CN106943359B - Stable mycophenolate mofetil for injection and preparation method thereof - Google Patents
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Abstract
The invention relates to a stable mycophenolate mofetil freeze-dried composition for injection, which is prepared from mycophenolate mofetil, citric acid, polysorbate 80, disodium tetraborate, a pH regulator and water for injection by the following method: adding the mycophenolate mofetil, citric acid and polysorbate 80 in the amount according to the prescription into a proper amount of water for injection, uniformly stirring, adjusting the pH value of the solution to 2.6-3.4 by using 1M hydrochloric acid, adding disodium tetraborate in the amount according to the prescription, fixing the volume to the total amount, and stirring the solution to a colorless clear liquid; filtering, bottling, freeze drying, and visual inspection to obtain the final product. The product of the invention is stable, and avoids the potential safety hazard to patients caused by the reduction of curative effect and the increase of impurities due to the degradation of the medicine. Meanwhile, the method has simple process and convenient operation, and is convenient to develop in industrialized production.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to stable mycophenolate mofetil for injection and a preparation method thereof.
Background
Approximately seventy thousand people worldwide receive organ transplants each year, the vast majority of which are kidney transplants. However, in China, 5000 patients receive kidney transplantation every year, and how to improve the long-term survival rate of transplanted organs is always a big problem in the medical field. The human immune system has the ability to recognize both "self" and "non-self," and generally produces an immune response only to foreign antigens, but is immunologically tolerant to self antigens, so rejection of the allograft organ by the immune system prevents success of the organ transplant. Although the immunosuppressive scheme consisting of immunosuppressive agents with macrolide antibiotic structures, calcium neuraminidase inhibitors and adrenocortical hormone is mature, up to 30-50% of kidney transplant patients suffer from various rejection reactions after surgery every year, and finally the transplant fails.
Mycophenolate mofetil, a novel immunosuppressive agent, is a 2-ethyl ester derivative of mycophenolic acid, which is defatted to form mycophenolic acid (MPA), a metabolite having immunosuppressive activity. MPA reversibly inhibits the rate-limiting enzyme inosinate dehydrogenase (IMPDH) in the classical synthetic pathway of guanine nucleotide (GMP), thereby blocking the classical synthetic pathway of guanine nucleotide, exhausting the guanine nucleotide and further blocking the synthesis of DNA and RNA. Thus, MMF selectively blocks the classical synthesis of guanine nucleotides in T and B lymphocytes by GMP depletion, thereby inhibiting T and B lymphocyte proliferation. Mycophenolate mofetil has the characteristics of unique action mechanism, strong rejection resistance, superior pharmacokinetic property, good safety, high cost performance and the like, and becomes an important component in a new triple therapy after organ transplantation.
Mycophenolate mofetil is easily degraded in water, and especially under the condition of increasing temperature, the degradation is accelerated; meanwhile, mycophenolate mofetil for injection is unstable in the storage process, and the preparation prepared by the prior art can not solve the problems.
Disclosure of Invention
In view of the above problems, the present invention provides a mycophenolate mofetil lyophilized composition: is prepared from mycophenolate mofetil, citric acid, polysorbate 80, disodium tetraborate, a pH regulator and water for injection.
The weight ratio of the mycophenolate mofetil to the disodium tetraborate is 25: 3-5, and preferably 25: 4.
The pH regulator is one or more of hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid and benzenesulfonic acid, and hydrochloric acid is preferred.
