CN101357120A - Water-soluble drug sustained release microsphere agents and preparation method thereof - Google Patents
Water-soluble drug sustained release microsphere agents and preparation method thereof Download PDFInfo
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- CN101357120A CN101357120A CNA2008101209076A CN200810120907A CN101357120A CN 101357120 A CN101357120 A CN 101357120A CN A2008101209076 A CNA2008101209076 A CN A2008101209076A CN 200810120907 A CN200810120907 A CN 200810120907A CN 101357120 A CN101357120 A CN 101357120A
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Abstract
The invention discloses a preparation method of a hydrophilic medicine controlled-release microspheres formulation, which comprises the following steps: 1) hydrophilic medicine and lactic acid-glycolic acid copolymer are added into organic solvent and blended, then oil phase is obtained; 2) the oil phase is added into aqueous phase outside for emulsion; 3) the organic solvent is removed from the matter obtained from the step 2), and then the matter obtained is filtered/centrifugated, washed, frozen and dried to obtain microspheres. The invention also simultaneously discloses the hydrophilic medicine controlled-release microspheres formulation. The hydrophilic medicine controlled-release microspheres formulation obtained by adopting the method of the invention is characterized by high medicine loading, high encapsulation efficiency, slow and continuous release, etc.
Description
Technical field
The present invention relates to the pharmaceutics field, relate in particular to a kind of water-soluble drug sustained release microsphere agents and preparation method thereof.
Background technology
Lactic acid-hydroxyacetic acid copolymer (PLGA) is the high-molecular copolymer that is polymerized under the effect of catalyst by lactide (LA) and two kinds of monomers of Acetic acid, hydroxy-, bimol. cyclic ester (GA).PLGA has favorable biological degradability and biocompatibility, can be degraded into lactic acid, water and carbon dioxide in vivo, participates in intravital metabolism, can not cause any toxic reaction in vivo.The biomedical tissue engineering be can be widely used in, suture material, the fixing tissue renovation material etc. that reaches of orthopaedics absorbed as controlled drug delivery system, organism.This material can be used for the device of slow releasing pharmaceutical carrier and the implantation of other human bodies by drugs approved by FDA.Medicine through the PLGA embedding, is made sustained-release micro-spheres, can improve the bioavailability of medicine, reduce administration number of times and dose, alleviate patient's misery, reduce medicine to greatest extent the whole body toxic and side effects of liver, kidney particularly.
Summary of the invention
The technical problem to be solved in the present invention provides the preparation method of the easy water-soluble drug sustained release microsphere agents of a kind of preparation technology, adopts the water-soluble drug sustained release microsphere agents of this method preparation to have drug loading height, envelop rate height, discharges the characteristics such as slow that continue.
In order to solve the problems of the technologies described above, the invention provides a kind of preparation method of water-soluble drug sustained release microsphere agents, may further comprise the steps:
1), hydrophilic medicament and lactic acid-hydroxyacetic acid copolymer are added in the organic solvent, mix, oil phase;
2), above-mentioned oil phase is joined outside aqueous phase emulsifying, the amount ratio of hydrophilic medicament and outside water is: 5～50mg/100ml, and the amount ratio of lactic acid-hydroxyacetic acid copolymer and outside water is: 50～400mg/100ml; Described outside aqueous phase contains the emulsifying agent of 0.1～3% weight ratio and the penetrating agent of 0.1～2% weight ratio, and all the other are water;
3), with step 2) gains remove organic solvent, filter again/centrifugal, washing and lyophilization, microsphere.
Above-mentioned removal organic solvent can adopt modes such as conventional extraction or volatilization.
Improvement as the preparation method of water-soluble drug sustained release microsphere agents of the present invention: earlier lactic acid-hydroxyacetic acid copolymer is dissolved in the organic solvent, mixed liquor; Again hydrophilic medicament is added in the above-mentioned mixed liquor, carry out probe type ultrasonic then, in 50～400w ultrasonic 60～120 seconds, obtain to be the oil phase of suspension.
