CN104399058A - Preparation method of decapeptide microballoons - Google Patents
Preparation method of decapeptide microballoons Download PDFInfo
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- CN104399058A CN104399058A CN201410601144.2A CN201410601144A CN104399058A CN 104399058 A CN104399058 A CN 104399058A CN 201410601144 A CN201410601144 A CN 201410601144A CN 104399058 A CN104399058 A CN 104399058A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 45
- 229920000642 polymer Polymers 0.000 claims abstract description 38
- HPPONSCISKROOD-OYLNGHKZSA-N acetic acid;(2s)-n-[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2r)-1-[[(2s)-1-[[(2s)-1-[(2s)-2-[(2-amino-2-oxoethyl)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1h-indol-3-yl)-1-oxopropan-2-y Chemical compound CC(O)=O.C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 HPPONSCISKROOD-OYLNGHKZSA-N 0.000 claims abstract description 32
- 229960000434 triptorelin acetate Drugs 0.000 claims abstract description 32
- 239000002994 raw material Substances 0.000 claims abstract description 31
- 239000011265 semifinished product Substances 0.000 claims abstract description 31
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims abstract description 30
- 229920000053 polysorbate 80 Polymers 0.000 claims abstract description 30
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims abstract description 25
- 239000000047 product Substances 0.000 claims abstract description 25
- 238000004945 emulsification Methods 0.000 claims abstract description 20
- 238000012216 screening Methods 0.000 claims abstract description 15
- 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 14
- 229930195725 Mannitol Natural products 0.000 claims abstract description 14
- 239000000594 mannitol Substances 0.000 claims abstract description 14
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- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims abstract description 5
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- 239000008346 aqueous phase Substances 0.000 claims description 47
- 239000000839 emulsion Substances 0.000 claims description 42
- 238000000034 method Methods 0.000 claims description 40
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- 238000001704 evaporation Methods 0.000 claims description 25
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- 239000012071 phase Substances 0.000 claims description 24
- XBBVURRQGJPTHH-UHFFFAOYSA-N 2-hydroxyacetic acid;2-hydroxypropanoic acid Chemical compound OCC(O)=O.CC(O)C(O)=O XBBVURRQGJPTHH-UHFFFAOYSA-N 0.000 claims description 23
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 22
- 238000002156 mixing Methods 0.000 claims description 22
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- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 claims description 20
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- 238000011049 filling Methods 0.000 claims description 17
- 230000018044 dehydration Effects 0.000 claims description 16
- 238000006297 dehydration reaction Methods 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 16
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 16
- 239000000463 material Substances 0.000 claims description 13
- 238000007873 sieving Methods 0.000 claims description 12
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- 229910021641 deionized water Inorganic materials 0.000 claims description 11
- 239000000725 suspension Substances 0.000 claims description 11
- 238000009413 insulation Methods 0.000 claims description 10
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 10
- 238000003860 storage Methods 0.000 claims description 9
- 239000004310 lactic acid Substances 0.000 claims description 5
- 235000014655 lactic acid Nutrition 0.000 claims description 5
- JCEGKJFZOJBPOL-UHFFFAOYSA-N ethanol;2-hydroxypropanoic acid Chemical compound CCO.CC(O)C(O)=O JCEGKJFZOJBPOL-UHFFFAOYSA-N 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
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- 239000000243 solution Substances 0.000 abstract description 106
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
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- 238000009825 accumulation Methods 0.000 description 5
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- 238000004140 cleaning Methods 0.000 description 4
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- VXKHXGOKWPXYNA-PGBVPBMZSA-N triptorelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)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)C1=CC=C(O)C=C1 VXKHXGOKWPXYNA-PGBVPBMZSA-N 0.000 description 3
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
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- 238000005516 engineering process Methods 0.000 description 2
- 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 description 2
- 229960004338 leuprorelin Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- ZBVJFYPGLGEMIN-OYLNGHKZSA-N (2s)-n-[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2r)-1-[[(2s)-1-[[(2s)-1-[(2s)-2-[(2-amino-2-oxoethyl)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1h-indol-3-yl)-1-oxopropan-2-yl]amino]-3-( Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1.C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)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)C1=CC=C(O)C=C1 ZBVJFYPGLGEMIN-OYLNGHKZSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 108010011459 Exenatide Proteins 0.000 description 1
- HTQBXNHDCUEHJF-XWLPCZSASA-N Exenatide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 description 1
- NMJREATYWWNIKX-UHFFFAOYSA-N GnRH Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CC(C)C)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 NMJREATYWWNIKX-UHFFFAOYSA-N 0.000 description 1
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- 102100024028 Progonadoliberin-1 Human genes 0.000 description 1
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 1
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 description 1
- 206010046798 Uterine leiomyoma Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229960001519 exenatide Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000011806 microball Substances 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 238000007781 pre-processing Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
- 229960001534 risperidone Drugs 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
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- 238000013268 sustained release Methods 0.000 description 1
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- 229960000294 triptorelin pamoate Drugs 0.000 description 1
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a preparation method of decapeptide microballoons. The preparation method comprises the following steps of pre-treating triptorelin acetate as a raw material, dissolving the treated triptorelin acetate in water to obtain an internal water phase solution, adding an acetic acid-glycollic acid polymer into dichloromethane to obtain an oil phase solution, preparing cured microballoons by a multi-phase emulsion method, carrying out tower layer screening washing, collecting decapeptide microballoon semi-finished products, adding mannitol into the decapeptide microballoon semi-finished products, suspending the decapeptide microballoon semi-finished products in a prepared mixed solution of a sodium carboxymethylcellulose solution and Tween-80, and carrying out freeze-drying on the decapeptide microballoons to obtain finished products. The decapeptide microballoons obtained by the tower layer screening-adopted wet screening have low burst release and stable release. The non-fusion extrusion and non-spray drying preparation method is used so that impurities are avoided, loss is reduced, product stability is improved and industrial production adaptability is obtained.
