CN106822043A - risperidone slow-release composition and preparation method thereof - Google Patents
risperidone slow-release composition and preparation method thereof Download PDFInfo
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- CN106822043A CN106822043A CN201710052706.6A CN201710052706A CN106822043A CN 106822043 A CN106822043 A CN 106822043A CN 201710052706 A CN201710052706 A CN 201710052706A CN 106822043 A CN106822043 A CN 106822043A
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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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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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
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5123—Organic compounds, e.g. fats, sugars
-
- 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
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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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
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
-
- 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
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
- A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
Abstract
The present invention discloses a kind of risperidone slow-release composition and preparation method thereof, the non-solvent preparing raw material of risperidone slow-release composition of the present invention includes Risperidone, slightly water-soluble polymer and release regulator, and the release regulator includes organic lipophilicity substance and organic hydrophilicity material.The preparing raw material of risperidone slow-release composition of the invention, add release regulator, the release regulator can effectively adjust rate of release of the Risperidone in the slow releasing composition, so that without obvious phase hangover or phenomenon of burst release after risperidone slow-release composition administration of the invention, with good sustained release performance, and can within several weeks or longer time maintaining treatment blood concentration, and with preferable stability, still be able to maintain its release behavior after long-time is stored.
Description
Technical field
The present invention relates to a kind of slow releasing composition and preparation method thereof, especially a kind of risperidone slow-release composition and its system
Preparation Method.
Background technology
In recent ten years, biodegradable polymer microballoon has turned into one of important research field of novel Drug Delivery Systems,
The delivery system can be as by microballoons obtained in framework material such as PLA (PLA), poly lactic coglycolic acids (PLGA)
The carrier of durative action preparation, can be administered to human body or animal with muscle or hypodermic mode, can limit drug releasing rate
And deenergized period, only can for a long time maintain effective medicine concentration with single administration, can minimization treatment needed for
The total dosage of medicine, it is possible to increase the compliance of drug therapy of patient.
Depot antipsychotics Risperidal Consta based on technological development disclosed in patent CN1137756 are (permanent
Moral) with the PLGA of molecular weight about 150kDa as carrier, Risperidone is API, every intramuscular injection in 2 weeks is once.Said preparation is prevented effectively from
The peak valley concentration that medication is produced daily, but only have a small amount of insoluble drug release in the first day, then there is the insoluble drug release up to about 3 weeks
Deadtime, thus 3 weeks after the microballoon is injected of patient it is interior also need to be can be only achieved by oral administration general formulation control curative effect
Really, Clinical practice is inconvenient, and patient compliance is poor.
There is researcher to think, due to Risperidone be shipwreck it is molten/microsolubility medicine, when microballoon drugloading rate is relatively low, initial drug
Release is little, causes medicine blood concentration the release deadtime of certain hour occur, and with the raising of drugloading rate, insoluble drug release stops
Demurrage progressively reduces, and when drugloading rate reaches certain limit, has insoluble drug release after administration.As patent CN101653422 is disclosed
A kind of Risperidone microsphere composition that can discharge several weeks, drug release deadtime is eliminated by improving carrying drug ratio (more than 45%),
But preparation stability is poor, after storing for a long time, the internal release behavior of microballoon can occur significant change.
Also there is researcher to think, during with PLGA as carrier, the ratio of hydrophobic components (LA) and hydrophilic component (GA) and
Release of the molecular size range to water soluble drug has significant impact, PLGA hydrophilic component ratios (such as LA higher:GA=50:
50), molecular weight is smaller, and drug-eluting is faster, is substantially shorter release deadtime.If patent CN 103338752 is with two kinds of differences
Molecular weight and monomer ratio (55-110kDa, LA:GA=65:35~90:10 and 4-35kDa, LA:GA=50:50~75:25)
PLGA mixture (weight ratio be 70~90:10~30) micro- into the Risperidone for discharging immediately in vivo as carrier preparation
Ball.However, this combination of polymers easily causes surface during radiation sterilization collapse, because different monomers ratio and molecular weight
PLGA palliating degradation degree is different under the radiation；Furthermore, because molecular weight is relatively low and GA monomer ratios PLGA higher was being stored
It is easier to degrade in journey, is unfavorable for the storage stability of preparation；Meanwhile, molecular weight is relatively low and GA component ratios are higher
The preparation of PLGA auxiliary materials, storage difficulty are larger, and cost is of a relatively high.
The content of the invention
Nothing substantially release after a kind of administration is provided it is an object of the invention to overcome above-mentioned the deficiencies in the prior art part
Period of delay or phenomenon of burst release, can within several weeks or longer time maintaining treatment blood concentration, with good release performance
With the risperidone slow-release composition of preferable stability.Meanwhile, another object of the present invention is to provide the risperidone slow-release
The preparation method of composition.
To achieve the above object, the technical scheme taken of the present invention is：A kind of risperidone slow-release composition, the Risperidone
The non-solvent preparing raw material of slow releasing composition includes Risperidone, slightly water-soluble polymer and release regulator, and the release is adjusted
Section agent is organic hydrophilicity material by organic hydrophilicity material and organic lipophilic material composition or the release regulator.This
The preparing raw material of invention risperidone slow-release composition includes non-solvent preparing raw material and solvent-borne type preparing raw material.Wherein, it is described
Non-solvent preparing raw material includes Risperidone, slightly water-soluble polymer and release regulator, not including surfactant；It is described molten
Formulation preparing raw material includes aqueous medium and organic solvent.
Contain release regulator in the non-solvent preparing raw material of risperidone slow-release composition of the present invention, and it is described
Release regulator includes organic lipophilicity substance and organic hydrophilicity material.The organic lipophilic material can finally turn in vivo
Carbon dioxide and water are turned to, microsphere surface and the internal permeability for producing duct, increasing body fluid can be made, promote the molten of Risperidone
Go out.The organic hydrophilicity material can also make microsphere surface and the trickle duct of internal generation, and these ducts can increase microballoon
The permeability of body fluid after being injected in vivo, promotes the dissolution of Risperidone, release deadtime is greatly shortened or avoid, while also promoting
The transfer of microballoon inside catabolite is entered.
Therefore, risperidone slow-release composition of the present invention, by organic lipophilic material and organic hydrophilicity material
The effect of release regulator, can not only avoid initial burst phenomenon, and Risperidone can be avoided poor and poly- because of water solubility
Sustained release platform when adduct molecule amount is larger and after the release of the first day of appearance, maintains effective blood drug concentration, also solves with height
The problem of the sustained release of the long period sustained-release micro-spheres that molecular weight and LA component ratios PLGA high are prepared as carrier.
As the preferred embodiment of risperidone slow-release composition of the present invention, the risperidone slow-release composition it is non-
In solvent-borne type preparing raw material, the weight/mass percentage composition of release regulator is 0.1~10%；Preferably, the risperidone slow-release group
In the non-solvent preparing raw material of compound, the weight/mass percentage composition of release regulator is 0.5~8%；Preferably, the Risperidone
In the non-solvent preparing raw material of slow releasing composition, the weight/mass percentage composition of release regulator is 1~6%.
Used as the preferred embodiment of risperidone slow-release composition of the present invention, the release regulator is by organic lipophilic
When property material and organic hydrophilicity material composition, quality percentage of the organic hydrophilicity material in the release regulator contains
Measure is more than 30%；Preferably, weight/mass percentage composition of the organic hydrophilicity material in the release regulator is 50%
More than；Preferably, weight/mass percentage composition of the organic hydrophilicity material in the release regulator is more than 70%.
Used as the preferred embodiment of risperidone slow-release composition of the present invention, the organic lipophilic material is fat
At least one in acid, fatty acid ester, grease；The organic hydrophilicity material is alcohol, sugar, amino acid, albumen, polyvinyl pyrrole
At least one in alkanone.As the more preferably implementation method of risperidone slow-release composition of the present invention, the organic lipophilic
Property material be aliphatic acid；The organic hydrophilicity material is at least one in alcohols, polyvinylpyrrolidone.
As the preferred embodiment of risperidone slow-release composition of the present invention, the aliphatic acid be oleic acid, stearic acid,
At least one in laurate, myristic acid, palmitic acid, arachidic acid, mountain Yu acid, lignin acid；The alcohol is for molecular weight
The polyethylene glycol of 400-6000Da.The aliphatic acid is preferably but not limited to C12~C24 alkanoic acids and its derivative, including but does not limit
In oleic acid, stearic acid, laurate, myristic acid, palmitic acid, arachidic acid, mountain Yu acid, preferably lignin acid, stearic acid, mountain Yu
Acid.The alcohols be preferably but not limited to molecular weight be 600-6000Da polyethylene glycol (PEG), such as PEG600, PEG1000,
PEG2000, PEG4000, PEG6000, preferred molecular weight are the polyethylene glycol (PEG) of 400~4000Da, and more preferably molecular weight is
The PEG of 400~3000Da.
As the preferred embodiment of risperidone slow-release composition of the present invention, the risperidone slow-release composition it is non-
In solvent-borne type preparing raw material, the weight/mass percentage composition of the Risperidone is 25~60%, the quality of the slightly water-soluble polymer
Percentage composition is 39.9-74.9%；Preferably, in the non-solvent preparing raw material of the risperidone slow-release composition, the profit
The weight/mass percentage composition for training ketone is 30~55%, and the weight/mass percentage composition of the slightly water-soluble polymer is 44.9-69.9%；It is excellent
Selection of land, in the non-solvent preparing raw material of the risperidone slow-release composition, the weight/mass percentage composition of the Risperidone for 35~
50%, the weight/mass percentage composition of the slightly water-soluble polymer is 49.9-64.9%.
Used as the preferred embodiment of risperidone slow-release composition of the present invention, the slightly water-soluble polymer is poly-
At least one in ester, makrolon, polyacetals, polyanhydride, poly-hydroxy fatty acid, their copolymer or blend.
