CN102836131A - Sustained release microsphere preparation for hypodermic injection of buprenorphine and preparation method thereof - Google Patents
Sustained release microsphere preparation for hypodermic injection of buprenorphine and preparation method thereof Download PDFInfo
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- CN102836131A CN102836131A CN2012103703917A CN201210370391A CN102836131A CN 102836131 A CN102836131 A CN 102836131A CN 2012103703917 A CN2012103703917 A CN 2012103703917A CN 201210370391 A CN201210370391 A CN 201210370391A CN 102836131 A CN102836131 A CN 102836131A
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- buprenorphine
- sustained release
- subcutaneous injection
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- release microsphere
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Abstract
The invention discloses a sustained release microsphere preparation for hypodermic injection of buprenorphine and a preparation method thereof. The sustained release microsphere preparation comprises 0.01-1 percent by mass of buprenorphine and 50-99.99 percent by mass of biodegradable medicinal high polymer material counted by the weight of microspheres. The sustained release microsphere preparation can be prepared by adopting a multi-emulsion method, a water-free method, a low-temperature spray extraction method, a method for preparing into nanoparticles and coating into a microsphere preparation, a phase agglomeration method and the like. The sustained release microsphere preparation can be released continuously for about 15 days, 30 days or 60 days in vitro, and can be released continuously for at least 30 days in a rat; and due to the adoption of the sustained release microsphere preparation, the administration times are reduced, the bioavailability is enhanced, the toxic and side effects on a whole body are reduced, and the compliance of a patient is improved.
Description
Technical field
The present invention relates to the buprenorphine sustained release microsphere agents, be specifically related to the buprenorphine subcutaneous injection with sustained release microsphere agents and preparation method thereof.
Background technology
At present, the preparation of buprenorphine has injection, sublingual lozenge etc., and these preparations are because elimination is very fast in vivo, so the medication number of times is frequent, and are poor for the patient's who receives ailing cancer patient who torments or postoperative pain for a long time toleration.It is that carrier material prepares microsphere that present technique adopts polyethylene glycol-lactic acid or polyethylene glycol-poly lactic coglycolic acid, has reached the purpose of its slow release release, has reduced the medication number of times, has increased patient's toleration.
Summary of the invention
The objective of the invention is for overcoming the deficiency of above-mentioned prior art, provide a kind of buprenorphine subcutaneous injection to use sustained release microsphere agents.
For realizing above-mentioned purpose, the present invention adopts following technical proposals:
The buprenorphine subcutaneous injection is used sustained release microsphere agents; It comprises in microsphere weight; Mass fraction be buprenorphine and the mass fraction of 0.01-1% be 50-99.99% can biodegradable pharmaceutical polymers, the particle diameter of said microsphere is between 10-150 μ m.
Buprenorphine subcutaneous injection of the present invention with sustained release microsphere agents through any preparation in the following method:
(1) multi-emulsion method: with buprenorphine dissolving or be suspended in the aqueous solution that contains nonionic emulsifier; Join in the organic solutions such as the dichloromethane that contains said pharmaceutical polymers or acetonitrile; After treatment, join the outer aqueous phase that contains nonionic emulsifier again and form microsphere.
(2) no water law: buprenorphine is joined in the organic solution that contains medicinal macromolecular material, behind ultrasonic suspendible, join in Oleum Gossypii semen or the Semen sojae atricolor wet goods oil phase, the extraction of decentralized photos such as water makes it be solidified into microsphere.
Preferably, the microsphere that curing is obtained adds light petroleum ether, makes its completion of cure.
(3) cold nebulization extraction method: buprenorphine is joined in the organic solutions such as the acetonitrile that contains medicinal macromolecular material or dichloromethane, form droplet through spraying, freezing in liquid nitrogen, make with low temperature organic cosolvent extracting dissolve polymer.
(4) phase coacervation: buprenorphine is joined in the organic solution that contains medicinal macromolecular material, in solution, add flocculating agent again, messenger drug reduces with the macromolecular material dissolubility and separates out, and forms microsphere.
Said pharmaceutical polymers is a Polyethylene Glycol 2,000-10,000-polylactic acid-glycolic guanidine-acetic acid copolymer or Polyethylene Glycol 2; 000-10,000-polylactic acid 10,000-50; 000, wherein the mass ratio of lactic acid and hydroxyacetic acid is 10:90-90:10 in the polylactic acid-glycolic guanidine-acetic acid copolymer.
