CN114569564B - Goserelin sustained-release microsphere composition - Google Patents
Goserelin sustained-release microsphere composition Download PDFInfo
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- CN114569564B CN114569564B CN202210279838.3A CN202210279838A CN114569564B CN 114569564 B CN114569564 B CN 114569564B CN 202210279838 A CN202210279838 A CN 202210279838A CN 114569564 B CN114569564 B CN 114569564B
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- goserelin
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- glycolide
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- 239000004005 microsphere Substances 0.000 title claims abstract description 109
- 108010069236 Goserelin Proteins 0.000 title claims abstract description 92
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)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)NNC(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 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 title claims abstract description 88
- 229960002913 goserelin Drugs 0.000 title claims abstract description 88
- 239000000203 mixture Substances 0.000 title claims abstract description 31
- 238000013268 sustained release Methods 0.000 title claims description 13
- 239000012730 sustained-release form Substances 0.000 title claims description 13
- 229920001577 copolymer Polymers 0.000 claims abstract description 29
- 238000009826 distribution Methods 0.000 claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000007858 starting material Substances 0.000 claims abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 64
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 63
- 238000001035 drying Methods 0.000 claims description 37
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- 238000010008 shearing Methods 0.000 claims description 30
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- 150000001875 compounds Chemical class 0.000 claims description 14
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- 238000004140 cleaning Methods 0.000 claims description 6
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical group OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical group CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003814 drug Substances 0.000 abstract description 43
- 238000005538 encapsulation Methods 0.000 abstract description 17
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 24
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- 238000000034 method Methods 0.000 description 14
- 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 description 12
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- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 239000007943 implant Substances 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 5
- 230000006399 behavior Effects 0.000 description 4
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical class 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 4
- 229960003690 goserelin acetate Drugs 0.000 description 4
- BLCLNMBMMGCOAS-UHFFFAOYSA-N n-[1-[[1-[[1-[[1-[[1-[[1-[[1-[2-[(carbamoylamino)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amin Chemical compound C1CCC(C(=O)NNC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)C(COC(C)(C)C)NC(=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 BLCLNMBMMGCOAS-UHFFFAOYSA-N 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
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- 229960003604 testosterone Drugs 0.000 description 4
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- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 description 3
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- 206010060862 Prostate cancer Diseases 0.000 description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 3
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 description 3
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000004945 emulsification Methods 0.000 description 3
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- 239000003163 gonadal steroid hormone Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
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- 241000282472 Canis lupus familiaris Species 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 206010046798 Uterine leiomyoma Diseases 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
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- 238000010924 continuous production Methods 0.000 description 2
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- 229920001184 polypeptide Polymers 0.000 description 2
- 208000006155 precocious puberty Diseases 0.000 description 2
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- 238000005464 sample preparation method Methods 0.000 description 2
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- 239000000126 substance Substances 0.000 description 2
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 201000000736 Amenorrhea Diseases 0.000 description 1
- 206010001928 Amenorrhoea Diseases 0.000 description 1
- 201000005670 Anovulation Diseases 0.000 description 1
- 206010002659 Anovulatory cycle Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 206010012205 Delayed puberty Diseases 0.000 description 1
- 108700012941 GNRH1 Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102000008238 LHRH Receptors Human genes 0.000 description 1
- 108010021290 LHRH Receptors Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 231100000540 amenorrhea Toxicity 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 231100000552 anovulation Toxicity 0.000 description 1
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- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000009513 drug distribution Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 239000012527 feed solution Substances 0.000 description 1
- 238000005189 flocculation Methods 0.000 description 1
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- 238000010255 intramuscular injection Methods 0.000 description 1
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- 239000008101 lactose Substances 0.000 description 1
- 201000010260 leiomyoma Diseases 0.000 description 1
- 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 1
- 229960004338 leuprorelin Drugs 0.000 description 1
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- 230000001354 painful effect Effects 0.000 description 1
- 238000007415 particle size distribution analysis Methods 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
- A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Reproductive Health (AREA)
- General Chemical & Material Sciences (AREA)
- Endocrinology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Dermatology (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses a goserelin slow-release microsphere composition, wherein the starting materials of the goserelin slow-release microsphere composition comprise goserelin or pharmaceutically acceptable salts thereof and glycolide-lactide copolymer; the glycolide-lactide copolymer has a molecular weight distribution of: the molecular weight is more than or equal to 40000Da and accounts for 0.1-2%, the molecular weight is less than or equal to 15000Da and accounts for 25-30%, the molecular weight is less than or equal to 8000Da and accounts for 33-37%, the molecular weight is less than or equal to 8000Da and accounts for 18-22%, the molecular weight is less than or equal to 5000Da and accounts for 14-16%, and the molecular weight is less than or equal to 500Da and less than or equal to 2000Da and accounts for 1-3%. The invention obviously reduces the dosage of auxiliary materials while obviously improving the medicine encapsulation efficiency, obviously reduces the unnecessary intake of the auxiliary materials in the body of a patient, and further improves the safety of the human body.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparation production, in particular to a goserelin slow-release microsphere composition.