A method for preparing a mycophenolate mofetil freeze-dried composition comprises the following steps:
adding the mycophenolate mofetil, citric acid and polysorbate 80 in the amount according to the prescription into a proper amount of water for injection, uniformly stirring, adjusting the pH value of the solution to 2.6-3.4 by using 1M hydrochloric acid, adding disodium tetraborate in the amount according to the prescription, fixing the volume to the total amount, and stirring the solution to a colorless clear liquid; filtering, bottling, freeze drying, and visual inspection to obtain the final product;
the freeze-drying method comprises the following steps:
1) a pre-freezing stage: raising the temperature of the plate layer to 30-40 ℃, and keeping the temperature for 30-40 min; then, the temperature of the plate layer is reduced to minus 45 to minus 35 ℃ for 210 to 270min, and the heat preservation time is 390 to 450 min;
2) a sublimation drying stage: when the vacuum degree in the drying box reaches 80 mTorr-120 mTorr, preserving the heat for 30-90 min at-45 to-35 ℃, raising the temperature of the plate layer to-17.5 to-12.5 ℃, and using for 150-210 min; preserving the heat for 540-660 min;
3) and a re-drying stage: raising the temperature of the plate layer to 50-60 ℃, and taking for 150-210 min; pumping the vacuum degree in the drying box to the limit vacuum, and keeping the temperature for 210-270 min; reducing the temperature to 20-30 ℃, and taking for 90-150 min; and keeping the temperature for 90-150 min to obtain the mycophenolate mofetil freeze-dried preparation.
A method for preparing a mycophenolate mofetil freeze-dried composition comprises the following steps:
adding the mycophenolate mofetil, the citric acid and the polysorbate 80 in the prescribed amount into a proper amount of water for injection, uniformly stirring, adjusting the pH value of the solution to 3.0 by using 1M hydrochloric acid, adding the disodium tetraborate in the prescribed amount, fixing the volume to the total amount, and stirring the solution to a colorless clear liquid; filtering, bottling, freeze drying, and visual inspection to obtain the final product;
the freeze-drying method comprises the following steps:
1) a pre-freezing stage: raising the temperature of the plate layer to 35 ℃, and keeping the temperature for 35 min; then reducing the temperature of the plate layer to-40 ℃ in 240min, and preserving the heat for 420 min;
2) a sublimation drying stage: keeping the vacuum degree in the drying oven at-40 deg.C for 60min to 100mTorr, and heating the plate layer to-15 deg.C for 180 min; preserving the heat for 600 min;
3) and a re-drying stage: raising the temperature of the plate layer to 55 ℃, and taking for 180 min; pumping the vacuum degree in the drying oven to the limit vacuum, and preserving the temperature for 240 min; cooling to 25 deg.C, and taking for 120 min; preserving the temperature for 120min to obtain the mycophenolate mofetil freeze-dried preparation.
Compared with the prior art, the mycophenolate mofetil freeze-dried preparation for injection provided by the invention has the advantages that: all indexes such as related substances and the like do not change obviously, the product is stable, and potential safety hazards to patients caused by reduction of curative effect and increase of impurities due to drug degradation are avoided; meanwhile, the method has simple process and convenient operation, and is convenient to develop in industrialized production.
Detailed Description
The advantageous effects of the present invention will now be further described by the following examples, which are for illustrative purposes only and do not limit the scope of the present invention, and variations and modifications apparent to those of ordinary skill in the art according to the present invention are also included in the scope of the present invention.
Example 1:
adding 2000ml of injection water precooled to room temperature into a dispensing tank, adding 250.0g of mycophenolate mofetil, 2.5g of citric acid and 8012.5g of polysorbate according to the prescription amount, uniformly stirring, adjusting the pH value of the solution to 3.4 by using 1M hydrochloric acid, adding 30.0g of disodium tetraborate, fixing the volume to 2500ml, and stirring the solution to colorless clear liquid; filtering, bottling, freeze drying, and visual inspection to obtain the final product.
The freeze drying process comprises the following steps:
pre-freezing: raising the temperature of the plate layer to 30 ℃, and preserving the heat for 30 min; then, the temperature of the plate layer is reduced to-45 ℃ within 210min, and the heat preservation time is 390 min;
sublimation drying: pumping the vacuum degree in the box body to 80mTorr, and preserving the heat for 30min at-35 ℃; raising the temperature of the plate layer to-17.5 ℃ within 150min, and keeping the temperature for 540 min;
and (3) drying again: heating the plate layer to 50 ℃ within 150min, pumping the vacuum degree in the drying oven to the limit vacuum, and preserving the temperature for 210 min; and then raising the temperature of the plate layer to 20 ℃ in 90min, and preserving the heat for 90min to obtain the mycophenolate mofetil freeze-dried preparation.