The mass ratio of buprenorphine and polyethylene glycol-lactic-co-glycolic acid or polyethylene glycol-lactic acid is 1:50-100.
The molecular weight of said polyethylene glycol-lactic acid is 10000-50000, and the molecular weight of polyethylene glycol-lactic-co-glycolic acid is 10000-50000.
Subcutaneous injection of the present invention also comprises surfactants such as emulsifying agent with sustained release microsphere agents.
Described surfactant is selected from poloxamer, lecithin, Polyethylene Glycol 2,000 or Polyethylene Glycol 5,000, aminoacid etc.
The invention has the beneficial effects as follows; It is carrier material that sustained release microsphere agents of the present invention adopts degradable pharmaceutical polymers polyethylene glycol-lactic acid or polyethylene glycol-poly lactic coglycolic acid, and about 15 days, 30 days or 60 days, sustainable release is at least 30 days in the rat body in external sustainable release; Reduced the medication number of times; Improve bioavailability, reduced systemic toxic side effect, increased patient's compliance.
Description of drawings
Fig. 1 is the particle size distribution figure of buprenorphine subcutaneous injection with sustained release microsphere agents;
Fig. 2 is the release in vitro curve of embodiment 1 gained buprenorphine subcutaneous injection with sustained release microsphere agents;
Fig. 3 is average blood drug level and a time curve behind the rat skin lower injection buprenorphine sustained-release micro-spheres.
The specific embodiment
Below in conjunction with accompanying drawing and embodiment the present invention is further set forth, should be noted that following explanation only is in order to explain the present invention, its content not to be limited.
Embodiment 1:
Multi-emulsion method prepares the buprenorphine subcutaneous injection and uses sustained release microsphere agents
The 1mg buprenorphine is dissolved in the gelatin solution that the 0.5mL mass concentration is 20mg/mL, and through 5, the 000rpm rotating speed joins 1.25mL and contains 50mg polyethylene glycol-lactic acid (10 after stirring 30s down; 000-50,000) in the dichloromethane solution, 5, the rotating speed of 000rmp stirs 2min down; Being added to 20mL then contains in the aqueous solution of 50mg Polyethylene Glycol (2,000-10,000); Carry out solvent evaporates with the stirring of 200rpm rotating speed, washing, centrifugal, lyophilization then, collection promptly gets.
Embodiment 2:
Anhydrous legal system is equipped with the buprenorphine subcutaneous injection and uses sustained release microsphere agents
100mg polyethylene glycol-poly lactic coglycolic acid (10,000-50,000) is dissolved in the 2mL dichloromethane; The buprenorphine that adds 1mg then joins in the 20-30mL soybean oil (containing lecithin or poloxamer etc. as emulsifying agent) stirring and emulsifying behind ultrasonic suspendible; Water makes it be solidified into microsphere as decentralized photo extraction dichloromethane; Add light petroleum ether (Tianjin Fu Yu Fine Chemical Co., Ltd, boiling point 60-90 ℃) then, make the microsphere completion of cure.
Embodiment 3:
The cold nebulization extraction method prepares the buprenorphine subcutaneous injection and uses sustained release microsphere agents
The buprenorphine of 1mg joined contain in 100mg polyethylene glycol-poly lactic coglycolic acid (10,000-50, the 000) acetonitrile solution, form droplet through spraying, freezing in liquid nitrogen, make with low temperature organic cosolvent extracting dissolve polymer.
Embodiment 4:
Be rolled into microball prepn again after processing nanoparticle earlier
After adopting natural macromolecular material and emulsion polymerization method to process nano-granule freeze-dried powder the 1mg buprenorphine; Joining 2mL contains in the dichloromethane solution of 100mg polyethylene glycol-lactic acid; After stirring, join in the 15mL water that contains 10mg pluronic F127 (Sigma Chemical Co.); Behind the stirring at low speed 4h, washing, centrifugal, lyophilization promptly get.
Embodiment 5:
The phase coacervation prepares the buprenorphine subcutaneous injection and uses sustained release microsphere agents
The 1mg buprenorphine is joined in the 5ml dichloromethane solution of polyethylene glycol-lactic acid that mass concentration is 100mg/mL, with 2, after the rotating speed of 000rpm stirs 1min; The reduction rotating speed is 200rpm, and adds silicone oil, after being separated; Suspension is changed in the normal hexane of 500mL, after 20 ℃ of rotating speeds with 300rpm of constant temperature stir 30min, collect microsphere; Shared 500mL normal hexane washing several, lyophilization promptly gets.