Further improvement as the preparation method of water-soluble drug sustained release microsphere agents of the present invention: hydrophilic medicament is the spacetabs type hydrophilic medicament, for example is beta-lactam class antibiotic, macrolide antibiotics, aminoglycoside antibiotics, polypeptide class or protide or the like.
Beta-lactam class antibiotic can be selected benzylpenicillin, amoxicillin, ampicillin, mezlocillin, cefalexin, cefalotin, cefazolin sodium, cefaclor, Cefuroxime Sodium, cefoxitin, ceftriaxone, cefotaxime, cefepime, cefpirome, meropenem, faropenem, aztreonam etc. for use.
Macrolide antibiotics can be selected erythromycin, midecamycin, spiramycin, acetylspiramycin, josamycin, kitasamycin, azithromycin, clarithromycin, Roxithromycin etc. for use.
Aminoglycoside antibiotics can be selected streptomycin, neomycin, paromomycin, kanamycin, dibekacin, amikacin, ribostamycin, gentamycin, sisomicin, netilmicin, micronomicin etc. for use.
Polypeptide drug can select for use thyroliberin, vassopressin, oxytocin, gastrin, thyrotrophin-releasing hormone, new deltorphin delta, paddy to take off sweet peptide, calcitonin, a1 thymosin etc.
Protein medicaments can be selected interferon, insulin human, erythropoietin, interleukin, human growth hormone etc. for use.
Further improvement as the preparation method of water-soluble drug sustained release microsphere agents of the present invention: emulsifying agent is sodium lauryl sulphate (SDS) or polyvinyl alcohol (PVA); Penetrating agent is a sodium chloride.
Further improvement as the preparation method of water-soluble drug sustained release microsphere agents of the present invention: the mass ratio of polylactic acid/glycolic is 50/50～90/10 in the lactic acid-hydroxyacetic acid copolymer, and molecular weight is 0.5～300,000.
Further improvement as the preparation method of water-soluble drug sustained release microsphere agents of the present invention: the volume ratio of organic solvent and outside water is 1: 20～1: 400, and organic solvent is dichloromethane, ethyl acetate, acetonitrile or the like.
Further improvement as the preparation method of water-soluble drug sustained release microsphere agents of the present invention: the microsphere particle diameter is 0.1～100 μ m.
Further improvement as the preparation method of water-soluble drug sustained release microsphere agents of the present invention: the amount ratio of hydrophilic medicament and outside water is: 12.5mg/100ml, and the amount ratio of lactic acid-hydroxyacetic acid copolymer and outside water is: 50mg/100ml; Outside aqueous phase contains the emulsifying agent of 2% weight ratio.
The present invention also provides the water-soluble drug sustained release microsphere agents for preparing according to the method described above and get simultaneously.
In the preparation method of water-soluble drug sustained release microsphere agents of the present invention, used PLGA, PLGA can form the skeleton of microsphere, slow hydrolysis takes place in the diffusion along with hydrone in aqueous medium, when framework material corrosion during until disintegrate, medicine just is released in the medium and goes, and therefore has the performance of certain control drug release.
In preparation method of the present invention, also used emulsifying agent and penetrating agent, the use of emulsifying agent can prevent microsphere in the balling-up process, stick together and can suppress medicine diffuse into outside water, thereby effectively improve the drug loading and the envelop rate of microsphere.Experiment can obviously improve the common burst effect of microsphere after showing the use penetrating agent, thereby reduces drug waste and side effect.
Water-soluble drug sustained release microsphere agents of the present invention, microspherulite diameter is evenly distributed, and the outward appearance rounding is smooth, has significantly improved envelop rate and drug loading to water soluble drug, and drug release is continued slowly.Under normal conditions, some the micromolecule hydrophilic medicament PLGA microsphere drug loading for preparing when the existing method of employing only is 1%; And the PLGA microsphere drug loading of the medicine of the same race that employing the inventive method makes can reach 10%, has significantly improved the encapsulation efficiency of microsphere.Use the PLGA of different lactic acid and glycolic ratio, can control the lasting release of microsphere Chinese medicine and not wait in 30 to 120 days.