Used as the preferred embodiment of risperidone slow-release composition of the present invention, the slightly water-soluble polymer is poly- third
Lactide (PLA), PGA (PGA), PLGA (PLGA), polycaprolactone (PCL), they and poly- second two
Alcohol copolymer (such as PLA-PEG, PLGA-PEG, PLGA-PEG-PLGA, PLA-PEG-PLA, PEG-PCL, PCL-PEG-PCL,
PEG-PLA-PEG, PEG-PLGA-PEG), poly butyric, poly- hydroxypentanoic acid, PPDO (PPDO), shitosan,
In alginic acid and its salt, polybutylcyanoacrylate, condensing model, poe, polyamide, polyphosphazene, polyphosphate at least one
Kind.
Used as the preferred embodiment of risperidone slow-release composition of the present invention, the slightly water-soluble polymer is poly- third
At least one in lactide (PLA), PLGA (PLGA), their copolymers with polyethylene glycol.As this
The preferred embodiment of the risperidone slow-release composition is invented, the slightly water-soluble polymer is polylactide (PLA), the third friendship
At least one in ester-glycolide copolymer (PLGA).
Used as the preferred embodiment of risperidone slow-release composition of the present invention, the slightly water-soluble polymer is poly- third
It is described during at least one in lactide (PLA), PLGA (PLGA), their copolymers with polyethylene glycol
Polylactide (PLA), PLGA (PLGA), they are equal with the weight average molecular weight of the copolymer of polyethylene glycol
It is 20000-100000Da.Preferably, the polylactide (PLA), PLGA (PLGA), they with it is poly-
The weight average molecular weight of the copolymer of ethylene glycol is 25000-90000Da.It is highly preferred that the polylactide (PLA), the third friendship
Ester-glycolide copolymer (PLGA), the weight average molecular weight of their copolymers with polyethylene glycol are 25000-80000Da.
Used as the preferred embodiment of risperidone slow-release composition of the present invention, the slightly water-soluble polymer is poly- third
It is described during at least one in lactide (PLA), PLGA (PLGA), their copolymers with polyethylene glycol
Polylactide (PLA), PLGA (PLGA), the viscosity of their copolymers with polyethylene glycol are 0.25-
(test condition is~0.5% (w/v), CHCl to 0.80dL/g3, 25 DEG C).Preferably, the polylactide (PLA), lactide-
Glycolide copolymer (PLGA), the viscosity of their copolymers with polyethylene glycol be 0.30-0.70dL/g (test condition for~
0.5% (w/v), CHCl3, 25 DEG C).It is highly preferred that the polylactide (PLA), PLGA (PLGA),
They are 0.30-0.65dL/g with the viscosity of the copolymer of polyethylene glycol, and (test condition is~0.5% (w/v), CHCl3, 25
℃)。
As the preferred embodiment of risperidone slow-release composition of the present invention, the molecule of the slightly water-soluble polymer
Chain carries anion or cation group, or does not carry anion or cation group.Preferably, the slightly water-soluble polymerization
Thing has end carboxyl or end ester group.It is highly preferred that the slightly water-soluble polymer has end carboxyl.
Used as the preferred embodiment of risperidone slow-release composition of the present invention, the slightly water-soluble polymer is poly- third
It is therein during at least one in lactide (PLA), PLGA (PLGA), its copolymer with polyethylene glycol
Lactide is 100 with the mol ratio of glycolide:0~65:35.Preferably, it is described can slightly water-soluble polymer be polylactide
(PLA), during at least one in PLGA (PLGA), its copolymer with polyethylene glycol, therein third hands over
Ester is 100 with the mol ratio of glycolide:0~70:30.It is highly preferred that the slightly water-soluble polymer be polylactide (PLA),
During at least one in PLGA (PLGA), its copolymer with polyethylene glycol, lactide therein and second
The mol ratio of lactide is 100:0~75:25.
In risperidone slow-release composition of the present invention, the slightly water-soluble polymer is biodegradable, bio-compatible water
Slightly solubility polymer.The slightly water-soluble polymer can be single polymer, or the mixture of multiple polymers.
Such as, lactide and glycolide mole when molecular weight is identical but carries the combination of group different PLGA and/or PLA；Lactide
From the combination for mole when carrying group is identical but molecular weight is different PLGA and/or PLA of glycolide, and molecular weight difference is not
More than 20kDa；The group of molecular weight and the carrying PLGA that group is identical but lactide is different from the mol ratio of glycolide and/or PLA
Close, and the percentage difference of glycolide is not more than 20%；The mol ratio of molecular weight, carrying group and lactide and glycolide is not
The combination of same PLGA and/or PLA, and molecular weight difference is not more than 20kDa, the percentage difference of glycolide is not more than 20%.
Molecular weight described above is weight average molecular weight, is measured by gel permeation chromatograph (GPC) and is obtained
Value；The viscosity is that Ubbelohde viscometer measures obtained value.
Used as the preferred embodiment of risperidone slow-release composition of the present invention, the non-solvent preparing raw material is also wrapped
Containing excipient, weight/mass percentage composition of the excipient in the non-solvent preparing raw material is 0~8%.Profit of the invention
In training ketone slow releasing composition, one or more excipient can also be included.Excipient can assign active medicine or micro-
Grain further feature, for example, increase the stability of particulate, active medicine or carrier, promote active medicine from the realizing controlled-release in particulate
Put or adjust the permeability of the biological organization of active medicine.Heretofore described excipient is including but not limited to anti-oxidant
Agent, buffer etc..
Used as the preferred embodiment of risperidone slow-release composition of the present invention, the excipient includes buffer and resists
Oxidant；
The buffer is at least one in organic acid, inorganic acid salt, and the buffer is in the risperidone slow-release group
Weight/mass percentage composition in the non-solvent preparing raw material of compound is 0~5%；Preferably, the buffer is in the Risperidone
Weight/mass percentage composition in the non-solvent preparing raw material of slow releasing composition is 0~3%；Preferably, the buffer is described
Weight/mass percentage composition in the non-solvent preparing raw material of risperidone slow-release composition is 0~2%；
The antioxidant is butylated hydroxyarisol, dibutylphenol, tocopherol, isopropyl myristate, d-a
Tocopherol acetate, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisol, butylatedhydroxyquinone, hydroxyl tonka-bean
Element, Yoshinox BHT, amass wealth by heavy taxation sour fatty acid ester, the third hydroxybenzoate, trihydroxybutyrophenone, vitamin E, vitamin E-
At least one in TPGS, ρ-hydroxybenzoate；Non-solvent of the antioxidant in the risperidone slow-release composition
Weight/mass percentage composition in preparing raw material is 0~1%；Preferably, the antioxidant is in the risperidone slow-release composition
Weight/mass percentage composition in non-solvent preparing raw material is 0~0.08%；Preferably, the antioxidant is slow in the Risperidone
It is 0~0.05% to release the weight/mass percentage composition in the non-solvent preparing raw material of composition.
It is described to amass wealth by heavy taxation sour fatty acid ester selected from such as ethyl ester, propyl ester, monooctyl ester, lauryl in the selection of the antioxidant, it is described
ρ-hydroxybenzoate is selected from such as methyl esters, ethyl ester, propyl ester, butyl ester.The antioxidant is produced with effectively removing in implant
Raw any free radical or the amount of peroxide are present in slow releasing composition.
Buffer of the present invention includes but is not limited to inorganic acid and acylate, such as carbonic acid, acetic acid, oxalic acid, citric acid,
The salt of phosphoric acid, hydrochloric acid, including calcium carbonate, calcium hydroxide, Pork and beans fringed pink acid calcium, calcium oleate, calcium palmitate, calcium stearate, calcium phosphate,
Calcium acetate, magnesium acetate, magnesium carbonate, magnesium hydroxide, magnesium phosphate, magnesium myristate, magnesium oleate, magnesium palmitate, magnesium stearate, carbonic acid
Zinc, zinc hydroxide, zinc oxide, Pork and beans fringed pink acid zinc, zinc oleate, zinc acetate, zinc chloride, zinc sulfate, zinc hydrogen sulfate, zinc carbonate, nitre
Sour zinc, zinc gluconate, zinc palmitate, zinc stearate, trbasic zinc phosphate, sodium carbonate, sodium acid carbonate, sodium hydrogensulfite, thiosulfuric acid
Sodium, Acetic acid-sodium acetate buffer salt, and combinations thereof.It is preferred that the zinc salt of inorganic acid and organic acid.
The excipient is added in interior oil phase.When the excipient is imperceptible powder, its particle diameter is less than 0.5 μ
M, preferably particle diameter are less than 0.1 μm, and more preferably particle diameter is less than 0.05 μm.In the excipient solvent and interior oil phase or with minimum
Grain is suspended in interior oil phase.
Used as the preferred embodiment of risperidone slow-release composition of the present invention, the risperidone slow-release composition is micro-
Ball or particulate.When the risperidone slow-release composition is microballoon, microballoon is generally used for drug administration by injection, and particulate or microballoon can be by
It is drawn into syringe, and is injected by thin pin.Preferably, route of delivery is injected using fine needle, including subcutaneous, flesh
Meat, intraocular etc..Pin at least 20G bores (580 μm of internal diameter) are meaned by thin pin, typically at about 22G (410 μm of internal diameter)
Between about 30G (150 μm of internal diameter), or more than 30G.Advantageously using thin at least syringe needle of 24G, it is more advantageous to thin
To at least syringe needle of 26G.
Used as the preferred embodiment of risperidone slow-release composition of the present invention, the geometry particle diameter of the microballoon is less than
200μm.Typically, the particle diameter of the microballoon is about 10~200 μm, preferably 15~150 μm, more preferably from about 20~120 μm.
