CN110123789A - A kind of PLGA mixture of microspheres and preparation method thereof carrying Risperidone - Google Patents
A kind of PLGA mixture of microspheres and preparation method thereof carrying Risperidone Download PDFInfo
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- CN110123789A CN110123789A CN201810104057.4A CN201810104057A CN110123789A CN 110123789 A CN110123789 A CN 110123789A CN 201810104057 A CN201810104057 A CN 201810104057A CN 110123789 A CN110123789 A CN 110123789A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
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Abstract
The invention discloses a kind of PLGA mixture of microspheres and preparation method thereof for carrying Risperidone, it uses improvement double emulsion-solvent evaporation technique, i.e. on the basis of multi-emulsion method, it is chelated in its kernel by sodium alginate and calcium ion and forms sustained-release gel, it is microsphere supported with PLGA, Risperidone is package object, prepares drug bearing microsphere.Its form rounding, even particle size distribution, average particle size distribution is in 30 microns, and drugloading rate is 30% or more, and for encapsulation rate 50% or so, tablets in vitro meets durative action preparation feature.
Description
Technical field
The present invention relates to a kind of poly lactide-glycolide acid (PLGA) mixture of microspheres and its preparation for carrying Risperidone
Method belongs to biologically active drug controlled release preparation and biological medical polymer material crossing research field.
Background technique
Schizophrenia is being one of most common emotion disturbance of thought disease now, it can enable the cognition of patient
Power is affected, and jeopardizes Mood during everyday life and the behavior of people gradually.Schizophrenia can be divided into positive and negative two classes
Symptom, this is determined by the type of its symptom and the difference of symptomatic reaction severity.Wherein positive symptom normally behaves as
Confusion of thinking and undiscipline are easy vain hope and even hallucinate and conduct disorder and mania etc.；Negative symptoms be then mental depression,
Seriously degenerate to extraneous understanding and its respond, lose sociability etc..Just because of the cause of disease of schizophrenia complexity and
Pathology, so it is the disease of a kind of popularity for all health care systems.
Risperidone (risperidone) is novel atypical antipsychotic agents, negative symptoms and positive disease to mental disease
Shape is effective in cure, and adverse reaction is small, and dosage is small and safety is preferable.From the point of view of form of administration, in addition to its common tablet,
Injection, capsule, suppository, oral administration solution etc., the new formulation of Risperidone such as Transdermal absorption are pasted, agent microparticle, Orally disintegrating
Piece, Risperidone derivative etc. occur in succession.
For the general formulation of Risperidone, it is necessary to adhere to taking medicine daily, and this is for most of mental patient
More difficult.When domestic and foreign scholars prepare the durative action preparation of Risperidone at present, frequently with solvent evaporation method, atomizing freeze drying
Method, phase separation method, spray drying process etc..Commonly used solvent evaporation method, microballoon made from this method are easy to discharge, and are easy
Existing phenomenon of burst release, it is difficult to reach permanently effective therapeutic effect.
Summary of the invention
A kind of PLGA mixture of microspheres carrying Risperidone, by the PLGA complex microsphere of load Risperidone and the PLGA of load Risperidone
General microballoon is obtained by mixing according to different proportion.The PLGA of the PLGA complex microsphere and load Risperidone that carry Risperidone drug is generally micro-
In ball, PLGA is made of in proportion the lactide-glycolide copolymer of different molecular weight；Wherein, lactide-glycolide copolymer
Molecular weight 0.5 ten thousand~5.2 ten thousand or lactide-glycolide copolymer molecular weight 5.2 ten thousand~15.9 ten thousand or lactide-
The molecular weight of glycolide copolymer is 15.9 ten thousand~730,000；The ratio of lactide and glycolide is any in 75/25 and 50/50
It is a kind of；The sealing end of lactide-glycolide copolymer is any one in ester sealing end, terminal hydroxy group and carboxyl end group.