Description
Technical field
The present invention relates to a kind of pharmaceutical preparations technology, especially a kind of preparation method of decapeptide microsphere.
Background technology
In microball preparation product, the Sustained-release polypeptide microspheres agent of Initial Public Offering be one of p-GLU-HIS-TRP-SER-TYR-D-TRP-LEU-ARG-PRO-GLY-NH2 music score of Chinese operas Rui Lin ?PLGA microsphere, medicine can reach one month by slow release.The LHRH slow releasing preparation kind of having gone on the market now also has a lot: the slow release leuprorelin microsphere of month, three months, six months, the injection triptorelin pamoate microsphere of different acid group, active component is the injection risperidone microsphere of chemical small molecule, and injection Exenatide microsphere etc.
Triptorelin is the analog of GnRH.Clinically, widely, this medicine is as the medicine for the treatment of endometriosis, infertility, hysteromyoma, sexual precosity and carcinoma of prostate etc. for the purposes of triptorelin.
There are very many methods to be used to prepare medicine microspheres, such as melt extrude rear pulverize at low temperature, spraying dry, be separated etc.
Relative to patent CN 1913924B and patent CN 102048699B, the present invention does not adopt the mode melt extruded; Relative to CN 101528206B, the present invention does not adopt spray-dired method, and what the present invention adopted is microsphere prepared by the method for w/o/w.
Comparatively speaking, above-mentioned preparation method may cause loss in medicine degeneration and preparation process excessive, and the method industrialization production that the present invention adopts is comparatively easy, cost is lower, by the processing mode that technique is special, effectively organic solvent residual can be dropped to conformance with standard, and possess and stablize controlled release mode.
Summary of the invention
For the weak point existed in the problems referred to above, the invention provides a kind of preparation method of decapeptide microsphere, the method technique is simple, is adapted to industrialization and produces.
A preparation method for decapeptide microsphere, the method comprises the following steps:
Step (1), carries out pretreatment to raw material triptorelin acetate, and described preprocessing process is relaundered by raw material, dry, removes impurity;
Step (2), puts into pretreated described raw material triptorelin acetate in water and dissolves as interior aqueous phase W solution;
Step (3), joins lactic acid-glycolic acid polymer in dichloromethane as oil phase O solution;
Step (4), by described interior aqueous phase W solution and the mixing of oil phase O solution, adopts ultrasonic emulsification method, regulates ultrasonic power to make mixed liquor become milky, obtain colostrum;
Step (5), poured into by described colostrum in the outer aqueous phase W solution of polyvinyl alcohol and stir, obtain emulsion, described emulsion whipping temp is 8-13 DEG C;
Step (6), is transferred to the described emulsion be stirred in evaporation equipment and evaporates dichloromethane is volatilized;
Step (7), remaining after evaporation material is sieved by the wet sieving mode of adding the screening of tower layer, collection obtains decapeptide microsphere semi-finished product, then adds the decapeptide microsphere semi-finished product collected described in deionized water wash, adds the mannitol solution that mass concentration is 5%;
Step (8), the carboxymethyl cellulose sodium solution of described decapeptide microsphere suspension, dissolving and polyoxyethylene sorbitan monooleate dehydration solution are mixed, said mixture is entered fill storage tank by circulating line, carries out twice pump by filling pump and inhale fill;
Step (9), carries out frozen dried by mixture good for described fill, obtains decapeptide finished microballoon products;
Wherein, in step (4), it is ultrasonic that described ultrasonic emulsification method comprises first stage ultrasonic and second stage, and ultrasonic power of described first stage is 10W, and the ultrasonic power of described second stage is 20-30W.
The lactic acid-ethanol polymer molecular weight of described use is at 2000-30000, and lactic acid and glycolic mol ratio are 50:50.
The lactic acid-glycolic acid polymer of described use selects linear acidic terminated polymer.
In step (5), described outer aqueous phase W liquor capacity and raw material triptorelin acetate weight ratio scope are 150:25-280:25.
In step (5), the rotating speed of described colostrum phase and outer aqueous phase W solution mix and blend is 2050-3500rpm.
In step (6), the described emulsion be stirred is transferred in evaporation equipment and evaporate 5 hours.
In step (8), carboxymethylcellulose sodium solution is obtained by soluble in water for sodium carboxymethyl cellulose, the mass concentration of described carboxymethylcellulose sodium solution is 0.5%-1.5%, polyoxyethylene sorbitan monooleate dehydration is soluble in water, and the mass ratio of described polyoxyethylene sorbitan monooleate dehydration and water is 0.05:99.95.
In step (9), the decapeptide microsphere semi-finished product frozen dried that described fill is good comprises: start with-30 DEG C of pre-freezes, within 8 hours, terminates, through the lyophilizing of 50 hours with 35 DEG C of insulations.
Beneficial effect of the present invention is:
1, within mixing aqueous phase and oil phase technical process in by technological parameter during adjustment mixing and emulsifying, control technological parameter and the time of whole process, have employed the preparation method that non-melt is extruded, improve production efficiency, avoid the problem of impurity and stability, have employed the mode of non-spray-drying, avoid the problem that loss is excessive.