Microspherulite diameter size is surveyed by dynamic light scattering method (such as laser diffractometry) or microtechnic (such as ESEM method)
Amount.
In addition, the present invention also provides a kind of preparation side that can be simply efficiently prepared above-mentioned risperidone slow-release composition
Method, in order to achieve this, the technical scheme that this hair is taken is：A kind of preparation method of risperidone slow-release composition as described above,
Comprise the following steps：
Be dissolved in the non-solvent preparing raw material in organic solvent by (1a), forms interior oil phase；
Surfactant is dissolved in aqueous medium by (2a), forms outer water phase；
Be added to the interior oil phase that step (1a) is obtained in outer water phase by (3a), is made emulsion, then by solvent evaporate or
Solvent extraction makes microsphere hardening, the collection particulate in solution, washs and dries, and obtains risperidone slow-release microsphere；
Or
Be dissolved in for remaining each material in addition to release regulator contained by the non-solvent preparing raw material organic molten by (1b)
In agent, interior oil phase is formed；
Release regulator and surfactant are dissolved in aqueous medium by (2b), form outer water phase；
Be added to the interior oil phase that step (1b) is obtained in outer water phase by (3b), is made emulsion, then by solvent evaporate or
Solvent extraction makes microsphere hardening, the collection particulate in solution, washs and dries, and obtains risperidone slow-release microsphere.
As the preferred embodiment of the preparation method of risperidone slow-release composition of the present invention, the step (1a) and
Slightly water-soluble polymer and the mass percent of organic solvent are 1~18% in (1b)；It is described in the step (2a) and (2b)
Weight/mass percentage composition of the surfactant in outer water phase is 0.1~10%；In the step (3a) and (3b), the outer water phase
Volume be more than 60 times of the interior oil phase volume.As risperidone slow-release composition of the present invention preparation method more
Preferred embodiment, in the step (1a) and (1b) mass percent of slightly water-soluble polymer and organic solvent for 1.5~
12%；In the step (2a) and (2b), weight/mass percentage composition of the surfactant in outer water phase is 0.5~8%；Institute
State in step (3a) and (3b), the volume of the outer water phase is more than 80 times of the interior oil phase volume.As of the present invention
The more preferably implementation method of the preparation method of risperidone slow-release composition, slightly water-soluble polymer in the step (1a) and (1b)
It is 3~10% with the mass percent of organic solvent；In the step (2a) and (2b), the surfactant is in outer water phase
Weight/mass percentage composition be 1~7%；In the step (3a) and (3b), the volume of the outer water phase is the interior oil phase volume
More than 100 times.
Type, the Weight-average molecular of slightly water-soluble polymer weight/mass percentage composition foundation polymer in organic solvent
The type of amount and organic solvent and change, usual its weight/mass percentage composition (slightly water-soluble of biodegradable and bio-compatible
Polymer quality/organic solvent quality × 100%) is 1~18%.
As the preferred embodiment of the preparation method of risperidone slow-release composition of the present invention, the step (1a) and
Organic solvent in (1b) is at least one in halogenated hydrocarbons, fatty acid ester, aromatic hydrocarbon；The halogenated hydrocarbons comprising dichloromethane,
Chloroform, chloroethanes, tetrachloro-ethylene, trichloro ethylene, dichloroethanes, trichloroethanes, carbon tetrachloride, fluorohydrocarbon, chlorobenzene, trichlorine fluorine first
Alkane；The fatty acid ester includes ethyl acetate, butyl acetate；The aromatic hydrocarbon includes benzene,toluene,xylene, phenmethylol.
The organic solvent can simultaneously dissolve slightly water-soluble polymer and Risperidone, boiling point less than water and insoluble in or it is difficult
Water is dissolved in, the organic solvent can be single organic solvent, or two kinds miscible and the organic solvent of the above.Institute
State organic solvent and be selected from halogenated hydrocarbons (such as dichloromethane, chloroform, chloroethanes, tetrachloro-ethylene, trichloro ethylene, dichloroethanes, three chloroethenes
Alkane, carbon tetrachloride, fluorohydrocarbon, chlorobenzene (single, double, triple substitution), Arcton 11 etc.), fatty acid ester (such as ethyl acetate, acetic acid
Butyl ester etc.), aromatic hydrocarbon (such as benzene,toluene,xylene, phenmethylol), preferably halogenated aliphatic hydro carbons solvent, more preferably dichloromethane
Alkane, chloroform.To press different pharmaceutical different for the ratio of organic solvent in the mixture, is allocated according to actual conditions.
As the preferred embodiment of the preparation method of risperidone slow-release composition of the present invention, the surfactant
It is anion surfactant, cationic surfactant, zwitterionic surfactant, nonionic surfactant, surface
At least one in active biomolecule；The cationic surfactant includes BZK, cetyltrimethylammonium base
Ammonium, bay acidic group dimethyl benzyl oronain, acylcarnitines hydrochloride, alky pyridinium halides；The anionic surface is lived
Property agent include alkyl sulfate, potassium laurate, mosanom, Sodium Polyacrylate and its derivative, alkyl Pluronic F-127 sulfuric ester,
Dioctyl sodium sulfosuccinate, phosphatide, glyceride, sodium carboxymethylcellulose, enuatrol, odium stearate, cholic acid and other bile
The sodium salt of acid；The nonionic surfactant includes polyoxyethylene aliphatic alcohol ether, polysorbate, polyoxyethylene fatty acid
Ester, castor oil derivatives, polyoxyethylene polypropylene glycol copolymers, sucrose fatty ester, cithrol,
Polyoxyethylene sorbitol acid anhydride mono fatty acid ester, polyoxyethylene sorbitol acid anhydride di fatty acid ester, polyoxyethylene glycerol monoester fat
Acid esters, polyoxyethylene glycerol di fatty acid ester, polyglyceryl fatty acid ester, polypropylene glycol monoesters, aryl burn base Aethoxy Sklerol, polyoxy second
Alkene-poiyoxypropylene copolymer, polyvinyl alcohol and its derivative, polyvinylpyrrolidone and polysaccharide；The Surface active biological point
Attached bag includes polyaminoacid, peptide, protein.
The surfactant (or stabilizer) can increase the wetting properties of organic phase, improve small liquid pearl in emulsion process
Stability and shape, it is to avoid small liquid pearl regroups, it is non-encapsulated to reduce or the quantity of the small spherical particles of part encapsulating so that
Reduce initial burst of the medicine during release.
The surfactant (or stabilizer) is anion surfactant, cationic surfactant, amphion
Live on surfactant, nonionic surfactant or compound as Surface active biological molecule, preferred anionic surface
Property agent, nonionic surfactant (or stabilizer) or Surface active biological molecule, more preferably nonionic surfactant
(or stabilizer) or Surface active biological molecule.
The cationic surfactant includes but is not limited to quaternary ammonium compound such as benzalkonium chloride, cetyltrimethylammonium
Base ammonium, bay acidic group dimethyl benzyl oronain, acylcarnitines hydrochloride or alky pyridinium halides.
The anion surfactant includes but is not limited to lauryl sodium sulfate, ammonium lauryl sulfate, octadecane
The alkyl sulfates such as base sodium sulphate, potassium laurate, mosanom, Sodium Polyacrylate and its derivative, alkyl Pluronic F-127 sulfuric acid
Ester, dioctyl sodium sulfosuccinate, phosphatide, glyceride, sodium carboxymethylcellulose, enuatrol, odium stearate, cholic acid and other courages
The sodium salt of juice acid (such as cholic acid, deoxycholic acid, glycocholic acid, taurocholate, glycodesoxycholic acid).
The nonionic surfactant includes but is not limited to polyoxyethylene aliphatic alcohol ether (Brij), polysorbate
(such as Tween 80, polysorbate60), polyoxyethylene fatty acid ester (OEO), castor oil derivatives, polyoxyethylene polypropylene glycol
Copolymer, sucrose fatty ester, cithrol, polyoxyethylene sorbitol acid anhydride mono fatty acid ester, polyoxyethylene mountain
Pears sugar alcohol acid anhydride di fatty acid ester, polyoxyethylene glycerol mono fatty acid ester, polyoxyethylene glycerol di fatty acid ester, polyglycerol fatty acid
Ester, polypropylene glycol monoesters, aryl burn base Aethoxy Sklerol, Pluronic F68 (poloxamer), polyvinyl alcohol
(PVA) and its derivative, PVP (PVP) and polysaccharide, preferred poloxamer, polyvinyl alcohol, polysorbate, poly-
Ethylene ratio pyrrolidone and polysaccharide, more preferably polyvinyl alcohol, polysaccharide.
The polysaccharide includes starch and starch derivatives, methylcellulose, ethyl cellulose, hydroxylated cellulose, hydroxypropyl
Cellulose, HPMC, Arabic gum, chitosan derivatives, gellan gum, alginate derivatives, glucan derivative and
Amorphous cellulose, preferably Hydroxypropyl methylcellulose, Chitosan-phospholipid complex, amylopectin or glucan and its derivative.
Surface active biological molecule includes polyaminoacid (such as poly-aspartate or polyglutamic acid or their analog), peptide
(such as basic peptide), protein (such as gelatin, casein, albumin, hirudin, hetastarch, preferably albumin).
As the preferred embodiment of the preparation method of risperidone slow-release composition of the present invention, the surfactant
Mass percentage concentration in outer water phase is 0.1~10%；Preferably, quality percentage of the surfactant in outer water phase
Concentration is 0.5~8%；It is highly preferred that mass percentage concentration of the surfactant in outer water phase is 1~7%.