Further preferred scheme, the compound microballoon of PLGA for carrying Risperidone drug and the PLGA for carrying Risperidone are generally micro-
In ball, organic solvent includes methylene chloride, ethyl acetate, chloroform, acetone, dimethyl methyl amine amide, tetrahydrofuran, hexafluoro isopropyl
Alcohol, at least one of benzyl alcohol.
The preparation method for carrying the PLGA complex microsphere of Risperidone, the complex microsphere drug release prepared using this method are flat
Surely, burst release is low, and drug treating time is long, realizes that the technical solution of appeal purpose is as follows:
(1) configuration of oily phase
PLGA and Risperidone are dissolved in organic solvent and form organic phase, the concentration of PLGA is 5%~30% (g/ml), benefit
The concentration for training ketone is 5%~15% (g/ml)；
(2) configuration of inner aqueous phase
Risperidone is suspended in the sodium alginate soln containing stabilizer and forms inner aqueous phase, Risperidone concentration be 0.5%~
5% (g/ml), the concentration of stabilizer are 0.5%~2.5% (g/ml).(3) inner aqueous phase is added under stiring for the preparation of colostrum
Colostrum is formed into oily phase to being slowly added dropwise；
(4) preparation of emulsion
Colostrum is added under stiring in outer aqueous phase 1, emulsion is formed, the outer aqueous phase 1 is the CaCl2 containing emulsifier
Aqueous solution, the concentration of emulsifier are 0.5%~3% (g/ml), and the concentration of CaCl2 is 0.5%~4% (g/ml)；
(5) formation of microballoon
Emulsion solution is transferred in outer aqueous phase 2, after stirring at low speed the lower organic solvent that volatilizees away, after centrifugation, washing
Microballoon is collected, the outer aqueous phase 2 is the CaCl2 aqueous solution containing emulsifier, and the concentration of emulsifier is 0.5%~3% (g/ml),
The concentration of CaCl2 is 0.5%~4% (g/ml)；
(6) it is freeze-dried
The microballoon that will be collected into after being suspended in the solution containing freeze drying protectant and filler, then is freeze-dried,
Obtain the PLGA complex microsphere for being loaded with Risperidone.
Further preferred scheme, it is described carry Risperidone drug the compound microballoon of PLGA preparation method in, in inner aqueous phase
The stabilizer contained is PLURONICS F87, poloxamer188, polysorbas20, Tween 80 or Emulsifier EL-60 and bright
Glue；Its concentration is 0.5%~2.5% (g/ml).
Further preferred scheme, it is described carry Risperidone drug the compound microballoon of PLGA preparation method in, in inner aqueous phase
The sodium alginate concentration contained is 0.5%~2.0% (g/ml).
Further preferred scheme, it is described carry Risperidone drug the compound microballoon of PLGA preparation method in, Risperidone is molten
Solution concentration in organic phase is 5%~30%, and the concentration being suspended in inner aqueous phase is 0.1%~10% (g/ml).
Further preferred scheme, it is described carry Risperidone drug the compound microballoon of PLGA preparation method in, formed just
When newborn, oil is mutually 1:1~1:10 with the volume ratio of inner aqueous phase；Emulsifying rate is 2000~20000rpm, and emulsification times are 1~30
Minute.
Further preferred scheme, it is described carry Risperidone drug the compound microballoon of PLGA preparation method in, 1 He of outer aqueous phase
Outer aqueous phase 2 is the CaCl containing a certain concentration emulsifier2Aqueous solution, emulsifier concentration are 0.1%~5% (g/ml), CaCl2
Concentration be 0.1%~5% (g/ml)；
Further preferred scheme, it is described carry Risperidone drug the compound microballoon of PLGA preparation method in, the cream
Agent is polyvinyl alcohol, polyethylene glycol, gelatin, polysorbas20 and polyvinylpyrrolidone wherein at least one.