Background
Goserelin is an artificially synthesized decapeptide, also a gonadotrophin releasing hormone (LHRH) analogue, and compared with LHRH, goserelin has more excellent stability and stronger affinity with LHRH receptors, and has potency more than hundreds of times that of LHRH. The goserelin efficacy is positively promoted and negatively regulated according to different administration modes and dosages, and plays a role in promoting pituitary-gonadal axis when short-term and low-dosage administration occurs, and can clinically treat symptoms such as sexual hypofunction, anovulation, delayed puberty and the like. The composition can inhibit LHRH secretion of pituitary-gonadal axis after long-term use, thereby causing the decrease of male serum testosterone and female serum estradiol, and can be clinically used for treating sex hormone dependent diseases such as prostatic cancer, breast cancer, hysteromyoma, endometriosis, sexual precocity and the like, and the effect can be reversed after stopping the drug.
After the goserelin sustained-release preparation is administrated in vivo, the drug on the surface of the carrier can cause the rapid rise of the blood concentration, so that the drug plays a role in stimulating the pituitary-gonadal axis in a clockwise manner, in the process, the level of the in-vivo sex hormone is briefly increased, and then the sustained-release period is entered, so that the drug plays a role in inhibiting the pituitary-gonadal axis for a long time, and the drug is particularly expressed as the reduction of the secretion capacity of the sex hormone. In one treatment every 28 days, testosterone concentration will remain in the concentration range after castration, thereby continuing to exert therapeutic effects. Therefore, proper early burst is necessary to trigger a negative feedback regulation mechanism, and after the early blood concentration is raised to a certain level, the later testosterone concentration can be ensured to be always kept in the concentration range after castration.
Currently commercially available goserelin long-acting preparation trade name(Norrad), an implant developed and marketed by Aspirin for a period of one month, was approved to be marketed in French in 1987, was approved to be marketed by FDA in 1989, at a dose of 3.6 mg/dose, and was indicated for advanced pre-amenorrhea breast cancer, endometriosis and prostate cancer. The implant is cylindrical granules with the diameter of 1.2mm and the length of 1cm, special equipment and professionals are needed for administration, the injection pre-drug suppository is preset in a disposable syringe, and the injection is carried out by adopting a 16-gauge needle (with the outer diameter of 1.61mm and the length of 30 mm). The implant has great trauma to the patient and great pain caused by injection, so the compliance is poor. In addition to (I)>Is heatA goserelin implant made by melt extrusion (HME), which has the following simple process flow: the continuous production process has a plurality of advantages that goserelin and PLGA are respectively dissolved in acetic acid, the solution is uniformly mixed, filtering and sterilizing, freeze drying, heating and extrusion, cutting and assembling and packaging: continuous production, few steps and small amplification effect (no solvent removal step such as drying in liquid), but the adoption of the HME technology for encapsulating polypeptide drugs inevitably increases related substances of the polypeptide to a higher level (total impurities are more than 2 percent) at high temperature and single acetic acid residue during extrusion, and the goserelin acetate implant quality review and analysis of drug analysis impurities.
Therefore, it is necessary to develop a long-acting sustained release agent of goserelin acetate with low levels of related substances and better compliance.
At present, a plurality of domestic enterprises invest in development of goserelin microspheres, and goserelin microspheres (CN 104107434B) are prepared from Shandong green leaves by an S/O/W method, and the method has great influence on drug activity and release behavior due to API granulation technology, so that the release behavior in the microspheres is easily unstable due to the difference of particle size distribution among API batches. From the API particle size distribution D50 (examples 0.067 to 3.44 μm) and microspheres D (4, 3) (volume square average diameter) (examples 88.5 to 157.4) disclosed therein, it can be presumed that a microsphere particle size distribution median diameter of 75 to 150 μm (converted from D (4, 3) to D50 relationship) requires 20 to 21G needle administration.
Sale medicine discloses a preparation method of goserelin implant (CN 102755627B), the preparation principle and the preparation method thereofSubstantially identical, only improved solvent residue did not address the painful effects of implant injection.
The Qilu pharmacy discloses a preparation method (CN 109692325A) of goserelin acetate microspheres, and various defects (wide particle size distribution, high solvent residue, high environmental pressure, high cost and small batch) of the complex coacervation method are not repeated.
Rizhu medicine adopts a double emulsion method to prepare goserelin microspheres (CN 104840429B), and the double emulsion method is successfully applied to the marketed product leuprorelin microspheresIn the (zanaton) process, the burst release is high, the encapsulation rate is low, which is the most common problem in the multiple emulsion process, in the patent, the closed cell effect is achieved by improving the drying process in the liquid and raising the temperature to be higher than the glass transition temperature (Tg) of the microspheres in the later period of the drying process in the liquid, so that the burst release effect caused by drug migration in the drying process in the liquid is reduced, the encapsulation rate of the microspheres is reduced, and the higher drug loading rate can only be obtained by increasing the drug loading rate, and in particular, the encapsulation rate is only about 90% (encapsulation rate=actual drug loading rate per theoretical drug loading rate of percentage×100%).
Disclosure of Invention
The invention aims to provide a goserelin sustained-release microsphere composition, which obviously reduces the dosage of auxiliary materials while obviously improving the drug encapsulation rate, obviously reduces the unnecessary auxiliary material intake in a patient, and further improves the safety of the human body.
The technical scheme adopted for solving the technical problems is as follows:
a goserelin sustained release microsphere composition, the starting materials of which comprise goserelin or pharmaceutically acceptable salts thereof and glycolide-lactide copolymer;
the glycolide-lactide copolymer has a molecular weight distribution of: the molecular weight is more than or equal to 40000Da and accounts for 0.1-2%, the molecular weight is less than or equal to 15000Da and accounts for 25-30%, the molecular weight is less than or equal to 8000Da and accounts for 33-37%, the molecular weight is less than or equal to 8000Da and accounts for 18-22%, the molecular weight is less than or equal to 5000Da and accounts for 14-16%, and the molecular weight is less than or equal to 500Da and less than or equal to 2000Da and accounts for 1-3%.