As the preferred embodiment of the preparation method of risperidone slow-release composition of the present invention, in the outer water phase also
Contain inorganic salts or organic salt；The inorganic salts are phosphoric acid, sulfuric acid, acetic acid, the sylvite of carbonic acid or sodium salt, Tris, MES, HEPES
In at least one；The weight/mass percentage composition of the inorganic salts or organic salt in the outer water phase is 0~5%.Further,
Inorganic salts or organic salt can also be contained in the outer water phase, water-soluble actives are molten to be oozed to water to reduce in microballoon solidification process
Xiang Zhong, its mechanism is to improve the osmotic pressure of foreign minister or reduce solubility of the active material in foreign minister.The inorganic salts include but
It is not limited to water miscible phosphoric acid, sulfuric acid, acetic acid, the sylvite of carbonic acid or sodium salt, Tris, MES, HEPES or their any mixing
Thing, its weight percent concentration in the aqueous solution is：0-5%, preferably 0.01-4%, more preferably 0.05-3%.PH scopes are
3-9, preferably 4-9, more preferably 5.5-8.5.
Used as the preferred embodiment of the preparation method of risperidone slow-release composition of the present invention, the outer water phase makes
Consumption, usually more than about the 60 of interior oil phase times volume, preferably from about 80 times volumes, more than even more preferably about 100 times volumes.
The method for being made emulsion is identical with well-known emulsification method, using the device for producing high shear force (such as
Magnetic stirring apparatus, mechanical agitator, high-shear homogenizer, Ultrasound Instrument, membrane emulsifier, Rotor-stator mixers, static mixer,
High pressure homogenizer etc.) by it is organic it is interior mix with external aqueous phase, to form homogeneous latex emulsion.
Solvent evaporation can apply following methods in the step (3a) and (3b)：
(A) organic solvent is boiled off by heating, decompression (or combined heat) and decompression；
(B) air-flow advertises liquid surface, and controls the speed of liquid phase and the contact area, emulsion stirring and circulation of gas phase
(such as JP-A-9-221418) accelerates the evaporation of organic solvent, the preferred nitrogen of air-flow；
(C) organic solvent (such as W00183594) is quickly boiled off with hollow fiber membrane, hollow fiber membrane is preferably for example
Silicon rubber pervaporation film (the pervaporation film for particularly being prepared by dimethyl silicone polymer).
Microballoon obtained in the step (3a) and (3b) is separated by way of centrifugation, sieving or filtering.
The method of dry microspheres is not particularly limited in the step (3a) and (3b), for example, can enumerate heating, decompression and do
Dry, freeze-drying, vacuum drying and combinations thereof.
Particulate of the invention or microballoon can encapsulate substantial amounts of active component, dosage can according to the type of active component with contain
Amount, formulation, release duration, administration subject, method of administration, administration purpose, targeted condition and symptom etc. and suitably select
Select.However, as long as active component can reach the expected duration in medicine effective concentration is in vivo maintained, then the dosage can be recognized
To be gratifying.
When microballoon is administered in suspending agent form, it can be made suspension formulations form with appropriate decentralized medium.
The decentralized medium includes nonionic surfactant (or stabilizer), castor oil derivatives, fiber
Plain thickener, sodium alginate, hyaluronic acid, dextrin, starch.Or it is selectable, can also be with other excipient such as isotonic agent (such as
Sodium chloride, mannitol, glycerine, sorbierite, lactose, xylitol, maltose, galactolipin, sucrose, glucose etc.), pH adjusting agent
(such as carbonic acid, acetic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid or these sour salt, such as sodium carbonate, sodium acid carbonate etc.), anti-corrosion
Agent (such as p-hydroxybenzoate, propylparaben, phenmethylol, chlorobutanol, sorbic acid, boric acid etc.) etc. is combined,
Solidified by methods such as freeze-drying, hypobaric drying method, spray drying after being made aqueous solution, using preceding again that solidfied material is molten
Solution obtains the decentralized medium of dispersion microsphere in distilled water for injection.
Additionally, slow-release injected can also be obtained by following methods：Particulate or microballoon are scattered in vegetable oil (such as sesame
Oil and corn oil) or be added with the vegetable oil of phosphatide (such as lecithin), or be scattered in medium chain triglyceride, to obtain
Oil-based suspension.
The microballoon that the present invention is obtained can be used for granular form, suspending agent form, implants form, injection form, viscous
Attached dosage form formula etc., it is possible to oral or parenteral administration (intramuscular injection, hypodermic injection, percutaneous dosing, mucosa delivery (cheek
In interior, intravaginal, rectum etc.)).
Risperidone slow-release composition of the invention is sufficiently stable, can with sustained release more than several weeks, such as up to about 2 weeks,
Such as it is up to about 4 weeks, is such as up to about 8 weeks, is such as up to about 12 weeks, or the longer time, can be carried out according to specific Treatment need
Regulation.
Specific embodiment
To better illustrate the object, technical solutions and advantages of the present invention, below in conjunction with specific embodiment to the present invention
It is described further.
In following examples, the computational methods of microballoon carrying drug ratio are：Drug quality/microspheres quality in carrying drug ratio=microballoon ×
100%；The computational methods of entrapment efficiency are：Medicine actual mass/medicine feeding quality × 100% in envelop rate=microballoon.
Embodiment 1
A kind of embodiment of risperidone slow-release composition of the present invention, risperidone slow-release composition described in the present embodiment it is non-molten
Component of the formulation preparing raw material comprising following weight/mass percentage composition：Risperidone 25%, slightly water-soluble polymer：PLA74.9%, releases
Put conditioning agent：The mixture 0.1% of stearic acid and PEG6000.Wherein, the weight average molecular weight of the PLA is 20kDa, and viscosity is
0.25dL/g, and the PLA has ester group end；In the release regulator, quality of the PEG6000 in the release regulator
Percentage composition is 70%.
Risperidone slow-release composition is prepared from using following preparation method described in the present embodiment：
(1) slightly water-soluble polymer is dissolved in dichloromethane, the quality of the slightly water-soluble polymer and dichloromethane
Percentage is 10%, is subsequently adding Risperidone and release regulator, is uniformly dissolved, and forms interior oil phase；
(2) it is PVA and potassium phosphate is soluble in water, outer water phase is formed, quality percentages of the PVA in the outer water phase contains
It is 0.1% to measure, and weight/mass percentage composition of the potassium phosphate in the outer water phase is 0.01%；
(3) the interior oil phase that step (1) is obtained is added in step (2) the outer water phase of gained, the volume of the outer water phase is
60 times of the interior oil phase, emulsification is made emulsion, and then by this solution, 6 hours of mechanical agitation consolidate microballoon at 500 rpm
Change, be collected by centrifugation microballoon, and with milli-Q water microballoon 5 times, freeze-drying obtains risperidone slow-release microsphere.
Gained risperidone slow-release microsphere profile rounding, surface are smooth in the present embodiment, and particle diameter is 22~95 μm, after measured its
Carrying drug ratio is 22.80%, and Risperidone envelop rate is 91.20%.
Embodiment 2
A kind of embodiment of risperidone slow-release composition of the present invention, risperidone slow-release composition described in the present embodiment it is non-molten
Component of the formulation preparing raw material comprising following weight/mass percentage composition：Risperidone 30%, slightly water-soluble polymer：PLA 69.5%,
Release regulator：Mountain Yu acid and the mixture 0.5% of PEG4000.Wherein, the weight average molecular weight of the PLA is 25kDa, viscosity
It is 0.30dL/g, and the PLA has ester group end；In the release regulator, matter of the PEG4000 in the release regulator
Amount percentage composition is 60%.
Risperidone slow-release composition is prepared from using following preparation method described in the present embodiment：
(1) slightly water-soluble polymer is dissolved in chloroform, the slightly water-soluble polymer is with the mass percent of chloroform
9.5%, Risperidone and release regulator are subsequently adding, it is uniformly dissolved, form interior oil phase；
(2) it is polysorbate and sodium phosphate is soluble in water, outer water phase is formed, the Hydroxypropyl methylcellulose is in the outer water
Weight/mass percentage composition in phase is 0.5%, and weight/mass percentage composition of the sodium phosphate in the outer water phase is 0.05%；
(3) the interior oil phase that step (1) is obtained is added in step (2) the outer water phase of gained, the volume of the outer water phase is
65 times of the interior oil phase, emulsification is made emulsion, and then by this solution, 6 hours of mechanical agitation consolidate microballoon at 500 rpm
Change, be collected by centrifugation microballoon, and with milli-Q water microballoon 5 times, freeze-drying obtains risperidone slow-release microsphere.
Gained risperidone slow-release microsphere profile rounding, surface are smooth in the present embodiment, and particle diameter is 30~103 μm, after measured
Its carrying drug ratio is 27.44%, and Risperidone envelop rate is 91.8%.
Embodiment 3
A kind of embodiment of risperidone slow-release composition of the present invention, risperidone slow-release composition described in the present embodiment it is non-molten
Component of the formulation preparing raw material comprising following weight/mass percentage composition：Risperidone 35%, slightly water-soluble polymer：PLA 64.2%,
Release regulator：Mountain Yu acid and the mixture 0.8% of PEG4000.Wherein, the weight average molecular weight of the PLA is 25kDa, viscosity
It is 0.31dL/g, and the PLA has c-terminus；In the release regulator, matter of the PEG4000 in the release regulator
Amount percentage composition is 50%.
Risperidone slow-release composition is prepared from using following preparation method described in the present embodiment：
(1) slightly water-soluble polymer is dissolved in dichloromethane, the quality of the slightly water-soluble polymer and tetrachloro-ethylene
Percentage is 9%, is subsequently adding Risperidone and release regulator, is uniformly dissolved, and forms interior oil phase；
(2) it is albumin is soluble in water, form outer water phase, weight/mass percentage composition of the albumin in the outer water phase
It is 1%；
(3) the interior oil phase that step (1) is obtained is added in step (2) the outer water phase of gained, the volume of the outer water phase is
70 times of the interior oil phase, emulsification is made emulsion, and then by this solution, 6 hours of mechanical agitation consolidate microballoon at 500 rpm
Change, be collected by centrifugation microballoon, and with milli-Q water microballoon 5 times, freeze-drying obtains risperidone slow-release microsphere.