Further preferred scheme, it is multiple being formed in the preparation method of the compound microballoon of PLGA for carrying Risperidone drug
When newborn, the volume ratio of colostrum and outer aqueous phase 1 is 1:10~1:50；The mixing speed that emulsion is formed is 1000rpm~2000rpm,
Emulsification times are 1~30 minute.
Further preferred scheme, it is described carry Risperidone drug the compound microballoon of PLGA preparation method in, outer aqueous phase 1 with
The volume ratio of outer aqueous phase 2 is 1:3~1:10；Mixing speed is 200rpm~1000rpm；Centrifugal speed be 1000rpm~
3000rpm；Centrifugation time is 5~10 minutes；Washing times are 2~6 times.
Further preferred scheme, it is described carry Risperidone drug the compound microballoon of PLGA preparation method in, made microballoon
The condition being freeze-dried in freeze drying protectant and filler are as follows: -15 DEG C, 48h；- 25 DEG C, 48h；- 50 DEG C, 48h.
Further preferred scheme, it is described carry Risperidone drug the compound microballoon of PLGA preparation method in, the jelly
Dry protective agent includes glycerol, sucrose, polyvinylpyrrolidone etc.；The filler includes mannitol, lactose, gelatin or chlorination
Sodium etc..
The preparation method of the general microballoon of PLGA of Risperidone is carried, the general microballoon of this method preparation, drug release is very fast, easily
Control can be rapidly reached blood concentration, realize that the technical solution of appeal purpose is as follows:
(1) configuration of oily phase
PLGA and Risperidone are dissolved in organic solvent and form organic phase；
(2) emulsion process
It is mutually added to oily in water phase 1 under stiring
(3) formation of microballoon
Solution water phase 1 after emulsification is transferred in water phase 2, after stirring at low speed the lower organic solvent that volatilizees away, centrifugation,
Microballoon is collected after washing；
(4) it is freeze-dried
It after the microballoon of collection is suspended in the solution containing freeze drying protectant and filler, then is freeze-dried, is obtained
To the general microballoon of PLGA for being loaded with Risperidone.
Further preferred scheme, it is described carry Risperidone drug the general microballoon of PLGA preparation method in, Risperidone dissolution
Concentration is 5%~30% in organic phase.
Further preferred scheme, it is described carry Risperidone drug the general microballoon of PLGA preparation method in, water phase 1 and water phase
2 is, containing a certain concentration emulsifier aqueous solution, emulsifier concentration are 0.1%~5% (g/ml).
Further preferred scheme, it is described carry Risperidone drug the general microballoon of PLGA preparation method in, emulsification when, oil
It is mutually 1:1~1:10 with the volume ratio of water phase 1；Emulsifying rate is 2000~20000rpm, and emulsification times are 1~30 minute.
Further preferred scheme, it is described carry Risperidone drug the general microballoon of PLGA preparation method in, water phase 1 and water phase
2 volume ratio is 1:1~1:20；Mixing speed is 200rpm~1000rpm；Centrifugal speed is 1000rpm~3000rpm；From
The heart time is 5~10 minutes；Washing times are 2~6 times.
Further preferred scheme, it is described carry Risperidone drug the general microballoon of PLGA preparation method in, made microballoon exists
The condition being freeze-dried in freeze drying protectant and filler are as follows: -15 DEG C, 48h；- 25 DEG C, 48h；- 50 DEG C, 48h.
Further preferred scheme, it is described carry Risperidone drug the general microballoon of PLGA preparation method in, the freeze-drying
Protective agent includes glycerol, sucrose, polyvinylpyrrolidone etc.；The filler includes mannitol, lactose, gelatin or sodium chloride
Deng.
PLGA complex microsphere preparation method of the invention is using improvement double emulsion-solvent evaporation technique, by PLGA and Risperidone
It is dissolved in organic solvent and forms organic phase；Risperidone is suspended in the sodium alginate soln containing stabilizer to water in being formed
Phase；Inner aqueous phase is added in organic phase under stiring, stirring and emulsifying is at colostrum (W/O)；Then under agitation by colostrum
It is added in outer aqueous phase 1 (the CaCl2 aqueous solution containing stabilizer), stirring forms emulsion；Emulsion is transferred to outer aqueous phase 2 again
It is stirred at low speed in (the CaCl2 aqueous solution containing stabilizer), so that organic solvent volatilization is complete；Centrifugation, washing, collect microballoon,
Freeze-drying obtains the compound microballoon of PLGA.