The copolymer with molecular weight distribution can be obtained by mixing PLGA with various molecular weight ranges purchased commercially or by purifying and preparing the mixture by conventional means. Or according to the technical scheme described in CN 112694605.
The molecular weight distribution of the polymer has great influence on microsphere release behaviours, and the invention unexpectedly improves the stability, obtains microsphere compositions with extremely ideal release behaviors, obtains microsphere preparations with small particle size range, optimizes microsphere particle size distribution, obviously improves the drug encapsulation efficiency (up to more than 95 percent), ensures the effective release period of 1 month and simultaneously reduces the injection pain by optimizing the molecular weight distribution of the polymer.
On the basis, the invention unexpectedly discovers that the effect of the medicine encapsulation rate (even reaching more than 100%) can be further and obviously improved by adding a certain amount of glacial acetic acid, and the purpose of the invention is to increase the encapsulation efficiency.
Preferably, the starting material of the goserelin slow release microsphere composition further comprises glacial acetic acid. The starting materials of the goserelin sustained-release microsphere composition can also comprise a lyoprotectant.
Preferably, the molar ratio of the glacial acetic acid to the goserelin is 0.1-1.1: 1. more preferably, the molar ratio of glacial acetic acid to goserelin is 0.3-0.7: 1.
preferably, the particle size distribution of the goserelin slow release microsphere composition is d10 1-3 mu m, d 50-50 mu m and d 90-100 mu m. More preferably, the particle size distribution of the microsphere composition is d10 1 to 2. Mu.m, d50 5 to 10. Mu.m, d90 to 30. Mu.m.
Preferably, the molar ratio of lactic acid units to glycolic acid units of the glycolide-lactide copolymer is 85:15-50:50. More preferably, the molar ratio of lactic acid units to glycolic acid units of the glycolide-lactide copolymer is 75:25.
Preferably, the weight average molecular weight of the glycolide-lactide copolymer is 10000-20000Da and the number average molecular weight is 6000-9000Da. More preferably, the glycolide-lactide copolymer has a weight average molecular weight in the range of 10000 to 15000Da and a number average molecular weight in the range of 7000 to 8500Da.
Preferably, the glycolide-lactide copolymer has a carboxyl terminal end.
Preferably, in the goserelin sustained-release microsphere composition, the weight content of the goserelin is 8-12%, the weight content of the glycolide-lactide copolymer is 73-80%, and the weight content of the freeze-drying protective agent is 12-15%. When goserelin is a salt thereof, the conversion can be based on molecular weight.
Preferably, the preparation method is as follows:
(1) Dissolving goserelin or pharmaceutically acceptable salts thereof in water to prepare an inner water phase; dissolving glycolide-lactide copolymer in organic solvent to prepare oil phase;
(2) Premixing an inner water phase and an oil phase, and shearing to form colostrum;
(3) Shearing the primary emulsion and an external water phase containing a surfactant to form a multiple emulsion;
(4) Drying the compound emulsion in a drying tank in liquid to remove the solvent, and continuously collecting;
(5) Cleaning microsphere, continuously collecting, adding freeze-drying protective agent, and freeze-drying.
Preferably, the preparation method is as follows:
(1) Dissolving goserelin or pharmaceutically acceptable salts thereof and glacial acetic acid in water to prepare an inner water phase; dissolving glycolide-lactide copolymer in organic solvent to prepare oil phase;
(2) Premixing an inner water phase and an oil phase, and shearing to form colostrum;
(3) Shearing the primary emulsion and an external water phase containing a surfactant to form a multiple emulsion;
(4) Drying the compound emulsion in a drying tank in liquid to remove the solvent, and continuously collecting;
(5) Cleaning microsphere, continuously collecting, adding freeze-drying protective agent, and freeze-drying.
Acetic acid is an important part of the internal water phase preparation process, but is removed from the finished microsphere product, and the removal process mainly comprises a liquid drying step. The addition of acetic acid can enhance the molecular forces between goserelin and the polymer, increasing encapsulation efficiency. In addition, the effect of acetic acid also includes regulating the level of drug distribution within the microsphere.
The concentration of the surfactant in the external aqueous phase is in the range of 0.1g/L to 20g/L, more preferably 1g/L to 10g/L, and the surfactant is preferably polyvinyl alcohol (PVA), and the molecular weight range thereof is not particularly limited.
In the process of drying in the liquid, the temperature of the liquid is always below the glass transition temperature (Tg) of the microspheres.
The lyoprotectant is not particularly limited herein and is primarily intended to prevent flocculation of the microspheres during lyophilization, and the ingredients include, but are not limited to, mannitol, lactose, glucose, amino acids (glycine), and more preferably mannitol.
The microsphere composition is mainly applied to prostate cancer, breast cancer, endometriosis, uterine fibroids, precocious puberty and infertility.
The microsphere composition provided by the invention can be prepared into a sterile powder form, wherein the sterile powder contains goserelin slow-release microsphere composition and mannitol, and the preparation method comprises the following steps: and after the material liquid of each phase is sterilized and filtered, aseptic production, freeze-drying, sieving, transferring, powder split charging and capping are carried out on a production line subjected to aseptic verification. Before administration, the sterile powder is dispersed in a sterile vehicle.
