CN107550853B - Preparation method of glatiramer acetate injection - Google Patents
Preparation method of glatiramer acetate injection Download PDFInfo
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- CN107550853B CN107550853B CN201610513675.5A CN201610513675A CN107550853B CN 107550853 B CN107550853 B CN 107550853B CN 201610513675 A CN201610513675 A CN 201610513675A CN 107550853 B CN107550853 B CN 107550853B
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Abstract
The invention provides a preparation method of glatiramer acetate injection, which comprises the following steps: 1) weighing mannitol in a prescription amount, adding water for injection at the temperature of less than 30 ℃, and stirring until the mannitol is completely dissolved; 2) weighing glatiramer acetate according to the prescription amount, adding water for injection at the temperature of less than 30 ℃, standing, and stirring until the glatiramer acetate is completely dissolved; 3) mixing the solutions obtained in the step 1) and the step 2), uniformly stirring, and metering the volume to be sufficient by using water for injection; 4) filtering the solution obtained in the step 3) under constant temperature protection, wherein the constant temperature is 10-22 ℃, a filtering system adopts a double-layer membrane with the diameter of 0.2 mu m +0.45 mu m, and the pressure of the front end of the filtering system is kept between 0.60bar and 1.30 bar. The average mole fraction and the controllability of molecular weight distribution of the glatiramer acetate injection obtained by the preparation method are improved, so that the quality stability of the product can be controlled.
Description
Technical Field
The invention relates to a preparation method of a pharmaceutical composition, and in particular relates to a preparation method of glatiramer acetate.
Background
Multiple sclerosis syndrome (MS) is a self-immune disease which can be clinically generated in the central nervous system of a human body, and is mainly characterized by white matter inflammatory demyelinating diseases of the central nervous system, the incidence of the MS is not only high-incidence diseases in countries such as Europe and America, but also is common in young and old people (particularly thirty years old people) in China, and the causes of the MS are generally related to the immune regulation disorder of the human body.
Glatiramer acetate (CAS: 147245-92-9) is a synthetic peptide compound developed and manufactured by TEVA, Israel pharmaceutical Mill, under the trade name
FDA approval for the treatment of multiple sclerosis was obtained in 1996 in the United states. Glatiramer acetate is composed of the following 4 amino acids of L-glutamic acid, L-alanine, L-lysine and L-tyrosine, and the average mole fractions are respectively 0.141, 0.427, 0.095 and 0.338 acetate. The average molecular weight of the glatiramer acetate is 5000-9000 daltons. The molecular structural formula is as follows:
(C5H9NO4·C3H7NO2·C6H14N2O2·C9H11NO3)x·xC2H4O2
currently, glatiramer acetate is clinically applied in a subcutaneous injection administration mode, and prescription information of 20mg/ml specification is as follows:
| glatiramer acetate | 20mg |
| Mannitol | 40mg |
| Water for injection | To 1ml |
The preparation patent of the glatiramer acetate is only reported, and the experimental scheme is obtained after experimental results of experimenters are carried out for many times.
The invention aims to increase the controllability of the average molar fraction and the average molecular weight. Further obtaining the molecular weight of the product and a stable interval of the molecular weight distribution, thereby achieving a controllable state for the quality stability of the product.
Disclosure of Invention
The invention aims to increase the controllability of the average molar fraction and the average molecular weight. Further obtaining the molecular weight of the product and a stable interval of the molecular weight distribution, thereby achieving a controllable state for the quality stability of the product.
In order to solve the technical problems, the invention provides a preparation method of glatiramer acetate injection, which comprises the following steps:
1) weighing mannitol in a prescription amount, adding water for injection at the temperature of less than 30 ℃, and stirring until the mannitol is completely dissolved;
2) weighing glatiramer acetate according to the prescription amount, adding water for injection at the temperature of less than 30 ℃, standing, and stirring until the glatiramer acetate is completely dissolved;
3) mixing the solutions obtained in the step 1) and the step 2), uniformly stirring, and metering the volume to be sufficient by using water for injection;
4) filtering the solution obtained in the step 3) under constant temperature protection, wherein the constant temperature is 10-22 ℃, a filtering system adopts a double-layer membrane with the diameter of 0.2 mu m +0.45 mu m, and the pressure of the front end of the filtering system is kept between 0.60bar and 1.30 bar. The double-layer membrane filter element (folding filter element) integrates pre-filtration and final filtration, and compared with the traditional two filters of pre-filtration and final filtration, the double-layer membrane filter element has the advantages of large dirt-holding capacity, stable pressure difference between the front end and the rear end, and easiness in stably controlling the pressure of the front end and the rear end.