2, the microsphere obtained by the method for the wet sieving adding the screening of tower layer is prominent to be released less, and drug release is more steady, solves Industrialization.
3, achieved the even fill of product by a kind of liquid circulation filling apparatus, the mode of being inhaled by flow circuit receiver twice pump achieves the uniformity of product fill.
Accompanying drawing explanation
Fig. 1 is the flow chart of the preparation method of decapeptide microsphere;
Fig. 2 is the mixture fill flow chart containing decapeptide microsphere.
Detailed description of the invention
In order to make object of the present invention, technical scheme and advantage clearly understand, below in conjunction with embodiment, the present invention is described in further detail.But example is not as a limitation of the invention.
This patent raw material with pharmacologically active used: triptorelin acetate means the acetic acid existence form of triptorelin, English Triptorelin Acetate by name.The y molecular weight that the present invention uses is at 2000-30000, and lactic acid and glycolic molar ratio are 50:50.
The present invention's other adjuvants used take pharmacopeia as standard.
Embodiment 1
In the interior aqueous phase W solution of investigation, triptorelin acetate and water consumption ratio are on dissolubility and the balanced impact of release
Pretreatment is carried out to raw material triptorelin acetate;
Being put in water by described pretreated 25mg triptorelin acetate raw material dissolves as interior aqueous phase W solution, and the volume of wherein said water is chosen 8 different values and carried out solution preparation within the scope of 5ml-600ml;
Joined by 1.1g lactic acid-glycolic acid polymer as oil phase O solution in 13.3ml dichloromethane, described lactic acid-glycolic acid polymer selects acid terminated polymer;
By aqueous phase W solution in described preparation and the mixing of oil phase O solution, adopt ultrasonic emulsification method, it is ultrasonic ultrasonic with second stage that described ultrasonic emulsification method comprises the first stage, first stage ultrasonic power is 10W, second stage ultrasonic power is 20W, regulate ultrasonic power to make mixed liquor become milky, obtain colostrum;
Poured into by the colostrum solution mixed in the outer aqueous phase solution W of 150ml polyvinyl alcohol, outer aqueous phase solution W volume is 150ml, and stirred under 3000rpm rotating speed by the mixed solution of above-mentioned colostrum solution and poly-vinyl alcohol solution, obtain emulsion, emulsion temperature is 13 DEG C;
The emulsion be stirred is transferred in evaporation equipment and evaporate 5 hours;
Remaining after evaporation material is sieved by the wet sieving mode of adding the screening of tower layer, collection obtains decapeptide microsphere semi-finished product, then add the decapeptide microsphere semi-finished product collected described in deionized water wash, add the mannitol solution 18ml that mass concentration is 5%;
0.05g polyoxyethylene sorbitan monooleate dehydration (tween 80) is dissolved in the water of 99.95g, obtained polyoxyethylene sorbitan monooleate dehydration mixed liquor.205mg carboxymethyl cellulose sodium is dissolved in 30mL water and obtains carboxymethylcellulose sodium solution, the polyoxyethylene sorbitan monooleate dehydration solution of decapeptide microsphere suspension that above-mentioned cleaning obtains and the above-mentioned preparation of 5ml is added in this solution, this mixture is entered in the fill storage tank of flowing by circulating line, carries out twice pump by filling pump and inhale fill;
By decapeptide microsphere semi-finished product good for fill, start with-30 DEG C of pre-freezes, within 8 hours, terminate with 35 DEG C of insulations, through 50 hours frozen drieds, obtain decapeptide finished microballoon products.
Conclusion: data are known from above table, when raw material weight is 25mg, in interior aqueous phase W solution, the dissolubility of the decapeptide finished microballoon products that the volume of water is made within the scope of 10-500ml and release harmony are the figure of merit, meet the demands.
Embodiment 2
Different lactic acid-glycolic acid polymer (plga) model is on the prominent impact releasing performance and drug release natural law of decapeptide microsphere
Pretreatment is carried out to raw material triptorelin acetate;
Being put in 50mg water by described pretreated 25mg triptorelin acetate raw material dissolves as interior aqueous phase W solution;
The lactic acid-glycolic acid polymer (plga) of 1.1g two kinds of different models is joined in 13.3ml dichloromethane as oil phase O solution, described lactic acid-glycolic acid polymer selects acid terminated polymer, select plga adjuvant to be linear plga, model is 50:50 (usage ratio of lactic acid and glycolic is 50:50); Select linear plga, model is 75:25 (usage ratio of lactic acid and glycolic is 75:25);
By aqueous phase W solution in described preparation and the mixing of oil phase O solution, adopt ultrasonic emulsification method, it is ultrasonic ultrasonic with second stage that described ultrasonic emulsification method comprises the first stage, first stage ultrasonic power is 10W, second stage ultrasonic power is 20W, regulate ultrasonic power to make mixed liquor become milky, obtain colostrum;
Poured into by the colostrum solution mixed in the outer aqueous phase solution W of polyvinyl alcohol, outer aqueous phase solution W volume is 280ml, and stirred under 3000rpm rotating speed by the mixed solution of above-mentioned colostrum solution and poly-vinyl alcohol solution, obtain emulsion, emulsion temperature is 10 DEG C;
The emulsion be stirred is transferred in evaporation equipment and evaporate 5 hours;
Remaining after evaporation material is sieved by the wet sieving mode of adding the screening of tower layer, collection obtains decapeptide microsphere semi-finished product, then add the decapeptide microsphere semi-finished product collected described in deionized water wash, add the mannitol solution 18ml that mass concentration is 5%;
The carboxymethyl cellulose sodium that 205mg dissolves is dissolved in 30mL water, itself and described decapeptide microsphere suspension and 5ml tween 80 mixed liquor are carried out mixing filling, wherein, in mixed liquor, the mass ratio of tween 80 and water is 0.05:99.95, mixture is entered the fill storage tank of flowing by circulating line, carry out twice pump by filling pump and inhale fill;
By decapeptide microsphere good for fill, start with-30 DEG C of pre-freezes, within 8 hours, terminate with 35 DEG C of insulations, through 50 hours frozen drieds, obtain decapeptide finished microballoon products.