The administration mode of the sterile goserelin sustained-release microsphere provided by the invention is subcutaneous injection and intramuscular injection.
The goserelin slow release microsphere provided by the invention is suitable for a 25G-26G needle.
The goserelin slow release microsphere provided by the invention can provide a release period of at least 30 days, and the goserelin can be released in an effective dose in the release period.
The beneficial effects of the invention are as follows: after in vivo administration, the invention has the effect time not lower than 28d, and has high drug loading, low administration dosage, small particle size, greatly reduced injection pain and improved patient compliance.
Drawings
FIG. 1 comparison of the off-release curves of goserelin microspheres of different PLGA molecular weight distributions;
fig. 2 shows a comparison of the release profile of goserelin microspheres with and without acetic acid in the aqueous phase;
FIG. 3 is a graph of the in vivo drug profile of goserelin microsphere dogs of example 1, wherein the 3a time axis is 0-35d and the 3b time axis is 0-1d;
fig. 4 is the castration levels of testosterone in goserelin microsphere dogs of example 1;
fig. 5 is a microscope image of goserelin microspheres of example 1.
Detailed Description
The technical scheme of the invention is further specifically described by the following specific examples.
In the present invention, the materials and equipment used are commercially available or commonly used in the art, unless otherwise specified. The methods in the following examples are conventional in the art unless otherwise specified.
General embodiment:
a goserelin sustained release microsphere composition, the starting materials of which comprise goserelin or pharmaceutically acceptable salts thereof and glycolide-lactide copolymer;
the glycolide-lactide copolymer has a molecular weight distribution of: the molecular weight is more than or equal to 40000Da and accounts for 0.1-2%, the molecular weight is less than or equal to 15000Da and accounts for 25-30%, the molecular weight is less than or equal to 8000Da and accounts for 33-37%, the molecular weight is less than or equal to 8000Da and accounts for 18-22%, the molecular weight is less than or equal to 5000Da and accounts for 14-16%, and the molecular weight is less than or equal to 500Da and less than or equal to 2000Da and accounts for 1-3%.
The starting materials of the goserelin slow-release microsphere composition also comprise glacial acetic acid. The molar ratio of the glacial acetic acid to the goserelin is 0.1-1.1: 1.
the particle size distribution of the goserelin slow release microsphere composition is d 10-3 mu m, d 50-50 mu m and d 90-100 mu m.
The molar ratio of lactic acid units to glycolic acid units of the glycolide-lactide copolymer is 85:15-50:50.
The weight average molecular weight of the glycolide-lactide copolymer ranges from 10000 Da to 20000Da, and the number average molecular weight ranges from 6000 Da to 9000Da.
The terminal end of the glycolide-lactide copolymer is carboxyl terminal end.
In the goserelin slow release microsphere composition, the weight content of the goserelin is 8-12%, the weight content of the glycolide-lactide copolymer is 73-80%, and the weight content of the freeze-drying protective agent is 12-15%.
The first preparation method is as follows:
(1) Dissolving goserelin or pharmaceutically acceptable salts thereof in water to prepare an inner water phase; dissolving glycolide-lactide copolymer in organic solvent to prepare oil phase;
(2) Premixing an inner water phase and an oil phase, and shearing to form colostrum;
(3) Shearing the primary emulsion and an external water phase containing a surfactant to form a multiple emulsion;
(4) Drying the compound emulsion in a drying tank in liquid to remove the solvent, and continuously collecting;
(5) Cleaning microsphere, continuously collecting, adding freeze-drying protective agent, and freeze-drying.
The second preparation method is as follows:
(1) Dissolving goserelin or pharmaceutically acceptable salts thereof and glacial acetic acid in water to prepare an inner water phase; dissolving glycolide-lactide copolymer in organic solvent to prepare oil phase;
(2) Premixing an inner water phase and an oil phase, and shearing to form colostrum;
(3) Shearing the primary emulsion and an external water phase containing a surfactant to form a multiple emulsion;
(4) Drying the compound emulsion in a drying tank in liquid to remove the solvent, and continuously collecting;
(5) Cleaning microsphere, continuously collecting, adding freeze-drying protective agent, and freeze-drying.
Definition: the temperature rise is to the temperature variation range, i.e. the highest temperature minus the lowest temperature.
In the following examples, "40000Da or more, 15000 to 40000Da, 8000 to 15000Da, 5000 to 8000Da, 2000 to 5000Da, 500 to 2000 Da" are simplified expressions, and the actual expressions mean: the molecular weight is greater than or equal to 40000Da, the molecular weight is less than or equal to 15000Da and less than or equal to 40000Da, the molecular weight is less than or equal to 8000Da and less than 15000Da, the molecular weight is less than or equal to 5000Da and less than 8000Da, the molecular weight is less than or equal to 2000Da and less than or equal to 5000Da, and the molecular weight is less than or equal to 500Da and less than 2000 Da.
