CN1739795A - Prepn process of slow release parathyroid hormone microballoon - Google Patents
Prepn process of slow release parathyroid hormone microballoon Download PDFInfo
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- CN1739795A CN1739795A CN 200510029277 CN200510029277A CN1739795A CN 1739795 A CN1739795 A CN 1739795A CN 200510029277 CN200510029277 CN 200510029277 CN 200510029277 A CN200510029277 A CN 200510029277A CN 1739795 A CN1739795 A CN 1739795A
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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 preparation process includes the following steps: A. dissolving parathyroid hormone in water solution of high molecular weight polysaccharide to form inner water phase; B. adding the inner water phase into the dichloromethane solution of polylactic acid-hydroxy acetic acid copolymer to form initial W/O emulsion; C. emulsifying the initial W/O emulsion into compound W/O/W emulsion via saturating outer water phase of PVA-NaCl aqua with dichloromethane and adding the initial W/O emulsion; D. adding compound W/O/W emulsion to NaCl aqua via stirring to solidify microballoon; and E. water washing the solidified microballoon and freeze drying. 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
The present invention relates to a kind of method of technical field of pharmaceuticals, specifically is a kind of preparation method 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.At present relevant slow release parathyroid hormone microballoon, preparation method still stays in traditional multi-emulsion method simple modification, there is the serious prominent phenomenon of releasing in the slow release parathyroid hormone polylactic-co-glycolic acid copolymer microsphere release in vitro curve of preparations such as Christopher Breuer, and discharges 69% in first day.Peter X.Ma etc. has prepared parathyroid hormone polylactic-co-glycolic acid copolymer microsphere, and external biological active testing result shows: 24 hours biologic activity drop to 6 hours 40%.
The research of at present relevant PTH sustained-release micro-spheres still stays in traditional multi-emulsion method simple modification.Find through literature search prior art, Christopher Breuer etc. are at 2005 the 40th phase 81-85 pages or leaves of Journal of Pediatric Surgery (child's surgical magazine), article autograph " Development of a parathyroidhormone-controlled release system as a potential surgical treatment forhypoparathyroidism " (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 the polylactic-co-glycolic acid copolymer (95.24%, w/w) preparation sustained-release micro-spheres.PTH phosphate-normal saline solution is dropwise dropped in the dichloromethane of polylactic-co-glycolic acid copolymer, form colostric fluid through vortex, ice-bath ultrasonic, colostrum adds to ultrasonic formation emulsion in the concentration 1%PVA solution again, continuation is transferred to emulsion in the 3%PVA solution, stir under the room temperature and removed dichloromethane in 3 hours, centrifugal collection microsphere, lyophilization obtains microsphere.But there is the serious prominent phenomenon of releasing in the outer release profiles of resulting microsphere, and discharges 69% in first day, does 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 preparation method 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, slow release parathyroid hormone microballoon component of the present invention and percentage by weight are: parathyroid hormone 2-20%, macromolecule polysaccharide 2-20%, small molecular sugar 0-10%, slow release macromolecule 75-95%, and its preparation method may further comprise the steps:
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, adopts the mode of magnetic agitation or homogenate, 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 employing homogenate or magnetic agitation are with the further emulsifying formation of colostrum W/O/W emulsion;
D) above-mentioned 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 10 hours, obtain slow release parathyroid hormone microballoon.
Described macromolecule polysaccharide is the one or any mixing in glucosan, soluble cellulose derivant, hyaluronic acid, the alginate; Can in macromolecule polysaccharide, add small molecular sugar, improve the stability of polypeptide in the dry run.
Described slow release macromolecule is selected the copolymer of polylactic acid or 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 percentage by weight of described parathyroid hormone and macromolecule polysaccharide from 10/1 to 1/10.
The dichloromethane solution of water and polylactic-co-glycolic acid copolymer percentage by weight from 1/2 to 1/50 mutually is preferably 1/5 to 1/10 in it.
Step b), the speed of magnetic agitation or homogenate was that 2500-10000rpm, time are 2-5 minute when the dichloromethane solution that interior water is scattered in the polylactic-co-glycolic acid copolymer formed colostrum mutually.
