CN102552169B - A kind of Aviptadil acetate sustained-release microsphere preparation and preparation method thereof - Google Patents
A kind of Aviptadil acetate sustained-release microsphere preparation and preparation method thereof Download PDFInfo
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- CN102552169B CN102552169B CN201210037028.3A CN201210037028A CN102552169B CN 102552169 B CN102552169 B CN 102552169B CN 201210037028 A CN201210037028 A CN 201210037028A CN 102552169 B CN102552169 B CN 102552169B
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Abstract
The invention discloses a kind of Aviptadil acetate sustained-release microsphere preparation and preparation method thereof.This sustained-release micro-spheres comprises in microspheres weight, account for the aviptadil of microspheres weight 0.01%-15% (w/w), the molecular weight accounting for microspheres weight 85%-99.99% is 5,000-300, the 000 daltonian biodegradable and macromolecular material of tool biocompatibility, and account for other adjuvants such as pharmaceutically acceptable emulsion stabilizer and excipient of microspheres weight 0%-10%.Sustained-release micro-spheres mean diameter of the present invention is 5-100 μm, and envelop rate is greater than 92%.This sustained-release micro-spheres slow-release period reaches more than 30 days, obviously reduces times for spraying, improves the bioavailability of acetic acid aviptadil, reduces the toxic and side effects of medicine, is conducive to 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 containing Aviptadil acetate sustained-release microsphere preparation and preparation method thereof.
Background technology:
Aviptadil is also known as vasoactive intestinal peptide, and be a kind of containing 28 amino acid whose polypeptide, molecular formula is C
147h
238n
44o
42s, molecular weight is 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 extracted from mucous membrane of small intestine, and its amino acid range is a part of glucagon (glucagon) and urges pancreatin (secretin).There is the effect that vasodilation can be made to reduce blood pressure, from Hepatic artery, to visceral vessel, there is stronger ability to function.To the secretion of intestinal juice, there is very strong facilitation, can inhibitory action be played to the secretion of gastric juice; Inhibitory action is produced to the contraction of gastrointestinal smooth muscle.In US and European country, use more than 20 years in the control formula experiment of human and animal.
Summary of the invention:
The technical problem to be solved in the present invention is to provide the Aviptadil acetate sustained-release microsphere preparation of a kind of can effectively extend acetic acid aviptadil action time in vivo, said preparation can reduce frequency injection and Drug tolerance, improve the adaptability of patient, facilitate Clinical practice and patient to accept.In addition, it further eliminates the vivo medicine concentration peak valley phenomenon that normal injection agent multiple dosing produces, valid density for a long time can be obtained steadily, reduce toxic and side effects, and total dosage reduces.
In addition, present invention also offers a kind of preparation method of Aviptadil acetate sustained-release microsphere preparation.
The present invention has prepared a kind of sustained release microsphere agents of the injection containing acetic acid aviptadil medicine, it is characterized in that, acetic acid aviptadil sustained-release micro-spheres in described preparation is containing the acetic acid aviptadil accounting for microspheres weight 0.01%-30% (w/w), the molecular weight accounting for microspheres weight 70%-99.99% is 5,000-100, the 000 daltonian biodegradable and macromolecular material of tool biocompatibility, and account for other adjuvants pharmaceutically acceptable of microspheres weight 0%-10%, described sustained-release micro-spheres size is 1-100 μm, and mean diameter is 5-50 μm.
The described biodegradable and macromolecular material of tool biocompatibility, optional from polylactide (PLA), PGA (PGA), polylactide-co-glycolide (PLGA), polyalkylcyanoacrylate, pla-pcl (PCL), poly hydroxybutyric acid (PHB), poly-hydroxyl valeric acid (PVA), poly-capric acid (PDA), condensing model, Polyhydroxybutyrate-co-hydroxyvalerate, polylactic acid-polyglycol, polyglycolic acid-Polyethylene Glycol one wherein or its mixture, preferred polylactide-co-glycolide.Described lactide and Acetic acid, hydroxy-, bimol. cyclic ester molecular weight ranges are all at 5,000-20, and 000 dalton, the proportion of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 25: 75-75: 25.
Described other adjuvants pharmaceutically acceptable comprise emulsion stabilizer and excipient, and described 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 one in sorbitol, mannitol, lactose, sucrose, glycine or its mixture, and preferred mannitol, its amount ranges is 0.1%-5%.