Alternatively, the prescribed amounts of the components of glatiramer acetate injection are, per 1ml of water for injection,
glatiramer acetate 20mg
Mannitol 40 mg.
Optionally, the amount of water for injection in step 1) is 30% to 60% (preferably 40% to 50%) of the total amount of water for injection, and the amount of water for injection in step 2) is 60% to 30% (preferably 50% to 40%) of the total amount of water for injection.
Optionally, the temperature of step 1) and step 2) is maintained at 20 ℃ to 30 ℃.
Alternatively, the filtration system employs a 0.2 μm +0.45 μm polyethersulfone bilayer membrane.
Optionally, the pressure at the front end of the filtering system is kept between 0.75bar and 1.15bar,
preferably, the back end pressure of the filtration system is maintained between 0.02bar and 0.07 bar.
Optionally, the constant temperature in the step 4) is 12-17 ℃; preferably, the isothermal temperature is 15 ℃.
In another aspect of the invention, the glatiramer acetate injection prepared by the preparation method is provided.
Preferably, the stable interval of the average mole fraction of the glatiramer acetate injection is 0.122-0.160 of glutamic acid, 0.378-0.476 of alanine, 0.080-0.110 of lysine, 0.298-0.378 of tyrosine, the stable interval of the molecular weight distribution is Mp: 6000-9400 Da, Mw: 7200-9600 Da, Mn: 4900-6400 Da.
The implementation scheme is as follows:
| glatiramer acetate | 20g |
| Mannitol | 40g |
| Water for injection | To 1000ml |
1) Mannitol in the prescribed amount is weighed, 50% of the total volume of the mannitol which is cooled is taken and added into water for injection (< 30 ℃), and the mixture is stirred until the mannitol is completely dissolved.
2) Weighing glatiramer acetate according to the prescription amount, adding cold water for injection (less than 30 ℃) with the total volume of 40 percent, standing for 15-25 minutes, and stirring until the glatiramer acetate is completely dissolved.
3) And (3) mixing the solution 1) and the solution 2), stirring uniformly, and metering to a sufficient volume.
4) The liquid medicine is protected at a constant temperature, the temperature is maintained to be 10-22 ℃, a filtering system adopts a double-layer membrane of 0.2 mu m +0.45 mu m and polyether sulfone, the pressure at the front end is maintained to be 0.75-1.15 bar, and the pressure at the rear end is maintained to be 0.04-0.07 bar.
Detailed Description
Example 1
| Glatiramer acetate | 20g |
| Mannitol | 40g |
| Water for injection | To 1000ml |
1) Mannitol in the prescribed amount is weighed, 50% of the total volume of the mannitol which is cooled is taken and added into water for injection (< 30 ℃), and the mixture is stirred until the mannitol is completely dissolved.
2) Weighing glatiramer acetate according to the prescription amount, adding cold water for injection (less than 30 ℃) with the total volume of 40 percent, standing for 15 minutes, and stirring until the glatiramer acetate is completely dissolved.
3) And (3) mixing the solution 1) and the solution 2), stirring uniformly, and metering to a sufficient volume.
4) The liquid medicine is protected at constant temperature, the temperature is maintained at 15 ℃, a filtering system adopts a 0.2 mu m +0.45 mu m and polyether sulfone double-layer membrane, the pressure at the front end is maintained at 0.77bar, and the pressure at the rear end is maintained at 0.04 bar.
Results of the experiment
Example 2
| Glatiramer acetate | 20g |
| Mannitol | 40g |
| Water for injection | To 1000ml |
1) Mannitol in the prescribed amount is weighed, 50% of the total volume of the mannitol which is cooled is taken and added into water for injection (< 30 ℃), and the mixture is stirred until the mannitol is completely dissolved.
2) Weighing glatiramer acetate according to the prescription amount, adding cold water for injection (less than 30 ℃) with the total volume of 40 percent, standing for 15 minutes, and stirring until the glatiramer acetate is completely dissolved.
3) And (3) mixing the solution 1) and the solution 2), stirring uniformly, and metering to a sufficient volume.