Gained risperidone slow-release microsphere profile rounding, surface are smooth in the present embodiment, and particle diameter is 29~96 μm, after measured its
Carrying drug ratio is 32.38%, and Risperidone envelop rate is 92.5%.
Embodiment 4
A kind of embodiment of risperidone slow-release composition of the present invention, risperidone slow-release composition described in the present embodiment include with
The component of lower weight/mass percentage composition：Risperidone 35%, slightly water-soluble polymer：PLGA 64%, release regulator：Stearic acid and
The mixture 1% of PEG1500.Wherein, in the PLGA, the mol ratio of lactide and glycolide is 95:5, the weight of the PLGA
Average molecular weight is 30kDa, and viscosity is 0.36dL/g, and the PLA has ester group end；In the release regulator, PEG1500 exists
Weight/mass percentage composition in the release regulator is 40%.
Risperidone slow-release composition is prepared from using following preparation method described in the present embodiment：
(1) slightly water-soluble polymer is dissolved in dichloromethane, the quality of the slightly water-soluble polymer and dichloromethane
Percentage is 9%, is subsequently adding Risperidone, release regulator, is uniformly dissolved, and forms interior oil phase；
(2) it is Hydroxypropyl methylcellulose is soluble in water, form outer water phase, matter of the polysorbate in the outer water phase
Amount percentage composition is 2%；
(3) the interior oil phase that step (1) is obtained is added in step (2) the outer water phase of gained, the volume of the outer water phase is
75 times of the interior oil phase, emulsification is made emulsion, and then by this solution, 6 hours of mechanical agitation consolidate microballoon at 500 rpm
Change, be collected by centrifugation microballoon, and with milli-Q water microballoon 5 times, freeze-drying obtains risperidone slow-release microsphere.
Gained risperidone slow-release microsphere profile rounding, surface are smooth in the present embodiment, and particle diameter is 30~105 μm, after measured
Its carrying drug ratio is 31.95%, and Risperidone envelop rate is 91.29%.
Embodiment 5
A kind of embodiment of risperidone slow-release composition of the present invention, risperidone slow-release composition described in the present embodiment it is non-molten
Component of the formulation preparing raw material comprising following weight/mass percentage composition：Risperidone 35%, slightly water-soluble polymer：PLGA 63%, releases
Put conditioning agent：The mixture 2% of stearic acid and PEG3000.Wherein, the mol ratio of lactide and glycolide is in the PLGA
85:The weight average molecular weight of 15, the PLGA is 30kDa, and viscosity is 0.38dL/g, and the PLA has ester group end；The release
In conditioning agent, weight/mass percentage compositions of the PEG3000 in the release regulator is 30%.
Risperidone slow-release composition is prepared from using following preparation method described in the present embodiment：
(1) it is 9 slightly water-soluble polymer to be dissolved in into volume ratio:In 1 dichloromethane/ethyl acetate, the slightly water-soluble
Polymer is 8.5% with the mass percent of solvent, is subsequently adding Risperidone, is uniformly dissolved, and forms interior oil phase；
(2) it is release regulator, benzalkonium chloride is soluble in water, outer water phase is formed, the benzalkonium chloride is in the outer water phase
In weight/mass percentage composition be 3%；
(3) the interior oil phase that step (1) is obtained is added in step (2) the outer water phase of gained, the volume of the outer water phase is
80 times of the interior oil phase, emulsification is made emulsion, and then by this solution, 6 hours of mechanical agitation consolidate microballoon at 500 rpm
Change, be collected by centrifugation microballoon, and with milli-Q water microballoon 5 times, freeze-drying obtains risperidone slow-release microsphere.
Gained risperidone slow-release microsphere profile rounding, surface are smooth in the present embodiment, and particle diameter is 32~116 μm, after measured
Its carrying drug ratio is 32.43%, and Risperidone envelop rate is 92.66%.
Embodiment 6
A kind of embodiment of risperidone slow-release composition of the present invention, risperidone slow-release composition described in the present embodiment it is non-molten
Component of the formulation preparing raw material comprising following weight/mass percentage composition：Risperidone 40%, slightly water-soluble polymer：PLA 57%, releases
Put conditioning agent：Lignin acid and the mixture 3% of PEG2000.Wherein, it is with c-terminus PLA and with ester group in the PLA
The mixture of PLA is held, and it is 1 wherein to have c-terminus PLA and the mass ratio with ester group end PLA:1, it is described with c-terminus
PLA and the weight average molecular weight with ester group end PLA are 35kDa, and viscosity is 0.40dL/g；In the release regulator,
Weight/mass percentage compositions of the PEG2000 in the release regulator is 45%.
Risperidone slow-release composition is prepared from using following preparation method described in the present embodiment：
(1) slightly water-soluble polymer is dissolved in dichloromethane, the quality hundred of the slightly water-soluble polymer and dimethylbenzene
Divide than being 8%, be subsequently adding Risperidone, release regulator, be uniformly dissolved, form interior oil phase；
(2) it is potassium laurate is soluble in water, form outer water phase, quality percentage of the potassium laurate in the outer water phase
Content is 4%；
(3) the interior oil phase that step (1) is obtained is added in step (2) the outer water phase of gained, the volume of the outer water phase is
85 times of the interior oil phase, emulsification is made emulsion, and then by this solution, 6 hours of mechanical agitation consolidate microballoon at 500 rpm
Change, be collected by centrifugation microballoon, and with milli-Q water microballoon 5 times, freeze-drying obtains risperidone slow-release microsphere.
Gained risperidone slow-release microsphere profile rounding, surface are smooth in the present embodiment, and particle diameter is 30~121 μm, after measured
Its carrying drug ratio is 37.30%, and Risperidone envelop rate is 93.25%.
Embodiment 7
A kind of embodiment of risperidone slow-release composition of the present invention, risperidone slow-release composition described in the present embodiment it is non-molten
Component of the formulation preparing raw material comprising following weight/mass percentage composition：Risperidone 40%, slightly water-soluble polymer：PLGA 56%, releases
Put conditioning agent：The mixture 4% of arachidic acid and polyvinylpyrrolidone.Wherein, lactide and glycolide rub in the PLGA
You are than being 85:The weight average molecular weight of 15, the PLGA is 40kDa, and viscosity is 0.42dL/g, and the PLGA has c-terminus；
In the release regulator, weight/mass percentage composition of the polyvinylpyrrolidone in the release regulator is 55%.
Risperidone slow-release composition is prepared from using following preparation method described in the present embodiment：
(1) slightly water-soluble polymer is dissolved in chloroform, the slightly water-soluble polymer is with the mass percent of chloroform
7.5%, Risperidone is subsequently adding, it is uniformly dissolved, form interior oil phase；
(2) it is release regulator, poloxamer is soluble in water, outer water phase is formed, the poloxamer is in the outer water phase
In weight/mass percentage composition be 5%；
(3) the interior oil phase that step (1) is obtained is added in step (2) the outer water phase of gained, the volume of the outer water phase is
90 times of the interior oil phase, emulsification is made emulsion, and then by this solution, 6 hours of mechanical agitation consolidate microballoon at 500 rpm
Change, be collected by centrifugation microballoon, and with milli-Q water microballoon 5 times, freeze-drying obtains risperidone slow-release microsphere.
Gained risperidone slow-release microsphere profile rounding, surface are smooth in the present embodiment, and particle diameter is 27~104 μm, after measured
Its carrying drug ratio is 38.1%, and Risperidone envelop rate is 95.25%.
Embodiment 8
A kind of embodiment of risperidone slow-release composition of the present invention, risperidone slow-release composition described in the present embodiment it is non-molten
Component of the formulation preparing raw material comprising following weight/mass percentage composition：Risperidone 40%, slightly water-soluble polymer：PLGA 55%, releases
Put conditioning agent：The mixture 5% of stearic acid and PEG1200.Wherein, lactide is with the mol ratio of glycolide in the PLGA
75:The weight average molecular weight of 25, the PLGA is 50kDa, and viscosity is 0.49dL/g, and the PLGA has c-terminus；It is described to release
Put in conditioning agent, weight/mass percentage compositions of the PEG1200 in the release regulator is 65%.
Risperidone slow-release composition is prepared from using following preparation method described in the present embodiment：
(1) it is 8 slightly water-soluble polymer to be dissolved in into volume ratio:In 2 dichloromethane/phenmethylol, the slightly water-soluble gathers
Compound is 7% with the mass percent of solvent, is subsequently adding Risperidone, release regulator, is uniformly dissolved, and forms interior oil phase；
(2) it is PVP is soluble in water, outer water phase is formed, weight/mass percentage compositions of the PVP in the outer water phase is 6%；
(3) the interior oil phase that step (1) is obtained is added in step (2) the outer water phase of gained, the volume of the outer water phase is
100 times of the interior oil phase, emulsification is made emulsion, and then by this solution, 6 hours of mechanical agitation consolidate microballoon at 500 rpm
Change, be collected by centrifugation microballoon, and with milli-Q water microballoon 5 times, freeze-drying obtains risperidone slow-release microsphere.
Gained risperidone slow-release microsphere profile rounding, surface are smooth in the present embodiment, and particle diameter is 28~107 μm, after measured
Its carrying drug ratio is 36.55%, and Risperidone envelop rate is 91.38%.