Example 1
Weighing 1.11g of goserelin, heating and dissolving in 1.00g of water to prepare an internal water phase, and cooling to room temperature; 10.0g PLGA (7525, mw12000, carboxyl terminal) was weighed and dissolved in 16.0g methylene chloride to prepare an oil phase; adding the oil phase into the inner water phase, premixing for 1min (3000 rpm), shearing for 3min (12000 rpm), and rapidly cooling; the colostrum and the outer water phase (2.5 g/L PVA) are introduced into an online shearing machine (IKA, 7000 rpm) according to the volume ratio of 1:150 to prepare compound emulsion; and then drying in liquid, controlling the temperature rise of the feed liquid to be not higher than 5 ℃ in the drying process, centrifugally collecting microsphere concentrated solution, adding mannitol with the solid content of 16.3wt% of wet microspheres, freeze-drying, and collecting microsphere finished products. The goserelin microsphere is obtained, the drug loading rate is 9.59%, and the 1d burst release is 10.46% and the stable release is 28d in PBS with pH 7.4.
Wherein the molecular weight distribution of the PLGA is as follows, the molecular weight more than 40000Da accounts for 0.47%, the molecular weight of 15000-40000 Da accounts for 27.02%, the molecular weight of 8000-15000 Da accounts for 34.66%, the molecular weight of 5000-8000 Da accounts for 20.70%, the molecular weight of 2000-5000 Da accounts for 14.81%, and the molecular weight of 500-2000 Da accounts for 2.32%.
Example 2
Weighing 1.11g of goserelin, heating and dissolving in 1.00g of water to prepare an internal water phase, and cooling to room temperature; 10.0g PLGA (7525, mw13500, carboxyl terminal) was weighed and dissolved in 16.0g methylene chloride to prepare an oil phase; adding the oil phase into the inner water phase, premixing for 1min (3000 rpm), shearing for 3min (12000 rpm), and rapidly cooling; the colostrum and the outer water phase (2.5 g/L PVA) are introduced into an online shearing machine (IKA, 7000 rpm) according to the volume ratio of 1:150 to prepare compound emulsion; and then drying in liquid, controlling the temperature rise of the feed liquid to be not higher than 5 ℃ in the drying process, centrifugally collecting microsphere concentrated solution, adding mannitol with the solid content of 16.3wt% of wet microspheres, freeze-drying, and collecting microsphere finished products. The goserelin microsphere is obtained, the drug loading rate is 9.66%, and the 1d burst release is 11.52% and the stable release is 28d in PBS with pH 7.4.
Wherein the PLGA molecular weight distribution is as follows, more than 40000Da account for 0.50%, 15000-40000 Da account for 29.98%, 8000-15000 Da account for 34.17%, 5000-8000 Da account for 18.46%, 2000-5000 Da account for 14.21%, 500-2000 Da account for 1.68%.
Example 3
Weighing 1.11g of goserelin, heating and dissolving in 1.00g of water to prepare an internal water phase, and cooling to room temperature; 10.0g PLGA (7525, mw11200, carboxyl terminal) was weighed and dissolved in 16.0g methylene chloride to prepare an oil phase; adding the oil phase into the inner water phase, premixing for 1min (3000 rpm), shearing for 3min (12000 rpm), and rapidly cooling; preparing the colostrum and the external water phase (2.5 g/L PVA) into compound emulsion according to the volume ratio of 1:150 (introducing into an online shearing machine (IKA, 7000 rpm), then drying in liquid, controlling the temperature rise of the feed liquid in the drying process to be not more than 5 ℃, centrifugally collecting microsphere concentrated solution, adding mannitol with the solid content of 16.3wt% of wet microspheres, freeze-drying, and collecting microsphere finished products, thereby obtaining the goserelin microsphere drug loading rate of 9.58%, pH7.4PBS, 1d burst release of 10.06%, and stable release of 28d.
Wherein the PLGA molecular weight distribution is as follows, more than 40000Da account for 1.18%, 15000-40000 Da account for 25.54%, 8000-15000 Da account for 35.36%, 5000-8000 Da account for 21.88%, 2000-5000 Da account for 15.39%, 500-2000 Da account for 1.65%.
Example 4 (exceeding the upper limit of the claimed PLGA molecular weight, late Release slows)
Weighing 1.11g of goserelin, heating and dissolving in 1.00g of water to prepare an internal water phase, and cooling to room temperature; 10.0g PLGA (7525, mw13500, carboxyl terminal) was weighed and dissolved in 16.0g methylene chloride to prepare an oil phase; adding the oil phase into the inner water phase, premixing for 1min (3000 rpm), shearing for 3min (12000 rpm), and rapidly cooling; the colostrum and the outer water phase (2.5 g/L PVA) are introduced into an online shearing machine (IKA, 7000 rpm) according to the volume ratio of 1:150 to prepare compound emulsion; and then drying in liquid, controlling the temperature rise of the feed liquid to be not higher than 5 ℃ in the drying process, centrifugally collecting microsphere concentrated solution, adding mannitol with the solid content of 16.3wt% of wet microspheres, freeze-drying, and collecting microsphere finished products. The medicine carrying amount of the goserelin microsphere is 10.1%, and the 1d burst release is 9.31% and the stable release is 28d in PBS with pH of 7.4.
Wherein the PLGA molecular weight distribution is more than 40000Da and accounts for 1.34%, 15000-40000 Da and accounts for 31.18%, 8000-15000 Da and accounts for 35.74%, 5000-8000 Da and accounts for 20.01%, 2000-5000 Da and accounts for 11.59%, 500-2000 Da and accounts for 0.14%.