4) The liquid medicine is protected at constant temperature, the temperature is maintained at 15 ℃, a filtering system adopts a 0.2 mu m +0.45 mu m and polyether sulfone double-layer membrane, the pressure at the front end is maintained at 0.95bar, and the pressure at the rear end is maintained at 0.04 bar.
Results of the experiment
Example 3
| Glatiramer acetate | 20g |
| Mannitol | 40g |
| Water for injection | To 1000ml |
1) Mannitol in the prescribed amount is weighed, 50% of the total volume of the mannitol which is cooled is taken and added into water for injection (< 30 ℃), and the mixture is stirred until the mannitol is completely dissolved.
2) Weighing glatiramer acetate according to the prescription amount, adding cold water for injection (less than 30 ℃) with the total volume of 40 percent, standing for 15 minutes, and stirring until the glatiramer acetate is completely dissolved.
3) And (3) mixing the solution 1) and the solution 2), stirring uniformly, and metering to a sufficient volume.
4) The liquid medicine is protected at constant temperature, the temperature is maintained at 15 ℃, a filtering system adopts a 0.2 mu m +0.45 mu m and polyether sulfone double-layer membrane, the pressure at the front end is maintained at 1.13bar, and the pressure at the rear end is maintained at 0.04 bar.
Results of the experiment
Example 4
| Glatiramer acetate | 20g |
| Mannitol | 40g |
| Water for injection | To 1000ml |
1) Mannitol in the prescribed amount is weighed, 50% of the total volume of water for injection (25 ℃) which has been cooled is added, and stirring is carried out until the mannitol is completely dissolved.
2) Weighing the glatiramer acetate with the prescription amount, adding the cooled water for injection (25 ℃) with the total volume of 40 percent, standing for 15 minutes, and stirring until the glatiramer acetate is completely dissolved.
3) And (3) mixing the solution 1) and the solution 2), stirring uniformly, and metering to a sufficient volume.
4) The liquid medicine is protected at constant temperature, the temperature is maintained at 15 ℃, a filtering system adopts a 0.2 mu m +0.45 mu m and polyether sulfone double-layer membrane, the pressure at the front end is maintained at 0.77bar, and the pressure at the rear end is maintained at 0.04 bar.
Results of the experiment
Example 5
| Glatiramer acetate | 20g |
| Mannitol | 40g |
| Water for injection | To 1000ml |
1) Mannitol in the prescribed amount is weighed, 50% of the total volume of water for injection (25 ℃) which has been cooled is added, and stirring is carried out until the mannitol is completely dissolved.
2) Weighing the glatiramer acetate with the prescription amount, adding the cooled water for injection (25 ℃) with the total volume of 40 percent, standing for 15 minutes, and stirring until the glatiramer acetate is completely dissolved.
3) And (3) mixing the solution 1) and the solution 2), stirring uniformly, and metering to a sufficient volume.
4) The liquid medicine is protected at constant temperature, the temperature is maintained at 15 ℃, a filtering system adopts a 0.2 mu m +0.45 mu m and polyether sulfone double-layer membrane, the pressure at the front end is maintained at 0.95bar, and the pressure at the rear end is maintained at 0.04 bar.
Results of the experiment
Example 6
| Glatiramer acetate | 20g |
| Mannitol | 40g |
| Water for injection | To 1000ml |
1) Mannitol in the prescribed amount is weighed, 50% of the total volume of water for injection (25 ℃) which has been cooled is added, and stirring is carried out until the mannitol is completely dissolved.
2) Weighing the glatiramer acetate with the prescription amount, adding the cooled water for injection (25 ℃) with the total volume of 40 percent, standing for 15 minutes, and stirring until the glatiramer acetate is completely dissolved.
3) And (3) mixing the solution 1) and the solution 2), stirring uniformly, and metering to a sufficient volume.
4) The liquid medicine is protected at constant temperature, the temperature is maintained at 15 ℃, a filtering system adopts a 0.2 mu m +0.45 mu m and polyether sulfone double-layer membrane, the pressure at the front end is maintained at 1.13bar, and the pressure at the rear end is maintained at 0.04 bar.
Results of the experiment
Example 7
| Glatiramer acetate | 20g |
| Mannitol | 40g |
| Water for injection | To 1000ml |
1) Mannitol in the prescribed amount is weighed, 50% of the total volume of the mannitol which is cooled is taken and added into water for injection (22 ℃), and the mixture is stirred until the mannitol is completely dissolved.
