CN114288384A - Preparation process of leuprorelin acetate sustained-release microspheres for injection - Google Patents
Preparation process of leuprorelin acetate sustained-release microspheres for injection Download PDFInfo
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- CN114288384A CN114288384A CN202111562558.5A CN202111562558A CN114288384A CN 114288384 A CN114288384 A CN 114288384A CN 202111562558 A CN202111562558 A CN 202111562558A CN 114288384 A CN114288384 A CN 114288384A
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Abstract
The invention provides a preparation process of leuprorelin acetate sustained-release microspheres for injection, which comprises the following steps: the method comprises the steps of dissolving leuprorelin acetate in a gelatin solution, adding a polylactic acid dichloromethane solution, pumping into a shearing machine for shearing, adjusting the pump speed and the shearing process conditions to prepare a primary emulsion, adding a lactide-glycolide copolymer into the primary emulsion, shearing at a high speed for emulsification, adjusting the shearing process conditions to prepare a multiple emulsion, filling into a rotary evaporator for vacuumizing, rotating and curing, adding a mannitol solution for freeze-drying to obtain the leuprorelin acetate sustained-release microspheres for injection, wherein the sustained-release microspheres for injection can maintain the slow release of the drug for a long time, are uniformly emulsified and dispersed, have stable dissolution and release trends and no obvious burst release, and lay the foundation for clinical application.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a preparation process of leuprorelin acetate sustained-release microspheres for injection.
Background
Leuprolide acetate (leuprolide) is a gonadotropin releasing hormone (GnRH or LH-RH) analogue used in the treatment of a variety of sex hormone related diseases including advanced prostate cancer, endometriosis and precocious puberty. It acts primarily on the anterior pituitary to cause a brief, early increase in gonadotropin release, and upon continued use leuprolide causes desensitization and/or down-regulation of the pituitary leading to reduced circulating levels of gonadotropins and sex hormones. In the prior art, the production and preparation technology of leuprorelin acetate microspheres is micro-production, so that the problems of unstable product quality, easy burst release effect and the like are caused once the yield is overlarge, the problem of burst release of the microspheres is prominent, side effects are easy to occur in the early stage, and the effective action time of the medicine is reduced.
Disclosure of Invention
In view of the above, the invention provides a preparation process of leuprorelin acetate sustained release microspheres for injection, which solves the above problems.
The technical scheme of the invention is realized as follows: a preparation process of leuprorelin acetate sustained-release microspheres for injection comprises the following steps: the method comprises the following steps:
s1, dissolving leuprorelin acetate in a gelatin solution to prepare a leuprorelin acetate gelatin solution with the mass concentration of 15-18% for later use, and dissolving polylactic acid in dichloromethane to prepare a polylactic acid dichloromethane solution with the mass concentration of 15-18% for later use; dissolving mannitol in water to prepare a mannitol solution with the mass concentration of 2-4% for later use;
s2, pumping the polylactic acid dichloromethane solution into a shearing machine, adjusting the pump speed to 2000-10000 rpm, adding the leuprorelin acetate gelatin solution, controlling the shearing pressure to be 3-6 bar, controlling the temperature to be 60-80 ℃, and shearing for 2-6 times to obtain primary emulsion;
s3, adding the lactide-glycolide copolymer into the colostrum, and performing shearing high-speed emulsification again, wherein the rotating speed is adjusted to be 6000-12000 rpm, the shearing pressure is controlled to be 2-4 bar, and the temperature is controlled to be 10-30 ℃, so that multiple emulsion is obtained;
s4, filling the multiple emulsion of S3 into a rotary evaporator, vacuumizing, rotating and curing for 1-3 hours at the rotating speed of 400-600 rpm, centrifuging, taking the precipitate, sieving, adding a mannitol solution, and freeze-drying to obtain the leuprorelin acetate sustained-release microspheres for injection.
Further, the volume ratio of the polylactic acid dichloromethane solution to the leuprorelin acetate gelatin solution in the S2 is 3-5: 1.
Further, the mass ratio of the lactide-glycolide copolymer to the primary emulsion in the S3 is 0.1-0.3: 2.
Further, the centrifugal rotating speed of the S4 is 5000-8000 rpm, and the centrifugal time is 10-50 min.
Further, the mass-to-volume ratio of the S4 precipitate to the mannitol solution is 1-3: 20.
Further, the S4 freeze-drying temperature is-40 to-50 ℃.