Example 5 (exceeding the lower limit of the claimed PLGA molecular weight, early burst is accelerated)
Weighing 1.11g of goserelin, heating and dissolving in 1.00g of water to prepare an internal water phase, and cooling to room temperature; 10.0g PLGA (7525, mw10500, carboxyl terminal) was weighed and dissolved in 16.0g methylene chloride to prepare an oil phase; adding the oil phase into the inner water phase, premixing for 1min (3000 rpm), shearing for 3min (12000 rpm), and rapidly cooling; the colostrum and the outer water phase (2.5 g/L PVA) are introduced into an online shearing machine (IKA, 7000 rpm) according to the volume ratio of 1:150 to prepare compound emulsion; and then drying in liquid, controlling the temperature rise of the feed liquid to be not higher than 5 ℃ in the drying process, centrifugally collecting microsphere concentrated solution, adding mannitol with the solid content of 16.3wt% of wet microspheres, freeze-drying, and collecting microsphere finished products. The obtained goserelin microsphere has the drug loading of 9.66%, and the 1d burst release is 13.63% and the stable release is 28d in PBS with pH of 7.4.
Wherein the PLGA molecular weight distribution is as follows, more than 40000Da account for 0.67%, 15000-40000 Da account for 17.71%, 8000-15000 Da account for 28.22%, 5000-8000 Da account for 35.29%, 2000-5000 Da account for 15.35%, 500-2000 Da account for 2.76%.
Example 6 (glacial acetic acid addition)
Weighing 1.11g of goserelin and 0.0008mol of glacial acetic acid, heating and dissolving in 1.00g of water to prepare an internal water phase, and cooling to room temperature; 10.0g PLGA (7525, mw12500, carboxyl terminal) was weighed and dissolved in 16.0g methylene chloride to prepare an oil phase; adding the oil phase into the inner water phase, premixing for 1min (3000 rpm), shearing for 3min (12000 rpm), and rapidly cooling; preparing a double emulsion by mixing the colostrum and an external water phase (2.5 g/LPVA) according to a volume ratio of 1:150 on-line shearing machine (IKA, 7000 rpm); and then drying in liquid, controlling the temperature rise of the feed liquid to be not higher than 5 ℃ in the drying process, centrifugally collecting microsphere concentrated solution, adding mannitol with the solid content of 16.3wt% of wet microspheres, freeze-drying, and collecting microsphere finished products. The goserelin microsphere is obtained, the drug loading rate is 10.5%, and the 1d burst release is 9.95% and the stable release is 28d in PBS with pH 7.4.
Wherein the molecular weight distribution of the PLGA is as follows, the molecular weight more than 40000Da accounts for 0.69%, the molecular weight of 15000-40000 Da accounts for 28.33%, the molecular weight of 8000-15000 Da accounts for 35.28%, the molecular weight of 5000-8000 Da accounts for 20.73%, the molecular weight of 2000-5000 Da accounts for 15.01%, and the molecular weight of 500-2000 Da accounts for 2.54%.
Example 7 (glacial acetic acid addition)
Weighing 1.11g of goserelin and 0.0004mol of glacial acetic acid, heating and dissolving in 1.00g of water to prepare an internal water phase, and cooling to room temperature; 10.0g PLGA (7525, mw12500, carboxyl terminal) was weighed and dissolved in 16.0g methylene chloride to prepare an oil phase; adding the oil phase into the inner water phase, premixing for 1min (3000 rpm), shearing for 3min (12000 rpm), and rapidly cooling; the colostrum and the external water phase (2.5 g/LPVA) are introduced into an online shearing machine (IKA, 7000 rpm) according to the volume ratio of 1:150 to prepare compound emulsion; and then drying in liquid, controlling the temperature rise of the feed liquid to be not higher than 5 ℃ in the drying process, centrifugally collecting microsphere concentrated solution, adding mannitol with the solid content of 16.3wt% of wet microspheres, freeze-drying, and collecting microsphere finished products. The goserelin microsphere is obtained, the drug loading rate is 10.2%, and the 1d burst release is 10.77% and the stable release is 28d in PBS with pH 7.4.
Wherein the molecular weight distribution of the PLGA is as follows, the molecular weight more than 40000Da accounts for 0.69%, the molecular weight of 15000-40000 Da accounts for 28.33%, the molecular weight of 8000-15000 Da accounts for 35.28%, the molecular weight of 5000-8000 Da accounts for 20.73%, the molecular weight of 2000-5000 Da accounts for 15.01%, and the molecular weight of 500-2000 Da accounts for 2.54%.
Example 8
Weighing 1.11g of goserelin, heating and dissolving in 1.00g of water to prepare an internal water phase, and cooling to room temperature; 10.0g PLGA (7525, mw12500, carboxyl terminal) was weighed and dissolved in 16.0g methylene chloride to prepare an oil phase; adding the oil phase into the inner water phase, premixing for 1min (3000 rpm), shearing for 3min (12000 rpm), and rapidly cooling; preparing the colostrum and the external water phase (2.5 g/L PVA) into compound emulsion according to the volume ratio of 1:150 (introducing into an online shearing machine (IKA, 7000 rpm), then drying in liquid, controlling the temperature rise of the feed liquid in the drying process to be not more than 5 ℃, centrifugally collecting microsphere concentrated solution, adding mannitol with the solid content of 16.3wt% of wet microspheres, freeze-drying, and collecting microsphere finished products, thereby obtaining the goserelin microsphere drug loading rate of 9.79%, pH7.4PBS, 1d burst release of 10.83%, and stable release of 28d.
