CN100460441C - Organism degradable star-type structure poly (glycolide-lactide) medicine carrier microsphere and preparation method thereof - Google Patents
Organism degradable star-type structure poly (glycolide-lactide) medicine carrier microsphere and preparation method thereof Download PDFInfo
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- CN100460441C CN100460441C CNB200610015923XA CN200610015923A CN100460441C CN 100460441 C CN100460441 C CN 100460441C CN B200610015923X A CNB200610015923X A CN B200610015923XA CN 200610015923 A CN200610015923 A CN 200610015923A CN 100460441 C CN100460441 C CN 100460441C
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Abstract
The present invention relates to one kind of biodegradable medicine-carrying polyglycolide-lactide microsphere in star structure and its preparation process. The biodegradable medicine-carrying polyglycolide-lactide microsphere has coating material of star polyglycolide-lactide, coated protein polypeptide medicine of bovine serum albumin or leuteinizing hormone-releasing homone (LH-RH) analog, medicine carrying amount of 17.56-67.51 mcg/mg microsphere and embedding rate of 28.68-78.39 wt%. It is prepared through a W/O/W composite emulsifying process to coat protein polypeptide medicine into star polyglycolide-lactide to form microsphere. Compared with linear medicine-carrying polyglycolide-lactide microsphere, the present invention has obviously increased medicine carrying amount and embedding rate and obvious long-acting and slowly releasing effect.
Description
Technical field
The present invention relates to biodegradable poly second rac-Lactide medicine carrying microballoons of a kind of protein polypeptide medicine carrying microballoons and preparation method thereof, particularly a kind of hub-and-spoke configuration and preparation method thereof.
Background technology
Along with biomedicine and development of biology, protein and peptide drugs is becoming the very important therapeutical agent of a class.They all have broad application prospects to cancer, autoimmune disorder, hypomnesis, insane, hypertension and some treatment cardiovascular and metabolic trouble, have become important diagnostic, monitoring, prevention and curative.The characteristics of this class medicine are that consumption is little, biological activity is strong, but very sensitive to strong acid and proteolytic ferment in stomach and intestine behind this class drug oral, and polypeptide, protein drug belong to the wetting ability macromolecular substance more, is difficult for seeing through intestinal mucosa, biological half-life is short, oral administration biaavailability is low, often needs non-enterally administer, repeatedly injection, cause the huge misery of patient, and increase the weight of patient economy burden.Therefore, the protein and peptide biopharmaceutical macromolecular drug slow select or controlled release preparation and non-injection administration approach research significant.Microballoon has biodegradability and low toxicity during as medicine controlled release carrier, can be made into various different-grain diameters, seals multiple medicine, and drug encapsulation amount height.To compare with liposome. microballoon is more stable, and internal metabolism is slower, favourable prolongation drug effect.Biodegradable microballoon is widely used in the controlled release and the targeting vector of medicine, especially for polypeptide class and protein drug.Biodegradable microballoon can by glycollide and (or) lactide monomer forms through ring-opening polymerization, is hydrolyzed into avirulent monomer in vivo.
Drug loading and embedding rate with line style poly (glycolide-lactide) parcel protein polypeptide system medicine carrying microballoons are all smaller, and drug loading is no more than tens micrograms/every milligram of microballoon, and embedding rate is no more than 20%.Recently a lot of researchs are devoted to line style poly(lactic acid) or poly (glycolide-lactide) chain structure are carried out modification, as prepare segmented copolymer (Liu S Q, Yang Y Y, and I iu X M, et al, Preparation and Characterization of Temperature-Sensitive Poly (N-isopropylacrylamide)-b-poly (D, L-lactide) Microspheres for Protein Delivery, Biomacromolecules, 2003,4:1784～1793), or in the medicine carrying microballoons preparation process, add to strengthen (Kim J H, TalujaA, and Knutson K such as additive with the albumen effect, et al, Stability of bovine serum albumin complexed withPEG-poly (L-histidine) diblock copolymer in PLG Amicrospheres, Journal of ControlledRelease, 2005,109 (1-3): 86～100), to improve the medicine carrying performance.These researchs have all obtained reasonable effect, to the highest can the reaching more than 60% of embedding rate of medicine.But their weak point is that because lapping structure or experimental system have been made bigger change, experimentation is relatively complicated.