| Model | Dash forward and release 1H | Release natural law | Shape |
| 50:50 | 5.8 | 30 | Line style |
| 50:50 | 5.6 | 35 | Line style |
| 75:25 | 15.2 | 30 | Line style |
| 75:25 | 14.8 | 35 | Line style |
Sum up: as can be seen from data in table, prominent the release 1H performance of linear lactic acid-glycolic acid polymer (plga) to decapeptide microsphere of different model has an impact.Model is that to be all less than model be that the prominent of linear plga of 75:25 releases performance for the prominent 1H of releasing of the linear plga of 50:50, too high prominent releasing can cause sense of discomfort to human body, therefore, the model of this patent select linear lactic acid-glycolic acid polymer is 50:50, and range of viscosities is 0.12-0.25dL/g.
Embodiment 3
Investigate the impact that outer aqueous phase volume is encapsulated for triptorelin acetate
Pretreatment is carried out to raw material triptorelin acetate;
Being put in 50ml water by described pretreated 25mg triptorelin acetate raw material dissolves as interior aqueous phase W solution;
Joined by 1.133g lactic acid-glycolic acid polymer as oil phase O solution in dichloromethane, wherein the concentration of lactic acid-ethanol is 2-40%, and described lactic acid-glycolic acid polymer selects acid terminated polymer;
By aqueous phase W solution in described preparation and the mixing of oil phase O solution, adopt ultrasonic emulsification method, it is ultrasonic ultrasonic with second stage that described ultrasonic emulsification method comprises the first stage, first stage ultrasonic power is 10W, second stage ultrasonic power is 30W, regulate ultrasonic power to make mixed liquor become milky, obtain colostrum;
The colostrum solution mixed is poured in the outer aqueous phase solution W of polyvinyl alcohol, outer aqueous phase solution W volume is chosen 6 different numerical value and is carried out solution preparation from 50-500ml, the mixed solution of above-mentioned colostrum solution and poly-vinyl alcohol solution is stirred under 3000rpm rotating speed, obtain emulsion, emulsion temperature is 10 DEG C;
The emulsion be stirred is transferred in evaporation equipment and evaporate 5 hours;
Remaining after evaporation material is sieved by the wet sieving mode of adding the screening of tower layer, collects and obtain decapeptide microsphere semi-finished product, then add the decapeptide microsphere semi-finished product collected described in deionized water wash, add the mannitol solution 18ml containing 5%;
The carboxymethyl cellulose sodium that 205mg dissolves is dissolved in 30mL water, the decapeptide microsphere suspension of itself and described cleaning and 5ml tween 80 mixed liquor are carried out mixing filling, wherein, in tween 80 mixed liquor, the mass ratio of tween 80 and water is 0.05:99.95, mixture is entered the fill storage tank of flowing by circulating line, carry out twice pump by filling pump and inhale fill;
By decapeptide microsphere good for fill, start with-30 DEG C of pre-freezes, within 8 hours, terminate with 35 DEG C of insulations, through the frozen dried of 50 hours, obtain decapeptide finished microballoon products.
Conclusion: data are known from above table, when raw material weight is certain, when outer aqueous phase W liquor capacity addition is less, envelop rate is low, organic solvent residual is poor with release equilibrium value, along with outer aqueous phase polyvinyl alcohol volume increases envelop rate raising; When poly-vinyl alcohol solution volume is 150ml, envelop rate is 95%, organic solvent residual and release equilibrium value excellent, when poly-vinyl alcohol solution volume is 280ml, envelop rate reaches maximum, organic solvent residual and release equilibrium value excellent; Continuation along with poly-vinyl alcohol solution volume increases envelop rate and substantially remains unchanged, and organic solvent residual and release equilibrium value are deteriorated on the contrary.Therefore, from performance and cost consideration, when raw material weight is 25mg, outer aqueous phase poly-vinyl alcohol solution preferred volume scope is 150-280ml.