1, microspherulite diameter is through following measuring:
With the size and the distribution thereof of Beckman particle size determination appearance micrometer ball, observe its particle size distribution situation.
(1) laboratory sample
Microsphere according to the preparation of embodiment of the invention 1-5 method.
(2) experimental apparatus
Beckman particle size determination appearance..
(3) experimental technique
Sample thief is an amount of, is diluted to suitable concentration, with the size and the distribution thereof of Beckman particle size determination appearance micrometer ball, observes its particle size distribution situation, and the result is as shown in Figure 1.
2, microsphere prominent released the mensuration with release profiles:
(1) laboratory sample
Microsphere according to the preparation of embodiment of the invention 1-5 method.
(2) experiment reagent
PH is 7.4 phosphate buffer.
(3) experimental apparatus
Constant-temperature shaking appearance, centrifuge, high phase chromatograph of liquid.
(4) experiment condition
Temperature: 37 ℃, rotating speed: 100rpm.
(5) experimental technique
Getting pastille microsphere 1ml puts in the 10mL centrifuge tube; Add an amount of PH and be 7.4 phosphate buffer; Place the water bath with thermostatic control shaking table; Under 37 ℃, 100rpm hunting speed, carry out the release in vitro degree of microsphere and measure, Fig. 2 is the release in vitro curve of embodiment 1 gained buprenorphine subcutaneous injection with sustained release microsphere agents.
3, microsphere is measured at the intravital sustained release property of rat:
(1) laboratory sample
Microsphere according to the preparation of the embodiment of the invention 1 method.
(2) laboratory animal
Healthy male Wistar rat.
(3) experimental technique
Get healthy male Wistar rat; After the random packet; Subcutaneous injection buprenorphine subcutaneous injection is used sustained-release micro-spheres solution, and 0,1,2,5,8,10,12,15,30,45,60 day eye socket is got blood after administration, and blood sample is through 10; Behind the centrifugal 5min of 000rpm, get supernatant and measure buprenorphine content (Fig. 3) wherein.
Though the above-mentioned accompanying drawing specific embodiments of the invention that combines is described; But be not restriction to protection domain of the present invention; On the basis of technical scheme of the present invention, those skilled in the art need not pay various modifications that creative work can make or distortion still in protection scope of the present invention.
Claims (10)
1. the buprenorphine subcutaneous injection is used sustained release microsphere agents; It is characterized in that; Comprise that in microsphere weight mass fraction is that buprenorphine and the mass fraction of 0.01-1% is that 50-99.99% can biodegradable pharmaceutical polymers, the particle diameter of said microsphere is between 10-150 μ m.
2. buprenorphine subcutaneous injection as claimed in claim 1 is used sustained release microsphere agents, it is characterized in that, said pharmaceutical polymers is a Polyethylene Glycol 2; 000-10,000-polylactic acid-glycolic guanidine-acetic acid copolymer, Polyethylene Glycol 2,000-10; 000-polylactic acid 10; 000-50,000, wherein the mass ratio of lactic acid and hydroxyacetic acid is 10:90-90:10 in the polylactic acid-glycolic guanidine-acetic acid copolymer.
3. buprenorphine subcutaneous injection as claimed in claim 2 is used sustained release microsphere agents, it is characterized in that, the mass ratio of buprenorphine and polyethylene glycol-lactic-co-glycolic acid or polyethylene glycol-lactic acid is 1:50-100.
4. buprenorphine subcutaneous injection as claimed in claim 2 is used sustained release microsphere agents, it is characterized in that, the molecular weight of said polyethylene glycol-lactic acid is 10000-50000, and the molecular weight of polyethylene glycol-lactic-co-glycolic acid is 10000-50000.
5. buprenorphine subcutaneous injection as claimed in claim 1 is used sustained release microsphere agents; It is characterized in that, also comprise surfactant, said surfactant is poloxamer, lecithin, Polyethylene Glycol 2; 000 or Polyethylene Glycol 5,000, amino acid whose wherein one or both.