Consider that the branched structure polymkeric substance has the advantage of aspects such as some physics, chemistry than linear structure polymkeric substance, many researchs begin to turn to more synthetic have the polymkeric substance of specific branched structure to improve certain performance index.Feng Xinde (DongC M, Qiu K Y, and Gu Z W, et al, Synthesis of star-shaped poly (D, L-lactic acid-alt-glycolicacid) with multifunctional initiator and SnOct
2Catalyst.Polymer, 2001,42:6891～6896) etc. utilize different initiators and ring-opening polymerization continuously, obtained two kinds of multi-arm poly (glycolide-lactide)s.They are catalyzer with the stannous octoate earlier, are initiator with multi-functional trihydroxy methyl propane or tetramethylolmethane, with the ring-opening polymerization of second rac-Lactide, obtain 3 arms and 4 arm poly (glycolide-lactide) alternating copolymers respectively.
Summary of the invention
The object of the present invention is to provide a kind of biodegradable star-type structure poly (glycolide-lactide) medicine carrier microsphere and preparation method thereof, the poly (glycolide-lactide) that adopts excellent biological compatibility and biodegradability is as lapping, utilize the special star branched structure of polymkeric substance, obtain the protein polypeptide medicine carrying microballoons that a kind of shape is good, drug loading obviously improves.Material preparation method step of the present invention is simple.
Biodegradable poly second rac-Lactide medicine carrying microballoons provided by the invention be poly (glycolide-lactide) with hub-and-spoke configuration as lapping, parcel protein polypeptide and a kind of medicine carrying microballoons of forming.
The number-average molecular weight of described star-like poly (glycolide-lactide) is 9000～15000, the protein polypeptide that is wrapped up is bovine serum albumin or r-hLH (LH-RH) analogue, molecular weight is 1000～70000, the drug loading of medicine carrying microballoons is 17.56～67.51 μ g/ (mg microballoons), embedding rate is 28.68%～78.39%, and median size is 80～150 μ m.
The concrete steps that the preparation method of organism degradable star-type structure poly (glycolide-lactide) medicine carrier microballoon provided by the invention comprises are as follows:
A with the aqueous solution of polyvinyl alcohol (0.01～0.2%, w/v) be solvent, the protein polypeptide medicine is dissolved in wherein, water in forming, the quality of used protein polypeptide medicine and the volume ratio of solvent are 5～25:100 (g/mL).
B is solvent with the methylene dichloride, four arm star poly (glycolide-lactide)s is dissolved in wherein, and oil phase in the formation, the quality of used star-like poly (glycolide-lactide) and the volume ratio of solvent are 5～100:100 (g/mL).
In ℃ scope of c20～80, interior water and middle oil phase that a and step b are set by step made mix, ultrasonic (Sonics﹠amp down; Materials VCX, 400W, 30s) uniform mixing, the colostrum of formation W/O, the volume ratio of interior water and middle oil phase is 1.5～10:100.
D is dissolved in sodium-chlor in 0.01～0.2% (w/v) polyvinyl alcohol water solution, forms outer water, and sodium chloride concentration is 0.01～2.5mg/mL.
E is injected into the outer aqueous phase of steps d gained with the W/O colostrum of step c gained under high-speed stirring, colostrum is 4～10:100 with the volume ratio of outer water, through emulsification formation W/O/W emulsion, is stirred to methylene dichloride and all volatilizees, and makes the curing balling-up; The microballoon of gained is centrifugal, collection, after lyophilize, stored refrigerated promptly obtains the organism degradable star-type poly (glycolide-lactide) medicine carrier microsphere.Described stirring velocity is 30～300r/min.
The preparation method of four arm star poly (glycolide-lactide)s is that employing rac-Lactide and glycollide are monomer (monomeric mol ratio is 3:1), stannous iso caprylate be catalyzer (with the ratio of the total amount of substance of monomer be 10000:1), tetramethylolmethane be multi-functional basic initiator (with the ratio of the total amount of substance of monomer be 50～100:1), carry out ring-opening polymerization at 150～200 ℃.
The organism degradable star-type poly (glycolide-lactide) medicine carrier microsphere of the present invention's preparation has improved the problem of line style poly (glycolide-lactide) to protein polypeptide medicine parcel ability, has improved drug loading and embedding rate greatly.
The medicine carrying microballoons of organism degradable star-type poly (glycolide-lactide) of the present invention, release in 30～50 hours is finished, and drug release process is more steady.
Description of drawings
Fig. 1 is the C of four arm star poly (glycolide-lactide)s
13The NMR spectrogram.
Fig. 2 is the molecular formula of four arm star poly (glycolide-lactide)s, and m, n are integer.