Compared with the prior art, the invention has the beneficial effects that:
the invention selects several raw material medicines of leuprorelin acetate, polylactic acid, lactide glycolide copolymer, mannitol and the like to control the release and dissolution of the microspheres, and the pre-stage burst is obviously improved by process adjustment and the multiple emulsion is subjected to parameter adjustment of centrifugation and freeze-drying, so that the slow release of the medicament can be maintained for a long time.
Drawings
FIG. 1 is a schematic dissolution diagram;
FIG. 2 is a schematic view of the release rate.
Detailed Description
In order to better understand the technical content of the invention, specific examples are provided below to further illustrate the invention.
The experimental methods used in the examples of the present invention are all conventional methods unless otherwise specified.
The materials, reagents and the like used in the examples of the present invention can be obtained commercially without specific description.
Example 1
A preparation process of leuprorelin acetate sustained-release microspheres for injection comprises the following steps: the method comprises the following steps:
s1, dissolving leuprorelin acetate in a gelatin solution to prepare a leuprorelin acetate gelatin solution with the mass concentration of 15% for later use, and dissolving polylactic acid in dichloromethane to prepare a polylactic acid dichloromethane solution with the mass concentration of 15% for later use; dissolving mannitol in water to obtain mannitol solution with mass concentration of 2%;
s2, pumping the polylactic acid dichloromethane solution into a shearing machine, adjusting the pump speed to 2000rpm, adding the leuprorelin acetate gelatin solution, controlling the volume ratio of the polylactic acid dichloromethane solution to the leuprorelin acetate gelatin solution to be 3:1, controlling the shearing pressure to be 3bar, controlling the temperature to be 60 ℃, and shearing for 2 times to obtain primary emulsion;
s3, adding the lactide-glycolide copolymer into the colostrum, wherein the mass ratio of the lactide-glycolide copolymer to the colostrum is 0.1:2, carrying out shearing high-speed emulsification again, adjusting the rotating speed to 6000rpm, controlling the shearing pressure to be 2bar and the temperature to be 10 ℃ to obtain multiple emulsion;
s4, filling the multiple emulsion of S3 into a rotary evaporator, vacuumizing, rotating and solidifying for 1h at the rotating speed of 400rpm, centrifuging for 10min at the rotating speed of 5000rpm, taking the precipitate, sieving, adding mannitol solution, freeze-drying at the temperature of-40 ℃, wherein the mass-to-volume ratio of the precipitate to the mannitol solution is 1:20, and obtaining the leuprorelin acetate sustained-release microspheres for injection.
Example 2
A preparation process of leuprorelin acetate sustained-release microspheres for injection comprises the following steps: the method comprises the following steps:
s1, dissolving leuprorelin acetate in a gelatin solution to prepare a leuprorelin acetate gelatin solution with the mass concentration of 18% for later use, and dissolving polylactic acid in dichloromethane to prepare a polylactic acid dichloromethane solution with the mass concentration of 18% for later use; dissolving mannitol in water to obtain mannitol solution with mass concentration of 4%;
s2, pumping the polylactic acid dichloromethane solution into a shearing machine, adjusting the pump speed to 10000rpm, adding the leuprorelin acetate gelatin solution, controlling the volume ratio of the polylactic acid dichloromethane solution to the leuprorelin acetate gelatin solution to be 5:1, controlling the shearing pressure to be 6bar, controlling the temperature to be 80 ℃, and shearing for 6 times to obtain primary emulsion;
s3, adding the lactide-glycolide copolymer into the colostrum, wherein the mass ratio of the lactide-glycolide copolymer to the colostrum is 0.3:2, carrying out shearing high-speed emulsification again, adjusting the rotating speed to 12000rpm, controlling the shearing pressure to be 4bar, and controlling the temperature to be 30 ℃ to obtain multiple emulsion;
s4, filling the compound emulsion of S3 into a rotary evaporator, vacuumizing, rotating and solidifying for 3h at the rotating speed of 600rpm, centrifuging for 50min at the rotating speed of 8000rpm, taking the precipitate, sieving, adding mannitol solution, freeze-drying at the temperature of 50 ℃ below zero, wherein the mass-to-volume ratio of the precipitate to the mannitol solution is 3:20, and obtaining the leuprorelin acetate sustained-release microspheres for injection.