Example 2:
adding 2000ml of injection water precooled to room temperature into a dispensing tank, adding 250.0g of mycophenolate mofetil, 2.5g of citric acid and 8012.5g of polysorbate according to the prescription amount, uniformly stirring, adjusting the pH value of the solution to 3.4 by using 1M hydrochloric acid, adding 50.0g of disodium tetraborate, fixing the volume to 2500ml, and stirring the solution to colorless clear liquid; filtering, bottling, freeze drying, and visual inspection to obtain the final product.
The freeze drying process comprises the following steps:
pre-freezing: raising the temperature of the plate layer to 40 ℃, and preserving the heat for 40 min; then, the temperature of the plate layer is reduced to-35 ℃ within 270min, and the heat preservation time is 450 min;
sublimation drying: pumping the vacuum degree in the box body to 120mTorr, and preserving the heat for 90min at-35 ℃; heating the plate layer to-12.5 ℃ within 210min, and keeping the temperature for 660 min;
and (3) drying again: heating the plate layer to 60 ℃ within 210min, pumping the vacuum degree in the drying oven to the limit vacuum, and keeping the temperature for 270 min; and then raising the temperature of the plate layer to 30 ℃ in 150min, and keeping the temperature for 150min to obtain the mycophenolate mofetil freeze-dried preparation.
Example 3:
adding 2000ml of injection water precooled to room temperature into a dispensing tank, adding 250.0g of mycophenolate mofetil, 2.5g of citric acid and 8012.5g of polysorbate according to the prescription amount, uniformly stirring, adjusting the pH value of the solution to 3.0 by using 1M hydrochloric acid, adding 40.0g of disodium tetraborate, fixing the volume to 2500ml, and stirring the solution to colorless clear liquid; filtering, bottling, freeze drying, and visual inspection to obtain the final product.
The freeze drying process comprises the following steps:
pre-freezing: raising the temperature of the plate layer to 35 ℃, and keeping the temperature for 35 min; then reducing the temperature of the plate layer to-40 ℃ in 240min, and keeping the temperature for 420 min;
sublimation drying: pumping the vacuum degree in the box body to 100mTorr, and preserving the heat for 60min at-40 ℃; raising the temperature of the plate layer to-15 ℃ in 180min, and keeping the temperature for 600 min;
and (3) drying again: raising the temperature of the plate layer to 55 ℃ in 180min, pumping the vacuum degree in the drying box to the limit vacuum, and preserving the temperature for 240 min; and then raising the temperature of the plate layer to 25 ℃ in 120min, and keeping the temperature for 120min to obtain the mycophenolate mofetil freeze-dried preparation.
Comparative example 1:
adding 2000ml of injection water precooled to room temperature into a dispensing tank, adding 250.0g of mycophenolate mofetil, 2.5g of citric acid and 8012.5g of polysorbate according to the prescription amount, uniformly stirring, adjusting the pH value of the solution to 3.0 by using 1M hydrochloric acid, fixing the volume to 2500ml, and stirring the solution to colorless clear liquid; filtering, bottling, freeze drying, and visual inspection to obtain the final product.
The freeze drying process comprises the following steps:
pre-freezing: raising the temperature of the plate layer to 35 ℃, and keeping the temperature for 35 min; then reducing the temperature of the plate layer to-40 ℃ in 240min, and keeping the temperature for 420 min;
sublimation drying: pumping the vacuum degree in the box body to 100mTorr, and preserving the heat for 60min at-40 ℃; raising the temperature of the plate layer to-15 ℃ in 180min, and keeping the temperature for 600 min;
and (3) drying again: raising the temperature of the plate layer to 55 ℃ in 180min, pumping the vacuum degree in the drying box to the limit vacuum, and preserving the temperature for 240 min; and then raising the temperature of the plate layer to 25 ℃ in 120min, and keeping the temperature for 120min to obtain the mycophenolate mofetil freeze-dried preparation.
