CN105287390A - Long-acting leuprorelin acetate microsphere and preparation method thereof - Google Patents
Long-acting leuprorelin acetate microsphere and preparation method thereof Download PDFInfo
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- CN105287390A CN105287390A CN201510813372.0A CN201510813372A CN105287390A CN 105287390 A CN105287390 A CN 105287390A CN 201510813372 A CN201510813372 A CN 201510813372A CN 105287390 A CN105287390 A CN 105287390A
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- 239000004005 microsphere Substances 0.000 title claims abstract description 81
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 title claims abstract description 62
- 229960004338 leuprorelin Drugs 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 108010010803 Gelatin Proteins 0.000 claims abstract description 38
- 229920000159 gelatin Polymers 0.000 claims abstract description 38
- 239000008273 gelatin Substances 0.000 claims abstract description 38
- 235000019322 gelatine Nutrition 0.000 claims abstract description 38
- 235000011852 gelatine desserts Nutrition 0.000 claims abstract description 38
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 claims abstract description 32
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 32
- 229930195725 Mannitol Natural products 0.000 claims abstract description 32
- 239000000594 mannitol Substances 0.000 claims abstract description 32
- 235000010355 mannitol Nutrition 0.000 claims abstract description 32
- 239000002994 raw material Substances 0.000 claims abstract description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 81
- 239000000243 solution Substances 0.000 claims description 70
- 239000011347 resin Substances 0.000 claims description 31
- 229920005989 resin Polymers 0.000 claims description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 25
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 15
- 239000007788 liquid Substances 0.000 claims description 15
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 15
- 229940068984 polyvinyl alcohol Drugs 0.000 claims description 15
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 15
- 230000001804 emulsifying effect Effects 0.000 claims description 14
- 238000004108 freeze drying Methods 0.000 claims description 14
- 238000000935 solvent evaporation Methods 0.000 claims description 12
- 238000002347 injection Methods 0.000 claims description 9
- 239000007924 injection Substances 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- 238000005303 weighing Methods 0.000 claims description 8
- 238000005119 centrifugation Methods 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 7
- 235000019628 coolness Nutrition 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 238000010792 warming Methods 0.000 claims description 7
- 239000002245 particle Substances 0.000 claims description 6
- 238000001704 evaporation Methods 0.000 claims description 5
- 108010000817 Leuprolide Proteins 0.000 claims description 2
- 238000004945 emulsification Methods 0.000 claims description 2
- 230000008020 evaporation Effects 0.000 claims description 2
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 abstract description 18
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 229920001577 copolymer Polymers 0.000 abstract 1
- 239000000047 product Substances 0.000 description 26
- 238000002474 experimental method Methods 0.000 description 12
- 239000002904 solvent Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000011806 microball Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 208000015474 Central precocious puberty Diseases 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 206010062767 Hypophysitis Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 206010046798 Uterine leiomyoma Diseases 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 229960001716 benzalkonium Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 210000003635 pituitary gland Anatomy 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 208000006155 precocious puberty Diseases 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004017 vitrification Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to a chemical drug microsphere preparation and a preparation method thereof, in particular to long-acting leuprorelin acetate microsphere and a preparation method thereof. The raw materials of the leuprorelin acetate microsphere include leuprorelin acetate, a glycolide lactide copolymer, mannitol and gelatin. The microsphere and the preparation process provided by the invention select appropriate PLGA and unique production process parameters, thus developing the leuprorelin acetate microsphere with release time up to 3 months. And the release rate and yield of the microsphere provided by the invention are superior to the prior art.
Description
Technical field:
The present invention relates to a kind of chemical drugs microball preparation and preparation method thereof, particularly long-acting leuprorelin acetate microsphere and preparation method thereof.