Fig. 3 is the molecular weight and the distribution plan (gel permeation chromatography sign) thereof of four arm star poly (glycolide-lactide)s.
Fig. 4 is the stereoscan photograph of embodiment 2.
Fig. 5 is drug loading, the embedding rate comparison diagram of embodiment 2,6 and reference examples 1,2.
Fig. 6 is the elution profiles of embodiment 3,5.
Embodiment:
Embodiment 1: with 0.3mol rac-Lactide, 0.1mol glycollide, 2 * 10
-3Mol tetramethylolmethane and 4 * 10
-5Pack into after the mol stannous iso caprylate mixes in the tube sealing, the mouth of pipe is shut in (30Pa) fusion under the vacuum condition, and 160 ℃ are reacted 8h down.Products therefrom dissolves after-filtration with methylene dichloride, drips anhydrous methanol and makes its precipitation, and precipitation promptly obtains four arm star poly (glycolide-lactide)s after vacuum-drying.Its number-average molecular weight is 9000.Its structure by
13(VARIAN JNITY-plus400) nuclear magnetic spectrogram is determined Fig. 1 to C NMR.Can find respectively in the spectrogram quaternary carbon atom in the tetramethylolmethane molecule peak f (the peak g of δ=62.25ppm) and mesomethylene carbon atom (and δ=15.71ppm), thus proved the hub-and-spoke configuration of polymkeric substance.
Embodiment 2: 70mg bovine serum albumin (molecular weight is 67000) is dissolved in the aqueous solution of 0.3mL 0.05% (w/v) polyvinyl alcohol (17-88, Beijing Organic Chemical Plant) water in forming.0.6g four arm star poly (glycolide-lactide)s are dissolved in the 12mL methylene dichloride oil phase in the formation.Heat under 60 ℃ of conditions, interior water and middle oil phase are mixed, ultrasonic (Sonics ﹠amp down; Materials VCX, 400W, 30s) uniform mixing, the colostrum of formation W/O.250mL 0.2% (w/v) polyvinyl alcohol water solution is as outer water.Aqueous phase outside the W/O colostrum is injected under high-speed stirring forms the W/O/W emulsion through emulsification, is stirred to methylene dichloride and all volatilizees, and makes the curing balling-up; The microballoon of gained is centrifugal, collect, after lyophilize, promptly obtain the medicine carrying microballoons of organism degradable star-type poly (glycolide-lactide).Its drug loading is 37.85 μ g/mg microballoons, and embedding rate is 31.9%.See Fig. 3.
Embodiment 3: present embodiment is identical with the operation steps of embodiment 2, and the amount of the star-like poly (glycolide-lactide) that different is adopts is 0.8g, and the drug loading of resulting medicine carrying microballoons is 31.18 μ g/mg microballoons, and embedding rate is 33.41%.
Embodiment 4: present embodiment is identical with the operation steps of embodiment 2, and the amount of the star-like poly (glycolide-lactide) that different is adopts is 1.0g, and the drug loading of resulting medicine carrying microballoons is 28.88 μ g/mg microballoons, and embedding rate is 49.1%.
Embodiment 5: present embodiment is identical with the operation steps of embodiment 3, different is that the lapping that adopts is that number-average molecular weight is 16000 star-like poly (glycolide-lactide), the drug loading of resulting medicine carrying microballoons is 52.28 μ g/mg microballoons, and embedding rate is 61.99%.
Embodiment 6: present embodiment is identical with embodiment 4 operation stepss, and different is that the medicine that wraps up is that ((its structure is [NAc-D2Nal to TX46 to r-hLH (LH-RH) analogue
1, DpClphe
2, D3Pal
3.8, Arg
5, dPA
8, D-Ala
10], functional polymer journal 2000,13 (4), 397-400, molecular weight 1468.7), the drug loading of resulting medicine carrying microballoons is 17.56 μ g/mg microballoons, embedding rate is 28.68%.
Reference examples 1: identical with the operation steps of embodiment 2, different is that the lapping that adopts is line style poly (glycolide-lactide) (number-average molecular weight also is 10000), and the drug loading of resulting medicine carrying microballoons is 11.48 μ g/mg microballoons, and embedding rate is 9.68%.
Reference examples 2: identical with the operation steps of embodiment 6, different is that the lapping that adopts is line style poly (glycolide-lactide) (number-average molecular weight also is 10000), and the drug loading of resulting medicine carrying microballoons is 7.13 μ g/mg microballoons, and embedding rate is 11.06%.