Embodiment 9
A kind of embodiment of risperidone slow-release composition of the present invention, risperidone slow-release composition described in the present embodiment it is non-molten
Component of the formulation preparing raw material comprising following weight/mass percentage composition：Risperidone 45%, slightly water-soluble polymer：PLGA 49%, releases
Put conditioning agent：Mountain Yu acid and the mixture 6% of PEG1000.Wherein, the PLGA is PLGA with c-terminus and with ester group
The mixture of the PLGA at end, and the mass ratio of the PLGA with c-terminus and the PLGA with ester group end is 2:1；It is described with carboxylic
Lactide and the mol ratio of glycolide are 85 in the PLGA of cardinal extremity:15, weight average molecular weight is 60kDa, and viscosity is 0.54dL/g；Institute
The mol ratio for stating lactide and glycolide in the PLGA with ester group end is 85:15, weight average molecular weight is 45kDa, and viscosity is
0.45dL/g；In the release regulator, weight/mass percentage compositions of the PEG1000 in the release regulator is 75%.
Risperidone slow-release composition is prepared from using following preparation method described in the present embodiment：
(1) slightly water-soluble polymer is dissolved in dichloromethane, the quality of the slightly water-soluble polymer and dichloromethane
Percentage is 6%, is subsequently adding Risperidone, release regulator, is uniformly dissolved, and forms interior oil phase；
(2) it is starch and potassium acetate is soluble in water, form outer water phase, quality percentage of the starch in the outer water phase
Content is 7%, and weight/mass percentage composition of the potassium acetate in the outer water phase is 4%；
(3) the interior oil phase that step (1) is obtained is added in step (2) the outer water phase of gained, the volume of the outer water phase is
105 times of the interior oil phase, emulsification is made emulsion, and then by this solution, 6 hours of mechanical agitation consolidate microballoon at 500 rpm
Change, be collected by centrifugation microballoon, and with milli-Q water microballoon 5 times, freeze-drying obtains risperidone slow-release microsphere.
Gained risperidone slow-release microsphere profile rounding, surface are smooth in the present embodiment, and particle diameter is 19~95 μm, after measured its
Carrying drug ratio is 41.17%, and Risperidone envelop rate is 91.49%.
Embodiment 10
A kind of embodiment of risperidone slow-release composition of the present invention, risperidone slow-release composition described in the present embodiment it is non-molten
Component of the formulation preparing raw material comprising following weight/mass percentage composition：Risperidone 50%, slightly water-soluble polymer：PLGA 41%, releases
Put conditioning agent：The mixture 7% of palmitic acid and PEG900, excipient：Buffer zinc palmitate 1.95%, antioxidant palmitic acid
Acid ascorbyl ester 0.05%.Wherein, lactide and the mol ratio of glycolide are 80 in the PLGA:20, the weight of the PLGA is equal
Molecular weight is 70kDa, and viscosity is 0.58dL/g, and the PLGA has ester group end；In the release regulator, PEG900 is in institute
It is 80% to state the weight/mass percentage composition in release regulator.
Risperidone slow-release composition is prepared from using following preparation method described in the present embodiment：
(1) slightly water-soluble polymer is dissolved in dichloromethane, the quality percentage of the slightly water-soluble polymer and chloroform
Than being 5%, Risperidone, release regulator and excipient are subsequently adding, be uniformly dissolved, form interior oil phase；
(2) it is shitosan is soluble in water, form outer water phase, weight/mass percentage composition of the shitosan in the outer water phase
It is 8%；
(3) the interior oil phase that step (1) is obtained is added in step (2) the outer water phase of gained, the volume of the outer water phase is
95 times of the interior oil phase, emulsification is made emulsion, and then by this solution, 6 hours of mechanical agitation consolidate microballoon at 500 rpm
Change, be collected by centrifugation microballoon, and with milli-Q water microballoon 5 times, freeze-drying obtains risperidone slow-release microsphere.
Gained risperidone slow-release microsphere profile rounding, surface are smooth in the present embodiment, and particle diameter is 24~95 μm, after measured its
Carrying drug ratio is 46.15%, and Risperidone envelop rate is 92.3%.
Embodiment 11
A kind of embodiment of risperidone slow-release composition of the present invention, risperidone slow-release composition described in the present embodiment it is non-molten
Component of the formulation preparing raw material comprising following weight/mass percentage composition：Risperidone 55%, slightly water-soluble polymer：PLGA 36%, releases
Put conditioning agent：The mixture 8% of myristic acid and PEG800, excipient：Buffer zinc nitrate 1%.Wherein, the PLGA is
(lactide is 70 with the mol ratio of glycolide to PLGA:30th, weight average molecular weight be 65kDa, viscosity be 0.56dL/g, with carboxyl
End) and PLGA (mol ratio of lactide and glycolide is 85:15th, weight average molecular weight be 80kDa, viscosity be 0.65dL/g, have
C-terminus) mixture；In the release regulator, weight/mass percentage compositions of the PEG800 in the release regulator is
90%.
Risperidone slow-release composition is prepared from using following preparation method described in the present embodiment：
(1) slightly water-soluble polymer is dissolved in dichloromethane, the quality of the slightly water-soluble polymer and dichloromethane
Percentage is 4%, is subsequently adding Risperidone, release regulator and excipient, is uniformly dissolved, and forms interior oil phase；
(2) gelatin is dissolved in MES solution, forms outer water phase, quality percentage of the gelatin in the outer water phase contains
It is 9% to measure, and weight/mass percentage compositions of the MES in the outer water phase is 2.5%；
(3) the interior oil phase that step (1) is obtained is added in step (2) the outer water phase of gained, the volume of the outer water phase is
80 times of the interior oil phase, emulsification is made emulsion, and then by this solution, 6 hours of mechanical agitation consolidate microballoon at 500 rpm
Change, be collected by centrifugation microballoon, and with milli-Q water microballoon 5 times, freeze-drying obtains risperidone slow-release microsphere.
Gained risperidone slow-release microsphere profile rounding, surface are smooth in the present embodiment, and particle diameter is 30~114 μm, after measured
Its carrying drug ratio is 49.62%, and Risperidone envelop rate is 90.21%.
Embodiment 12
A kind of embodiment of risperidone slow-release composition of the present invention, risperidone slow-release composition described in the present embodiment it is non-molten
Component of the formulation preparing raw material comprising following weight/mass percentage composition：Risperidone 60%, slightly water-soluble polymer：PLGA 30%, releases
Put conditioning agent：The mixture 10% of laurate and PEG600.Wherein, in the PLGA, the mol ratio of lactide and glycolide is
65:The weight average molecular weight of 35, the PLGA is 90kDa, and viscosity is 0.7dL/g, and the PLA has c-terminus；The release
In conditioning agent, weight/mass percentage compositions of the PEG600 in the release regulator is 95%.
Risperidone slow-release composition is prepared from using following preparation method described in the present embodiment：
(1) slightly water-soluble polymer is dissolved in trichloroethanes, the quality of the slightly water-soluble polymer and trichloroethanes
Percentage is 3.5%, is subsequently adding Risperidone and release regulator, is uniformly dissolved, and forms interior oil phase；
(2) it is polyvinyl alcohol is soluble in water, form outer water phase, quality percentage of the polyvinyl alcohol in the outer water phase
Content is 10%；
(3) the interior oil phase that step (1) is obtained is added in step (2) the outer water phase of gained, the volume of the outer water phase is
100 times of the interior oil phase, emulsification is made emulsion, and then by this solution, 6 hours of mechanical agitation consolidate microballoon at 500 rpm
Change, be collected by centrifugation microballoon, and with milli-Q water microballoon 5 times, freeze-drying obtains risperidone slow-release microsphere.
Gained risperidone slow-release microsphere profile rounding, surface are smooth in the present embodiment, and particle diameter is 35~128 μm, after measured
Its carrying drug ratio is 53.85%, and Risperidone envelop rate is 89.75%.
Embodiment 13
A kind of embodiment of risperidone slow-release composition of the present invention, risperidone slow-release composition described in the present embodiment it is non-molten
Component of the formulation preparing raw material comprising following weight/mass percentage composition：Risperidone 35%, slightly water-soluble polymer：PLGA61%, releases
Put conditioning agent：Mountain Yu acid and the mixture 4% of PEG400.Wherein, in the PLGA, the mol ratio of lactide and glycolide is
75:The weight average molecular weight of 25, the PLGA is 100kDa, and viscosity is 0.80dL/g, and the PLA has ester group end；It is described to release
Put in conditioning agent, weight/mass percentage compositions of the PEG400 in the release regulator is 70%.
Risperidone slow-release composition is prepared from using following preparation method described in the present embodiment：
(1) slightly water-soluble polymer is dissolved in dichloromethane, the quality of the slightly water-soluble polymer and butyl acetate
Percentage is 3%, is subsequently adding Risperidone and release regulator, is uniformly dissolved, and forms interior oil phase；
(2) it is ethyl cellulose is soluble in water, form outer water phase, quality of the ethyl cellulose in the outer water phase
Percentage composition is 4%；
(3) the interior oil phase that step (1) is obtained is added in step (2) the outer water phase of gained, the volume of the outer water phase is
105 times of the interior oil phase, emulsification is made emulsion, and then by this solution, 6 hours of mechanical agitation consolidate microballoon at 500 rpm
Change, be collected by centrifugation microballoon, and with milli-Q water microballoon 5 times, freeze-drying obtains risperidone slow-release microsphere.
Gained risperidone slow-release microsphere profile rounding, surface are smooth in the present embodiment, and particle diameter is 20~88 μm, after measured its
Carrying drug ratio is 32.53%, and Risperidone envelop rate is 92.94%.
Embodiment 14
The vitro release of poorly water soluble drugs slow releasing composition of the present invention is determined
Poorly water soluble drugs sustained-release micro-spheres that embodiment 1~13 prepares are respectively adopted as test group 1~13, use
Following four comparative example is as a control group：
Comparative example 1, preparation method with embodiment 1 in patent CN1137756, wherein feeding intake：Risperidone 35%, PLGA (75/
25,100kDa, 0.80dL/g, ester group end) 65%.Gained risperidone slow-release microsphere profile rounding, particle diameter is 30-127 μm, through surveying
Fixed its carrying drug ratio is 31.15%, and Risperidone envelop rate is 89.00%.