The composition percentage by weight of the outer aqueous phase solution of step c) preparation " W/O/W " emulsion is: polyvinyl alcohol 0.1-5%, sodium chloride 0.5-20%, outer water need to carry out saturated absorption with dichloromethane.
Step c), during preparation W/O/W emulsion, the speed of magnetic agitation or homogenate is 1500-3500rpm, time to be 30-50 second.
Step d), the concentration of used sodium chloride solution are 0.5-25%, further are 5-10%, mixing time 3-4 hour.
The present invention is a substrate with degradable high polymer material polylactic acid-glycolic guanidine-acetic acid copolymer, the macromolecule polysaccharide granule is as " interior aqueous favoring ", add 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.The microsphere that the present invention makes can improve the release profiles of parathyroid hormone microsphere, improve 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 of the embodiment of the invention 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 the embodiment of the invention 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 present embodiment 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 present embodiment makes is approaching or be not less than 85% of medicine carrying capacity, does not have prominent releasing and incomplete release phenomenon.
Claims (10)
1, a kind of preparation method of slow release parathyroid hormone microballoon, it is characterized in that, described slow release parathyroid hormone microballoon component and percentage by weight are: parathyroid hormone 2-20%, macromolecule polysaccharide 2-20%, small molecular sugar 0-10%, slow release macromolecule 75-95%, and its preparation may further comprise the steps:
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, adopts the mode of magnetic agitation or homogenate, 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 employing homogenate or magnetic agitation are with the further emulsifying formation of colostrum W/O/W emulsion;
D) above-mentioned 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 10 hours, obtain slow release parathyroid hormone microballoon.
2, the preparation method of slow release parathyroid hormone microballoon according to claim 1 is characterized in that, described macromolecule polysaccharide is the one or any mixing in glucosan, soluble cellulose derivant, hyaluronic acid, the alginate; Perhaps in macromolecule polysaccharide, add small molecular sugar, improve the stability of polypeptide in the dry run.
3, the preparation method of slow release parathyroid hormone microballoon according to claim 1 is characterized in that, described slow release macromolecule is selected the copolymer of polylactic acid or lactic acid and hydroxyacetic acid for use.
4, the preparation method of slow release parathyroid hormone microballoon according to claim 1 is characterized in that, the straight-chain polypeptide molecule that described parathyroid hormone is made up of 84 amino acid residues, molecular mass 9000; Or comprise the aminoterminal 1～34 of biologically-active moiety, i.e. 34 peptide molecules that aminoacid is formed.
5, according to the preparation method of claim 1 or 4 described slow release parathyroid hormone microballoons, it is characterized in that the percentage by weight of described parathyroid hormone and macromolecule polysaccharide from 10/1 to 1/10.
6, the preparation method of slow release parathyroid hormone microballoon according to claim 1 is characterized in that, the dichloromethane solution of water and polylactic-co-glycolic acid copolymer percentage by weight from 1/2 to 1/50 mutually in it.
7, the preparation method of slow release parathyroid hormone microballoon according to claim 1, it is characterized in that, step b), when the dichloromethane solution that interior water is scattered in the polylactic-co-glycolic acid copolymer formed colostrum mutually, the speed of magnetic agitation or homogenate was that 2500-10000rpm, time are 2-5 minute.
8, the preparation method of slow release parathyroid hormone microballoon according to claim 1, it is characterized in that, step c), the composition percentage by weight of the outer aqueous phase solution of preparation " W/O/W " emulsion is: polyvinyl alcohol 0.1-5%, sodium chloride 0.5-20%, outer water need to carry out saturated absorption with dichloromethane.
9, according to the preparation method of claim 1 or 8 described slow release parathyroid hormone microballoons, it is characterized in that, step c), during preparation W/O/W emulsion, the speed of magnetic agitation or homogenate is 1500-3500rpm, time to be 30-50 second.
10, the preparation method of slow release parathyroid hormone microballoon according to claim 1 is characterized in that, step d), the concentration of used sodium chloride solution are 0.5-25%, solidifies, and makes microsphere in mixing time 3-4 hour.
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