The general method for preparing microsphere of PLGA of the invention is to be dissolved PLGA and Risperidone using emulsification-evaporation method
Organic phase is formed in organic solvent；Organic phase is added under stiring in water phase 1, stirring and emulsifying is at emulsion (O/W)；Again will
Emulsion is transferred in water phase 2 and stirs at low speed, so that organic solvent volatilization is complete；Centrifugation, collects microballoon, is freeze-dried at washing
To the general microballoon of PLGA.
The positive effect of the present invention is: it is compound micro- that the present invention uses improvement double emulsion-solvent evaporation technique to prepare load Risperidone
Ball prepares the general microballoon in Risperidone using emulsification-evaporation method.After two kinds of microballoons are mixed in proportion, benefit is obtained
Train ketone mixture of microspheres.Relative to the microballoon that existing emulsification-evaporation method is prepared, load Risperidone of the present invention is micro-
Ball mixture stable preparation process, feasible, microballoon form rounding, surface is smooth, compact structure, good fluidity, size distribution
Uniform, average grain diameter is in 30 microns, and drugloading rate is 20% or more, and encapsulation rate is 50% or so, and tablets in vitro burst release is small,
Release in vitro meets durative action preparation feature.Risperidone drug is made into durative action preparation, the action time of drug can be extended, mentioned
The curative effect of high drug, and facilitate patient medication.
Detailed description of the invention
Fig. 1 stereoscan photograph prepared by the present invention for carrying the compound microballoon of Risperidone PLGA；
Fig. 2 tablets in vitro curve prepared by the present invention for carrying the compound microballoon of Risperidone PLGA；
Fig. 3 release profiles prepared by the present invention for carrying the compound microballoon of Risperidone PLGA and O/W type mixture of microspheres.
Specific implementation method
The invention will be further described for following embodiment, so that those skilled in the art further understands this hair
It is bright, but the invention is not limited in any way.Any modification made within the spirit and principles in the present invention, Yi Jigen are not being departed from
The equivalent replacement or improvement made according to ordinary skill knowledge and customary means should all include in protection model of the invention
In enclosing.
Embodiment one: a kind of PLGA mixture of microspheres carrying Risperidone, by the PLGA complex microsphere and load benefit of load Risperidone
The general microballoon of PLGA of training ketone is obtained by mixing according to different proportion.It carries the compound microballoon of PLGA of Risperidone drug and carries Risperidone
The general microballoon of PLGA in, PLGA is made of in proportion the lactide-glycolide copolymer of different molecular weight；Wherein, lactide-
The molecular weight of glycolide copolymer is 0.5 ten thousand；The ratio of lactide and glycolide is 75/25；Lactide-glycolide copolymer
Sealing end is that ester blocks.
Embodiment two: a kind of PLGA mixture of microspheres carrying Risperidone, by the PLGA complex microsphere and load benefit of load Risperidone
The general microballoon of PLGA of training ketone is obtained by mixing according to different proportion.It carries the compound microballoon of PLGA of Risperidone drug and carries Risperidone
The general microballoon of PLGA in, PLGA is made of in proportion the lactide-glycolide copolymer of different molecular weight；Wherein, lactide-
The molecular weight of glycolide copolymer is 5.2 ten thousand, and the ratio of lactide and glycolide is 50/50；Lactide-glycolide copolymer
Sealing end is terminal hydroxy group.
