CN1739796A - Slow release parathyroid hormone microballoon - Google Patents
Slow release parathyroid hormone microballoon Download PDFInfo
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- CN1739796A CN1739796A CN 200510029278 CN200510029278A CN1739796A CN 1739796 A CN1739796 A CN 1739796A CN 200510029278 CN200510029278 CN 200510029278 CN 200510029278 A CN200510029278 A CN 200510029278A CN 1739796 A CN1739796 A CN 1739796A
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- parathyroid hormone
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- microballoon
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Abstract
The slow release parathyroid hormone microballoon contains parathyroid hormone 2-20 wt%, high molecular weight polysaccharide 2-20 wt%, small molecular weight saccharide 0-10 wt%, and slow release polymer 75-95 wt%. The high molecular weight polysaccharide particles as the inner hydrophilic phase are dispersed inside microballoon matrix comprising slow release polymer, and parathyroid hormone exists inside the inner hydrophilic polysaccharide phase. The present invention has high molecular weight polysaccharide to increase the viscosity of the water phase, to regulate the release curve, and reduce the coagulation adsorption on polymer surface of parathyroid hormone molecules. The present invention has improved release curve of parathyroid hormone microballoon, high stability of parathyroid hormone and increased medicine carrying amount of the microballoon.
Description
Technical field
What the present invention relates to is a kind of compositions of technical field of pharmaceuticals, specifically is a kind of slow release parathyroid hormone microballoon.
Background technology
1997 people's recombined parathyroid hormone (1～84 aminoacid) carrying out the II clinical trial phase, the parathyroid hormone of Lilly (1～34) product teriparatide (Teriparatide Forteo) is used for the treatment of postmenopausal women's osteoporosis and primary osteoporosis through drugs approved by FDA in June, 2002.Because the plasma half-life very short (20-30min) of parathyroid hormone, directly do not absorbed, treatment cycle is long, the parathyroid hormone extract for treating adopts 3～5 subcutaneous injection 40～100 micrograms weekly at present, long-time treatment patient is difficult to tolerance, above-mentioned reason brings very big difficulty for parathyroid hormone medication treatment, therefore needs research slow release parathyroid hormone dosage form.
Find through literature search prior art, Christopher Breuer etc. are at " Journal ofPediatric Surgery " (child's surgical magazine) 2005 the 40th phase 81-85 pages or leaves, article autograph " Development of a parathyroid hormone-controlled release system as apotential surgical treatment for hypoparathyroidism " (the slow release parathyroid hormone system is used for the treatment of the hypokinetic progress of parathyroid hormone), propose to adopt parathyroid hormone (4.76%, w/w) and polylactic-co-glycolic acid copolymer research obtain microsphere composition (95.24%, w/w) preparation sustained-release micro-spheres, but there is the serious prominent phenomenon of releasing in the microsphere composition release in vitro curve of gained, discharged 69% in first day, and do not reach ideal slow release effect.
Summary of the invention
The objective of the invention is at the deficiencies in the prior art, a kind of slow release parathyroid hormone microballoon is provided, make its release profiles that can improve microsphere, improve drug loading, and in preparation, storage, dispose procedure, stablize parathyroid hormone.
The present invention is achieved by the following technical solutions, and slow release parathyroid hormone microballoon of the present invention comprises parathyroid hormone, macromolecule polysaccharide, small molecular sugar, slow release macromolecule.The percentage by weight of each component is: parathyroid hormone 2-20%, macromolecule polysaccharide 2-20%, small molecular sugar 0-10%, slow release macromolecule 75-95%.
The present invention makes by the following method: a) parathyroid hormone is dissolved in earlier in the macromolecule polysaccharide aqueous solution as interior water; B) interior water adds in the dichloromethane solution of polylactic-co-glycolic acid copolymer, forms the W/O colostrum; C) aqueous solution of 4 ℃ of polyvinyl alcohol and sodium chloride is as outer water, and with the saturated outer water of dichloromethane, colostrum adds to wherein earlier, and colostrum emulsifying is formed the W/O/W emulsion; D) the W/O/W emulsion is added in 4 ℃ of sodium chloride solutions, stir, microsphere is solidified; E) with solidified microsphere water flush away polyvinyl alcohol and sodium chloride postlyophilization, obtain slow release parathyroid hormone microballoon.