Example 3
A preparation process of leuprorelin acetate sustained-release microspheres for injection comprises the following steps: the method comprises the following steps:
s1, dissolving leuprorelin acetate in a gelatin solution to prepare a leuprorelin acetate gelatin solution with the mass concentration of 17% for later use, and dissolving polylactic acid in dichloromethane to prepare a polylactic acid dichloromethane solution with the mass concentration of 17% for later use; dissolving mannitol in water to obtain mannitol solution with mass concentration of 3%;
s2, pumping the polylactic acid dichloromethane solution into a shearing machine, adjusting the pump speed to 6000rpm, adding the leuprorelin acetate gelatin solution, controlling the volume ratio of the polylactic acid dichloromethane solution to the leuprorelin acetate gelatin solution to be 4:1, controlling the shearing pressure to be 5bar, controlling the temperature to be 70 ℃, and shearing for 4 times to obtain primary emulsion;
s3, adding the lactide-glycolide copolymer into the colostrum, wherein the mass ratio of the lactide-glycolide copolymer to the colostrum is 0.2:2, carrying out shearing high-speed emulsification again, adjusting the rotating speed to 9000rpm, controlling the shearing pressure to be 3bar and the temperature to be 20 ℃, and obtaining multiple emulsion;
s4, putting the multiple emulsion of S3 into a rotary evaporator, vacuumizing, rotating and solidifying for 2h at the rotating speed of 500rpm, centrifuging for 20min at the rotating speed of 6000rpm, taking the precipitate, sieving, adding mannitol solution, freeze-drying at the temperature of 45 ℃ below zero, and obtaining the leuprorelin acetate sustained-release microspheres for injection, wherein the mass-volume ratio of the precipitate to the mannitol solution is 2: 20.
Example 4
The difference between this embodiment and embodiment 3 is that the centrifugal rotation speed of S4 in the preparation process of the leuprolide acetate sustained release microsphere for injection is 4000rpm, and the centrifugal time is 60min, specifically:
s1, dissolving leuprorelin acetate in a gelatin solution to prepare a leuprorelin acetate gelatin solution with the mass concentration of 17% for later use, and dissolving polylactic acid in dichloromethane to prepare a polylactic acid dichloromethane solution with the mass concentration of 17% for later use; dissolving mannitol in water to obtain mannitol solution with mass concentration of 3%;
s2, pumping the polylactic acid dichloromethane solution into a shearing machine, adjusting the pump speed to 6000rpm, adding the leuprorelin acetate gelatin solution, controlling the volume ratio of the polylactic acid dichloromethane solution to the leuprorelin acetate gelatin solution to be 4:1, controlling the shearing pressure to be 5bar, controlling the temperature to be 70 ℃, and shearing for 4 times to obtain primary emulsion;
s3, adding the lactide-glycolide copolymer into the colostrum, wherein the mass ratio of the lactide-glycolide copolymer to the colostrum is 0.2:2, carrying out shearing high-speed emulsification again, adjusting the rotating speed to 9000rpm, controlling the shearing pressure to be 3bar and the temperature to be 20 ℃, and obtaining multiple emulsion;
s4, putting the multiple emulsion of S3 into a rotary evaporator, vacuumizing, rotating and solidifying for 2h at the rotating speed of 500rpm, centrifuging for 60min at the rotating speed of 4000rpm, taking the precipitate, sieving, adding mannitol solution, freeze-drying at the temperature of 45 ℃ below zero, and obtaining the leuprorelin acetate sustained-release microspheres for injection, wherein the mass-volume ratio of the precipitate to the mannitol solution is 2: 20.