In addition, present invention also offers the method for preparation containing acetic acid acetic acid aviptadil medicine, the first step, is first dissolved in acetic acid aviptadil in aqueous gelatin solution or glycerol, obtains drug solution, is interior aqueous phase; Separately polylactide-co-glycolide is dissolved in organic solvent, obtains oil phase; Be placed in agitator by oil phase and interior aqueous phase, breast is even at a high speed, forms W/O emulsion; Then join in polyvinyl alcohol water solution by W/O emulsion, breast is even at a high speed, forms W/O/W emulsion;
Second step, moves into W/O/W emulsion in polyvinyl alcohol water solution, stirring at low speed, centrifugal, collects thus obtained microsphere, with distilled water wash repeatedly after, then collected by centrifugation, lyophilization, obtains acetic acid aviptadil sustained-release micro-spheres.
Accompanying drawing illustrates:
Take drug release time as abscissa, accumulative releasing degree is vertical coordinate, draws Aviptadil acetate sustained-release microsphere preparation tablets in vitro curve chart prepared by embodiment 1,2,3, the results are shown in Figure of description 1,2,3.
Detailed description of the invention:
Below in conjunction with embodiment, embodiment of the present invention are described in detail, but it will be understood to those of skill in the art that the following example only for illustration of the present invention, and should not be considered as limiting scope of the present invention.
Embodiment 1
Taking 35mg acetic acid aviptadil is dissolved in aqueous gelatin solution, obtains interior aqueous phase; Taking 1000mg polylactide-co-glycolide (polymerization ratio=40: 60, molecular weight 20000) is dissolved in dichloromethane, obtains oil phase.Compound concentration be 3% poly-vinyl alcohol solution 50ml and concentration be 0.3% poly-vinyl alcohol solution 500ml.First being moved into by acetic acid aviptadil solution is dissolved with in the dichloromethane solution of polylactide-co-glycolide, even 20 seconds of (25000rpm) breast is at a high speed placed on emulsion dispersion machine under room temperature, then the w/o type Emulsion of gained being transferred to 50ml concentration is in the poly-vinyl alcohol solution of 3%, be placed on emulsion dispersion machine with the rotating speed of 5000rpm, even 1 minute of breast, obtain W/O/W type emulsion, move in the poly-vinyl alcohol solution of 500ml0.3%, be placed on mechanical agitator, with the rotating speed stirring at low speed 2.5 hours of 500rpm, centrifugal, collect thus obtained microsphere, repeatedly wash with distilled water, and then collected by centrifugation, lyophilization and get final product, thus obtained microsphere particle diameter is 10-50 μm, mean diameter is 30 μm.
The medicine carrying acetic acid aviptadil sustained-release micro-spheres 4.5mg that precision takes embodiment 1 preparation is dissolved in 1mL dichloromethane, gradation adds 4mL and 2mL double distilled water and extracts medicine, vortex extraction 1min, the centrifugal 2min of 25000rpm, draw and merge supernatant, pipette supernatant 0.5mL and be settled to 10mL with double distilled water, sample introduction 20 μ l, HPLC measures content, drawing standard curve, calculate the medicine carrying acetic acid aviptadil sustained-release micro-spheres drug content of embodiment 1 preparation according to standard curve, calculated yield and envelop rate drug loading are 78.5% and 68.8% respectively accordingly.
Embodiment 2
Taking 20mg acetic acid aviptadil is dissolved in distilled water, obtains interior aqueous phase; Taking 800mg polylactide-co-glycolide (polymerization ratio=30: 70, molecular weight 15000) is dissolved in dichloromethane, obtains oil phase.Compound concentration be 5% poly-vinyl alcohol solution 50ml and concentration be 0.5% poly-vinyl alcohol solution 500ml.First being moved into by acetic acid aviptadil solution is dissolved with in the dichloromethane solution of polylactide-co-glycolide, even 20 seconds of (30000rpm) breast is at a high speed placed on emulsion dispersion machine under room temperature, then the w/o type Emulsion of gained being transferred to 50ml concentration is in the poly-vinyl alcohol solution of 5%, be placed on emulsion dispersion machine with the rotating speed of 5000rpm, even 1 minute of breast, obtain W/O/W type emulsion, move in the poly-vinyl alcohol solution of 500ml0.5%, be placed on mechanical agitator, with the rotating speed stirring at low speed 3 hours of 500rpm, centrifugal, collect thus obtained microsphere, repeatedly wash with distilled water, and then collected by centrifugation, lyophilization and get final product, thus obtained microsphere particle diameter is 20-60 μm, mean diameter is 40 μm.