Comparative example 2:
adding 5000ml of injection water precooled to room temperature into a dispensing tank, adding 1000.0g of mycophenolate mofetil, 10.0g of citric acid and 400.0g of polyethylene glycol-12-hydroxystearate according to the prescription amount, uniformly stirring, adjusting the pH value of the solution to 3.0 by using 1M hydrochloric acid, fixing the volume to 2500ml, and stirring the solution to colorless clear liquid; filtering, bottling, freeze drying, and visual inspection to obtain the final product.
The freeze drying process comprises the following steps:
pre-freezing: raising the temperature of the plate layer to 35 ℃, and keeping the temperature for 35 min; then reducing the temperature of the plate layer to-40 ℃ in 240min, and keeping the temperature for 420 min;
sublimation drying: pumping the vacuum degree in the box body to 100mTorr, and preserving the heat for 60min at-40 ℃; raising the temperature of the plate layer to-15 ℃ in 180min, and keeping the temperature for 600 min;
and (3) drying again: raising the temperature of the plate layer to 55 ℃ in 180min, pumping the vacuum degree in the drying box to the limit vacuum, and preserving the temperature for 240 min; and then raising the temperature of the plate layer to 25 ℃ in 120min, and keeping the temperature for 120min to obtain the mycophenolate mofetil freeze-dried preparation.
Comparative example 3:
adding 2000ml of injection water precooled to room temperature into a dispensing tank, adding 250.0g of mycophenolate mofetil, 2.5g of citric acid and 8012.5g of polysorbate according to the prescription amount, uniformly stirring, adjusting the pH value of the solution to 3.8 by using 1M hydrochloric acid, adding 40.0g of disodium tetraborate, fixing the volume to 2500ml, and stirring the solution to colorless clear liquid; filtering, bottling, freeze drying, and visual inspection to obtain the final product.
The freeze drying process comprises the following steps:
pre-freezing: raising the temperature of the plate layer to 35 ℃, and keeping the temperature for 35 min; then reducing the temperature of the plate layer to-40 ℃ in 240min, and keeping the temperature for 420 min;
sublimation drying: pumping the vacuum degree in the box body to 100mTorr, and preserving the heat for 60min at-40 ℃; raising the temperature of the plate layer to-15 ℃ in 180min, and keeping the temperature for 600 min;
and (3) drying again: raising the temperature of the plate layer to 55 ℃ in 180min, pumping the vacuum degree in the drying box to the limit vacuum, and preserving the temperature for 240 min; and then raising the temperature of the plate layer to 25 ℃ in 120min, and keeping the temperature for 120min to obtain the mycophenolate mofetil freeze-dried preparation.
Comparative example 4:
adding 2000ml of injection water precooled to room temperature into a dispensing tank, adding 250.0g of mycophenolate mofetil, 2.5g of citric acid and 8012.5g of polysorbate according to the prescription amount, uniformly stirring, adjusting the pH value of the solution to 3.4 by using 1M hydrochloric acid, fixing the volume to 2500ml, and stirring the solution to colorless clear liquid; filtering, bottling, freeze drying, and visual inspection to obtain the final product.
The freeze drying process comprises the following steps:
pre-freezing: raising the temperature of the plate layer to 35 ℃, and keeping the temperature for 35 min; then reducing the temperature of the plate layer to-40 ℃ in 240min, and keeping the temperature for 420 min;
sublimation drying: pumping the vacuum degree in the box body to 100mTorr, and preserving the heat for 60min at-40 ℃; raising the temperature of the plate layer to-15 ℃ in 180min, and keeping the temperature for 600 min;
and (3) drying again: raising the temperature of the plate layer to 55 ℃ in 180min, pumping the vacuum degree in the drying box to the limit vacuum, and preserving the temperature for 240 min; and then raising the temperature of the plate layer to 25 ℃ in 120min, and keeping the temperature for 120min to obtain the mycophenolate mofetil freeze-dried preparation.