Example 5
The difference between the present embodiment and embodiment 3 is that the preparation process of the sustained-release leuprolide acetate microspheres for injection has a lyophilization temperature of-30 ℃ in the S4, specifically:
s1, dissolving leuprorelin acetate in a gelatin solution to prepare a leuprorelin acetate gelatin solution with the mass concentration of 17% for later use, and dissolving polylactic acid in dichloromethane to prepare a polylactic acid dichloromethane solution with the mass concentration of 17% for later use; dissolving mannitol in water to obtain mannitol solution with mass concentration of 3%;
s2, pumping the polylactic acid dichloromethane solution into a shearing machine, adjusting the pump speed to 6000rpm, adding the leuprorelin acetate gelatin solution, controlling the volume ratio of the polylactic acid dichloromethane solution to the leuprorelin acetate gelatin solution to be 4:1, controlling the shearing pressure to be 5bar, controlling the temperature to be 70 ℃, and shearing for 4 times to obtain primary emulsion;
s3, adding the lactide-glycolide copolymer into the colostrum, wherein the mass ratio of the lactide-glycolide copolymer to the colostrum is 0.2:2, carrying out shearing high-speed emulsification again, adjusting the rotating speed to 9000rpm, controlling the shearing pressure to be 3bar and the temperature to be 20 ℃, and obtaining multiple emulsion;
s4, putting the multiple emulsion of S3 into a rotary evaporator, vacuumizing, rotating and solidifying for 2h at the rotating speed of 500rpm, centrifuging for 20min at the rotating speed of 6000rpm, taking the precipitate, sieving, adding mannitol solution, freeze-drying at the temperature of-30 ℃, wherein the mass-volume ratio of the precipitate to the mannitol solution is g/mL of 2:20, and obtaining the leuprorelin acetate sustained-release microspheres for injection.
Comparative example 1
The difference between the comparative example and the example 3 is that the pump speed in the shearing machine in the preparation process S2 of the leuprorelin acetate sustained-release microspheres for injection is 12000rpm, which specifically comprises the following steps:
s1, dissolving leuprorelin acetate in a gelatin solution to prepare a leuprorelin acetate gelatin solution with the mass concentration of 17% for later use, and dissolving polylactic acid in dichloromethane to prepare a polylactic acid dichloromethane solution with the mass concentration of 17% for later use; dissolving mannitol in water to obtain mannitol solution with mass concentration of 3%;
s2, pumping the polylactic acid dichloromethane solution into a shearing machine, adjusting the pump speed to 12000rpm, adding the leuprorelin acetate gelatin solution, controlling the volume ratio of the polylactic acid dichloromethane solution to the leuprorelin acetate gelatin solution to be 4:1, controlling the shearing pressure to be 5bar, controlling the temperature to be 70 ℃, and shearing for 4 times to obtain primary emulsion;
s3, adding the lactide-glycolide copolymer into the colostrum, wherein the mass ratio of the lactide-glycolide copolymer to the colostrum is 0.2:2, carrying out shearing high-speed emulsification again, adjusting the rotating speed to 9000rpm, controlling the shearing pressure to be 3bar and the temperature to be 20 ℃, and obtaining multiple emulsion;
s4, putting the multiple emulsion of S3 into a rotary evaporator, vacuumizing, rotating and solidifying for 2h at the rotating speed of 500rpm, centrifuging for 20min at the rotating speed of 6000rpm, taking the precipitate, sieving, adding mannitol solution, freeze-drying at the temperature of 45 ℃ below zero, and obtaining the leuprorelin acetate sustained-release microspheres for injection, wherein the mass-volume ratio of the precipitate to the mannitol solution is 2: 20.
Comparative example 2
The difference between the comparative example and the example 3 is that the shear pressure in the preparation process S2 of the leuprorelin acetate sustained-release microspheres for injection is 8 bar; the method specifically comprises the following steps:
s1, dissolving leuprorelin acetate in a gelatin solution to prepare a leuprorelin acetate gelatin solution with the mass concentration of 17% for later use, and dissolving polylactic acid in dichloromethane to prepare a polylactic acid dichloromethane solution with the mass concentration of 17% for later use; dissolving mannitol in water to obtain mannitol solution with mass concentration of 3%;
s2, pumping the polylactic acid dichloromethane solution into a shearing machine, adjusting the pump speed to 6000rpm, adding the leuprorelin acetate gelatin solution, controlling the volume ratio of the polylactic acid dichloromethane solution to the leuprorelin acetate gelatin solution to be 4:1, controlling the shearing pressure to be 5bar, controlling the temperature to be 70 ℃, and shearing for 4 times to obtain primary emulsion;
s3, adding the lactide-glycolide copolymer into the colostrum, wherein the mass ratio of the lactide-glycolide copolymer to the colostrum is 0.2:2, carrying out shearing high-speed emulsification again, adjusting the rotating speed to 9000rpm, controlling the shearing pressure to be 8bar and the temperature to be 20 ℃, and obtaining multiple emulsion;
s4, putting the multiple emulsion of S3 into a rotary evaporator, vacuumizing, rotating and solidifying for 2h at the rotating speed of 500rpm, centrifuging for 20min at the rotating speed of 6000rpm, taking the precipitate, sieving, adding mannitol solution, freeze-drying at the temperature of 45 ℃ below zero, and obtaining the leuprorelin acetate sustained-release microspheres for injection, wherein the mass-volume ratio of the precipitate to the mannitol solution is 2: 20.
