CN102552169A - Aviptadil acetate sustained-release microsphere preparation and preparation method thereof - Google Patents
Aviptadil acetate sustained-release microsphere preparation and preparation method thereof Download PDFInfo
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- CN102552169A CN102552169A CN2012100370283A CN201210037028A CN102552169A CN 102552169 A CN102552169 A CN 102552169A CN 2012100370283 A CN2012100370283 A CN 2012100370283A CN 201210037028 A CN201210037028 A CN 201210037028A CN 102552169 A CN102552169 A CN 102552169A
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- aviptadil
- acetic acid
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Abstract
The invention discloses an aviptadil acetate sustained-release microsphere preparation and a preparation method thereof. Sustained-release microspheres comprise 0.01 to 15 percent (w/w) of aviptadil, 85 to 99.99 percent of polymer material, 0 to 10 percent of pharmaceutically acceptable emulsification stabilizer, and other excipients such as an excipient, wherein the polymer material has the molecular weight of 5,000 to 300,000D, is biodegradable and has the biocompatibility. The average particle size of the sustained-release microspheres is 5 to 100mu m; and the entrapment efficiency is over 92 percent. The sustained-release period of the sustained-release microspheres can reach over 30 days, the medication times are remarkably reduced, the bioavailability of aviptadil acetate is improved, the toxic or side effect of the medicine is reduced, and the preparation is favorable for clinical treatment.
Description
Technical field:
The present invention relates to a kind of sustained release microsphere agents field, be specifically related to a kind of acetic acid aviptadil sustained release microsphere agents and preparation method thereof that contains.
Background technology:
Aviptadil is claimed vasoactive intestinal peptide again, is a kind of 28 amino acid whose polypeptide that contain, and molecular formula is C
147H
238N
44O
42S, molecular weight are 3325.80, and its aminoacid mechanism is as follows:
His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys?Tyr-Leu-Asn-Ser-Ile-Leu-Asn。
Aviptadil is a kind of linear peptides that extracts from mucous membrane of small intestine, and its aminoacid is arranged as a part of glucagon (glucagon) and urges pancreatin (secretin).Have the effect that vasodilation is brought high blood pressure down, begin, visceral vessel is had stronger ability to function from Hepatic artery.Secretion to intestinal juice has very strong facilitation, can play inhibitory action to the secretion of gastric juice; Contraction to gastrointestinal smooth muscle produces inhibitory action., in human and animal's control formula experiment, use above 20 years in US and European country.
Summary of the invention:
The technical problem that the present invention will solve provides a kind of can effectively prolong acetic acid aviptadil acetic acid aviptadil sustained release microsphere agents of action time in vivo; Said preparation can reduce frequency injection and Drug tolerance; Improve patient's adaptability, convenient clinical use and patient accept.In addition, it has also eliminated the vivo medicine concentration peak valley phenomenon that normal injection agent multiple dosing produces, and can obtain steadily valid density for a long time, has reduced toxic and side effects, and total dosage reduces.
In addition, the present invention also provides a kind of method for preparing of acetic acid aviptadil sustained release microsphere agents.
The present invention has prepared a kind of sustained release microsphere agents that contains the injection of acetic acid aviptadil medicine; It is characterized in that; Acetic acid aviptadil sustained-release micro-spheres in the said preparation contains the acetic acid aviptadil that accounts for microsphere weight 0.01%-30% (w/w), and the molecular weight that accounts for microsphere weight 70%-99.99% is 5,000-100; The macromolecular material of 000 daltonian biodegradable and tool biocompatibility; And pharmaceutically acceptable other adjuvants that account for microsphere weight 0%-10%, described sustained-release micro-spheres size is 1-100 μ m, mean diameter is 5-50 μ m.
The macromolecular material of said biodegradable and tool biocompatibility; Optional from polylactide (PLA), gather Acetic acid, hydroxy-, bimol. cyclic ester (PGA), polylactide-co-glycolide (PLGA), paracyanogen base alkyl acrylate, pla-pcl (PCL), poly hydroxybutyric acid (PHB), gather hydroxyl valeric acid (PVA), gather capric acid (PDA), gather anhydride, poly butyric ester-hydroxyl valerate, polylactic acid-polyglycol, polyglycolic acid-Polyethylene Glycol a kind of or its mixture wherein, preferred polylactide-co-glycolide.Described lactide and Acetic acid, hydroxy-, bimol. cyclic ester molecular weight ranges be all 5,000-20, and 000 dalton, the proportion of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 25: 75-75: 25.