Wherein the molecular weight distribution of the PLGA is as follows, the molecular weight more than 40000Da accounts for 0.69%, the molecular weight of 15000-40000 Da accounts for 28.33%, the molecular weight of 8000-15000 Da accounts for 35.28%, the molecular weight of 5000-8000 Da accounts for 20.73%, the molecular weight of 2000-5000 Da accounts for 15.01%, and the molecular weight of 500-2000 Da accounts for 2.54%.
Example 9 (other model PLGA)
Weighing 1.11g of goserelin, heating and dissolving in 1.00g of water to prepare an internal water phase, and cooling to room temperature; 10.0g PLGA (5050, mw17500, carboxyl terminal) was weighed and dissolved in 16.0g methylene chloride to prepare an oil phase; adding the oil phase into the inner water phase, premixing for 1min (3000 rpm), shearing for 3min (12000 rpm), and rapidly cooling; the colostrum and the outer water phase (2.5 g/L PVA) are introduced into an online shearing machine (IKA, 7000 rpm) according to the volume ratio of 1:150 to prepare compound emulsion; and then drying in liquid, controlling the temperature rise of the feed liquid to be not higher than 5 ℃ in the drying process, centrifugally collecting microsphere concentrated solution, adding mannitol with the solid content of 16.3wt% of wet microspheres, freeze-drying, and collecting microsphere finished products. The goserelin microsphere is obtained, the drug loading rate is 9.55%, and the 1d burst release is 20.56% and the stable release is 28d in PBS with pH 7.4.
Example 10
The method for detecting acetic acid in the microsphere comprises the following steps:
the acetic acid residue analysis was performed on examples 1-9 using gas chromatography (Shimadzu GC-2014), and the sample preparation method was: precisely weighing 20mg of dried microsphere, adding 1mL of dimethyl sulfoxide for complete dissolution, and injecting 1 μl. The chromatographic conditions were as follows: chromatographic column: rtx-1301 (0.32 mm. Times.30 m,1.8 μm, GC-004)
Column temperature: the temperature is initially raised to 110℃at 10℃per minute and to 180℃at 30℃per minute.
The results are shown in Table 1
TABLE 1 microsphere acetic acid residue detection results
| Examples | Microsphere acetic acid residue/% |
| Example 1 | Not detected |
| Example 2 | Not detected |
| Example 3 | Not detected |
| Example 4 | Not detected |
| Example 5 | Not detected |
| Example 6 | Not detected |
| Example 7 | Not detected |
| Example 8 | Not detected |
| Example 9 | Not detected |
Acetic acid is a process auxiliary agent, and a certain proportion of acetic acid added into the internal water phase is removed in the subsequent step.
Example 11
The microsphere particle size distribution detection method comprises the following steps:
particle size distribution analysis was performed on examples 1-9 using a particle size analyzer (Mastersizer 3000), wet measurement was selected, 0.5% sds solution was used as the medium, and sonication was performed for 30s before sample injection.
The results are shown in Table 2
TABLE 2 results of microsphere particle size distribution measurements of examples
| Examples | D10/μm | D50/μm | D90/μm | span | D(4,3) |
| Example 1 | 2.23 | 7.50 | 25.0 | 3.036 | 11.5 |
| Example 2 | 2.19 | 7.20 | 25.2 | 3.196 | 11.4 |
| Example 3 | 2.35 | 7.38 | 27.1 | 3.354 | 12.1 |
| Example 4 | 2.19 | 8.33 | 27.7 | 3.062 | 8.81 |
| Example 5 | 1.99 | 5.11 | 16.1 | 2.761 | 7.87 |
| Example 6 | 2.38 | 10.5 | 29.7 | 2.602 | 12.9 |
| Example 7 | 2.61 | 8.05 | 28.6 | 3.228 | 9.27 |
| Example 8 | 2.66 | 7.95 | 24.9 | 2.797 | 9.85 |
| Example 9 | 2.50 | 11.32 | 33.7 | 2.756 | 13.7 |
Example 12
The method for detecting the goserelin content in the microsphere comprises the following steps:
the drug loading was determined for examples 1-9 by HPLC (Agilent 1260 index II) and the encapsulation was calculated according to the dosage, sample preparation method as follows: precisely weighing 10mg of dried microsphere, adding 2mL of acetonitrile for complete dissolution, filtering with a 0.22 mu m filter membrane, and injecting 10 mu L of sample.
20% acetonitrile (containing 0.05% trifluoroacetic acid) as mobile phase, column: c18 (150 mm. Times.4.6mm. Times.5 μm), goserelin peak areas were detected at 220nm, and drug content was calculated from standard curve:
drug loading (%) = measured drug content/microsphere mass x 100;
encapsulation (%) = percent drug loading measured/percent theoretical drug dosage x 100.
The results are shown in Table 3
TABLE 3 microsphere encapsulation efficiency and drug loading test results for examples
| Examples | Encapsulation efficiency/% | Drug loading/% (goserelin) | Drug loading/% (goserelin acetate) |
| Example 1 | 95.9 | 9.59 | 10.07 |
| Example 2 | 96.6 | 9.66 | 10.14 |
| Example 3 | 95.8 | 9.58 | 10.06 |
| Example 4 | 97.7 | 9.77 | 10.25 |
| Example 5 | 96.6 | 9.66 | 10.14 |
| Example 6 | 105.0 | 10.5 | 11.02 |
| Example 7 | 102.0 | 10.2 | 10.71 |
| Example 8 | 97.9 | 9.79 | 10.28 |
| Example 9 | 95.5 | 9.55 | 10.02 |
In the process of drying in liquid, a small amount of medicine can migrate to the outer water phase, and along with the removal of the organic solvent, part of low molecular weight PLGA also can migrate to the outer water phase, so the medicine encapsulation rate is over 100 percent.