Comparative example 3
The difference between the comparative example and the example 3 is that the multiple emulsion of S4 is not vacuumized and rotationally solidified in the preparation process of the leuprorelin acetate sustained-release microspheres for injection; the method specifically comprises the following steps:
s1, dissolving leuprorelin acetate in a gelatin solution to prepare a leuprorelin acetate gelatin solution with the mass concentration of 17% for later use, and dissolving polylactic acid in dichloromethane to prepare a polylactic acid dichloromethane solution with the mass concentration of 17% for later use; dissolving mannitol in water to obtain mannitol solution with mass concentration of 3%;
s2, pumping the polylactic acid dichloromethane solution into a shearing machine, adjusting the pump speed to 6000rpm, adding the leuprorelin acetate gelatin solution, controlling the volume ratio of the polylactic acid dichloromethane solution to the leuprorelin acetate gelatin solution to be 4:1, controlling the shearing pressure to be 5bar, controlling the temperature to be 70 ℃, and shearing for 4 times to obtain primary emulsion;
s3, adding the lactide-glycolide copolymer into the colostrum, wherein the mass ratio of the lactide-glycolide copolymer to the colostrum is 0.2:2, carrying out shearing high-speed emulsification again, adjusting the rotating speed to 9000rpm, controlling the shearing pressure to be 3bar and the temperature to be 20 ℃, and obtaining multiple emulsion;
s4, centrifuging the multiple emulsion of S3 at the rotating speed of 6000rpm for 20min, taking the precipitate, sieving, adding mannitol solution, freeze-drying at the temperature of 45 ℃ below zero, and obtaining the leuprorelin acetate sustained-release microspheres for injection, wherein the mass-volume ratio of the precipitate to the mannitol solution is 2: 20.
Firstly, in vitro dissolution and release determination:
(1) dissolution rate in vitro
20mg of each of the samples of examples 1 to 5 and comparative examples 1 to 3 was taken, 8mL of a phosphate buffer solution having a pH of 4.5 was added, the mixture was shaken by a shaker in a water bath at 37. + -. 0.5 ℃ and filtered, and the cumulative dissolution was calculated by a dissolution rate measurement method (XC second method, appendix of second part of the year 2015 in Chinese pharmacopoeia), and the results are shown in FIG. 1.
(2) Degree of release
According to the results shown in fig. 1, 30mg of the samples of example 3 and comparative examples 1 to 3 were selected, placed in a 50mL test tube, added with 30mL of a solvent, placed in a 37 ± 0.5 ℃ incubator, and the release degrees were measured at 0 day, 5 days, 10 days, 20 days, 40 days, 50 days, 60 days, and 90 days according to the first method of the second release degree measurement appendix XD of the pharmacopoeia 2010 edition of traditional Chinese medicine, and the results are shown in fig. 2.
As can be seen from the results of fig. 1 and 2, in comparative example 1 in fig. 1, the dissolution rate decreased after day 10, the dissolution rate increased after day 40, and the dissolution tendency was unstable, as compared with comparative example 1, in fig. 1, the burst release was also evident in the early stage, and the slow increase was followed after the decrease after day 10, which indicates that the pump speed of the shearing machine was slightly higher in step S2, resulting in non-uniform dispersion and emulsification effect;
compared with the comparative example 2, fig. 1 shows that a certain burst is released before 5 days, the speed is higher than that of the example group, the dissolution curve is reduced at the 10 th day, the dissolution is obvious at the 20 th day, and the release degree curves in fig. 2 are the same, which shows that the shearing pressure in the step S2 has a certain influence on the shearing effect of the colostrum;
compared with the comparative example 3, fig. 1 and fig. 2 show that the burst release is obvious before 5 days, the dissolution rate is high, the drop is realized on the 10 th day, and the dissolution and release trends are extremely unstable, which indicates that the multiple emulsion of S4 is not vacuumized, rotated and solidified, so that the diffusion channels of the microspheres are more, which is not beneficial to the uniform dispersion of the drug and cannot release the drug for a long time;
compared with the examples 4 and 5, the pre-burst release of the multiple emulsion is obviously improved after the parameters of centrifugation and freeze-drying are adjusted.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (6)
