
(b) docetaxel is added in the dehydrated alcohol, then in airtight container, be stirred to whole dissolvings;
(c) Solutol HS15 is heated 50-60 ℃ of dissolving, join mix homogeneously in the dehydrated alcohol of the pastille for preparing;
(d) regulate pH value to 3.7 with citric acid soln, fill the nitrogen fill to the 7ml cillin bottle, half tamponade;
(e) place in the freeze dryer, remove ethanol;
(f) sample behind the Zha Gai is put in the rotary water bath formula sterilizing cabinet, adopted and excessively to kill the method sterilization, sterilising conditions is selected from 121 ℃ of lower sterilizations 12 minutes, and a kind of in 126 ℃ of lower sterilizations 4 minutes namely gets docetaxel and penetrate liquid after sterilization.
3. injection according to claim 1, it is characterized in that, be processed into by following composition: 20g docetaxel, 500ml dehydrated alcohol are joined in the container, be stirred well to dissolving, the needle-use activated carbon (w/v) of adding 0.1%, absorption was stirred 5 minutes, the decarburization of 0.45um filter membrane, add the 500ml Solutol HS15, mixed 10 minutes; Add anhydrous citric acid and regulate pH value to 3.4-4.1, add dehydrated alcohol and be settled to 1000ml, stirred 10 minutes; Fill, except ethanol, the button plug rolls lid; To rotary water-bath sterilizing cabinet, sterilized 4 minutes and get final product at 126 ℃.
4. injection according to claim 1 is characterized in that, is processed into by following composition: 20g docetaxel, 500ml dehydrated alcohol are added in the container, are stirred well to dissolving, add 0.1% needle-use activated carbon (w/v), absorption was stirred 5 minutes; 0.45um filter membrane decarburization; Add the 250ml Solutol HS15, mixed 10 minutes; Add anhydrous citric acid and regulate pH value to 3.4-4.1, add dehydrated alcohol and be settled to 1000ml, stirred 10 minutes; Fill, except ethanol, the button plug rolls lid; To rotary water-bath sterilizing cabinet, 126 ℃ of sterilizations 4 minutes; And get final product.
5. the preparation method of injection claimed in claim 1 is characterized in that, comprises the steps:
(a) it is for subsequent use to take by weighing respectively docetaxel, dehydrated alcohol, the Solutol HS15 of recipe quantity;
(b) docetaxel is added in the dehydrated alcohol, then in airtight container, be stirred to whole dissolvings;
(c) Solutol HS15 is heated 50-60 ℃ of dissolving, join mix homogeneously in the dehydrated alcohol of the pastille for preparing;
(d) regulate pH value to 3.7 with citric acid soln, fill the nitrogen fill to the 7ml cillin bottle, half tamponade;
(e) place in the freeze dryer, remove ethanol;
(f) sample behind the Zha Gai is put in the rotary water bath formula sterilizing cabinet, adopted and excessively to kill the method sterilization, sterilising conditions is selected from 121 ℃ of lower sterilizations 12 minutes, and a kind of in 126 ℃ of lower sterilizations 4 minutes namely gets docetaxel and penetrate liquid after sterilization.
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| CN105395477A (en)* | 2015-11-26 | 2016-03-16 | 李宏 | Docetaxel injection and preparation method thereof |
| CN105496956A (en)* | 2015-12-22 | 2016-04-20 | 上海方予健康医药科技有限公司 | Docetaxel composition as well as preparation method and application thereof |
| CN107157926A (en)* | 2017-07-20 | 2017-09-15 | 四川汇宇制药有限公司 | A kind of preparation method of injection docetaxel |
| CN107412153A (en)* | 2017-04-17 | 2017-12-01 | 南京健友生化制药股份有限公司 | A kind of Glycopyrronium bromide injection and preparation method thereof |
| CN108066335A (en)* | 2016-11-11 | 2018-05-25 | 北京康辰药业股份有限公司 | A kind of pharmaceutical composition containing taxol or its analog and preparation method thereof |
| CN111557934A (en)* | 2020-06-10 | 2020-08-21 | 四川汇宇制药股份有限公司 | Pharmaceutical composition containing docetaxel, preparation method and application thereof |
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| CN107157926B (en)* | 2017-07-20 | 2020-08-21 | 四川汇宇制药股份有限公司 | A kind of preparation method of docetaxel injection |
| CN111557934A (en)* | 2020-06-10 | 2020-08-21 | 四川汇宇制药股份有限公司 | Pharmaceutical composition containing docetaxel, preparation method and application thereof |
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