Described macromolecule polysaccharide can be selected one or several the mixture in glucosan, soluble cellulose derivant, hyaluronic acid, the alginate for use; Can add small molecular sugar to improve the stability of polypeptide in the dry run.
But described slow release macromolecule can be selected the copolymer of lactic acid and hydroxyacetic acid for use.
The straight-chain polypeptide molecule that described parathyroid hormone is made up of 84 amino acid residues, molecular mass 9000, aminoterminal are active ends, and cause biological effect after the target tissue receptors bind, c-terminus is biologically active not, and biologically-active moiety is mainly at aminoterminal 1～34; The peptide molecule that parathyroid hormone also can be made up of the 1-34 amino acids.
The present invention is a substrate with the degradable controlled release macromolecular material; The macromolecule polysaccharide granule is evenly dispersed in the degradable macromolecule substrate as " interior aqueous favoring ", and its particle diameter is not more than 6 microns; Parathyroid hormone is scattered in the macromolecule polysaccharide microgranule.The present invention adds the rate of release that macromolecule polysaccharide can be regulated parathyroid hormone jointly with the slow release macromolecule at interior aqueous phase, according to treatment needs sustained release speed; Add macromolecule polysaccharide at interior aqueous phase and can block the outside water leakage of parathyroid hormone, thereby improve the microsphere drug loading; Add the mobility of macromolecule polysaccharide at interior aqueous phase, reduce the generation of clustering phenomena by increased viscosity reduction parathyroid hormone molecule; Macromolecule polysaccharide and parathyroid hormone have good biocompatibility, can reduce highly owing to parathyroid hormone directly contacts the absorption that causes with high molecular, can improve the stability of parathyroid hormone in preparation, storage, dispose procedure.
Compared with prior art, the present invention by use macromolecule polysaccharide increase in aqueous viscosity, the adjustment release curve reduces the gathering of parathyroid hormone molecule and in the absorption of macromolecule surface.The present invention can improve the release profiles of parathyroid hormone microsphere, improves the stability of parathyroid hormone in preparation, storage, dispose procedure, the drug loading of increase microsphere.The sustainable release two weeks to three month and first Tiantu are released and are not more than 15% of medicine carrying capacity, total burst size near or be not less than 85% of medicine carrying capacity.
The specific embodiment
Embodiment 1
Preparation of parathyroid hormone microsphere and extracorporeal releasing experiment
A) with parathyroid hormone (2%, w/w) be dissolved in earlier macromolecule polysaccharide (2%, w/w), (1%, w/w) aqueous solution 200mg is as interior water for small molecular sugar;
B) interior water add to the polylactic-co-glycolic acid copolymer (95%, among dichloromethane solution 400mg w/w), adopt magnetic agitation 10000rpm, 2 minutes, form the W/O colostrum;
C) 4 ℃ of polyvinyl alcohol (0.1%, w/w) and sodium chloride (20%, w/w) aqueous solution is as outer water, and with the saturated outer water of dichloromethane, colostrum adds to wherein earlier, employing homogenate mode, 1500rpm, 50 seconds, the further emulsifying formation of colostrum W/O/W emulsion;
D) above-mentioned W/O/W emulsion is added in 4 ℃ of 0.5% sodium chloride solution, stirred 3 hours, microsphere is solidified;
E) with solidified microsphere water flush away polyvinyl alcohol and sodium chloride postlyophilization 10 hours, obtain slow release parathyroid hormone microballoon.
Precision weighing 10mg microsphere adds 1mlPBS solution, in 37 ℃, the cultivation of 60rpm gas bath shaking table, regularly take out supernatant and add buffer medium, adopt the method for microbca to test parathyroid hormone cellulose content in the supernatant, deduct blank microsphere reading, calculate the microsphere release.
Experimental result shows: the steady slow release of parathyroid hormone microsphere composition, first Tiantu are released and are not more than 15% of medicine carrying capacity, and total burst size is approaching or be not less than 85% of medicine carrying capacity, do not have prominent releasing and incomplete release phenomenon.