Background technology:
Leuprorelin acetate (LeuprorelinAcetate) is potent GuRH-A (GnRHa), can secrete promoting sexual gland hormone by Stimulation of Pituitary Gland, bring out genitals and generate steroid.Clinically for endometriosis, hysteromyoma, Central precocious puberty, carcinoma of prostate.Injection leuprorelin acetate microsphere, is used by leuprorelin acetate polymer substance to embed to make microsphere, makes the leuprorelin acetate slow releasing in microsphere, thus reach therapeutical effect, be particularly useful for the patient of lifelong medication, as patients with prostate cancer.Because microball preparation preparation technology has high technology content feature, microsphere embedded material PLGA type kind used is many, and the domestic research to microsphere is still in the starting stage.The domestic leuprorelin acetate microsphere getting the Green Light production is only released to the product of month at present, and being released to trimestral long-acting leuprorelin acetate microsphere does not also have domestic relevant unit to study.
Summary of the invention:
The object of the present invention is to provide a kind of long-acting leuprorelin acetate microsphere and preparation method thereof.
Microsphere raw material:
Leuprorelin acetate 11.25 weight portion
Glycolide third hands over resin copolymer 80 ~ 350 weight portion
Mannitol 1 ~ 5 weight portion
Gelatin 1 ~ 2 weight portion;
Microsphere raw material is preferred:
Leuprorelin acetate 11.25 weight portion
Glycolide third hands over resin copolymer 85 weight portion
Mannitol 4 weight portion
Gelatin 1 weight portion;
Leuprorelin acetate 11.25 weight portion
Glycolide third hands over resin copolymer 300 weight portion
Mannitol 2 weight portion
Gelatin 1.5 weight portion;
Leuprorelin acetate 11.25 weight portion
Glycolide third hands over resin copolymer 215 weight portion
Mannitol 3 weight portion
Gelatin 1.5 weight portion.
Method for preparing microsphere of the present invention:
(1) dosing
Take the gelatin of recipe quantity, add about 50 ~ 60 DEG C of water, make concentration 13-16% aqueous gelatin solution, the leuprorelin acetate taking formula ratio is dissolved in aqueous gelatin solution, makes the leuprorelin gelatin solution that mass concentration is 16.7% ~ 25.0%, for subsequent use;
The glycolide third taking formula ratio hands over resin copolymer, is dissolved in dichloromethane and is mixed with the solution that mass concentration is 18 ~ 25%, for subsequent use;
Take the mannitol of formula ratio, be dissolved in water, make mass concentration be 5.0% mannitol solution for subsequent use;
Weighing polyvinyl alcohol, adds water, and is the aqueous solution of 0.5% ~ 1.5% in 80 DEG C ~ 90 DEG C compound concentrations, for subsequent use;
(2) emulsifying: handed over by above-mentioned glycolide third resin copolymer solution to be added in described leuprorelin acetate solution, vibration emulsifying, is prepared into W1/O phase product, and in 12 ~ 18 DEG C of water-bath coolings;
(3) homogenizing: described W1/O phase injections is entered homogenizing process in described poly-vinyl alcohol solution, makes the microsphere of suitable particle size scope;
(4) solvent evaporation: the dichloromethane contained in the medicinal liquid after homogenizing is removed;
(5) microsphere is collected: the medicinal liquid after removing dichloromethane is carried out frozen centrifugation, and sucking filtration discards solution, obtains described microsphere.
(6) lyophilizing: cryodesiccated step is carried out to the described microsphere collected.
Raw material glycolide third of the present invention hands over the molecular weight of resin copolymer (PLGA) to be 20000 ~ 100000, viscosity: 0.2 ~ 0.8; Preferred molecular weight is molecular weight is 40000 ~ 80000.The dosing concentration of step of the present invention (1) is preferred:
Take gelatin, be dissolved in hot water, the leuprorelin acetate taking formula ratio is dissolved in aqueous gelatin solution, makes the solution that mass concentration is 18%, 20%, 21% or 24%, for subsequent use;
The glycolide third taking formula ratio hands over resin copolymer, is dissolved in dichloromethane and is mixed with the solution that mass concentration is 21%, 24%, 27% or 29%, for subsequent use;
Take the mannitol of formula ratio, be dissolved in water, make mass concentration be 8% or 9% mannitol solution for subsequent use;
Weighing polyvinyl alcohol adds water, and is the aqueous solution of 0.8% or 1% in 80 DEG C ~ 90 DEG C of compound concentrations, for subsequent use.