Comparative example 2, preparation method is with the embodiment of the present invention 5, wherein feeding intake：Without release regulator, Risperidone 35%, water
Slightly solubility polymer 65%.Gained risperidone slow-release microsphere profile rounding, surface are smooth, and particle diameter is 28-86 μm, after measured its load
Medicine rate is 31.53%, and Risperidone envelop rate is 90.08%.
Comparative example 3, preparation method is with the embodiment of the present invention 6, wherein feeding intake：Without release regulator, Risperidone 40%, water
Slightly solubility polymer 60%.Gained risperidone slow-release microsphere profile rounding, surface are smooth, and particle diameter is 23-91 μm, after measured its load
Medicine rate is 36.09%, and Risperidone envelop rate is 90.23%.
Comparative example 4, preparation method is with the embodiment of the present invention 7, wherein feeding intake：Without release regulator, Risperidone 40%, water
Slightly solubility polymer 60%.Gained risperidone slow-release microsphere profile rounding, surface are smooth, and particle diameter is 22-93 μm, after measured its load
Medicine rate is 36.84%, and Risperidone envelop rate is 92.10%.
Method of testing：Each 20mg of microballoon that precision weighs embodiment 1-13 and comparative example 1-4 preparations puts 200mL centrifuge tubes
In, plus pH7.4PBS (containing 0.05% Tween 80,0.05% sodium azide) 50mL, it is placed in 37 DEG C, 150rpm waters bath with thermostatic control vibration
In device, 1mL release liquids are taken out in Preset Time point, be placed in after supplement equivalent fresh medium in thermostatic control oscillator vibration and continue to discharge
Degree experiment.Take out liquid and release amount of medicine is detected using high performance liquid chromatography (HPLC), as a result as shown in Table 1 and Table 2.
The release in vitro data of the sustained-release micro-spheres of table 1
| Time/day | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | Embodiment 7 | Embodiment 8 |
| 0.04 | 0 | 0 | 0.17 | 0.19 | 0 | 0 | 0 | 0.12 |
| 0.5 | 0.34 | 0.32 | 0.39 | 0.56 | 0.26 | 0.12 | 0.50 | 0.43 |
| 1 | 0.86 | 0.44 | 0.95 | 1.31 | 0.58 | 0.63 | 1.30 | 1.42 |
| 2 | 1.23 | 0.97 | 3.88 | 2.73 | 1.69 | 1.15 | 3.70 | 3.57 |
| 7 | 12.89 | 10.11 | 16.42 | 15.84 | 11.89 | 6.73 | 19.79 | 20.33 |
| 14 | 25.45 | 22.05 | 34.32 | 37.05 | 28.72 | 18.63 | 39.04 | 45.25 |
| 21 | 43.61 | 39.98 | 49.55 | 55.65 | 45.62 | 30.30 | 57.33 | 72.42 |
| 28 | 65.20 | 57.87 | 68.63 | 77.72 | 64.26 | 45.89 | 70.42 | 97.48 |
| 35 | 90.38 | 83.87 | 87.24 | 90.14 | 78.16 | 61.34 | 84.56 | 99.41 |
| 42 | 98.86 | 95.53 | 97.33 | 99.00 | 90.50 | 74.11 | 94.24 | 100.00 |
| 49 | 100.00 | 99.05 | 100.20 | 100.15 | 100.00 | 87.15 | 100.00 | 100.00 |
| 56 | 100.00 | 100.00 | 100.00 | 100.00 | 100.00 | 96.30 | 100.00 | |
| 63 | 100.00 | 100.00 | ||||||
| 70 | 100.00 |
The release in vitro data of the sustained-release micro-spheres of table 2
As can be seen from Table 1 and Table 2, sustained-release micro-spheres of the invention do not have burst effect, and first day release rate is no more than 2%,
And in 4-12 weeks to approach the release of zero level trend, with obvious slow release effect, and can be released or preceding without occurring dashing forward
Phase discharges the phenomenon of slow later stage release aggravation, illustrates that the degradation rate of the polymer of these microballoon top layers and core does not occur
Visible difference, illustrates that release regulator therein produces space so that the acid product that the degraded of microballoon inside is produced is passed in time
Deliver to outside, it is to avoid or greatly reduce the phenomenon for the quickening of core polymer self-catalysis degradation speed occur, effectively overcome PLA
Or the drawbacks of PLGA body degradation effects.
Embodiment can be seen that microballoon relative contrast example substantially contracting of the invention with the contrast of comparative example from Tables 1 and 2
Short sustained release phase, and without phenomenon of burst release, illustrate of the invention can significantly improve slow by adding release regulator
The release behavior of microballoon is released, the release lag phase of microballoon is greatly shortened, makes patient avoid or reduce injection oral common after taking medicine
Preparation, dramatically increases to drug compliance and convenience.
Embodiment 15
The stabilizing effect experiment of poorly water soluble drugs sustained-release micro-spheres of the present invention.
According to Chinese Pharmacopoeia (2015 editions four) 9001 material medicines and preparation stability test direction principle, it is necessary in ice
(4-8 DEG C) accelerated test of the thermally sensitive medicine of preservation of case, in 25 DEG C ± 2 DEG C, the bar of relative humidity 60% ± 10%
Carried out under part, the time is 6 months.The microballoon of embodiment 1~13 and comparative example 1~4 is placed in 25 DEG C ± 2 DEG C, relative humidity
Accelerated stability is investigated in 60% ± 10% testing chamber for medicine stability, was sampled respectively at the 30th day, the 90th day and the 180th day
(n=3) release behavior is surveyed, release behavior assay method is with embodiment 14.Result is as shown in table 3~8.Embodiment 1~13 and right
The microballoon release behavior of the 0th day of ratio 1~4 is shown in Tables 1 and 2.
The 30th day release in vitro data of accelerated stability sample of table 3
| Time/day | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | Embodiment 7 | Embodiment 8 |
| 0.04 | 0 | 0 | 0.13 | 0.16 | 0 | 0 | 0.02 | 0.15 |
| 0.5 | 0.34 | 0.33 | 0.37 | 0.55 | 0.29 | 0.25 | 0.45 | 0.41 |
| 1 | 0.86 | 0.46 | 0.90 | 1.33 | 0.65 | 0.82 | 1.39 | 1.4 |
| 2 | 1.23 | 0.96 | 3.90 | 2.80 | 1.67 | 1.44 | 3.69 | 3.59 |
| 7 | 12.89 | 9.96 | 16.4 | 15.86 | 11.95 | 7.58 | 20.32 | 20.36 |
| 14 | 25.45 | 22.15 | 34.4 | 37.10 | 28.85 | 19.32 | 39.55 | 45.00 |
| 21 | 43.61 | 40.00 | 49.68 | 55.87 | 46.34 | 31.85 | 61.39 | 71.56 |
| 28 | 65.20 | 57.82 | 68.79 | 77.64 | 65.54 | 46.18 | 74.80 | 96.58 |
| 35 | 90.38 | 83.94 | 87.69 | 90.20 | 79.29 | 62.42 | 88.21 | 100.00 |
| 42 | 98.86 | 95.56 | 97.7 | 98.87 | 91.20 | 76.75 | 95.90 | 100.00 |
| 49 | 100.00 | 99.21 | 100.00 | 100.00 | 100.00 | 87.43 | 100.30 | |
| 56 | 100.00 | 100.00 | 100.00 | 100.00 | 100.00 | 96.55 | 100.00 | |
| 63 | 100.00 | 100.00 | ||||||
| 70 | 100.00 |
The 30th day release in vitro data of accelerated stability sample of table 4
The 90th day release in vitro data of accelerated stability sample of table 5
| Time/day | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | Embodiment 7 | Embodiment 8 |
| 0.04 | 0 | 0 | 0.21 | 0.24 | 0.02 | 0.01 | 0.07 | 0.2 |
| 0.5 | 0.33 | 0.38 | 0.46 | 0.60 | 0.36 | 0.37 | 0.64 | 0.49 |
| 1 | 0.88 | 0.5 | 0.99 | 1.40 | 0.72 | 1.04 | 1.55 | 1.55 |
| 2 | 1.25 | 1.03 | 3.94 | 2.83 | 1.84 | 1.78 | 3.93 | 3.66 |
| 7 | 12.89 | 10.86 | 16.87 | 16.42 | 13.05 | 8.33 | 22.18 | 21.20 |
| 14 | 25.44 | 23.54 | 35.00 | 38.34 | 30.12 | 20.25 | 42.76 | 46.80 |
| 21 | 43.65 | 41.47 | 50.01 | 56.63 | 48.73 | 33.78 | 63.00 | 73.68 |
| 28 | 65.28 | 59.30 | 69.38 | 78.89 | 67.10 | 48.55 | 77.31 | 98.43 |
| 35 | 90.35 | 84.88 | 88.33 | 92.66 | 81.56 | 64.79 | 90.32 | 100.00 |
| 42 | 98.80 | 96.95 | 98.83 | 100.00 | 93.49 | 78.40 | 97.20 | 100.00 |
| 49 | 100.00 | 100.00 | 100.00 | 100.00 | 100.00 | 89.45 | 100.00 | |
| 56 | 100.00 | 100.00 | 100.000 | 100.00 | 98.70 | 100.00 | ||
| 63 | 100.00 | |||||||
| 70 | 100.00 |
The 90th day release in vitro data of accelerated stability sample of table 6
The 180th day release in vitro data of accelerated stability sample of table 7
| Time/day | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | Embodiment 7 | Embodiment 8 |
| 0.04 | 0 | 0.09 | 0.29 | 0.37 | 0.13 | 0.05 | 0.13 | 0.28 |
| 0.5 | 0.38 | 0.45 | 0.55 | 0.71 | 0.58 | 0.64 | 0.86 | 0.59 |
| 1 | 0.94 | 0.64 | 1.12 | 1.52 | 0.93 | 1.46 | 2.12 | 1.76 |
| 2 | 1.30 | 1.21 | 4.06 | 2.97 | 2.06 | 2.13 | 4.91 | 3.80 |
| 7 | 13.10 | 12.20 | 17.80 | 17.11 | 14.96 | 10.25 | 25.30 | 21.74 |
| 14 | 25.69 | 25.06 | 36.05 | 39.08 | 32.52 | 22.8 | 47.10 | 47.77 |
| 21 | 44.60 | 43.13 | 51.75 | 58.05 | 50.38 | 36.34 | 66.65 | 75.22 |
| 28 | 66.21 | 60.77 | 71.00 | 79.65 | 69.33 | 51.75 | 83.43 | 99.40 |
| 35 | 91.59 | 86.32 | 89.98 | 94.38 | 84.02 | 67.50 | 96.09 | 100.42 |
| 42 | 100.00 | 98.46 | 100.00 | 100.00 | 96.62 | 82.40 | 100.00 | 100.00 |
| 49 | 100.00 | 100.00 | 100.00 | 100.00 | 100.00 | 94.31 | 100.00 | |
| 56 | 100.00 | 100.00 | 100.00 | |||||
| 63 | 100.00 |
The 180th day release in vitro data of accelerated stability sample of table 8
Contrast table 3~8 can be seen that thus obtained microsphere of the present invention under accelerated stability determination of the environment, and release behavior does not have
It is obvious to change, and the sample of comparative example increases with standing time, its release behavior there occurs obvious change, embody
For the shortening of release lag phase, first release time shift to an earlier date, release was advanced to and starts within 2-14 days release by 14-21 days.If pressed
According to the medication of commercially available prod (permanent moral), because medicine discharges in advance, the dosage being administered orally is superimposed, patient blood can be caused
In haemoconcentration increase.For this kind of antipsychotic drug of the poorly water soluble drugs such as Risperidone, haemoconcentration increase will cause
More serious side reaction is produced, treatment, live and work to patient cause very important influence.