Described pharmaceutically acceptable other adjuvants comprise emulsion stabilizer and excipient, and said emulsion stabilizer is selected from polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), sodium polymethacrylate, sodium polyacrylate, sodium carboxymethyl cellulose etc.Emulsion stabilizer preferably polyethylene alcohol, its amount ranges is 0.1%-5%.
Excipient is selected from a kind of or its mixture in sorbitol, mannitol, lactose, sucrose, the glycine, preferred mannitol, and its amount ranges is 0.1%-5%.
In addition, the present invention also provides preparation to contain the method for acetic acid acetic acid aviptadil medicine, and the first step at first is dissolved in the acetic acid aviptadil in aqueous gelatin solution or the glycerol, obtains drug solution, is interior water; In addition polylactide-co-glycolide is dissolved in the organic solvent, gets oil phase; Oil phase and interior water are placed in the agitator, and breast is even at a high speed, forms the W/O emulsion; Then the W/O emulsion is joined in the polyvinyl alcohol water solution, breast is even at a high speed, forms the W/O/W emulsion;
Second step moved into the W/O/W emulsion in the polyvinyl alcohol water solution, and stirring at low speed is centrifugal, collects thus obtained microsphere, with distilled water wash repeatedly after, centrifugal again collection, lyophilization promptly gets acetic acid aviptadil sustained-release micro-spheres.
Description of drawings:
With the drug release time is abscissa, and accumulative total degree of release is a vertical coordinate, draws the external release curve chart of acetic acid aviptadil sustained release microsphere agents of embodiment 1,2,3 preparations, and the result sees Figure of description 1,2,3.
The specific embodiment:
To combine embodiment that embodiment of the present invention are described in detail below, but it will be understood to those of skill in the art that the following example only is used to explain the present invention, and should not be regarded as limiting scope of the present invention.
Embodiment 1
Take by weighing 35mg acetic acid aviptadil and be dissolved in the aqueous gelatin solution, water in getting; Take by weighing 1000mg polylactide-co-glycolide (polymerization ratio=40: 60, molecular weight 20000) and be dissolved in the dichloromethane, get oil phase.Compound concentration is that 3% poly-vinyl alcohol solution 50ml and concentration are 0.3% poly-vinyl alcohol solution 500ml.Earlier acetic acid aviptadil solution is moved into and be dissolved with in the dichloromethane solution of polylactide-co-glycolide, placed on the emulsifying dispersion machine at a high speed (25000rpm) breast under the room temperature even 20 seconds, then the w/o type Emulsion of gained being transferred to 50ml concentration is in 3% the poly-vinyl alcohol solution, places on the emulsifying dispersion machine rotating speed with 5000rpm; Even 1 minute of breast gets W/O/W type emulsion, moves in the poly-vinyl alcohol solution of 500ml0.3%; Place on the mechanical agitator, with the rotating speed stirring at low speed of 500rpm 2.5 hours, centrifugal; Collect thus obtained microsphere, repeatedly wash with distilled water, and then centrifugal collection; Lyophilization promptly gets, and the thus obtained microsphere particle diameter is 10-50 μ m, and mean diameter is 30 μ m.
The medicine carrying acetic acid aviptadil sustained-release micro-spheres 4.5mg that precision takes by weighing embodiment 1 preparation is dissolved in the 1mL dichloromethane, and gradation adds 4mL and the 2mL double distilled water extracts medicine, vortex extraction 1min; The centrifugal 2min of 25000rpm; Draw the merging supernatant, pipette supernatant 0.5mL and be settled to 10mL, sample introduction 20 μ l with double distilled water; HPLC measures content; The drawing standard curve calculates the medicine carrying acetic acid aviptadil sustained-release micro-spheres Chinese medicine content that embodiment 1 prepares according to standard curve, and calculated yield and envelop rate drug loading are respectively 78.5% and 68.8% in view of the above.
Embodiment 2
Take by weighing 20mg acetic acid aviptadil and be dissolved in the distilled water, water in getting; Take by weighing 800mg polylactide-co-glycolide (polymerization ratio=30: 70, molecular weight 15000) and be dissolved in the dichloromethane, get oil phase.Compound concentration is that 5% poly-vinyl alcohol solution 50ml and concentration are 0.5% poly-vinyl alcohol solution 500ml.Earlier acetic acid aviptadil solution is moved into and be dissolved with in the dichloromethane solution of polylactide-co-glycolide, placed on the emulsifying dispersion machine at a high speed (30000rpm) breast under the room temperature even 20 seconds, then the w/o type Emulsion of gained being transferred to 50ml concentration is in 5% the poly-vinyl alcohol solution, places on the emulsifying dispersion machine rotating speed with 5000rpm; Even 1 minute of breast gets W/O/W type emulsion, moves in the poly-vinyl alcohol solution of 500ml0.5%; Place on the mechanical agitator, with the rotating speed stirring at low speed of 500rpm 3 hours, centrifugal; Collect thus obtained microsphere, repeatedly wash with distilled water, and then centrifugal collection; Lyophilization promptly gets, and the thus obtained microsphere particle diameter is 20-60 μ m, and mean diameter is 40 μ m.