Water-bath chilling temperature in step of the present invention (2) emulsion process preferably 13 DEG C, 15 DEG C or 17 DEG C.
Cryodesiccated step of the present invention can be:
A, by shelf pre-freeze to after-30 DEG C, product inlet; And continue holding plate temperature-30 DEG C to product fully charge;
B, panel temperature are warming up to-20 DEG C with the programming rate of 0.5 ~ 2 DEG C/h, after reaching-20 DEG C, start evacuation, carry out lyophilization, freeze-drying time about 24 ~ 48 hours.
The evaporation conditions of step of the present invention (4) is preferred:
Work as homogenizing, do not heat up half an hour, be then warmed up to 25 degree, keep 4 hours, then be warmed up to 33 degree, keep 2 hours.
Microsphere of the present invention and preparation technology thereof are all better than prior art in release and yield, by thousands of experiments, to the release mode of various model PLGA, the microsphere of various explained hereafter is studied, have selected suitable PLGA and the processing parameter of uniqueness, have developed and reach three months leuprorelin acetate microspheres release time.Following experimental example and embodiment are used for further illustrating but are not limited to the present invention.
The detection method of institute release experiment of the present invention is as follows:
With sodium dihydrogen phosphate-benzalkonium chloride-water (4.6: 0.1: 1000) mixed solution (regulating pH to 7.1 ± 0.1 with the sodium hydroxide of 1mol/L) for solvent.Get this product 30mg, accurately weighed, put in 50ml tool plug test tube, add solvent 30ml, be placed in 37 DEG C of (± 1 DEG C) calorstats, at 1 day, 4 days, 7 days, 14 days, 21 days, 30 days, 40 days, 50 days, 60 days, 70 days, 80 days, 90 days, 2.5ml is taken out respectively with syringe, with 0.45 μ membrane filtration, the former test tube of first filtrate 0.2ml add-back, precision takes subsequent filtrate 2g (± 0.02g) and is placed in sample injection bottle, add mobile phase 2ml and make need testing solution, the former test tube of remaining liquid add-back also supplements 2ml solvent immediately, measures by method under assay item.This product the cumulative release amount of 4 hours, 72 hours, 28 days be respectively≤30%, 45 ± 10%, 100 ± 10%, all should conform with the regulations.
An experimental example 1:8 sample 90 days releasing research
This method adopts the preparation method of embodiment 1 to prepare 8 samples respectively, selects different PLGA models respectively, microsphere is carried out drug loading and vitro release mensuration.PLGA is the crux factor affecting release, and long-acting release needs larger molecular weight and viscosity just can reach good effect, and the different PLGA of this experiment paper examines is on the impact of release.Its molecular weight is 20000 ~ 100000, intrinsic viscosity: 20 ~ 80g/ml.
Table 1: different model PLGA experimental design
Table 2: each time point release of each sample
Conclusion:
1, PLGA model is that the microsphere release that 85155A, DL1A, DL4A, DL5A do can reach release requirement in three months, and PLGA75254A is not reaching requirement, and especially better with 100DL4A, 5A, molecular weight is 40000 ~ 80000.
Experimental example 2 investigates raw material and ratio of adjuvant to the impact of yield
This experiment method of embodiment 1 prepares 4 groups of samples, and often organize sample difference and be only the different proportion (seeing the following form 3) arranging raw material and adjuvant PLGA respectively, the ratio of this experiment paper examines raw material and adjuvant PLGA changes.
Table 3 experimental result:
Sum up: when proportioning is 11.25:85, yield is best, and the microsphere of preparation all can be discharged into three months, meets the requirements.