1. A preparation process of leuprorelin acetate sustained release microspheres for injection is characterized in that: the method comprises the following steps:
s1, dissolving leuprorelin acetate in a gelatin solution to prepare a leuprorelin acetate gelatin solution with the mass concentration of 15-18% for later use, and dissolving polylactic acid in dichloromethane to prepare a polylactic acid dichloromethane solution with the mass concentration of 15-18% for later use; dissolving mannitol in water to prepare a mannitol solution with the mass concentration of 2-4% for later use;
s2, pumping the polylactic acid dichloromethane solution into a shearing machine, adjusting the pump speed to 2000-10000 rpm, adding the leuprorelin acetate gelatin solution, controlling the shearing pressure to be 3-6 bar, controlling the temperature to be 60-80 ℃, and shearing for 2-6 times to obtain primary emulsion;
s3, adding the lactide-glycolide copolymer into the colostrum, and performing shearing high-speed emulsification again, wherein the rotating speed is adjusted to be 6000-12000 rpm, the shearing pressure is controlled to be 2-4 bar, and the temperature is controlled to be 10-30 ℃, so that multiple emulsion is obtained;
s4, filling the multiple emulsion of S3 into a rotary evaporator, vacuumizing, rotating and curing for 1-3 hours at the rotating speed of 400-600 rpm, centrifuging, taking the precipitate, sieving, adding a mannitol solution, and freeze-drying to obtain the leuprorelin acetate sustained-release microspheres for injection.
2. The preparation process of the leuprorelin acetate sustained-release microspheres for injection as claimed in claim 1, wherein: the volume ratio of the polylactic acid dichloromethane solution to the leuprorelin acetate gelatin solution in the S2 is 3-5: 1.
3. The preparation process of the leuprorelin acetate sustained-release microspheres for injection as claimed in claim 1, wherein: the mass ratio of the lactide-glycolide copolymer to the primary emulsion in the S3 is 0.1-0.3: 2.
4. The preparation process of the leuprorelin acetate sustained-release microspheres for injection as claimed in claim 1, wherein: the centrifugal rotating speed of the S4 is 5000-8000 rpm, and the centrifugal time is 10-50 min.
5. The preparation process of the leuprorelin acetate sustained-release microspheres for injection as claimed in claim 1, wherein: the mass-to-volume ratio of the S4 precipitate to the mannitol solution is 1-3: 20.
6. The preparation process of the leuprorelin acetate sustained-release microspheres for injection as claimed in claim 1, wherein: the freeze-drying temperature of the S4 is-40 to-50 ℃.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114940746A (en) * | 2022-06-17 | 2022-08-26 | 山东采采医疗科技有限公司 | Star-shaped lactide-glycolide copolymer and application thereof as drug sustained-release carrier |
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| CN103211773A (en) * | 2013-04-10 | 2013-07-24 | 上海丽珠制药有限公司 | Method for preparing leuprolide acetate microspheres |
| CN106038492A (en) * | 2016-05-19 | 2016-10-26 | 丽珠医药集团股份有限公司 | Preparation method of sustained-release leuprolide acetate microspheres |
| CN106668831A (en) * | 2016-12-22 | 2017-05-17 | 浙江圣兆药物科技股份有限公司 | Preparation method of leuprorelin microspheres |
| CN106794147A (en) * | 2014-07-28 | 2017-05-31 | Sk化学株式会社 | There is comprising Leuprorelin and simultaneously the pharmaceutical composition of release and sustained release property immediately |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103211773A (en) * | 2013-04-10 | 2013-07-24 | 上海丽珠制药有限公司 | Method for preparing leuprolide acetate microspheres |
| CN106794147A (en) * | 2014-07-28 | 2017-05-31 | Sk化学株式会社 | There is comprising Leuprorelin and simultaneously the pharmaceutical composition of release and sustained release property immediately |
| CN106038492A (en) * | 2016-05-19 | 2016-10-26 | 丽珠医药集团股份有限公司 | Preparation method of sustained-release leuprolide acetate microspheres |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114940746A (en) * | 2022-06-17 | 2022-08-26 | 山东采采医疗科技有限公司 | Star-shaped lactide-glycolide copolymer and application thereof as drug sustained-release carrier |
| CN114940746B (en) * | 2022-06-17 | 2024-04-26 | 山东采采医疗科技有限公司 | Star-shaped lactide-glycolide copolymer and application thereof as drug slow-release carrier |
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