The medicine carrying acetic acid aviptadil sustained-release micro-spheres 4.5mg that precision takes by weighing embodiment 2 preparations is dissolved in the 1mL dichloromethane, and gradation adds 4mL and the 2mL double distilled water extracts medicine, vortex extraction 1min; The centrifugal 3min of 15000rpm; Draw the merging supernatant, pipette supernatant 0.5mL and be settled to 10mL, sample introduction 20 μ l with double distilled water; HPLC measures content; The drawing standard curve calculates the medicine carrying acetic acid aviptadil sustained-release micro-spheres Chinese medicine content that embodiment 2 prepares according to standard curve, and calculated yield and envelop rate drug loading are respectively 82.9% and 81.3% in view of the above.
Embodiment 3
Take by weighing 10mg acetic acid aviptadil and be dissolved in the distilled water, water in getting; Take by weighing 600mg polylactide-co-glycolide (polymerization ratio=60: 40) and be dissolved in the dichloromethane, get oil phase.Compound concentration is that 5% poly-vinyl alcohol solution 50ml and concentration are 0.5% poly-vinyl alcohol solution 500ml.Earlier acetic acid aviptadil solution is moved into and be dissolved with in the dichloromethane solution of polylactide-co-glycolide, placed on the emulsifying dispersion machine at a high speed (30000rpm) breast under the room temperature even 30 seconds, then the w/o type Emulsion of gained being transferred to 50ml concentration is in 5% the poly-vinyl alcohol solution, places on the emulsifying dispersion machine rotating speed with 5000rpm; Even 1 minute of breast gets W/O/W type emulsion, moves in the poly-vinyl alcohol solution of 500ml0.5%; Place on the mechanical agitator, with the rotating speed stirring at low speed of 500rpm 2 hours, centrifugal; Collect thus obtained microsphere, repeatedly wash with distilled water, and then centrifugal collection; Lyophilization promptly gets, and the thus obtained microsphere particle diameter is 30-80 μ m, and mean diameter is 50 μ m.
The medicine carrying acetic acid aviptadil sustained-release micro-spheres 4.5mg that precision takes by weighing embodiment 3 preparations is dissolved in the 1mL dichloromethane, and gradation adds 4mL and the 2mL double distilled water extracts medicine, vortex extraction 1min; The centrifugal 3min of 15000rpm; Draw the merging supernatant, pipette supernatant 0.5mL and be settled to 10mL, sample introduction 20 μ l with double distilled water; HPLC measures content; The drawing standard curve calculates the medicine carrying acetic acid aviptadil sustained-release micro-spheres Chinese medicine content that embodiment 3 prepares according to standard curve, and calculated yield and envelop rate drug loading are respectively 62.8% and 69.7% in view of the above.
Embodiment 4
Respectively the acetic acid aviptadil sustained release microsphere agents to embodiment 1,2,3 preparations is carried out external release and investigate, method is following:
The accurate respectively acetic acid aviptadil sustained-release micro-spheres that takes by weighing some parts of embodiment 1,2,3 preparations, every part of 5mg places the cillin bottle of 35 10mL, and every part of adding contains the Na of 0.1M
2HPO
4NaH with 0.1M
2PO
4The phosphate buffer solution of pH7.4, place 37 ℃ of waters bath with thermostatic control, took out at the 0th, 1,4,8,12,16,20,24,28,35 day respectively; Centrifugal, (1: 1v/v), chromatographic column is C18 50 * 2mm to be dispersed in the acetate dichloromethane buffer again; Mobile phase is 1: 1 containing 0.1% trifluoracetic acid and containing 1% trifluoroacetic 50% acetonitrile mixed solution; Flow velocity 1.0ml/min detects at the 240nm place, measures remaining dose in the microsphere; Calculate accumulative total degree of release according to external standard method, it is as shown in table 1 that the result is measured in the external release of the acetic acid aviptadil sustained release microsphere agents of embodiment 1,2,3 preparations:
The external release experimental result of the acetic acid aviptadil sustained release microsphere agents of table 1 embodiment 1,2,3 preparations
With the drug release time is abscissa, and accumulative total degree of release is a vertical coordinate, draws the external release curve of acetic acid aviptadil sustained release microsphere agents of embodiment 1,2,3 preparations, and the result sees Figure of description 1,2,3.