The medicine carrying acetic acid aviptadil sustained-release micro-spheres 4.5mg that precision takes embodiment 2 preparation is dissolved in 1mL dichloromethane, gradation adds 4mL and 2mL double distilled water and extracts medicine, vortex extraction 1min, the centrifugal 3min of 15000rpm, draw and merge supernatant, pipette supernatant 0.5mL and be settled to 10mL with double distilled water, sample introduction 20 μ l, HPLC measures content, drawing standard curve, calculate the medicine carrying acetic acid aviptadil sustained-release micro-spheres drug content of embodiment 2 preparation according to standard curve, calculated yield and envelop rate drug loading are 82.9% and 81.3% respectively accordingly.
Embodiment 3
Taking 10mg acetic acid aviptadil is dissolved in distilled water, obtains interior aqueous phase; Take 600mg polylactide-co-glycolide (polymerization ratio=60: 40) be dissolved in dichloromethane, obtain oil phase.Compound concentration be 5% poly-vinyl alcohol solution 50ml and concentration be 0.5% poly-vinyl alcohol solution 500ml.First being moved into by acetic acid aviptadil solution is dissolved with in the dichloromethane solution of polylactide-co-glycolide, even 30 seconds of (30000rpm) breast is at a high speed placed on emulsion dispersion machine under room temperature, then the w/o type Emulsion of gained being transferred to 50ml concentration is in the poly-vinyl alcohol solution of 5%, be placed on emulsion dispersion machine with the rotating speed of 5000rpm, even 1 minute of breast, obtain W/O/W type emulsion, move in the poly-vinyl alcohol solution of 500ml0.5%, be placed on mechanical agitator, with the rotating speed stirring at low speed 2 hours of 500rpm, centrifugal, collect thus obtained microsphere, repeatedly wash with distilled water, and then collected by centrifugation, lyophilization and get final product, thus obtained microsphere particle diameter is 30-80 μm, mean diameter is 50 μm.
The medicine carrying acetic acid aviptadil sustained-release micro-spheres 4.5mg that precision takes embodiment 3 preparation is dissolved in 1mL dichloromethane, gradation adds 4mL and 2mL double distilled water and extracts medicine, vortex extraction 1min, the centrifugal 3min of 15000rpm, draw and merge supernatant, pipette supernatant 0.5mL and be settled to 10mL with double distilled water, sample introduction 20 μ l, HPLC measures content, drawing standard curve, calculate the medicine carrying acetic acid aviptadil sustained-release micro-spheres drug content of embodiment 3 preparation according to standard curve, calculated yield and envelop rate drug loading are 62.8% and 69.7% respectively accordingly.
Embodiment 4
Carry out tablets in vitro investigation to the Aviptadil acetate sustained-release microsphere preparation prepared embodiment 1,2,3 respectively, method is as follows:
The accurate acetic acid aviptadil sustained-release micro-spheres taking some parts of embodiments 1,2,3 and prepare respectively, every part of 5mg, is placed in the cillin bottle of 35 10mL, every part of Na added containing 0.1M
2hPO
4with the NaH of 0.1M
2pO
4the phosphate buffer solution of pH7.4, be placed in 37 DEG C of waters bath with thermostatic control, respectively the 0th, 1, 4, 8, 12, 16, 20, 24, 28, within 35 days, take out, centrifugal, again acetate dichloromethane buffer (1: 1v/v) is dispersed in, chromatographic column is C18 50 × 2mm, mobile phase be 1: 1 containing 0.1% trifluoracetic acid with containing 1% trifluoroacetic 50% acetonitrile mixed solution, flow velocity 1.0ml/min, detect at 240nm place, measure remaining dose in microsphere, accumulative releasing degree is calculated according to external standard method, embodiment 1, 2, the tablets in vitro measurement result of the Aviptadil acetate sustained-release microsphere preparation of 3 preparations is as shown in table 1:
The tablets in vitro experimental result of Aviptadil acetate sustained-release microsphere preparation prepared by table 1 embodiment 1,2,3
Take drug release time as abscissa, accumulative releasing degree is vertical coordinate, draws Aviptadil acetate sustained-release microsphere preparation tablets in vitro curve prepared by embodiment 1,2,3, the results are shown in Figure of description 1,2,3.