Embodiment 4
Investigate emulsion temperature to the Determination of Residual Organic Solvents of decapeptide microsphere and the prominent impact releasing performance
Pretreatment is carried out to raw material leuprorelin acetate;
Being put in 50mg water by described pretreated 25mg triptorelin acetate raw material dissolves as interior aqueous phase W solution;
Joined by 1.1g lactic acid-glycolic acid polymer as oil phase O solution in 13.3ml dichloromethane, described lactic acid-glycolic acid polymer selects acid terminated polymer;
By aqueous phase W solution in described preparation and the mixing of oil phase O solution, adopt ultrasonic emulsification method, it is ultrasonic ultrasonic with second stage that described ultrasonic emulsification method comprises the first stage, first stage ultrasonic power is 10W, second stage ultrasonic power is 30W, regulate ultrasonic power to make mixed liquor become milky, obtain colostrum;
The colostrum solution mixed is poured in the outer aqueous phase solution W of 280ml polyvinyl alcohol,, the mixed solution of above-mentioned colostrum solution and poly-vinyl alcohol solution is stirred under 3000rpm rotating speed, obtains emulsion, emulsion temperature chooses 7 numerical value from 2 DEG C-19 DEG C, stirs at different emulsion temperature;
The emulsion be stirred is transferred in evaporation equipment and evaporate 5 hours;
Remaining after evaporation material is sieved by the wet sieving mode of adding the screening of tower layer, collection obtains decapeptide microsphere semi-finished product, then add the decapeptide microsphere semi-finished product collected described in deionized water wash, add the mannitol solution 18ml containing 5% (g/g);
The carboxymethyl cellulose sodium of described decapeptide microsphere suspension, dissolving and the polyoxyethylene sorbitan monooleate dehydration mixture of dissolving are entered the fill storage tank of flow circuit by pipeline, carries out twice pump by filling pump and inhale fill;
By decapeptide microsphere good for fill, start with-30 DEG C of pre-freezes, within 8 hours, terminate with 35 DEG C of insulations, through 50 hours frozen drieds, obtain decapeptide finished microballoon products.
| Emulsion temperature | Determination of Residual Organic Solvents | Accumulation 1H release |
| 2 | 0.004％ | 15.68％ |
| 4 | 0.005％ | 10.00％ |
| 8 | 0.012％ | 8.63％ |
| 10 | 0.03％ | 6.81％ |
| 13 | 0.021％ | 7.65％ |
| 17 | 0.011％ | 9.82％ |
| 19 | 0.009 | 14.56％ |
Conclusion: from above data, emulsion temperature affects Determination of Residual Organic Solvents and the accumulation 1H release of decapeptide microsphere, and when emulsion temperature is 8-13 DEG C, the accumulation 1H release of microsphere is lower, meets the adaptability of human body to medicine.Although Determination of Residual Organic Solvents numerical value is large relative to other temperature when emulsion temperature is 8-13 DEG C, but when temperature is 10 DEG C, Determination of Residual Organic Solvents be 0.03% far above country to Determination of Residual Organic Solvents required standard, therefore, emulsion temperature is proper at about 8-13 DEG C.
Embodiment 5
Investigate the particle diameter of mixing speed on decapeptide microsphere and the impact of cumulative release 1H
Pretreatment is carried out to raw material triptorelin acetate;
Being put in 50mg water by described pretreated 25mg triptorelin acetate raw material dissolves as interior aqueous phase W solution;
Joined by 1.1g lactic acid-glycolic acid polymer as oil phase O solution in 13.3ml dichloromethane, described lactic acid-glycolic acid polymer selects acid terminated polymer;
By aqueous phase W solution in described preparation and the mixing of oil phase O solution, adopt ultrasonic emulsification method, it is ultrasonic ultrasonic with second stage that described ultrasonic emulsification method comprises the first stage, first stage ultrasonic power is 10W, second stage ultrasonic power is 30W, regulate ultrasonic power to make mixed liquor become milky, obtain colostrum;
The colostrum solution mixed is poured in the outer aqueous phase solution W of 280ml polyvinyl alcohol, the mixed solution of above-mentioned colostrum solution and poly-vinyl alcohol solution is stirred, mixing speed is chosen 7 different numerical value and is tested from 1050-4050rpm, emulsion temperature 10 DEG C.
The emulsion be stirred is transferred in evaporation equipment and evaporate 5 hours;
Remaining after evaporation material is sieved by the wet sieving mode of adding the screening of tower layer, collects and obtain decapeptide microsphere semi-finished product, then add the decapeptide microsphere semi-finished product collected described in deionized water wash, add the mannitol solution 18ml containing 5%;
The carboxymethyl cellulose sodium that 205mg dissolves is dissolved in 30mL water, itself and described decapeptide microsphere suspension and 5ml polyoxyethylene sorbitan monooleate dehydration mixed liquor are carried out mixing filling, wherein, in tween 80 mixed liquor, the mass ratio of tween 80 and water is 0.05:99.95, mixture is entered the fill storage tank of flowing by circulating line, carry out twice pump by filling pump and inhale fill;
By decapeptide microsphere semi-finished product good for fill, start with-30 DEG C of pre-freezes, within 8 hours, terminate with 35 DEG C of insulations, through 50 hours frozen drieds, obtain decapeptide finished microballoon products.
| Rotating speed rpm | Particle diameter μm | Cumulative release 1H |
| 1050 | 82 | 1.2 |
| 1500 | 70 | 2.5 |
| 2050 | 56 | 5.1 |
| 2500 | 50 | 6.5 |
| 2950 | 45 | 8.0 |
| 3500 | 35 | 10 |
| 4050 | 28 | 15.6 |
Sum up: data from above table, when emulsion speed of agitator is lower, microsphere particle size is large and discontented podocytic process releases effect, along with the increase microsphere particle size of rotating speed reduces, when rotating speed is 2050-3500rpm, microspherulite diameter is 35-56um, microsphere in this particle size range meets the efficacy requirement of medicine, meet the requirement to drug accumulation release 1H simultaneously, discharge a month demand and be applicable to injection again.Rotating speed continues to increase, and microspherulite diameter reduces, and medicine effect does not reach requirement, so the range of speeds selects 2050-3500rpm.