6. method for preparing the buprenorphine subcutaneous injection of claim 1 with sustained release microsphere agents; It is characterized in that; With buprenorphine dissolving or be suspended in the aqueous solution that contains nonionic emulsifier; Join in the organic solution that contains said pharmaceutical polymers, after treatment, join the outer aqueous phase that contains nonionic emulsifier again and form microsphere.
7. method for preparing the buprenorphine subcutaneous injection of claim 1 with sustained release microsphere agents; It is characterized in that; Buprenorphine is joined in the organic solution that contains medicinal macromolecular material, behind ultrasonic suspendible, join in the oil phase, make it be solidified into microsphere with the decentralized photo extraction.
8. a kind of method for preparing the buprenorphine subcutaneous injection of claim 1 with sustained release microsphere agents as claimed in claim 7 is characterized in that, said curing thus obtained microsphere is added light petroleum ether, makes the microsphere completion of cure.
9. method for preparing the buprenorphine subcutaneous injection of claim 1 with sustained release microsphere agents; It is characterized in that; Buprenorphine is joined in the organic solution that contains medicinal macromolecular material; Form droplet through spraying, freezing in liquid nitrogen, make with low temperature organic cosolvent extracting dissolve polymer.
10. method for preparing the buprenorphine subcutaneous injection of claim 1 with sustained release microsphere agents; It is characterized in that, buprenorphine is joined in the organic solution that contains medicinal macromolecular material, in solution, add flocculating agent again; Messenger drug reduces with the macromolecular material dissolubility and separates out, and forms microsphere.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2012103703917A CN102836131A (en) | 2012-09-28 | 2012-09-28 | Sustained release microsphere preparation for hypodermic injection of buprenorphine and preparation method thereof |
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| CN2012103703917A CN102836131A (en) | 2012-09-28 | 2012-09-28 | Sustained release microsphere preparation for hypodermic injection of buprenorphine and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105596298A (en) * | 2015-12-18 | 2016-05-25 | 山东大学 | PEG-PLGA sustained release microsphere with encapsulated buprenorphine and preparation method thereof |
| CN115317453A (en) * | 2022-09-01 | 2022-11-11 | 广东嘉博制药有限公司 | Sustained-release microsphere preparation and preparation method and application thereof |
Citations (4)
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| CN1382051A (en) * | 1999-08-27 | 2002-11-27 | 南方研究所 | Injectable bupernorphine microparticle compositions and their use |
| CN1872063A (en) * | 2005-06-03 | 2006-12-06 | 中国人民解放军军事医学科学院毒物药物研究所 | Microspheres or composition in use for long acting injection of Nalmefene or its salt, and preparation method |
| CN101874782A (en) * | 2009-04-30 | 2010-11-03 | 北京华素制药股份有限公司 | Sustained-release microballoons of dihydroetorphine or salt thereof and injection type prolonged action preparation thereof |
| CN102462680A (en) * | 2010-11-04 | 2012-05-23 | 中国人民解放军军事医学科学院毒物药物研究所 | Long-acting slow release microballoons of thienorphine, and composition and preparation method thereof |
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2012
- 2012-09-28 CN CN2012103703917A patent/CN102836131A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1382051A (en) * | 1999-08-27 | 2002-11-27 | 南方研究所 | Injectable bupernorphine microparticle compositions and their use |
| CN1872063A (en) * | 2005-06-03 | 2006-12-06 | 中国人民解放军军事医学科学院毒物药物研究所 | Microspheres or composition in use for long acting injection of Nalmefene or its salt, and preparation method |
| CN101874782A (en) * | 2009-04-30 | 2010-11-03 | 北京华素制药股份有限公司 | Sustained-release microballoons of dihydroetorphine or salt thereof and injection type prolonged action preparation thereof |
| CN102462680A (en) * | 2010-11-04 | 2012-05-23 | 中国人民解放军军事医学科学院毒物药物研究所 | Long-acting slow release microballoons of thienorphine, and composition and preparation method thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105596298A (en) * | 2015-12-18 | 2016-05-25 | 山东大学 | PEG-PLGA sustained release microsphere with encapsulated buprenorphine and preparation method thereof |
| CN105596298B (en) * | 2015-12-18 | 2018-08-14 | 山东大学 | A kind of PEG-PLGA sustained-release micro-spheres and preparation method thereof containing buprenorphine |
| CN115317453A (en) * | 2022-09-01 | 2022-11-11 | 广东嘉博制药有限公司 | Sustained-release microsphere preparation and preparation method and application thereof |
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Application publication date: 20121226 |