Experimental example 3: investigating PLGA concentration affects release
This experiment method of embodiment 1 prepares 3 groups of samples, and often organize sample difference and be only the variable concentrations arranging PLGA respectively, the concentration of this experiment paper examines PLGA is on the impact of microsphere yield.(see table 4)
Table 4: experimental result
| PLGA concentration | Yield | Release |
| 25％ | 52％ | Can three months be discharged, |
| 20％ | 64％ | Can three months be discharged |
| 15％ | 54％ | Can three months be discharged, slightly soon |
Sum up:
1, the concentration of PLGA has certain influence to microsphere yield, and wherein concentration is about 20% for best, and 25% concentration viscosity is excessive, affects yield, and 15% concentration is excessively rare, affects yield, and the microsphere particle size of preparation is slightly little, discharges slightly fast.
Experimental example 4: homogenizing temperature is on the impact of microsphere
This experiment method of embodiment 1 prepares 3 groups of samples, and often organize sample difference and be only to arrange different homogenizing temperatures respectively, this experiment paper examines homogenizing temperature is on the impact of microsphere.(see table 5)
Table 5: experimental result
| Homogenizing temperature | Yield | Release |
| 25℃ | 52％ | Discharge three months, slightly soon |
| 15℃ | 63％ | Discharge three months |
| 5℃ | 34％ | Discharge three months |
Sum up:
1, during homogenizing temperature about 15 DEG C, yield is best.
2, temperature about 5 DEG C, due to emulsion condensation, has a strong impact on microsphere yield.
3, during temperature about 25 DEG C, due to partial solvent volatilization, yield is affected.
Experimental example 5: homogenizing speed affects microsphere release
This experiment method of embodiment 1 prepares 3 groups of samples, and often organize sample difference and be only to arrange different homogenizing speed respectively, this experiment paper examines homogenizing speed is on the impact of microsphere.(see table 6)
Table 6: experimental result
| Homogenizing speed | Yield affects | Release affects |
| 5mL/min | 48％ | Discharge slightly fast |
| 10mL/min1 | 62％ | Release three months |
| 15mL/min | 56％ | Release is slightly slow |
Sum up
1, homogenizing speed is about 10mL/min1 the best, and the microsphere particle size size of formation is proper, and yield is higher, and release is also relatively good.
2, when homogenizing speed is 5mL/min1, homogenizing time is long, and microsphere particle size is less than normal, and release is very fast.
3, when homogenizing speed is 15mL/min1, the microsphere particle size of formation is comparatively large, discharges slower.
Experimental example 6: solvent evaporating temperature, time are on the impact of microsphere
This experiment method of embodiment 1 prepares 3 groups of samples, often organizes sample difference and is only to arrange different evaporating temperatures and time respectively, and this tests main evaporating temperature and time to the impact of microsphere.(see table 7)
3 sample design are as follows:
1. do not heat up half an hour, be then warmed up to 25 degree, keep 4 hours, then be warmed up to 33 degree, keep 2 hours.
2. do not heat up half an hour, be warmed up to 20 degree, keep 4 hours, then be warmed up to 28 degree, keep 2 hours.
3. do not heat up half an hour, be warmed up to 30 degree, keep 4 hours, then be warmed up to 40 degree, keep 2 hours.
Table 7: experimental result
| Temperature and time changes | Dichloromethane remains | Release affects |
| 25 DEG C, 4 hours, 33 DEG C, 2 hours | 0.03％ | Discharge three months |
| 20 DEG C, 4 hours, 28 DEG C, 2 hours | 0.78％ | Discharge three months |
| 30 DEG C, 4 hours, 40 DEG C, 2 hours | 0.0％ | Release is fast |
Sum up:
1, work as homogenizing, do not heat up half an hour, be then warmed up to 25 degree, keep 4 hours, then be warmed up to 33 degree, keep 2 hours.The microsphere dichloromethane of preparation is residual lower, and meet national requirements, release is also better.
2, work as homogenizing, be warmed up to 20 degree, keep 4 hours, then be warmed up to 28 degree, keep 2 hours.The microsphere dichloromethane of preparation is residual higher, does not meet national requirements.