Embodiment three: a kind of PLGA mixture of microspheres carrying Risperidone, by the PLGA complex microsphere and load benefit of load Risperidone
The general microballoon of PLGA of training ketone is obtained by mixing according to different proportion.It carries the compound microballoon of PLGA of Risperidone drug and carries Risperidone
The general microballoon of PLGA in, PLGA is made of in proportion the lactide-glycolide copolymer of different molecular weight；Wherein, lactide-
The molecular weight of glycolide copolymer is 15.9 ten thousand；The ratio of lactide and glycolide is 75/25；Lactide-glycolide copolymer
Sealing end be carboxyl end group.
Example IV: a kind of PLGA mixture of microspheres carrying Risperidone, by the PLGA complex microsphere and load benefit of load Risperidone
The general microballoon of PLGA of training ketone is obtained by mixing according to different proportion.It carries the compound microballoon of PLGA of Risperidone drug and carries Risperidone
The general microballoon of PLGA in, PLGA is made of in proportion the lactide-glycolide copolymer of different molecular weight；Wherein, lactide-
The molecular weight of glycolide copolymer is 730,000；The ratio of lactide and glycolide is 50/50；Lactide-glycolide copolymer
Sealing end is that ester blocks.
In the PLGA mixture of microspheres for carrying Risperidone, organic solvent includes methylene chloride, ethyl acetate, chloroform, and third
Ketone, dimethyl methyl amine amide, tetrahydrofuran, hexafluoroisopropanol, at least one of benzyl alcohol.
A kind of embodiment five: preparation method for the PLGA complex microsphere carrying Risperidone
(1) configuration of oily phase
Weigh the PLGA (75/25,0.52A) that 320mg molecular weight is 74,000, the PLGA that 80mg molecular weight is 25,000
The Risperidone of the PLGA and 280mg of (50/50,0.25A) are dissolved in 4ml methylene chloride and form organic phase；
(2) configuration of inner aqueous phase
30mg Risperidone, 20mg PLURONICS F87 and 30mg sodium alginate are dissolved in 1ml water and form inner aqueous phase；
(3) preparation of colostrum
It draws inner aqueous phase 1ml to be added under stiring in 4ml organic phase, be formed just in the emulsified 1min of 12000rpm condition
Cream；
(4) preparation of emulsion
200mg polyvinyl alcohol and the anhydrous CaCl2 of 500mg is taken to be dissolved in 20ml water and obtain outer aqueous phase 1；Colostrum 1ml is being stirred
It mixes down and is added in 20ml outer aqueous phase 1, under the conditions of 8000rpm, emulsify 1min, form emulsion；
(5) formation of microballoon
500mg polyvinyl alcohol and the anhydrous CaCl2 of 600mg is taken to be dissolved in 100ml water and obtain outer aqueous phase 2；By 20ml emulsion
Solution is transferred in 100ml outer aqueous phase 2, after the organic solvent that volatilizees away under 400rpm stirring, be centrifuged under the conditions of 2000rpm,
Washing, collects microballoon afterwards repeatedly for three times；
(6) freeze-drying obtains the PLGA complex microsphere for being loaded with Risperidone.
The microballoon that will be obtained after washing is suspended in the aqueous solution containing 2% mannitol, freezes under the conditions of -50 DEG C, 48h
The PLGA complex microsphere that fluffy white powder shape carries Risperidone is obtained after dry.
Embodiment six: carrying the preparation method of the general microballoon of PLGA of Risperidone,
(1) configuration of oily phase
PLGA and Risperidone are dissolved in organic solvent and form organic phase；Concentration is 5%~30% in organic phase；
(2) emulsion process
It is mutually added to oily in water phase 1 under stiring, a certain concentration emulsifier aqueous solution, emulsifier is contained in water phase 1
Concentration is 0.1% (g/ml)；
(3) formation of microballoon
Solution water phase 1 after emulsification is transferred in water phase 2, after stirring at low speed the lower organic solvent that volatilizees away, centrifugation,
Microballoon is collected after washing；Wherein, a certain concentration emulsifier aqueous solution is contained in water phase 2, emulsifier concentration is 0.1% (g/
ml)；
(4) it is freeze-dried
It after the microballoon of collection is suspended in the solution containing freeze drying protectant and filler, then is freeze-dried, is obtained
To the general microballoon of PLGA for being loaded with Risperidone.