Comparative example 5:
adding 2000ml of injection water precooled to room temperature into a dispensing tank, adding 250.0g of mycophenolate mofetil, 2.5g of citric acid and 8012.5g of polysorbate according to the prescription amount, uniformly stirring, adjusting the pH value of the solution to 2.0 by using 1M hydrochloric acid, adding 40.0g of disodium tetraborate, fixing the volume to 2500ml, and stirring the solution to colorless clear liquid; filtering, bottling, freeze drying, and visual inspection to obtain the final product.
The freeze drying process comprises the following steps:
pre-freezing: raising the temperature of the plate layer to 35 ℃, and keeping the temperature for 35 min; then reducing the temperature of the plate layer to-40 ℃ in 240min, and keeping the temperature for 420 min;
sublimation drying: pumping the vacuum degree in the box body to 100mTorr, and preserving the heat for 60min at-40 ℃; raising the temperature of the plate layer to-15 ℃ in 180min, and keeping the temperature for 600 min;
and (3) drying again: raising the temperature of the plate layer to 55 ℃ in 180min, pumping the vacuum degree in the drying box to the limit vacuum, and preserving the temperature for 240 min; and then raising the temperature of the plate layer to 25 ℃ in 120min, and keeping the temperature for 120min to obtain the mycophenolate mofetil freeze-dried preparation.
EXAMPLES AND COMPARATIVE EXAMPLES formulation review
(1) Formulation sample comparison
The appearance, pH, moisture, related substances and contents of the finished preparations obtained in the examples 1 to 3 of the present invention and the comparative examples 1 to 5 were examined, and the test results are shown in Table 1
Table 1 test results
| Examples | Appearance character | pH | Moisture (%) | About (%) | Content (%) |
| 1 | Off-white lyophilized cake | 2.6 | Qualified | 0.22 | 99.92 |
| 2 | Off-white lyophilized cake | 3.4 | Qualified | 0.23 | 99.89 |
| 3 | Off-white lyophilized cake | 3.0 | Qualified | 0.21 | 100.09 |
| 1 (comparison) | Off-white lyophilized cake | 3.0 | Qualified | 0.53 | 99.95 |
| 2 (comparison) | Off-white lyophilized cake | 3.0 | Qualified | 0.59 | 100.00 |
| 3 (comparison) | Off-white lyophilized cake | 3.8 | Qualified | 0.65 | 99.98 |
| 4 (comparison) | Off-white lyophilized cake | 3.4 | Qualified | 0.53 | 99.98 |
| 5 (comparison) | Off-white lyophilized cake | 2.0 | Qualified | 0.69 | 99.96 |
From the examination of the formulations obtained in examples 1 to 3 and comparative examples 1 to 5, it can be seen that: each index of examples 1 to 3 and comparative examples 1 to 5 is in accordance with the specification, but the relevant substances of the preparation obtained in examples 1 to 3 are obviously superior to those of comparative examples 1 to 5.
(2) Test for influencing factor
Finished preparations prepared in the embodiments 1-3 of the invention are placed in a constant temperature and humidity box with a high temperature of 60 ℃, samples are taken respectively on the 5 th day and the 10 th day, the change of properties, pH, moisture, related substances and contents is examined, and the test results are shown in table 2.
TABLE 2 influence factor test (60 ℃ C. at high temperature) results
According to the influence factor test, the following results are obtained: each index in examples 1-3 and comparative examples 1-5 meets the specification, but the sample quality stability in examples 1-3 is obviously better than that in comparative examples 1-5.