Embodiment 6
Investigate colostrum ultrasonic power to the impact of microsphere drug Cumulative release amount
Pretreatment is carried out to raw material triptorelin acetate;
Pretreated for described 25mg triptorelin acetate raw material is put in 100ml water and dissolves as interior aqueous phase W solution;
Joined by 1.1g lactic acid-glycolic acid polymer as oil phase O solution in 13.3ml dichloromethane, described lactic acid-glycolic acid polymer selects acid terminated polymer;
By aqueous phase W solution in described preparation and the mixing of oil phase O solution, adopt ultrasonic emulsification method, first stage ultrasonic power scope is 6-26W, second stage ultrasonic power scope is 10-30W, selects nine pairs of data to carry out batch (-type) adjustment to colostrum ultrasonic power, make mixed liquor become milky from two groups of numerical rangies, obtain colostrum, colostrum solution temperature controls, at 25 DEG C, to select acid end-blocking, and in mixing, the container of aqueous phase and oil phase is provided with the water-bath circulating device of 30 DEG C of constant temperature;
Poured into by the colostrum solution mixed in 200ml poly-vinyl alcohol solution (outer aqueous phase W), speed of agitator is 3000rpm, stirs and obtain emulsion to mixing material, and emulsion temperature is 13 DEG C;
The emulsion be stirred is transferred in evaporation equipment and evaporate 5 hours;
Remaining after evaporation material is sieved by the wet sieving mode of adding the screening of tower layer, collects and obtain decapeptide microsphere semi-finished product, then add the decapeptide microsphere semi-finished product collected described in deionized water wash, add the mannitol solution 18ml containing 5%;
The carboxymethyl cellulose sodium that 205mg dissolves is dissolved in 30mL water, itself and described decapeptide microsphere suspension and 5ml polyoxyethylene sorbitan monooleate dehydration mixed liquor are carried out mixing filling, wherein, in tween 80 mixed liquor, the mass ratio of polyoxyethylene sorbitan monooleate dehydration and water is 0.05:99.95.Said mixture is entered the fill storage tank of flowing by circulating line, carry out twice pump by filling pump and inhale fill;
By decapeptide microsphere good for fill, start with-30 DEG C of pre-freezes, within 8 hours, terminate with 35 DEG C of insulations, through 50 hours frozen drieds, obtain decapeptide finished microballoon products.
Sum up: data from above table, colostrum ultrasonic power has an impact to microsphere drug Cumulative release amount, and the excessive or too small drug administration thing that all can cause of power adds up increasing of 1H burst size, and more release amount of medicine can make receptor sense of discomfort strengthen.So the ultrasonic first stage power of colostrum is 10W, and ultrasonic second stage power is that 20W-30W is proper.
Embodiment 7
The screening mode of adding tower layer is on the impact of decapeptide microspherulite diameter concentration degree and Accumulation dissolution
Pretreatment is carried out to raw material acetic acid music score of Chinese operas Rayleigh;
Being put in water by described pretreated 25mg triptorelin acetate raw material dissolves as interior aqueous phase W solution, and the volume of wherein said water is 600ml;
Joined by 1.1g lactic acid-glycolic acid polymer as oil phase O solution in 13.3ml dichloromethane, described lactic acid-glycolic acid polymer selects acid terminated polymer;
By aqueous phase W solution in described preparation and the mixing of oil phase O solution, adopt ultrasonic emulsification method, it is ultrasonic ultrasonic with second stage that described ultrasonic emulsification method comprises the first stage, first stage ultrasonic power is 10W, second stage ultrasonic power is 30W, regulate ultrasonic power to make mixed liquor become milky, obtain colostrum;
Poured into by the colostrum solution mixed in the outer aqueous phase solution W of 150ml polyvinyl alcohol, outer aqueous phase solution W volume is 150ml, and stirred under 3500rpm rotating speed by the mixed solution of above-mentioned colostrum solution and poly-vinyl alcohol solution, obtain emulsion, emulsion temperature is 10 DEG C;
The emulsion be stirred is transferred in evaporation equipment and evaporate 5 hours;
Remaining after evaporation material is sieved respectively by the wet sieving mode of adding the screening of tower layer and the mode of not adding tower layer, collection obtains decapeptide microsphere semi-finished product, then add the decapeptide microsphere semi-finished product collected described in deionized water wash, add the mannitol solution 18ml that mass concentration is 5%;
The tween 80 mixed liquor that the carboxymethyl cellulose sodium of described decapeptide microsphere suspension, dissolving and 5ml dissolve is carried out mixing filling, in described polyoxyethylene sorbitan monooleate dehydration mixed liquor, the mass ratio of polyoxyethylene sorbitan monooleate dehydration and water is 0.05:99.95, and the mass concentration of described carboxymethyl cellulose sodium (CMC-Na) solution is chosen 6 values and carried out preparation fill from 0.25%-2.5%;
By decapeptide microsphere semi-finished product good for fill, start with-30 DEG C of pre-freezes, within 8 hours, terminate with 35 DEG C of insulations, through 50 hours frozen drieds, obtain decapeptide finished microballoon products.
To adding tower layer and the microsphere that do not add tower layer carries out particle size distribution test, test result is as shown in the table,
| Microspherulite diameter distributes | D10 | D50 | D90 |
| Do not add the particle size distribution of tower layer | 8.75μm | 73.48μm | 138.21μm |
| Add the particle size distribution of tower layer | 25.96μm | 57.26μm | 88.56μm |
As can be seen from data in upper table, compared with not adding the particle size distribution of tower layer, add tower layer control after microsphere particle size distribution evenly.