In the preparation method of the general microballoon of PLGA of above-mentioned load Risperidone drug, in emulsification, the volume of oil phase and water phase 1
Than for 1:1~1:10；Emulsifying rate is 2000~20000rpm, and emulsification times are 1~30 minute.
Further preferred scheme, it is described carry Risperidone drug the general microballoon of PLGA preparation method in, water phase 1 and water phase
2 volume ratio is 1:1~1:20；Mixing speed is 200rpm~1000rpm；Centrifugal speed is 1000rpm~3000rpm；From
The heart time is 5~10 minutes；Washing times are 2~6 times.
In the preparation method of the general microballoon of PLGA of above-mentioned load Risperidone drug, made microballoon is in freeze drying protectant and filling
The condition being freeze-dried in agent are as follows: -15 DEG C, 48h；- 25 DEG C, 48h；- 50 DEG C, 48h.
Further preferred scheme, it is described carry Risperidone drug the general microballoon of PLGA preparation method in, the freeze-drying
Protective agent includes glycerol, sucrose, polyvinylpyrrolidone etc.；The filler includes mannitol, lactose, gelatin or sodium chloride
Deng.
The present invention is described in further detail for above-mentioned specific embodiment.But it is above-mentioned that this should not be interpreted as to the present invention
The range of theme is only limitted to embodiment below, and all technical solutions implemented based on the content of present invention are each fallen in of the invention
Range.
Claims (24)
1. a kind of PLGA mixture of microspheres for carrying Risperidone, which is characterized in that by the PLGA complex microsphere and load benefit of load Risperidone
The training general microballoon of ketone mixes in proportion.
2. a kind of PLGA mixture of microspheres for carrying Risperidone as described in claim 1, which is characterized in that carry the PLGA of Risperidone
Complex microsphere and the ratio for carrying the general microballoon of PLGA of Risperidone are 10:1~1:10.
3. a kind of PLGA mixture of microspheres for carrying Risperidone as described in claim 1, which is characterized in that carry the PLGA of Risperidone
Complex microsphere and general microballoon are made of the lactide-glycolide copolymer of different molecular weight.
4. a kind of PLGA mixture of microspheres for carrying Risperidone as claimed in claim 3, which is characterized in that uncapped third is handed over
Ester-glycolide copolymer include molecular weight 0.5 ten thousand~5.2 ten thousand lactide-glycolide copolymer or molecular weight 5.2 ten thousand
~15.9 ten thousand lactide-glycolide copolymer or molecular weight in 15.9 ten thousand~730,000 lactide-glycolide copolymer at least
It is a kind of.
5. a kind of PLGA mixture of microspheres for carrying Risperidone as claimed in claim 3, which is characterized in that the lactide-
The ratio of lactide and glycolide is any one in 75/25 and 50/50 in glycolide copolymer.
6. a kind of PLGA mixture of microspheres for carrying Risperidone as claimed in claim 3, which is characterized in that the lactide-
The sealing end of glycolide copolymer is any one in ester sealing end, terminal hydroxy group and carboxyl end group.
7. a kind of PLGA mixture of microspheres for carrying Risperidone as described in claim 1, which is characterized in that the organic solvent
Including methylene chloride, ethyl acetate, chloroform, acetone, dimethyl methyl amine amide, tetrahydrofuran, hexafluoroisopropanol, in benzyl alcohol
It is at least one.