In clinical treatment, must reach certain blood drug level ability onset after the administration, because existing micromolecule hydrophilic medicament PLGA microsphere drug loading is low, and the PLGA microsphere has the feature that can not discharge medicine fully under some situation, so often can not keep permanently effective therapeutic effect or be unsuitable for commercial production because of the cost problem.And the water-soluble drug sustained release microsphere agents drug loading height that adopts the inventive method to make, the shortcoming of PLGA microsphere in the time of can overcoming parcel micromolecule hydrophilic medicament of the prior art.
Description of drawings
Below in conjunction with accompanying drawing the specific embodiment of the present invention is described in further detail.
Fig. 1 is the sem photograph of embodiment 1 thus obtained microsphere preparation;
Fig. 2 is the sem photograph of embodiment 6 thus obtained microsphere preparations;
Fig. 3 is the medicine cumulative in vitro release profiles of embodiment 6 thus obtained microsphere preparations.
The specific embodiment
The present invention is further elaborated by following embodiment.Unless otherwise indicated, described percentage ratio is by total amount.
The preparation method of embodiment 1, a kind of water-soluble drug sustained release microsphere agents, carry out following steps successively:
Take by weighing PLGA (polylactic acid/glycolic mass ratio 85/15) 100mg and be dissolved in the 2ml dichloromethane, get mixed liquor; Again the 25mg cefradine is added in the above-mentioned mixed liquor,, obtain to be the oil phase of suspension in 200w probe type ultrasonic 90s.
Then above-mentioned oil phase is poured into the newborn at a high speed even 1min of outside aqueous phase 10000rpm of 200ml rapidly; This outside aqueous phase contains the PVA of 2% weight ratio and the Nacl of 0.5% weight ratio, and all the other are water.
After above-mentioned emulsifying finishes, room temperature rotary evaporation 40min, centrifugal 2000rpm 10min, the distillation washing repeats twice postlyophilization of this centrifuge washing process, gets microsphere.
The mean diameter of the water-soluble drug sustained release microsphere agents of gained is 29.8 μ m, and theoretical drug loading is 20%, and actual drug loading is 60 μ g/mg, and envelop rate is 30%, and the time of sustainable release is 35d.
The preparation method of embodiment 2, a kind of water-soluble drug sustained release microsphere agents, carry out following steps successively:
Take by weighing PLGA (polylactic acid/glycolic=85/15) 100mg and be dissolved in the 2ml dichloromethane, get mixed liquor; Again the 15mg gentamycin is added in the above-mentioned mixed liquor,, obtain to be the oil phase of suspension in 200w probe type ultrasonic 90s.
Then above-mentioned oil phase is poured into the newborn at a high speed even 1min of outside aqueous phase 10000rpm of 200ml rapidly; This outside aqueous phase contains the PVA of 2% weight ratio and the Nacl of 0.5% weight ratio, and all the other are water.
After above-mentioned emulsifying finishes, room temperature rotary evaporation 40min, centrifugal 2000rpm 10min, the distillation washing repeats twice postlyophilization of this centrifuge washing process, gets microsphere.
The mean diameter of the water-soluble drug sustained release microsphere agents of gained is 25.3 μ m, and theoretical drug loading is 13%, and actual drug loading is 40 μ g/mg, and envelop rate is 31%, and the time of sustainable release is 38d.
The preparation method of embodiment 3, a kind of water-soluble drug sustained release microsphere agents, carry out following steps successively:
Take by weighing PLGA (polylactic acid/glycolic=50/50) 100mg and be dissolved in the 2ml dichloromethane, get mixed liquor; Again 25mg erythromycin is added in the above-mentioned mixed liquor,, obtain to be the oil phase of suspension in 200w probe type ultrasonic 90s.
Then above-mentioned oil phase is poured into the newborn at a high speed even 1min of outside aqueous phase 10000rpm of 100ml rapidly; This outside aqueous phase contains the PVA of 2% weight ratio and the Nacl of 0.5% weight ratio, and all the other are water.
After above-mentioned emulsifying finishes, room temperature rotary evaporation 40min, centrifugal 2000rpm 10min, the distillation washing repeats twice postlyophilization of this centrifuge washing process, gets microsphere.