3, work as homogenizing, be warmed up to 30 degree, keep 4 hours, then be warmed up to 40 degree, keep 2 hours.It is zero that the microsphere dichloromethane of preparation remains, but due to the higher vitrification point close to PLGA of temperature, therefore destroys microsphere very large, affect yield and the release of microsphere.
Embodiment 1:
Leuprorelin acetate 11.25g
Glycolide third hands over resin copolymer 85g
Mannitol 4g
Gelatin 1g;
Method for making:
(1) dosing
Take gelatin, add 50 ~ 60 DEG C of water, make concentration 15% aqueous gelatin solution, take leuprorelin acetate and be dissolved in aqueous gelatin solution, make the leuprorelin acetate solution that mass concentration is 20%, for subsequent use;
The glycolide third taking formula ratio hands over resin copolymer 4A, is dissolved in dichloromethane and is mixed with the solution that mass concentration is 20%, for subsequent use;
Take the mannitol of formula ratio, be dissolved in water, make mass concentration be 5% mannitol solution for subsequent use;
Weighing polyvinyl alcohol adds water, and is the aqueous solution of 0.8% in 80 DEG C ~ 90 DEG C compound concentrations, for subsequent use;
(2) emulsifying: handed over by above-mentioned glycolide third resin copolymer solution to be added in described leuprorelin acetate solution, vibration emulsifying, is prepared into W1/O phase product, and in 10 DEG C of water-bath coolings;
(3) homogenizing: described W1/O phase product is injected into homogenizing process in described poly-vinyl alcohol solution with 5mL/min injection speed;
(4) solvent evaporation: the dichloromethane contained in the medicinal liquid after homogenizing is removed; Solvent evaporation conditions is: do not heat up half an hour, is then warmed up to 25 degree, keeps 4 hours, then is warmed up to 33 degree, keeps 2 hours.
(5) microsphere is collected: the medicinal liquid after removing dichloromethane is carried out frozen centrifugation, and sucking filtration discards solution, obtains described microsphere.
(6) lyophilizing: cryodesiccated step is carried out to the described microsphere collected, after shelf pre-freeze extremely-30 DEG C, product inlet; And continue holding plate temperature-30 DEG C to product fully charge; Panel temperature is warming up to-20 DEG C with the programming rate of 1 DEG C/h, carries out lyophilization, freeze-drying time 36 hours.
Embodiment 2:
Leuprorelin acetate 11.25g
Glycolide third hands over resin copolymer 300g
Mannitol 2g
Gelatin 1.5g;
Method for making:
(1) dosing
Take gelatin, add 50 ~ 60 DEG C of water, make concentration 15% aqueous gelatin solution, take leuprorelin acetate and be dissolved in aqueous gelatin solution, make the leuprorelin acetate solution that mass concentration is 20%, for subsequent use;
The glycolide third taking formula ratio hands over resin copolymer, is dissolved in dichloromethane and is mixed with the solution that mass concentration is 25%, for subsequent use;
Take the mannitol of formula ratio, be dissolved in water, make mass concentration be 8% mannitol solution for subsequent use;
Weighing polyvinyl alcohol adds water, and is the aqueous solution of 1% in 80 DEG C ~ 90 DEG C compound concentrations, for subsequent use;
(2) emulsifying: handed over by above-mentioned glycolide third resin copolymer solution to be added in described leuprorelin acetate solution, vibration emulsifying, is prepared into W1/O phase product, and in 15 DEG C of water-bath coolings;
(3) homogenizing: described W1/O phase product is injected into homogenizing process in described poly-vinyl alcohol solution with 8mL/min injection speed;
(4) solvent evaporation: the dichloromethane contained in the medicinal liquid after homogenizing is removed; Solvent evaporation conditions is: do not heat up half an hour, is then warmed up to 25 degree, keeps 4 hours, then is warmed up to 33 degree, keeps 2 hours.
(5) microsphere is collected: the medicinal liquid after removing dichloromethane is carried out frozen centrifugation, and sucking filtration discards solution, obtains described microsphere.