Embodiment 2
A) with parathyroid hormone (20%, w/w) be dissolved in earlier macromolecule polysaccharide (2%, w/w), (3%, w/w) aqueous solution 200mg is as interior water for small molecular sugar;
B) interior water add to the polylactic-co-glycolic acid copolymer (75%, among dichloromethane solution 10g w/w), adopt magnetic agitation 2500rpm, 5 minutes, form the W/O colostrum;
C) 4 ℃ of polyvinyl alcohol (5%, w/w) and sodium chloride (0.5%, w/w) aqueous solution is as outer water, and with the saturated outer water of dichloromethane, colostrum adds to wherein earlier, employing homogenate mode, 3500rpm, 30 seconds, the further emulsifying formation of colostrum W/O/W emulsion;
D) above-mentioned W/O/W emulsion is added in 4 ℃ of 25% sodium chloride solution, stirred 4 hours, microsphere is solidified;
E) with solidified microsphere water flush away polyvinyl alcohol and sodium chloride postlyophilization 10 hours, obtain slow release parathyroid hormone microballoon.The total burst size of the microsphere that makes is approaching or be not less than 85% of medicine carrying capacity, does not have prominent releasing and incomplete release phenomenon.
Embodiment 3
A) with parathyroid hormone (11%, w/w) be dissolved in earlier macromolecule polysaccharide (2%, w/w), (2%, w/w) aqueous solution 200mg is as interior water for small molecular sugar;
B) interior water add to the polylactic-co-glycolic acid copolymer (85%, among dichloromethane solution 4.2g w/w), adopt magnetic agitation 6250rpm, 3.5 minutes, form the w/O colostrum;
C) 4 ℃ of polyvinyl alcohol (2.55%, w/w) and sodium chloride (10.25%, w/w) aqueous solution is as outer water, and with the saturated outer water of dichloromethane, colostrum adds to wherein earlier, employing homogenate mode, 2500rpm, 40 seconds, the further emulsifying formation of colostrum W/O/W emulsion;
D) above-mentioned W/O/W emulsion is added in 4 ℃ of 12.75% sodium chloride solution, stirred 3.5 hours, microsphere is solidified;
E) with solidified microsphere water flush away polyvinyl alcohol and sodium chloride postlyophilization 10 hours, obtain slow release parathyroid hormone microballoon.The steady slow release of parathyroid hormone microsphere composition, first Tiantu are released and are not more than 15% of medicine carrying capacity, and total burst size is approaching or be not less than 85% of medicine carrying capacity, do not have prominent releasing and incomplete release phenomenon
Embodiment 4
A) with parathyroid hormone (5%, w/w) be dissolved in earlier macromolecule polysaccharide (20%, w/w), (0%, w/w) aqueous solution 200mg is as interior water for small molecular sugar;
B) interior water adds to the polylactic-co-glycolic acid copolymer (75%, among dichloromethane solution 400mg w/w), homogenate 10000rpm 2 minutes, forms the W/O colostrum;
C) 4 ℃ of polyvinyl alcohol (0.1%, w/w) and sodium chloride (20%, w/w) aqueous solution is as outer water, and with the saturated outer water of dichloromethane, colostrum adds to wherein earlier, employing homogenate mode, 1500rpm, 50 seconds, the further emulsifying formation of colostrum W/O/W emulsion;
D) above-mentioned W/O/W emulsion is added in 4 ℃ of 0.5% sodium chloride solution, stirred 3 hours, microsphere is solidified;
E) with solidified microsphere water flush away polyvinyl alcohol and sodium chloride postlyophilization 10 hours, obtain slow release parathyroid hormone microballoon.The total burst size of the microsphere that makes is approaching or be not less than 85% of medicine carrying capacity, does not have prominent releasing and incomplete release phenomenon.