Claims (3)
1. A mycophenolate mofetil freeze-dried composition is characterized by being prepared from mycophenolate mofetil, citric acid, polysorbate 80, disodium tetraborate, a pH regulator and water for injection; the weight ratio of the mycophenolate mofetil to the disodium tetraborate is 25: 3-5; the pH regulator is hydrochloric acid; the preparation method comprises the following steps:
adding the mycophenolate mofetil, citric acid and polysorbate 80 in the amount according to the prescription into a proper amount of water for injection, uniformly stirring, adjusting the pH value of the solution to 2.6-3.4 by using 1M hydrochloric acid, adding disodium tetraborate in the amount according to the prescription, fixing the volume to the total amount, and stirring the solution to a colorless clear liquid; filtering, bottling, freeze drying, and visual inspection to obtain the final product;
the freeze-drying method comprises the following steps:
1) a pre-freezing stage: raising the temperature of the plate layer to 30-40 ℃, and keeping the temperature for 30-40 min; then, the temperature of the plate layer is reduced to minus 45 to minus 35 ℃ for 210 to 270min, and the heat preservation time is 390 to 450 min;
2) a sublimation drying stage: when the vacuum degree in the drying box reaches 80 mTorr-120 mTorr, preserving the heat for 30-90 min at-45 to-35 ℃, raising the temperature of the plate layer to-17.5 to-12.5 ℃, and using for 150-210 min; preserving the heat for 540-660 min;
3) and a re-drying stage: raising the temperature of the plate layer to 50-60 ℃, and taking for 150-210 min; pumping the vacuum degree in the drying box to the limit vacuum, and keeping the temperature for 210-270 min; reducing the temperature to 20-30 ℃, and taking for 90-150 min; and keeping the temperature for 90-150 min to obtain the mycophenolate mofetil freeze-dried preparation.
2. The lyophilized mycophenolate mofetil composition of claim 1, wherein the weight ratio of mycophenolate mofetil to disodium tetraborate is 25: 4.
3. The lyophilized mycophenolate mofetil composition according to claim 1, wherein the preparation method comprises the following steps:
adding the mycophenolate mofetil, the citric acid and the polysorbate 80 in the prescribed amount into a proper amount of water for injection, uniformly stirring, adjusting the pH value of the solution to 3.0 by using 1M hydrochloric acid, adding the disodium tetraborate in the prescribed amount, fixing the volume to the total amount, and stirring the solution to a colorless clear liquid; filtering, bottling, freeze drying, and visual inspection to obtain the final product;
the freeze-drying method comprises the following steps:
1) a pre-freezing stage: raising the temperature of the plate layer to 35 ℃, and keeping the temperature for 35 min; then reducing the temperature of the plate layer to-40 ℃ in 240min, and preserving the heat for 420 min;
2) a sublimation drying stage: keeping the vacuum degree in the drying oven at-40 deg.C for 60min to 100mTorr, and heating the plate layer to-15 deg.C for 180 min; preserving the heat for 600 min;
3) and a re-drying stage: raising the temperature of the plate layer to 55 ℃, and taking for 180 min; pumping the vacuum degree in the drying oven to the limit vacuum, and preserving the temperature for 240 min; cooling to 25 deg.C, and taking for 120 min; preserving the temperature for 120min to obtain the mycophenolate mofetil freeze-dried preparation.
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Citations (2)
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| CN101953807A (en) * | 2010-10-09 | 2011-01-26 | 山西普德药业有限公司 | Mycophenolate mofetil lyophilized powder injection for injection and preparation method thereof |
| WO2011061761A2 (en) * | 2009-11-17 | 2011-05-26 | Matrix Laboratories Ltd | Pharmaceutical composition for parenteral use |
-
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2011061761A2 (en) * | 2009-11-17 | 2011-05-26 | Matrix Laboratories Ltd | Pharmaceutical composition for parenteral use |
| CN101953807A (en) * | 2010-10-09 | 2011-01-26 | 山西普德药业有限公司 | Mycophenolate mofetil lyophilized powder injection for injection and preparation method thereof |
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