Claims (7)
1. an Aviptadil acetate sustained-release microsphere preparation, it is characterized in that: the acetic acid aviptadil sustained-release micro-spheres in described preparation is containing the acetic acid aviptadil accounting for microspheres weight 0.01%-30% (w/w), the molecular weight accounting for microspheres weight 70%-99.99% is 5, 000-100, the 000 daltonian biodegradable and macromolecular material polylactide-Acetic acid, hydroxy-, bimol. cyclic ester of tool biocompatibility, and account for other adjuvants pharmaceutically acceptable of microspheres weight 0%-10%, the preparation method of described sustained release microsphere agents is: adopt emulsion-intra-liquid desiccation method, prepare microsphere in two steps, the first step, first acetic acid aviptadil is dissolved in aqueous gelatin solution or glycerol, obtain drug solution, for interior aqueous phase, separately polylactide-Acetic acid, hydroxy-, bimol. cyclic ester is dissolved in organic solvent, obtains oil phase, be placed in agitator by oil phase and interior aqueous phase, breast is even at a high speed, forms W/O emulsion, then join in polyvinyl alcohol water solution by W/O emulsion, breast is even at a high speed, forms W/O/W emulsion, second step, W/O/W emulsion is moved in polyvinyl alcohol water solution, stirring at low speed, centrifugal, collect thus obtained microsphere, with distilled water wash repeatedly after, collected by centrifugation again, lyophilization, obtains acetic acid aviptadil sustained-release micro-spheres, described sustained-release micro-spheres size is 1-100 μm, and mean diameter is 5-50 μm.
2. Aviptadil acetate sustained-release microsphere preparation according to claim 1, it is characterized in that: the molecular weight ranges of described polylactide-Acetic acid, hydroxy-, bimol. cyclic ester is 5,000-20,000 dalton, in polylactide-Acetic acid, hydroxy-, bimol. cyclic ester, the proportion of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 25:75-75:25.
3. Aviptadil acetate sustained-release microsphere preparation according to claim 2, is characterized in that: described lactide and the preferred 50:50 of the ratio of Acetic acid, hydroxy-, bimol. cyclic ester.
4. Aviptadil acetate sustained-release microsphere preparation according to claim 1, is characterized in that: the amount ranges of polyvinyl alcohol is 0.1%-5%.
5. the preparation method of Aviptadil acetate sustained-release microsphere preparation according to claim 1, is characterized in that adopting emulsion-intra-liquid desiccation method, prepares microsphere in two steps:
The first step, is first dissolved in acetic acid aviptadil in aqueous gelatin solution or glycerol, obtains drug solution, is interior aqueous phase; Separately polylactide-Acetic acid, hydroxy-, bimol. cyclic ester is dissolved in organic solvent, obtains oil phase; Be placed in agitator by oil phase and interior aqueous phase, breast is even at a high speed, forms W/O emulsion; Then join in polyvinyl alcohol water solution by W/O emulsion, breast is even at a high speed, forms W/O/W emulsion;
Second step, moves into W/O/W emulsion in polyvinyl alcohol water solution, stirring at low speed, centrifugal, collects thus obtained microsphere, with distilled water wash repeatedly after, then collected by centrifugation, lyophilization, obtains acetic acid aviptadil sustained-release micro-spheres.
6. the preparation method of Aviptadil acetate sustained-release microsphere preparation according to claim 5, is characterized in that: described organic solvent is selected from dichloromethane, chloroform, ethyl acetate, ether, acetone, dioxane or oxolane.
7. the preparation method of Aviptadil acetate sustained-release microsphere preparation according to claim 5, is characterized in that: the preferred dichloromethane of organic solvent.
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| US7456254B2 (en) * | 2004-04-15 | 2008-11-25 | Alkermes, Inc. | Polymer-based sustained release device |
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