8. a kind of preparation method for the PLGA complex microsphere for carrying Risperidone, which comprises the following steps:
(1) configuration of oily phase
PLGA and Risperidone are dissolved in organic solvent and form organic phase, the concentration of PLGA is 5%~30% (g/ml), Risperidone
Concentration be 5%~15% (g/ml)；
(2) configuration of inner aqueous phase
Risperidone is suspended in the sodium alginate soln containing stabilizer and forms inner aqueous phase, Risperidone concentration is 0.5%~5%
(g/ml), the concentration of stabilizer is 0.5%~2.5% (g/ml), and the concentration of sodium alginate is 0.5%~2.0% (g/ml)；
(3) preparation of colostrum
Inner aqueous phase is added to be slowly added dropwise under stiring and forms colostrum into oily phase；
(4) preparation of emulsion
Colostrum is added under stiring in outer aqueous phase 1, emulsion is formed, the outer aqueous phase 1 is that the CaCl2 containing emulsifier is water-soluble
Liquid, the concentration of emulsifier are 0.5%~3% (g/ml), and the concentration of CaCl2 is 0.5%~4% (g/ml)；
(5) formation of microballoon
Emulsion solution is transferred in outer aqueous phase 2, after stirring at low speed the lower organic solvent that volatilizees away, is collected after centrifugation, washing
Microballoon, the outer aqueous phase 2 are the CaCl2 aqueous solution containing emulsifier, and the concentration of emulsifier is 0.5%~3% (g/ml),
The concentration of CaCl2 is 0.5%~4% (g/ml)；
(6) it is freeze-dried
The microballoon that will be collected into after being suspended in the solution containing freeze drying protectant and filler, then is freeze-dried, is obtained
It is loaded with the PLGA complex microsphere of Risperidone.
9. a kind of preparation method of PLGA complex microsphere for carrying Risperidone as claimed in claim 8, which is characterized in that inner aqueous phase
In the stabilizer that contains be PLURONICS F87, poloxamer188, polysorbas20, Tween 80 or Emulsifier EL-60 and bright
Glue；Its concentration is 0.5%~2.5% (g/ml).
10. a kind of preparation method of PLGA complex microsphere for carrying Risperidone as claimed in claim 8, which is characterized in that interior water
The sodium alginate concentration contained in phase is 0.5%~2.0% (g/ml).
11. a kind of preparation method of PLGA complex microsphere for carrying Risperidone as claimed in claim 8, which is characterized in that Li Pei
It is 5%~30% that ketone, which is dissolved in concentration in organic phase, and the concentration being suspended in inner aqueous phase is 0.1%~10%.
12. a kind of preparation method of PLGA complex microsphere for carrying Risperidone as claimed in claim 8, which is characterized in that step
(3), oil is mutually 1:1~1:10 with the volume ratio of inner aqueous phase；Emulsifying rate is 2000~20000rpm, and emulsification times are 1~30
Minute.
13. a kind of preparation method of PLGA complex microsphere for carrying Risperidone as claimed in claim 8, which is characterized in that outer water
Phase 1 and outer aqueous phase 2 are the CaCl containing a certain concentration emulsifier2Aqueous solution, emulsifier concentration are 0.1%~5% (g/ml),
CaCl2Concentration be 0.1%~5% (g/ml).
14. a kind of preparation method of PLGA complex microsphere for carrying Risperidone as claimed in claim 8, which is characterized in that described
Emulsifier be polyvinyl alcohol, polyethylene glycol, gelatin, polysorbas20 and polyvinylpyrrolidone wherein at least one.
15. a kind of preparation method of PLGA complex microsphere for carrying Risperidone as claimed in claim 8, which is characterized in that in shape
When at emulsion, the volume ratio of colostrum and outer aqueous phase 1 is 1:10~1:50；Emulsion formed mixing speed be 1000rpm~
2000rpm, emulsification times are 1~30 minute.
16. a kind of preparation method of PLGA complex microsphere for carrying Risperidone as claimed in claim 8, which is characterized in that step
(5), the volume ratio of outer aqueous phase 1 and outer aqueous phase 2 is 1:3~1:10；Mixing speed is 200rpm~1000rpm；Centrifugal speed is
1000rpm~3000rpm；Centrifugation time is 5~10 minutes；Washing times are 2~6 times.