Claims (10)
1. acetic acid aviptadil sustained release microsphere agents; It is characterized in that: the acetic acid aviptadil sustained-release micro-spheres in the said preparation contains the acetic acid aviptadil that accounts for microsphere weight 0.01%-30% (w/w); The molecular weight that accounts for microsphere weight 70%-99.99% is 5; 000-100, the macromolecular material of 000 daltonian biodegradable and tool biocompatibility, and pharmaceutically acceptable other adjuvants that account for microsphere weight 0%-10%; Described sustained-release micro-spheres size is 1-100 μ m, and mean diameter is 5-50 μ m.
2. acetic acid aviptadil sustained release microsphere agents according to claim 1; It is characterized in that: the macromolecular material of said biodegradable and tool biocompatibility, optional from polylactide (PLA), gather Acetic acid, hydroxy-, bimol. cyclic ester (PGA), polylactide-co-glycolide (PLGA), paracyanogen base alkyl acrylate, polycaprolactone (PCL), poly hydroxybutyric acid (PHB), gather hydroxyl valeric acid (PVA), gather capric acid (PDA), gather anhydride, poly butyric ester-hydroxyl valerate, polylactic acid-polyglycol, polyglycolic acid-Polyethylene Glycol a kind of or its mixture wherein.
3. acetic acid aviptadil sustained release microsphere agents according to claim 2; It is characterized in that: the said biodegradable and macromolecular material tool biocompatibility is a polylactide-co-glycolide; Molecular weight ranges is all 5; 000-20,000 dalton, the proportion of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 25: 75-75: 25.
4. acetic acid aviptadil sustained release microsphere agents according to claim 3 is characterized in that: preferred 50: 50 of the ratio of described lactide and Acetic acid, hydroxy-, bimol. cyclic ester.
5. acetic acid aviptadil sustained release microsphere agents according to claim 1; It is characterized in that: described pharmaceutically acceptable other adjuvants comprise glycerol, gelatin and emulsion stabilizer and excipient, and said emulsion stabilizer is selected from polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), sodium polymethacrylate, sodium polyacrylate, sodium carboxymethyl cellulose, polysaccharide etc.
6. acetic acid aviptadil sustained release microsphere agents according to claim 5 is characterized in that: emulsion stabilizer preferably polyethylene alcohol, its amount ranges is 0.1%-5%.
7. acetic acid aviptadil sustained release microsphere agents according to claim 5 is characterized in that: excipient is selected from a kind of or its mixture in sorbitol, mannitol, lactose, sucrose, the glycine.
8. acetic acid aviptadil sustained release microsphere agents according to claim 5 is characterized in that: the preferred mannitol of excipient, its amount ranges are 0.1%-5%.
9. the method for preparing of acetic acid aviptadil sustained release microsphere agents according to claim 1 is characterized in that adopting emulsion-liquid drying method, prepares microsphere in two steps, it is characterized in that:
The first step at first is dissolved in the acetic acid aviptadil in aqueous gelatin solution or the glycerol, obtains drug solution, is interior water; In addition polylactide-co-glycolide is dissolved in the organic solvent, gets oil phase; Oil phase and interior water are placed in the agitator, and breast is even at a high speed, forms the W/O emulsion; Then the W/O emulsion is joined in the polyvinyl alcohol water solution, breast is even at a high speed, forms the W/O/W emulsion;
Second step moved into the W/O/W emulsion in the polyvinyl alcohol water solution, and stirring at low speed is centrifugal, collects thus obtained microsphere, with distilled water wash repeatedly after, centrifugal again collection, lyophilization promptly gets acetic acid aviptadil sustained-release micro-spheres.
10. acetic acid aviptadil sustained-release micro-spheres method for preparing according to claim 9, it is characterized in that: described organic solvent comprises dichloromethane, chloroform, ethyl acetate, ether, acetone, dioxane or oxolane etc., preferred dichloromethane.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103948911A (en) * | 2014-04-23 | 2014-07-30 | 深圳市健元医药科技有限公司 | Echinocandin antifungal pharmaceutical composition sustained release microsphere preparation and preparation method thereof |
| CN104447963A (en) * | 2014-11-14 | 2015-03-25 | 杭州阿德莱诺泰制药技术有限公司 | Method for preparing aviptadil |
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| CN103948911A (en) * | 2014-04-23 | 2014-07-30 | 深圳市健元医药科技有限公司 | Echinocandin antifungal pharmaceutical composition sustained release microsphere preparation and preparation method thereof |
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