Embodiment 5
A) with parathyroid hormone (5%, w/w) be dissolved in earlier macromolecule polysaccharide (10%, w/w), (10%, w/w) aqueous solution 200mg is as interior water for small molecular sugar;
B) interior water adds to the polylactic-co-glycolic acid copolymer (75%, among dichloromethane solution 4.2g w/w), homogenate 2500rpm 5 minutes, forms the W/O colostrum;
C) 4 ℃ of polyvinyl alcohol (5%, w/w) and sodium chloride (0.5%, w/w) aqueous solution is as outer water, and with the saturated outer water of dichloromethane, colostrum adds to wherein earlier, employing homogenate mode, 3500rpm, 30 seconds, the further emulsifying formation of colostrum W/O/W emulsion;
D) above-mentioned W/O/W emulsion is added in 4 ℃ of 25% sodium chloride solution, stirred 4 hours, microsphere is solidified;
E) with solidified microsphere water flush away polyvinyl alcohol and sodium chloride postlyophilization 10 hours, obtain slow release parathyroid hormone microballoon.The total burst size of the microsphere that makes is approaching or be not less than 85% of medicine carrying capacity, does not have prominent releasing and incomplete release phenomenon.
Embodiment 6
A) with parathyroid hormone (10%, w/w) be dissolved in earlier macromolecule polysaccharide (10%, w/w), (5%, w/w) aqueous solution 200mg is as interior water for small molecular sugar;
B) interior water adds to the polylactic-co-glycolic acid copolymer (75%, among dichloromethane solution 10g w/w), homogenate 6250rpm 3.5 minutes, forms the W/O colostrum;
C) 4 ℃ of polyvinyl alcohol (2.55%, w/w) and sodium chloride (10.25%, w/w) aqueous solution is as outer water, and with the saturated outer water of dichloromethane, colostrum adds to wherein earlier, employing homogenate mode, 2500rpm, 40 seconds, the further emulsifying formation of colostrum W/O/W emulsion;
D) above-mentioned W/O/W emulsion is added in 4 ℃ of 12.75% sodium chloride solution, stirred 3.5 hours, microsphere is solidified;
E) with solidified microsphere water flush away polyvinyl alcohol and sodium chloride postlyophilization 10 hours, obtain slow release parathyroid hormone microballoon.The total burst size of the microsphere that makes is approaching or be not less than 85% of medicine carrying capacity, does not have prominent releasing and incomplete release phenomenon.
Claims (7)
1, a kind of slow release parathyroid hormone microballoon, it is characterized in that, each component and percentage by weight are: parathyroid hormone 2-20%, macromolecule polysaccharide 2-20%, small molecular sugar 0-10%, slow release macromolecule 75-95%, the macromolecule polysaccharide microgranule is scattered in the microsphere substrate of slow release macromolecule formation as interior aqueous favoring, and parathyroid hormone is present in polysaccharide in-laws aqueous phase.
2, slow release parathyroid hormone microballoon according to claim 1 is characterized in that, aqueous-favoring macromolecule polysaccharide in the described conduct is one or several mixture in glucosan, soluble cellulose derivant, hyaluronic acid, the alginate.
3, according to claim 1 or 2 described slow release parathyroid hormone microballoons, it is characterized in that, in macromolecule polysaccharide, add small molecular sugar, to improve the stability of polypeptide in the dry run.
According to claim 1 or 2 described slow release parathyroid hormone microballoons, it is characterized in that 4, particulate diameter of aqueous favoring macromolecule polysaccharide is smaller or equal to 6 microns in it.
5, slow release parathyroid hormone microballoon according to claim 1 is characterized in that, described slow release macromolecule is selected polylactic acid or lactic acid and co-glycolic acid for use.
6, slow release parathyroid hormone microballoon according to claim 1 is characterized in that, the molecular mass that described parathyroid hormone is made up of 84 amino acid residues is 9000 peptide molecule.
7, according to claim 1 or 6 described slow release parathyroid hormone microballoons, it is characterized in that described parathyroid hormone or the peptide molecule of forming by the 1-34 amino acids.
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Effective date of registration: 20120314 Address after: 215400 No. 1 Jin Meng Road, Shaxi Town, Taicang, Jiangsu, Suzhou Patentee after: Suzhou Genemen Biotech Co., Ltd. Address before: 200240 Dongchuan Road, Shanghai, No. 800, No. Patentee before: Shanghai Jiao Tong University |
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Address after: 215400 No. 1 Jin Meng Road, Shaxi Town, Taicang, Jiangsu, Suzhou Patentee after: Xinlitai (Suzhou) Pharmaceutical Co., Ltd. Address before: 215400 No. 1 Jin Meng Road, Shaxi Town, Taicang, Jiangsu, Suzhou Patentee before: Suzhou Genemen Biotech Co., Ltd. |