2) Weighing the glatiramer acetate with the prescription amount, adding the cooled water for injection (22 ℃) with the total volume of 40 percent, standing for 20 minutes, and stirring until the glatiramer acetate is completely dissolved.
3) And (3) mixing the solution 1) and the solution 2), stirring uniformly, and metering to a sufficient volume.
4) The liquid medicine is protected at constant temperature, the temperature is maintained at 15 ℃, a filtering system adopts a 0.2 mu m +0.45 mu m and polyether sulfone double-layer membrane, the pressure at the front end is maintained at 0.92bar, and the pressure at the rear end is maintained at 0.05 bar.
The experimental results are as follows:
the results of examples 1 to 7 show that the preparation method of the present invention can effectively increase the controllability of the average molar fraction and the average molecular weight, and is more stable in the acceleration test. Wherein the temperature of the step 1) and the step 2) is controlled below 30 ℃, or is accurately controlled at 25 ℃ or 22 ℃, so that better test results are obtained.
Example 8: comparative example
| Glatiramer acetate | 20g |
| Mannitol | 40g |
| Water for injection | To 1000ml |
1) Weighing mannitol with the prescription amount, adding water for injection (less than 30 ℃) with the total volume of 50%, and stirring at constant temperature until the mannitol is completely dissolved.
2) Weighing glatiramer acetate according to the prescription amount, adding water for injection (less than 30 ℃) with the total volume of 40 percent, standing for 10 minutes at constant temperature, and stirring until the glatiramer acetate is completely dissolved.
3) And (3) mixing the solution 1) and the solution 2), stirring uniformly, and metering to a sufficient volume.
4) The liquid medicine is protected at constant temperature, the temperature is maintained at 14 ℃, a filtering system adopts a double-layer membrane of 0.2 mu m +0.45 mu m and polyether sulfone, the front end pressure is 1.42bar, and the rear end pressure is 0.02 bar.
The experimental results are as follows:
example 9: comparative example
1) Weighing mannitol with the prescription amount, adding water for injection (less than 30 ℃) with the total volume of 50%, and stirring at constant temperature until the mannitol is completely dissolved.
2) Weighing glatiramer acetate according to the prescription amount, adding water for injection (less than 30 ℃) with the total volume of 40 percent, standing for 10 minutes, and stirring at constant temperature until the glatiramer acetate is completely dissolved.
3) And (3) mixing the solution 1) and the solution 2), stirring uniformly, and metering to a sufficient volume.
4) The liquid medicine is protected at constant temperature, the temperature is maintained at 15 ℃, a filtering system adopts a double-layer membrane of 0.2 mu m +0.45 mu m and polyether sulfone, the front end pressure is 0.50bar, and the rear end pressure is 0.02 bar.
The experimental results are as follows:
it can be seen from the comparison of examples 8 to 9 that the pressure of the filtration system has a significant effect on the test results, especially the front end pressure, and the controllability is deteriorated when the front end pressure exceeds the range of the present invention, either toward a larger trend or a smaller trend.
Example 10: comparative example
| Glatiramer acetate | 20g |
| Mannitol | 40g |
| Water for injection | To 1000ml |
1) Mannitol in the prescribed amount is weighed, 50% of the total volume of water for injection (25 ℃) which has been cooled is added, and stirring is carried out until the mannitol is completely dissolved.
2) Weighing the glatiramer acetate with the prescription amount, adding the cooled water for injection (25 ℃) with the total volume of 40 percent, standing for 15 minutes, and stirring until the glatiramer acetate is completely dissolved.
3) And (3) mixing the solution 1) and the solution 2), stirring uniformly, and metering to a sufficient volume.
4) The liquid medicine is protected at constant temperature, the temperature is maintained at 15 ℃, a filtering system adopts a cellulose acetate membrane with the diameter of 0.2 mu m +0.45 mu m, the pressure at the front end is maintained at 0.77bar, and the pressure at the rear end is maintained at 0.04 bar.
Example 11: comparative example
| Glatiramer acetate | 20g |
| Mannitol | 40g |
| Water for injection | To 1000ml |
1) Mannitol in the prescribed amount is weighed, 50% of the total volume of water for injection (25 ℃) which has been cooled is added, and stirring is carried out until the mannitol is completely dissolved.
2) Weighing the glatiramer acetate with the prescription amount, adding the cooled water for injection (25 ℃) with the total volume of 40 percent, standing for 15 minutes, and stirring until the glatiramer acetate is completely dissolved.