Carry out dashing forward release performance test to adding tower layer and the microsphere that do not add tower layer, test result is as shown in the table,
As can be seen from data in upper table we, the prominent performance of releasing of decapeptide microsphere prepared by the decapeptide microsphere prepared by the method for adding tower layer and the method for not adding tower layer contrasts, along with the increase of accumulative release time after medication, decapeptide microsphere prepared by the method for adding tower layer prominent is released value and releases value lower than not adding the prominent of microsphere prepared by tower layer.Release the too high sense of discomfort that can produce human body of value because prominent, so decapeptide microsphere prepared by the method for adding tower layer has control the prominent advantage released preferably, this patent is selected to adopt the method for adding tower layer.
Embodiment 8
The concentration of carboxymethyl cellulose sodium is on the impact of product appearance and solubility after the fill uniformity of product and lyophilizing
Pretreatment is carried out to raw material triptorelin acetate;
Being put in water by described pretreated 25mg triptorelin acetate raw material dissolves as interior aqueous phase W solution, and the volume of wherein said water is 100ml;
Joined by 1.1g lactic acid-glycolic acid polymer as oil phase O solution in 13.3ml dichloromethane, described lactic acid-glycolic acid polymer selects acid terminated polymer;
By aqueous phase W solution in described preparation and the mixing of oil phase O solution, adopt ultrasonic emulsification method, it is ultrasonic ultrasonic with second stage that described ultrasonic emulsification method comprises the first stage, first stage ultrasonic power is 10W, second stage ultrasonic power is 20W, regulate ultrasonic power to make mixed liquor become milky, obtain colostrum;
Poured into by the colostrum solution mixed in the outer aqueous phase solution W of 150ml polyvinyl alcohol, outer aqueous phase solution W volume is 150ml, and stirred under 3000rpm rotating speed by the mixed solution of above-mentioned colostrum solution and poly-vinyl alcohol solution, obtain emulsion, emulsion temperature is 10 DEG C;
The emulsion be stirred is transferred in evaporation equipment and evaporate 5 hours;
Remaining after evaporation material is sieved by the wet sieving mode of adding the screening of tower layer, collection obtains decapeptide microsphere semi-finished product, then add the decapeptide microsphere semi-finished product collected described in deionized water wash, add the mannitol solution 18ml that mass concentration is 5%;
By the tween 80 mixing filling of the decapeptide microsphere suspension of described cleaning, the carboxymethyl cellulose sodium of dissolving and dissolving, the mass concentration of described carboxymethyl cellulose sodium (CMC-Na) solution chooses 6 values from 0.25%-2.5% (g/g);
By decapeptide microsphere semi-finished product good for fill, start with-30 DEG C of pre-freezes, within 8 hours, terminate with 35 DEG C of insulations, through 50 hours frozen drieds, obtain decapeptide finished microballoon products.
Conclusion: data from above table, carboxymethyl cellulose na concn has an impact to product appearance and solubility after content uniformity and lyophilizing, when carboxymethyl cellulose sodium concentration of polymer solution is within the scope of 0.5%-1.5%, decapeptide microsphere has lower fill content uniformity, preferably product appearance and good solubility.
Embodiment 9
To the pretreatment of 19g raw material triptorelin acetate, by pretreated material dissolution in 40g water, by 910.3g lactic acid-ethanol dissolution of polymer in the dichloromethane of 2721.6g, the solution of two kinds of above-mentioned preparations mixes and carries out emulsifying after degerming, carry out double emulsion under the rotating speed of high-speed stirred with 3000rpm, then transfer in special container and remove dichloromethane, remaining after evaporation material is sieved by the wet sieving mode of adding the screening of tower layer, collection obtains decapeptide microsphere semi-finished product, then the decapeptide microsphere semi-finished product collected described in deionized water wash are added, add the mannitol 13.6L that mass concentration is 5%, the polyoxyethylene sorbitan monooleate dehydration mixture of the decapeptide microsphere suspension of described cleaning, the carboxymethyl cellulose sodium of dissolving and dissolving is entered the fill storage tank of flow circuit by pipeline, carry out twice pump by filling pump and inhale fill, the lyophilizing of fill solution is obtained triptorelin acetate microsphere in 50 hours.
The decapeptide finished microballoon products obtained to this experiment carries out 250mg fill, and from the decapeptide finished microballoon products of fill, extract 50 samples carry out quality and weigh, the product quality data result after 50 lyophilizing is as shown in the table,
| Numbering | Weight mg | Numbering | Weight mg |
| 1 | 251 | 26 | 249 |
| 2 | 253 | 27 | 249 |
| 3 | 246 | 28 | 253 |
| 4 | 255 | 29 | 247 |
| 5 | 252 | 30 | 251 |
| 6 | 251 | 31 | 252 |
| 7 | 250 | 32 | 247 |
| 8 | 251 | 33 | 246 |
| 9 | 253 | 34 | 251 |
| 10 | 251 | 35 | 254 |
| 11 | 253 | 36 | 253 |
| 12 | 254 | 37 | 254 |
| 13 | 252 | 38 | 248 |
| 14 | 248 | 39 | 249 |
| 15 | 251 | 40 | 250 |
| 16 | 249 | 41 | 251 |
| 17 | 253 | 42 | 250 |
| 18 | 254 | 43 | 246 |
| 19 | 249 | 44 | 253 |
| 20 | 253 | 45 | 252 |
| 21 | 249 | 46 | 253 |
| 22 | 248 | 47 | 252 |
| 23 | 251 | 48 | 247 |
| 24 | 253 | 49 | 248 |
| 25 | 254 | 50 | 253 |
From in upper table data, the mass range of 50 fill decapeptide microspheres is 246mg-254mg, and on about 250mg, lower deviation is very little, and standard is higher than national regulation.As shown in Figure 2, achieved the even fill of product by a kind of liquid circulation filling apparatus, the mode of being inhaled by flow circuit receiver twice pump achieves the uniformity of product fill.