17. a kind of preparation method of PLGA complex microsphere for carrying Risperidone as claimed in claim 8, which is characterized in that described
Freeze drying protectant include glycerol, sucrose, polyvinylpyrrolidone etc.；The filler include mannitol, lactose, gelatin or
Sodium chloride etc..
18. a kind of preparation method for the general microballoon of PLGA for carrying Risperidone, which comprises the following steps:
(1) configuration of oily phase
PLGA and Risperidone are dissolved in organic solvent and form organic phase；
(2) emulsion process
It is mutually added to oily in water phase 1 under stiring
(3) formation of microballoon
Solution water phase 1 after emulsification is transferred in water phase 2, after stirring at low speed the lower organic solvent that volatilizees away, centrifugation, washing
After collect microballoon；
(4) it is freeze-dried
It after the microballoon of collection is suspended in the solution containing freeze drying protectant and filler, then is freeze-dried, is carried
There is the general microballoon of the PLGA of Risperidone.
19. a kind of preparation method of general microballoon of PLGA for carrying Risperidone as claimed in claim 18, which is characterized in that PLGA
Concentration in organic phase is 5%~30%.
20. a kind of preparation method of general microballoon of PLGA for carrying Risperidone as claimed in claim 18, which is characterized in that step
(2) in, oil is mutually 1:1~1:10 with the volume ratio of water phase 1；Emulsifying rate is 2000~20000rpm, and emulsification times are 1~30
Minute.
21. a kind of preparation method of general microballoon of PLGA for carrying Risperidone as claimed in claim 18, which is characterized in that described
Water phase 1 and water phase 2 are containing a certain concentration emulsifier aqueous solution, and emulsifier concentration is 0.1%~5% (g/ml).
22. a kind of preparation method of general microballoon of PLGA for carrying Risperidone as claimed in claim 18, which is characterized in that step
(3), the volume ratio of water phase 1 and water phase 2 is 1:1~1:20；Mixing speed is 200rpm~1000rpm；Centrifugal speed is
1000rpm~3000rpm；Centrifugation time is 5~10 minutes；Washing times are 2~6 times.
23. a kind of preparation method of general microballoon of PLGA for carrying Risperidone as claimed in claim 18, which is characterized in that made
The condition that microballoon is freeze-dried in freeze drying protectant and filler are as follows: -15 DEG C, 48h；- 25 DEG C, 48h；- 50 DEG C, 48h.
24. a kind of preparation method of general microballoon of PLGA for carrying Risperidone as claimed in claim 18, which is characterized in that described
Freeze drying protectant include glycerol, sucrose, polyvinylpyrrolidone etc.；The filler include mannitol, lactose, gelatin or
Sodium chloride etc..
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4233844A4 (en) * | 2020-11-09 | 2023-10-25 | Shenzhen Sciencare Pharmaceutical Co., Ltd. | SUSTAINED RELEASE COMPOSITION FROM A NALTREXONE AND RISPERIDONE COMBINATION |
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| CN106794147A (en) * | 2014-07-28 | 2017-05-31 | Sk化学株式会社 | There is comprising Leuprorelin and simultaneously the pharmaceutical composition of release and sustained release property immediately |
| CN106963746A (en) * | 2017-03-17 | 2017-07-21 | 广州帝奇医药技术有限公司 | A kind of shipwreck is molten/microsolubility pharmaceutical sustained release compositions |
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| US4897268A (en) * | 1987-08-03 | 1990-01-30 | Southern Research Institute | Drug delivery system and method of making the same |
| CN102727899A (en) * | 2012-04-20 | 2012-10-17 | 中山大学附属第三医院 | Protein-medicament-carrying PLGA composite microspheres and preparation method thereof |
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| EP4233844A4 (en) * | 2020-11-09 | 2023-10-25 | Shenzhen Sciencare Pharmaceutical Co., Ltd. | SUSTAINED RELEASE COMPOSITION FROM A NALTREXONE AND RISPERIDONE COMBINATION |
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