Embodiment 16
The animal experiment of poorly water soluble drugs slow releasing composition of the present invention
Take New Zealand large ear rabbit of the weight in 2.0kg-3.0kg, every 6 one group (random packet), male and female half and half, every group
Intramuscular injection respectively contains the physiology salts of the 1.2ml containing 0.5%CMC-Na of microballoon prepared by embodiment 1~13 and comparative example 1~4
The suspension of the aqueous solution, the poorly water soluble drugs content of the sustained-release micro-spheres in suspension per dosage is 18mg, respectively at the
0.04d, 0.25d, 0.5d, 1d, 3d, 7d, 14d, 21d, 28d, 35d, 42d, 49d, 56d, 63d, 77d, 84d, 91d and 98d, in
Rabbit auricular vein takes blood 5mL.The blood sample of all collections takes -70 DEG C of supernatant and freezes after 8000rpm is centrifuged 10min, then
The blood concentration of poorly water soluble drugs in above-mentioned all blood samples is detected using means known in the art, is averaged.The results are shown in Table 9
With table 10.
The blood concentration result (ng/ml) of table 9
The blood concentration result (ng/ml) of table 10
Be can be seen that by table 9 and table 10, Risperidone microballoon of the invention shows good slow release effect, increases quickly after administration
Concentration is healed, and comparative example needs the time of similar 2-4 weeks to can be only achieved more than 5ng/mL, has with release in vitro behavior
It is similar.The blood concentration of slightly water-soluble sustained-release micro-spheres of the present invention can last up to about 20-60 days in the range of 5-30ng/mL；And
Comparative example lasts about 20-28 days.Illustrate that Risperidone microballoon of the invention has more preferable action effect, can be in longer time
It is interior to keep certain blood concentration, administration dosage period can be extended, mitigate side effect, improve sufferer compliance.
It is last to should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention rather than the present invention is protected
The limitation of scope is protected, although being explained in detail to the present invention with reference to preferred embodiment, one of ordinary skill in the art should
Understand, technical scheme can be modified or equivalent, without deviating from the essence of technical solution of the present invention
And scope.
Claims (11)
1. a kind of risperidone slow-release composition, it is characterised in that the non-solvent preparing raw material of the risperidone slow-release composition
Comprising Risperidone, slightly water-soluble polymer and release regulator, the release regulator is by organic hydrophilicity material and organic parent
Oily matter is constituted or the release regulator is organic hydrophilicity material.
2. risperidone slow-release composition as claimed in claim 1, it is characterised in that the risperidone slow-release composition it is non-molten
In formulation preparing raw material, the weight/mass percentage composition of release regulator is 0.1~10%；Preferably, the risperidone slow-release combination
In the non-solvent preparing raw material of thing, the weight/mass percentage composition of release regulator is 0.5~8%；Preferably, the Risperidone delays
Release in the non-solvent preparing raw material of composition, the weight/mass percentage composition of release regulator is 1~6%.
3. risperidone slow-release composition as claimed in claim 1 or 2, it is characterised in that the release regulator is by organic parent
When oily matter and organic hydrophilicity material composition, quality percentage of the organic hydrophilicity material in the release regulator
Content is more than 30%；Preferably, weight/mass percentage composition of the organic hydrophilicity material in the release regulator is
More than 50%；Preferably, weight/mass percentage composition of the organic hydrophilicity material in the release regulator is more than 70%.
4. the risperidone slow-release composition as described in claim 1 or 2 or 3, it is characterised in that the organic lipophilic material is
At least one in aliphatic acid, fatty acid ester, grease；The organic hydrophilicity material is alcohol, sugar, amino acid, albumen, polyethylene
At least one in pyrrolidones.
5. risperidone slow-release composition as claimed in claim 4, it is characterised in that the aliphatic acid is oleic acid, stearic acid, the moon
At least one in cinnamic acid, myristic acid, palmitic acid, arachidic acid, mountain Yu acid, lignin acid；The alcohol is that molecular weight is 400-
The polyethylene glycol of 6000Da.
6. the risperidone slow-release composition as described in any one of Claims 1 to 5, it is characterised in that the risperidone slow-release group
In the non-solvent preparing raw material of compound, the weight/mass percentage composition of the Risperidone is 25~60%, the slightly water-soluble polymerization
The weight/mass percentage composition of thing is 39.9-74.9%；Preferably, the non-solvent preparing raw material of the risperidone slow-release composition
In, the weight/mass percentage composition of the Risperidone is 30~55%, and the weight/mass percentage composition of the slightly water-soluble polymer is 44.9-
69.9%；Preferably, in the non-solvent preparing raw material of the risperidone slow-release composition, the quality percentage of the Risperidone contains
It is 35~50% to measure, and the weight/mass percentage composition of the slightly water-soluble polymer is 49.9-64.9%.
7. risperidone slow-release composition as claimed in claim 6, it is characterised in that the slightly water-soluble polymer is poly- third to hand over
At least one in ester, PLGA and their copolymers with polyethylene glycol.
8. risperidone slow-release composition as claimed in claim 7, it is characterised in that the polylactide, lactide coglycolide
Copolymer, the weight average molecular weight of their copolymers with polyethylene glycol are 20000-100000Da；Preferably, described poly- third hand over
Ester, PLGA, the weight average molecular weight of their copolymers with polyethylene glycol are 25000-90000Da；More
Preferably, the polylactide, PLGA, they are equal with the weight average molecular weight of the copolymer of polyethylene glycol
It is 25000-80000Da.
9. risperidone slow-release composition as claimed in claim 7 or 8, it is characterised in that the polylactide, lactide-second
Lactide copolymers, the viscosity of their copolymers with polyethylene glycol are 0.25-0.80dL/g；Preferably, the polylactide,
PLGA, the viscosity of their copolymers with polyethylene glycol are 0.30-0.70dL/g；It is highly preferred that institute
State polylactide, PLGA, the viscosity of their copolymers with polyethylene glycol and be 0.30-0.65dL/g.
10. risperidone slow-release composition as claimed in claim 7, it is characterised in that the slightly water-soluble polymer is poly- third
At least one in lactide, PLGA, its copolymer with polyethylene glycol, and wherein lactide is handed over second
The mol ratio of ester is 100:0~65:35；Preferably, wherein lactide and the mol ratio of glycolide is 100:0~70:30；It is more excellent
Selection of land, wherein lactide are 100 with the mol ratio of glycolide:0~75:25.
The 11. risperidone slow-release composition as described in any one of claim 1~10, it is characterised in that the risperidone slow-release
The preparation method of composition is comprised the following steps：
Be dissolved in the non-solvent preparing raw material in organic solvent by (1a), forms interior oil phase；
Surfactant is dissolved in aqueous medium by (2a), forms outer water phase；
Be added to the interior oil phase that step (1a) is obtained in outer water phase by (3a), is made emulsion, is then evaporated or solvent by solvent
Extraction makes microsphere hardening, the collection particulate in solution, washs and dries, and obtains risperidone slow-release microsphere；
Or
Be dissolved in remaining each material in addition to release regulator contained by the non-solvent preparing raw material in organic solvent by (1b),
Oil phase in being formed；
Release regulator and surfactant are dissolved in aqueous medium by (2b), form outer water phase；
Be added to the interior oil phase that step (1b) is obtained in outer water phase by (3b), is made emulsion, is then evaporated or solvent by solvent
Extraction makes microsphere hardening, the collection particulate in solution, washs and dries, and obtains risperidone slow-release microsphere.
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| WO2018137630A1 (en) * | 2017-01-24 | 2018-08-02 | 广州帝奇医药技术有限公司 | Risperidone sustained release composition and preparation method therefor |
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