The mean diameter of the water-soluble drug sustained release microsphere agents of gained is 30 μ m, and theoretical drug loading is 20%, and actual drug loading is 56 μ g/mg, and envelop rate is 28%, and the time of sustainable release is 34 days.
The preparation method of embodiment 4, a kind of water-soluble drug sustained release microsphere agents, carry out following steps successively:
Take by weighing PLGA (polylactic acid/glycolic=85/15) 100mg and be dissolved in the 2ml dichloromethane, get mixed liquor; Again the 25mg kanamycin is added in the above-mentioned mixed liquor,, obtain to be the oil phase of suspension in 200w probe type ultrasonic 90s.
Then above-mentioned oil phase is poured into the newborn at a high speed even 1min of outside aqueous phase 10000rpm of 200ml rapidly; This outside aqueous phase contains the SDS of 2% weight ratio and the Nacl of 0.2% weight ratio, and all the other are water.
After above-mentioned emulsifying finishes, room temperature rotary evaporation 40min, centrifugal 2000rpm 10min, the distillation washing repeats twice postlyophilization of this centrifuge washing process, gets microsphere.
The mean diameter of the water-soluble drug sustained release microsphere agents of gained is 36.2 μ m, and theoretical drug loading is 20%, and actual drug loading is 96 μ g/mg, and envelop rate is 48%, and the time of sustainable release is 45d.
The preparation method of embodiment 5, a kind of water-soluble drug sustained release microsphere agents, carry out following steps successively:
Take by weighing PLGA (polylactic acid/glycolic=85/15) 100mg and be dissolved in the 2ml dichloromethane, get mixed liquor; Again the 25mg benzylpenicillin is added in the above-mentioned mixed liquor,, obtain to be the oil phase of suspension in 200w probe type ultrasonic 90s.
Then above-mentioned oil phase is poured into the newborn at a high speed even 1min of outside aqueous phase 10000rpm of 200ml rapidly; This outside aqueous phase contains the SDS of 2% weight ratio and the Nacl of 0.2% weight ratio, and all the other are water.
After above-mentioned emulsifying finishes, room temperature magnetic agitation 2h, centrifugal 2000rpm 10min, the distillation washing repeats twice postlyophilization of this centrifuge washing process, gets microsphere.
The mean diameter of the water-soluble drug sustained release microsphere agents of gained is 33.5 μ m, and theoretical drug loading is 20%, and actual drug loading is 70 μ g/mg, and envelop rate is 35%, and the time of sustainable release is 50d.
The preparation method of embodiment 6, a kind of water-soluble drug sustained release microsphere agents, carry out following steps successively:
Take by weighing PLGA (polylactic acid/glycolic=85/15) 100mg and be dissolved in the 2ml dichloromethane, get mixed liquor; Again the 25mg meropenem is added in the above-mentioned mixed liquor,, obtain to be the oil phase of suspension in 200w probe type ultrasonic 90s.
Then above-mentioned oil phase is poured into the newborn at a high speed even 1min of outside aqueous phase 8000rpm of 200ml rapidly; This outside aqueous phase contains the SDS of 2% weight ratio and the Nacl of 0.2% weight ratio, and all the other are water.
After above-mentioned emulsifying finishes, room temperature rotary evaporation 40min, centrifugal 2000rpm 10min, the distillation washing repeats twice postlyophilization of this centrifuge washing process, gets microsphere.
The mean diameter of the water-soluble drug sustained release microsphere agents of gained is 5.9 μ m, and theoretical drug loading is 20%, and actual drug loading is 88 μ g/mg, and envelop rate is 44%, and the time of sustainable release is 60 days.
The preparation method of embodiment 7, a kind of water-soluble drug sustained release microsphere agents, carry out following steps successively:
Take by weighing PLGA (polylactic acid/glycolic=85/15) 100mg and be dissolved in the 2ml dichloromethane, get mixed liquor; Again the 25mg interferon is added in the above-mentioned mixed liquor,, obtain to be the oil phase of suspension in 200w probe type ultrasonic 90s.