In addition, the addition of acetic acid continues to increase the molecular forces between goserelin and the polymer, resulting in an increase in encapsulation efficiency.
Example 13
Goserelin microsphere external release detection method:
release medium: isotonic PBS pH7.4 containing 0.02% sodium azide was tested at 37℃for rest. Sampling points 1h, 2h, 6h, 1d, 4d, 7d, 14d, 21d, 28d, 35d, 42d. The feed solution was taken out and filtered into HPLC.
The results of the measurements are shown in FIGS. 1-2, and FIG. 1 shows that only molecular weights within the scope of the present invention can achieve a satisfactory release profile, either too fast or too slow.
Figure 2 shows that the addition or absence of acetic acid has little effect on drug release and also increases encapsulation efficiency.
Figures 3-4 show in vivo administration and changes in index for each agent according to a preferred embodiment of the present invention.
Fig. 5 goserelin microsphere microscopy shows that the microsphere size is small and uniform.
The above-described embodiment is only a preferred embodiment of the present invention, and is not limited in any way, and other variations and modifications may be made without departing from the technical aspects set forth in the claims.
Claims (5)
1. A goserelin sustained release microsphere composition, characterized in that the starting materials of the goserelin sustained release microsphere composition comprise goserelin or pharmaceutically acceptable salts thereof and glycolide-lactide copolymer;
the glycolide-lactide copolymer has a molecular weight distribution of: 0.1-2% of molecular weight not less than 40000Da, 25-30% of molecular weight not less than 15000Da and less than 40000Da, 33-37% of molecular weight not less than 8000Da and less than 15000Da, 18-22% of molecular weight not less than 5000Da and less than 8000Da, 14-16% of molecular weight not less than 2000Da and less than 5000Da, and 1-3% of molecular weight not less than 500Da and less than 2000 Da;
the particle size distribution of the goserelin slow release microsphere composition is d10 < 1 > -2.66 mu m, d 50-10.5 mu m and d 90-29.7 mu m;
the starting materials of the goserelin slow-release microsphere composition also comprise glacial acetic acid, and the molar ratio of the glacial acetic acid to the goserelin is 0.1-1.1: 1, a step of;
the weight average molecular weight of the glycolide-lactide copolymer ranges from 10000 Da to 20000Da, and the number average molecular weight ranges from 6000 Da to 9000Da;
in the goserelin slow release microsphere composition, the weight content of the goserelin is 8-12%, the weight content of the glycolide-lactide copolymer is 73-80%, and the weight content of the freeze-drying protective agent is 12-15%.
2. The goserelin sustained release microsphere composition of claim 1, wherein the molar ratio of lactic acid units to glycolic acid units of the glycolide-lactide copolymer is 85:15-50:50.
3. The goserelin slow release microsphere composition of claim 1, wherein the glycolide-lactide copolymer is carboxyl-terminated.
4. Goserelin slow release microsphere composition according to claim 1, characterized in that the preparation method is as follows:
(1) Dissolving goserelin or pharmaceutically acceptable salts thereof in water to prepare an inner water phase; dissolving glycolide-lactide copolymer in organic solvent to prepare oil phase;
(2) Premixing an inner water phase and an oil phase, and shearing to form colostrum;
(3) Shearing the primary emulsion and an external water phase containing a surfactant to form a multiple emulsion;
(4) Drying the compound emulsion in a drying tank in liquid to remove the solvent, and continuously collecting;
(5) Cleaning microsphere, continuously collecting, adding freeze-drying protective agent, and freeze-drying.
5. Goserelin slow release microsphere composition according to claim 1, characterized in that the preparation method is as follows:
(1) Dissolving goserelin or pharmaceutically acceptable salts thereof and glacial acetic acid in water to prepare an inner water phase; dissolving glycolide-lactide copolymer in organic solvent to prepare oil phase;
(2) Premixing an inner water phase and an oil phase, and shearing to form colostrum;
(3) Shearing the primary emulsion and an external water phase containing a surfactant to form a multiple emulsion;
(4) Drying the compound emulsion in a drying tank in liquid to remove the solvent, and continuously collecting;
(5) Cleaning microsphere, continuously collecting, adding freeze-drying protective agent, and freeze-drying.
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| CN104436169A (en) * | 2014-12-15 | 2015-03-25 | 深圳市健元医药科技有限公司 | Sustained-release microsphere preparation of goserelin composition |
| CN104840429A (en) * | 2015-04-23 | 2015-08-19 | 丽珠医药集团股份有限公司 | Preparation method of acetic acid goserelin microspheres |
| CN105878190A (en) * | 2016-04-26 | 2016-08-24 | 广州帝奇医药技术有限公司 | Preparation method of slow-released microgranules, prepared slow-released microgranules and application thereof |
| CN109394705A (en) * | 2018-12-04 | 2019-03-01 | 沈阳药科大学 | A kind of Goserelin release microsphere freeze-dried powder and preparation method thereof |
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| CN104840429A (en) * | 2015-04-23 | 2015-08-19 | 丽珠医药集团股份有限公司 | Preparation method of acetic acid goserelin microspheres |
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