(6) lyophilizing: cryodesiccated step is carried out to the described microsphere collected, after shelf pre-freeze extremely-30 DEG C, product inlet; And continue holding plate temperature-30 DEG C to product fully charge; Panel temperature is warming up to-20 DEG C with the programming rate of 1 DEG C/h, carries out lyophilization, freeze-drying time 40 hours.
Embodiment 3:
Leuprorelin acetate 11.25g
Glycolide third hands over resin copolymer 215g
Mannitol 3g
Gelatin 1.5g.
Method for making:
(1) dosing
Take gelatin, add 50 ~ 60 DEG C of water, make concentration 15% aqueous gelatin solution, take leuprorelin acetate and be dissolved in aqueous gelatin solution, make the leuprorelin acetate solution that mass concentration is 20%, for subsequent use;
The glycolide third taking formula ratio hands over resin copolymer, is dissolved in dichloromethane and is mixed with the solution that mass concentration is 18%, for subsequent use;
Take the mannitol of formula ratio, be dissolved in water, make mass concentration be 5% mannitol solution for subsequent use;
Weighing polyvinyl alcohol adds water, and is the aqueous solution of 1% in 80 DEG C ~ 90 DEG C compound concentrations, for subsequent use;
(2) emulsifying: handed over by above-mentioned glycolide third resin copolymer solution to be added in described leuprorelin acetate solution, vibration emulsifying, is prepared into W1/O phase product, and in 15 DEG C of water-bath coolings;
(3) homogenizing: described W1/O phase product is injected into homogenizing process in described poly-vinyl alcohol solution with 5mL/min injection speed;
(4) solvent evaporation: the dichloromethane contained in the medicinal liquid after homogenizing is removed; Solvent evaporation conditions is: do not heat up half an hour, is then warmed up to 25 degree, keeps 4 hours, then is warmed up to 33 degree, keeps 2 hours.
(5) microsphere is collected: the medicinal liquid after removing dichloromethane is carried out frozen centrifugation, and sucking filtration discards solution, obtains described microsphere.
(6) lyophilizing: cryodesiccated step is carried out to the described microsphere collected, after shelf pre-freeze extremely-30 DEG C, product inlet; And continue holding plate temperature-30 DEG C to product fully charge; Panel temperature is warming up to-20 DEG C with the programming rate of 1 DEG C/h, carries out lyophilization, freeze-drying time 40 hours.
Embodiment 4:
Leuprorelin acetate 11.25g
Glycolide third hands over resin copolymer 350g
Mannitol 1g
Gelatin 2g;
Method for making:
(1) dosing
Take gelatin, add 50 ~ 60 DEG C of water, make concentration 15% aqueous gelatin solution, take leuprorelin acetate and be dissolved in aqueous gelatin solution, make the leuprorelin acetate solution that mass concentration is 20%, for subsequent use;
The glycolide third taking formula ratio hands over resin copolymer, is dissolved in dichloromethane and is mixed with the solution that mass concentration is 20%, for subsequent use;
Take the mannitol of formula ratio, be dissolved in water, make mass concentration be 5% mannitol solution for subsequent use;
Weighing polyvinyl alcohol adds water, and is the aqueous solution of 1% in 80 DEG C ~ 90 DEG C compound concentrations, for subsequent use;
(2) emulsifying: handed over by above-mentioned glycolide third resin copolymer solution to be added in described leuprorelin acetate solution, vibration emulsifying, is prepared into W1/O phase product, and in 17 DEG C of water-bath coolings;
(3) homogenizing: described W1/O phase product is injected into homogenizing process in described poly-vinyl alcohol solution with 5mL/min injection speed;
(4) solvent evaporation: the dichloromethane contained in the medicinal liquid after homogenizing is removed; Solvent evaporation conditions is: do not heat up half an hour, is then warmed up to 25 degree, keeps 4 hours, then is warmed up to 33 degree, keeps 2 hours.
(5) microsphere is collected: the medicinal liquid after removing dichloromethane is carried out frozen centrifugation, and sucking filtration discards solution, obtains described microsphere.