Embodiment 10
Raw material 25mg triptorelin acetate is processed, emulsifying is carried out in the dichloromethane plga of 5.05g being dissolved in 18ml, carry out double emulsion when 2500rpm, through the evaporation process of 5 hours, adding mannitol 18ml by the collection mode of tower layer is suspended in the sodium carboxymethyl cellulose of 50ml and the mixed solution of tween 80, the canning means inhaled by secondary pump is filled in 5ml cillin bottle, put into freeze dryer by the lyophilizing tamponade of 50 hours, complete the preparation of triptorelin acetate microsphere.
Embodiment 11
Raw material 1g triptorelin acetate is processed, emulsifying is carried out in the dichloromethane plga of 20g being dissolved in 750ml, carry out double emulsion when 2700rpm, through the evaporation process of 7 hours, the mannitol 720ml that mass concentration is 5% is added by the collection mode of tower layer, then be suspended in the sodium carboxymethyl cellulose of 2000ml and the mixed solution of tween 80, the canning means inhaled by secondary pump is filled in 5ml cillin bottle, put into freeze dryer by the lyophilizing tamponade of 50 hours, complete the preparation of triptorelin acetate microsphere.Above-mentioned decapeptide microsphere prepares under B+A level regional environment, namely refers to prepare under the environmental condition of sterile production.
Claims (8)
1. a preparation method for decapeptide microsphere, is characterized in that, the method comprises the following steps:
Step (1), carries out pretreatment to raw material triptorelin acetate;
Step (2), puts into pretreated described raw material triptorelin acetate in water and dissolves as interior aqueous phase W solution;
Step (3), joins lactic acid-glycolic acid polymer in dichloromethane as oil phase O solution;
Step (4), by described interior aqueous phase W solution and the mixing of oil phase O solution, adopts ultrasonic emulsification method, regulates ultrasonic power to make mixed liquor become milky, obtain colostrum;
Step (5), poured into by described colostrum in the outer aqueous phase W solution of polyvinyl alcohol and stir, obtain emulsion, described emulsion whipping temp is 8-13 DEG C;
Step (6), is transferred to the described emulsion be stirred in evaporation equipment and evaporates dichloromethane is volatilized;
Step (7), remaining after evaporation material is sieved by the wet sieving mode of adding the screening of tower layer, collection obtains decapeptide microsphere semi-finished product, then adds the decapeptide microsphere semi-finished product collected described in deionized water wash, adds the mannitol solution that mass concentration is 5%;
Step (8), the carboxymethyl cellulose sodium solution of described decapeptide microsphere suspension, dissolving and polyoxyethylene sorbitan monooleate dehydration solution are mixed, said mixture is entered fill storage tank by circulating line, carries out twice pump by filling pump and inhale fill;
Step (9), carries out frozen dried by mixture good for described fill, obtains decapeptide finished microballoon products;
Wherein, in step (4), it is ultrasonic that described ultrasonic emulsification method comprises first stage ultrasonic and second stage, and ultrasonic power of described first stage is 10W, and the ultrasonic power of described second stage is 20-30W.
2. the preparation method of a kind of decapeptide microsphere according to claim 1, it is characterized in that, in step (3), the lactic acid-ethanol polymer molecular weight of described use is at 2000-30000, and lactic acid and glycolic mol ratio are 50:50.
3. the preparation method of a kind of decapeptide microsphere according to claim 2, it is characterized in that, the lactic acid-glycolic acid polymer of described use selects linear acidic terminated polymer.
4. the preparation method of a kind of decapeptide microsphere according to claim 1, it is characterized in that, in step (5), described outer aqueous phase W liquor capacity and raw material triptorelin acetate weight ratio scope are 150:25-280:25.
5. the preparation method of a kind of decapeptide microsphere according to claim 1, it is characterized in that, in step (5), the rotating speed of described colostrum phase and outer aqueous phase W solution mix and blend is 2050-3500rpm.
6. the preparation method of a kind of decapeptide microsphere according to claim 1, is characterized in that, in step (6), transferred in evaporation equipment by the described emulsion be stirred and evaporate.
7. the preparation method of a kind of decapeptide microsphere according to claim 1, it is characterized in that, in step (8), carboxymethylcellulose sodium solution is obtained by soluble in water for sodium carboxymethyl cellulose, the mass concentration of described carboxymethylcellulose sodium solution is 0.5%-1.5%, and described is 0.05:99.95 by the mass ratio of polyoxyethylene sorbitan monooleate dehydration and water in polyoxyethylene sorbitan monooleate dehydration mixed liquor.
8. the preparation method of a kind of decapeptide microsphere according to claim 1, it is characterized in that, in step (9), the decapeptide microsphere semi-finished product frozen dried that described fill is good comprises: start with-30 DEG C of pre-freezes, within 8 hours, terminate, through the lyophilizing of 50 hours with 35 DEG C of insulations.
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