Then above-mentioned oil phase is poured into the newborn at a high speed even 1min of outside aqueous phase 8000rpm of 200ml rapidly; This outside aqueous phase contains the SDS of 3% weight ratio and the Nacl of 0.2% weight ratio, and all the other are water.
After above-mentioned emulsifying finishes, room temperature rotary evaporation 40min, centrifugal 2000rpm 10min, the distillation washing repeats twice postlyophilization of this centrifuge washing process, gets microsphere.
The mean diameter of the water-soluble drug sustained release microsphere agents of gained is 35 μ m, and theoretical drug loading is 20%, and actual drug loading is 15 μ g/mg, and envelop rate is 75%, and the time of sustainable release is 50d.
The preparation method of embodiment 8, a kind of water-soluble drug sustained release microsphere agents, carry out following steps successively:
Take by weighing PLGA (polylactic acid/glycolic=70/30) 300mg and be dissolved in the 2.5ml ethyl acetate, get mixed liquor; Again the 50mg spiramycin is added in the above-mentioned mixed liquor,, obtain to be the oil phase of suspension in 100w probe type ultrasonic 120s.
Then above-mentioned oil phase is poured into the newborn at a high speed even 1min of outside aqueous phase 10000rpm of 100ml rapidly; This outside aqueous phase contains the PVA of 0.5% weight ratio and the Nacl of 2% weight ratio, and all the other are water.
After above-mentioned emulsifying finishes, room temperature rotary evaporation 40min, centrifugal 2000rpm 10min, the distillation washing repeats twice postlyophilization of this centrifuge washing process, gets microsphere.
The mean diameter of the water-soluble drug sustained release microsphere agents of gained is 28 μ m, and theoretical drug loading is 14.3%, and actual drug loading is 7.8 μ g/mg, and envelop rate is 54.5%, and the time of sustainable release is 45d.
In order to prove superiority of the present invention, the inventor has made following reference examples:
Take by weighing PLGA (polylactic acid/glycolic=85/15) 100mg and be dissolved in the 2ml dichloromethane, cefazolin sodium is received 25mg and is dissolved in the 0.2ml distilled water, above-mentioned biphasely mix in 200w probe type ultrasonic 90s; Pour into rapidly then PVA that 200ml contains 2% weight ratio, 0.5% weight ratio Nacl, all the other are the outside aqueous phase of water, 10000rpm is the even 1min of breast at a high speed, rotary evaporation 40min, centrifugal 3000rpm 10min, the distillation washing repeats twice postlyophilization of this centrifuge washing process.
The preparation mean diameter of gained is 34.6 μ m, and theoretical drug loading is 20%, and actual drug loading is 3%, and envelop rate is 15%, and the time of sustainable release is 16 days.
At last, it is also to be noted that what more than enumerate only is several specific embodiments of the present invention.Obviously, the invention is not restricted to above embodiment, many distortion can also be arranged.All distortion that those of ordinary skill in the art can directly derive or associate from content disclosed by the invention all should be thought protection scope of the present invention.
Claims (10)
1, a kind of preparation method of water-soluble drug sustained release microsphere agents is characterized in that may further comprise the steps:
1), hydrophilic medicament and lactic acid-hydroxyacetic acid copolymer are added in the organic solvent, mix, oil phase;
2), above-mentioned oil phase is joined outside aqueous phase emulsifying, the amount ratio of hydrophilic medicament and outside water is: 5～50mg/100ml, and the amount ratio of lactic acid-hydroxyacetic acid copolymer and outside water is: 50～400mg/100ml; Described outside aqueous phase contains the emulsifying agent of 0.1～3% weight ratio and the penetrating agent of 0.1～2% weight ratio, and all the other are water;
3), with step 2) gains remove organic solvent, filter again/centrifugal, washing and lyophilization, microsphere.
2, the preparation method of water-soluble drug sustained release microsphere agents according to claim 1 is characterized in that: earlier lactic acid-hydroxyacetic acid copolymer is dissolved in the organic solvent, gets mixed liquor; Again hydrophilic medicament is added in the above-mentioned mixed liquor, carry out probe type ultrasonic then, in 50～400w ultrasonic 60～120 seconds, obtain to be the oil phase of suspension.