(6) lyophilizing: cryodesiccated step is carried out to the described microsphere collected, after shelf pre-freeze extremely-30 DEG C, product inlet; And continue holding plate temperature-30 DEG C to product fully charge; Panel temperature is warming up to-20 DEG C with the programming rate of 1 DEG C/h, carries out lyophilization, freeze-drying time 40 hours.
Embodiment 5:
Leuprorelin acetate 11.25g
Glycolide third hands over resin copolymer 80g
Mannitol 5g
Gelatin 1g;
Method for making:
(1) dosing
The leuprorelin acetate taking formula ratio is dissolved in the water, and makes the leuprorelin acetate solution that mass concentration is 25%, for subsequent use;
The glycolide third taking formula ratio hands over resin copolymer, is dissolved in dichloromethane and is mixed with the solution that mass concentration is 20%, for subsequent use;
Take the mannitol of formula ratio, be dissolved in water, make mass concentration be 5% mannitol solution for subsequent use;
Weighing polyvinyl alcohol adds water, and is the aqueous solution of 0.8% in 80 DEG C ~ 90 DEG C compound concentrations, for subsequent use;
(2) emulsifying: handed over by above-mentioned glycolide third resin copolymer solution to be added in described leuprorelin acetate solution, vibration emulsifying, is prepared into W1/O phase product, and in 15 DEG C of water-bath coolings;
(3) homogenizing: described W1/O phase product is injected into homogenizing process in described poly-vinyl alcohol solution with 7mL/min injection speed;
(4) solvent evaporation: the dichloromethane contained in the medicinal liquid after homogenizing is removed; Solvent evaporation conditions is: do not heat up half an hour, is then warmed up to 25 degree, keeps 4 hours, then is warmed up to 33 degree, keeps 2 hours.
(5) microsphere is collected: the medicinal liquid after removing dichloromethane is carried out frozen centrifugation, and sucking filtration discards solution, obtains described microsphere.
(6) lyophilizing: cryodesiccated step is carried out to the described microsphere collected, after shelf pre-freeze extremely-30 DEG C, product inlet; And continue holding plate temperature-30 DEG C to product fully charge; Panel temperature is warming up to-20 DEG C with the programming rate of 1 DEG C/h, carries out lyophilization, freeze-drying time 40 hours.
Claims (10)
1. a long-acting leuprorelin acetate microsphere, is characterized in that this microsphere is made up of following raw material:
Leuprorelin acetate 11.25 weight portion
Glycolide third hands over resin copolymer 80 ~ 350 weight portion
Mannitol 1 ~ 5 weight portion
Gelatin 1 ~ 2 weight portion.
2. long-acting leuprorelin acetate microsphere as claimed in claim 1, is characterized in that this microsphere is made up of following raw material:
Leuprorelin acetate 11.25 weight portion
Glycolide third hands over resin copolymer 85 weight portion
Mannitol 4 weight portion
Gelatin 1 weight portion.
3. long-acting leuprorelin acetate microsphere as claimed in claim 1, is characterized in that this microsphere is made up of following raw material:
Leuprorelin acetate 11.25 weight portion
Glycolide third hands over resin copolymer 300 weight portion
Mannitol 2 weight portion
Gelatin 1.5 weight portion.
4. long-acting leuprorelin acetate microsphere as claimed in claim 1, is characterized in that this microsphere is made up of following raw material:
Leuprorelin acetate 11.25 weight portion
Glycolide third hands over resin copolymer 215 weight portion
Mannitol 3 weight portion
Gelatin 1.5 weight portion.
5. the long-acting leuprorelin acetate microsphere as described in as arbitrary in claim 1-4, is characterized in that described raw material glycolide third hands over the molecular weight of resin copolymer to be 20000 ~ 100000, viscosity: 0.2 ~ 0.8; Preferred molecular weight is molecular weight is 40000 ~ 80000.