Claims (4)
1. biodegradable poly (glycolide-lactide) medicine carrier microsphere, be that poly (glycolide-lactide) with hub-and-spoke configuration is as lapping, a kind of medicine carrying microballoons that wraps up protein polypeptide and form, the number-average molecular weight that it is characterized in that described star-like poly (glycolide-lactide) is 9000～15000, the protein polypeptide that is wrapped up is bovine serum albumin or r-hLH LH-RH analogue, and molecular weight is 1000～70000.
2. the preparation method of the described biodegradable poly (glycolide-lactide) medicine carrier microsphere of claim 1 is characterized in that the step that comprises is as follows:
A is a solvent with the aqueous solution of 0.01～0.2%w/v polyvinyl alcohol, and the protein polypeptide medicine is dissolved in wherein, water in forming, and the quality of used protein polypeptide medicine and the volume ratio of solvent are per 100 milliliter of 5～25 gram;
B is solvent with the methylene dichloride, four arm star poly (glycolide-lactide)s is dissolved in wherein, and oil phase in the formation, the quality of used star-like poly (glycolide-lactide) and the volume ratio of solvent are per 100 milliliter of 5～100 gram;
In 20～80 ℃ of scopes of c, interior water and middle oil phase that a and step b are set by step made mix, and ultrasonic uniform mixing down forms the colostrum of W/O, and the volume ratio of interior water and middle oil phase is 1.5～10:100;
D is dissolved in sodium-chlor in the aqueous solution of 0.01～0.2%w/v polyvinyl alcohol, forms outer water, and sodium chloride concentration is 0.01～2.5 milligram every milliliter;
E under agitation is injected into the outer aqueous phase of steps d gained with the W/O colostrum of step c gained, and colostrum is 4～10:100 with the volume ratio of outer water, through emulsification formation W/O/W emulsion, is stirred to methylene dichloride and all volatilizees, and makes the curing balling-up; The microballoon of gained is centrifugal, collect, after lyophilize, stored refrigerated can obtain the medicine carrying microballoons of organism degradable star-type poly (glycolide-lactide).
3. the preparation method of biodegradable poly (glycolide-lactide) medicine carrier microsphere according to claim 2, the preparation method of described star-like poly (glycolide-lactide) is that employing rac-Lactide and glycollide are monomer, amount of substance is than being 3:1, tetramethylolmethane is multi-functional basic initiator, stannous iso caprylate is a catalyzer, the body melt polymerization is characterized in that:
Tetramethylolmethane is 50～100:1 with the ratio of the quality of the total material of monomer;
Stannous iso caprylate is 10000:1 with the ratio of the quality of the total material of monomer.
4. the preparation method of biodegradable poly (glycolide-lactide) medicine carrier microsphere according to claim 2 is characterized in that described stirring velocity is 30～300r/min.
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| CN104434817B (en) * | 2014-09-17 | 2018-02-13 | 黑龙江泰华源生物技术有限责任公司 | A kind of slow-release microshpere formulation for injection of Liraglutide |
| CN111019107A (en) * | 2019-12-27 | 2020-04-17 | 山东谷雨春生物科技有限公司 | Preparation method of multi-branched poly (glycolide-lactide) |
| CN113180066A (en) * | 2021-05-08 | 2021-07-30 | 宁波帕柯斯新材料科技有限公司 | High-concentration slow-release antibacterial aqueous solution and preparation method thereof |
| CN114940746A (en) * | 2022-06-17 | 2022-08-26 | 山东采采医疗科技有限公司 | Star-shaped lactide-glycolide copolymer and application thereof as drug sustained-release carrier |
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| US5922338A (en) * | 1983-08-26 | 1999-07-13 | Novartis Ag | Polyol esters, their preparation and use in depot forms of pharmacologically active agents |
| US5688530A (en) * | 1989-07-07 | 1997-11-18 | Novartis Ag | Sustained release formulations of water soluble peptides |
| CN1578664A (en) * | 2001-10-30 | 2005-02-09 | 诺瓦提斯公司 | Depot formulations of iloperidone and a star polymer |
| US20060095122A1 (en) * | 2004-10-29 | 2006-05-04 | Advanced Cardiovascular Systems, Inc. | Implantable devices comprising biologically absorbable star polymers and methods for fabricating the same |
| CN1660412A (en) * | 2004-12-27 | 2005-08-31 | 中山大学 | Method of preparing microsphere of ethoxyl copolymer PLGA in interferon poly acid |
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