3, the preparation method of water-soluble drug sustained release microsphere agents according to claim 1 and 2 is characterized in that: described hydrophilic medicament is the spacetabs type hydrophilic medicament.
4, the preparation method of water-soluble drug sustained release microsphere agents according to claim 3 is characterized in that: described spacetabs type hydrophilic medicament is beta-lactam class antibiotic, macrolide antibiotics, aminoglycoside antibiotics, polypeptide class or protide.
5, the preparation method of water-soluble drug sustained release microsphere agents according to claim 4 is characterized in that: described emulsifying agent is sodium lauryl sulphate or polyvinyl alcohol; Described penetrating agent is a sodium chloride.
6, the preparation method of water-soluble drug sustained release microsphere agents according to claim 5 is characterized in that: the mass ratio of polylactic acid and glycolic is 50/50～90/10 in the described lactic acid-hydroxyacetic acid copolymer.
7, the preparation method of water-soluble drug sustained release microsphere agents according to claim 6 is characterized in that: the volume ratio of described organic solvent and outside water is 1: 20～1: 400; Described organic solvent is at least a in dichloromethane, ethyl acetate and the acetonitrile.
8, the preparation method of water-soluble drug sustained release microsphere agents according to claim 7 is characterized in that: described microsphere particle diameter is 0.1～100 μ m.
9, the preparation method of water-soluble drug sustained release microsphere agents according to claim 8, it is characterized in that: the amount ratio of described hydrophilic medicament and outside water is: 12.5mg/100ml, the amount ratio of lactic acid-hydroxyacetic acid copolymer and outside water are 50mg/100ml; Described outside aqueous phase contains the emulsifying agent of 2% weight ratio.
10, the water-soluble drug sustained release microsphere agents that gets as any one method preparation in the claim 1～9.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102114003A (en) * | 2011-02-24 | 2011-07-06 | 浙江大学 | Sustained-release pellet of hydroxysafflor yellow A as well as preparation method and applications thereof |
| CN106984247A (en) * | 2017-05-11 | 2017-07-28 | 青岛大学 | A kind of preparation method for the polymer microcapsule for carrying hydrophilic material |
| CN109453137A (en) * | 2018-12-07 | 2019-03-12 | 上海交通大学 | A kind of red blood cell living carries the sustained release preparation and the preparation method and application thereof of betamethasone sodium phosphate |
| CN109966174A (en) * | 2017-12-25 | 2019-07-05 | 万华化学集团股份有限公司 | A kind of preparation method and applications of capsules disperse body |
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2008
- 2008-09-04 CN CNA2008101209076A patent/CN101357120A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102114003A (en) * | 2011-02-24 | 2011-07-06 | 浙江大学 | Sustained-release pellet of hydroxysafflor yellow A as well as preparation method and applications thereof |
| CN102114003B (en) * | 2011-02-24 | 2012-05-09 | 浙江大学 | Sustained-release pellet of hydroxysafflor yellow A as well as preparation method and applications thereof |
| CN106984247A (en) * | 2017-05-11 | 2017-07-28 | 青岛大学 | A kind of preparation method for the polymer microcapsule for carrying hydrophilic material |
| CN106984247B (en) * | 2017-05-11 | 2019-11-12 | 青岛大学 | A kind of preparation method for the polymer microcapsule carrying hydrophilic material |
| CN109966174A (en) * | 2017-12-25 | 2019-07-05 | 万华化学集团股份有限公司 | A kind of preparation method and applications of capsules disperse body |
| CN109966174B (en) * | 2017-12-25 | 2022-04-22 | 万华化学集团股份有限公司 | Preparation method and application of capsule dispersion |
| CN109453137A (en) * | 2018-12-07 | 2019-03-12 | 上海交通大学 | A kind of red blood cell living carries the sustained release preparation and the preparation method and application thereof of betamethasone sodium phosphate |
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Open date: 20090204 |