6. the preparation method of the long-acting leuprorelin acetate microsphere as described in as arbitrary in claim 1-5, is characterized in that the method is:
(1) dosing
Take the gelatin of recipe quantity, add about 50 ~ 60 DEG C of water, make concentration 13-16% aqueous gelatin solution, the leuprorelin acetate taking formula ratio is dissolved in aqueous gelatin solution, makes the leuprorelin gelatin solution that mass concentration is 16.7% ~ 25.0%, for subsequent use;
The glycolide third taking formula ratio hands over resin copolymer, is dissolved in dichloromethane and is mixed with the solution that mass concentration is 18 ~ 25%, for subsequent use;
Take the mannitol of formula ratio, be dissolved in water, make mass concentration be 5.0% mannitol solution for subsequent use;
Weighing polyvinyl alcohol, adds water, and is the aqueous solution of 0.5% ~ 1.5% in 80 DEG C ~ 90 DEG C compound concentrations, for subsequent use;
(2) emulsifying: handed over by above-mentioned glycolide third resin copolymer solution to be added in described leuprorelin acetate solution, vibration emulsifying, is prepared into W1/O phase product, and in 12 ~ 18 DEG C of water-bath coolings;
(3) homogenizing: described W1/O phase injections is entered homogenizing process in described poly-vinyl alcohol solution, makes the microsphere of suitable particle size scope;
(4) solvent evaporation: the dichloromethane contained in the medicinal liquid after homogenizing is removed;
(5) microsphere is collected: the medicinal liquid after removing dichloromethane is carried out frozen centrifugation, and sucking filtration discards solution, obtains described microsphere.
(6) lyophilizing: cryodesiccated step is carried out to the described microsphere collected.
7. the preparation method of long-acting leuprorelin acetate microsphere as claimed in claim 6, is characterized in that the dosing concentration of step described in the method (1) is:
Take gelatin, be dissolved in hot water, the leuprorelin acetate taking formula ratio is dissolved in aqueous gelatin solution, makes the solution that mass concentration is 18%, 20%, 21% or 24%, for subsequent use;
The glycolide third taking formula ratio hands over resin copolymer, is dissolved in dichloromethane and is mixed with the solution that mass concentration is 21%, 24%, 27% or 29%, for subsequent use;
Take the mannitol of formula ratio, be dissolved in water, make mass concentration be 8% or 9% mannitol solution for subsequent use.
8. the preparation method of long-acting leuprorelin acetate microsphere as claimed in claim 6, is characterized in that the water-bath chilling temperature preferably 13 DEG C in step described in the method (2) emulsion process, 15 DEG C or 17 DEG C.
9. the preparation method of long-acting leuprorelin acetate microsphere as claimed in claim 6, is characterized in that described in the method, cryodesiccated step is:
A, by shelf pre-freeze to after-30 DEG C, product inlet; And continue holding plate temperature-30 DEG C to product fully charge;
B, panel temperature are warming up to-20 DEG C with the programming rate of 0.5 ~ 2 DEG C/h, after reaching-20 DEG C, start evacuation, carry out lyophilization, freeze-drying time about 24 ~ 48 hours.
10. the preparation method of long-acting leuprorelin acetate microsphere as claimed in claim 6, is characterized in that the evaporation conditions of step described in the method (4) is: work as homogenizing, do not heat up half an hour, then 25 degree are warmed up to, keep 4 hours, then be warmed up to 33 degree, keep 2 hours.
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| CN116270492A (en) * | 2023-03-30 | 2023-06-23 | 北京博恩特药业有限公司 | Leuprolide acetate sustained-release microsphere for injection and preparation method and application thereof |
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| CN113440597A (en) * | 2021-07-02 | 2021-09-28 | 山东谷雨春生物科技有限公司 | Method for preparing leuprorelin microspheres |
| CN114344279A (en) * | 2021-12-30 | 2022-04-15 | 佛山市中医院 | A kind of multifunctional slow-release microsphere loaded with traditional Chinese medicine and its preparation method and application |
| CN116270492A (en) * | 2023-03-30 | 2023-06-23 | 北京博恩特药业有限公司 | Leuprolide acetate sustained-release microsphere for injection and preparation method and application thereof |
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