3) And (3) mixing the solution 1) and the solution 2), stirring uniformly, and metering to a sufficient volume.
4) The liquid medicine is protected at constant temperature, the temperature is maintained at 15 ℃, a filtering system adopts a 0.2 mu m +0.45 mu m polyvinylidene fluoride double-layer membrane, the front end pressure is maintained at 0.77bar, and the rear end pressure is maintained at 0.04 bar.
As is clear from the comparison of examples 10 to 11, the selection of the material of the bilayer film also affects the test results, and the molecular weight and the content of impurities rapidly change in stability in the accelerated test.
Claims (11)
1. A preparation method of glatiramer acetate injection comprises the following steps:
1) weighing mannitol in a prescription amount, adding water for injection at the temperature of less than 30 ℃, and stirring until the mannitol is completely dissolved;
2) weighing glatiramer acetate according to the prescription amount, adding water for injection at the temperature of less than 30 ℃, standing, and stirring until the glatiramer acetate is completely dissolved;
3) mixing the solutions obtained in the step 1) and the step 2), uniformly stirring, and metering the volume to be sufficient by using water for injection;
4) filtering the solution obtained in the step 3) under constant temperature protection, wherein the constant temperature is 10-22 ℃, a filtering system adopts a polyether sulfone double-layer membrane of 0.2 mu m +0.45 mu m, and the front end pressure of the filtering system is kept at 0.60-1.30 bar.
2. The process according to claim 1, wherein the components of the glatiramer acetate injection are formulated in amounts such that, per 1ml of water for injection,
3. The preparation method according to any one of claims 1 to 2, wherein the amount of water for injection in step 1) is 30% to 60% of the total amount of water for injection, and the amount of water for injection in step 2) is 60% to 30% of the total amount of water for injection.
4. The preparation method according to claim 3, wherein the amount of the water for injection in step 1) is 40-50% of the total amount of the water for injection, and the amount of the water for injection in step 2) is 50-40% of the total amount of the water for injection.
5. The production method according to any one of claims 1 to 2, wherein the temperature of step 1) and step 2) is maintained at 20 ℃ to 30 ℃.
6. The production method according to any one of claims 1 to 2, wherein the pressure of the front end of the filtration system is maintained at 0.75bar to 1.15 bar.
7. The production method according to any one of claims 1 to 2, wherein a back end pressure of the filtration system is maintained at 0.02bar to 0.07 bar.
8. The production method according to any one of claims 1 to 2, wherein the constant temperature in step 4) is 12 ℃ to 17 ℃.
9. The production method according to claim 8, wherein the constant temperature is 15 ℃.
10. Glatiramer acetate injection prepared by the preparation method of any one of claims 1 to 9.
11. The glatiramer acetate injection according to claim 10, wherein the average mole fraction stability interval is glutamic acid 0.122 to 0.160, alanine 0.378 to 0.476, lysine 0.080 to 0.110, tyrosine 0.298 to 0.378, the stability interval of the molecular weight distribution is Mp: 6000-9400 Da, Mw: 7200-9600 Da, Mn: 4900-6400 Da.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006029411A2 (en) * | 2004-09-09 | 2006-03-16 | Yeda Research And Development Co. Ltd. | Mixtures of polypeptides, compositions containing and processes for preparing same, and uses thereof |
| CN102625657A (en) * | 2009-08-20 | 2012-08-01 | 医达研究发展有限公司 | Low frequency glatiramer acetate therapy |
| US9155775B1 (en) * | 2015-01-28 | 2015-10-13 | Teva Pharmaceutical Industries, Ltd. | Process for manufacturing glatiramer acetate product |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103110949A (en) * | 2013-03-05 | 2013-05-22 | 扬州中宝制药有限公司 | Ribavirin small-capacity injection preparation and preparation method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006029411A2 (en) * | 2004-09-09 | 2006-03-16 | Yeda Research And Development Co. Ltd. | Mixtures of polypeptides, compositions containing and processes for preparing same, and uses thereof |
| CN102625657A (en) * | 2009-08-20 | 2012-08-01 | 医达研究发展有限公司 | Low frequency glatiramer acetate therapy |
| US9155775B1 (en) * | 2015-01-28 | 2015-10-13 | Teva Pharmaceutical Industries, Ltd. | Process for manufacturing glatiramer acetate product |
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