CN107213136B - Long-acting sustained-release medicinal preparation and preparation method thereof - Google Patents
Long-acting sustained-release medicinal preparation and preparation method thereof Download PDFInfo
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- CN107213136B CN107213136B CN201710425540.8A CN201710425540A CN107213136B CN 107213136 B CN107213136 B CN 107213136B CN 201710425540 A CN201710425540 A CN 201710425540A CN 107213136 B CN107213136 B CN 107213136B
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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
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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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
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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
- A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
Abstract
The invention discloses a long-acting sustained-release medicinal preparation, which comprises 25-60% of water-insoluble or slightly-soluble medicament and 40-75% of high molecular polymer, wherein after the medicinal preparation is administrated by single intramuscular injection, the ratio of the highest blood concentration to the lowest blood concentration in a main release period is less than 5; under the in vitro simulated release condition, the slope of a linear trend line of the accumulated release curve is less than 8; the daily release amount is less than 8.5%, and the simulated release condition is a buffer solution with the temperature of 37 +/-0.5 ℃ and the pH value of 6.5-8.4. The long-acting sustained-release pharmaceutical preparation prepared by the invention has no obvious release delay period or burst release phenomenon after administration, can quickly reach steady-state blood concentration, can maintain the blood concentration with smaller fluctuation range within a plurality of weeks or longer by single administration, and has quick response speed and good patient compliance.
Description
Technical Field
The invention belongs to the field of long-acting sustained-release pharmaceutical preparations, and particularly relates to a long-acting sustained-release pharmaceutical preparation with quick response, small daytime release rate difference and small blood concentration fluctuation range and a preparation method thereof.
Background
In the process of continuous constant-speed administration (such as intravenous infusion) or fractional constant administration of the drug, the blood concentration can gradually increase, and can reach stable and effective blood concentration through 4-5 half-lives, at the moment, the drug absorption speed and the elimination speed reach balance, the blood concentration is relatively stable at a certain level, and the blood concentration is called as the steady-state blood concentration and is also called as a plateau value.
In the administration regimen, not only the effective blood concentration of the drug is concerned, but also the range of the effective blood concentration is considered. The greater the steady state plasma concentration fluctuations, the more likely it is that drugs with a narrower therapeutic window (e.g., aminophylline, etc.) will be adversely affected as the dosing interval is extended.
The increase of the administration times can improve the steady-state blood concentration and reduce the fluctuation, but can not accelerate the time for reaching the steady-state blood concentration; increasing the dose increases the steady-state plasma concentration, but does not increase the time to reach the steady-state plasma concentration. The time to reach steady state plasma concentration is determined only by the half-life, independent of the dose, the interval and the route of administration, but the dose and the interval can affect the steady state plasma concentration fluctuation.
The sustained-release preparation and other drug delivery systems released at a specific rate reduce the times of drug administration, stabilize the blood concentration, avoid the peak-valley phenomenon, have important values for improving the drug administration compliance of patients, reducing the toxic and side effects and improving the curative effect, and particularly for the symptoms (such as schizophrenia) needing long-term drug administration treatment, the long-acting drug delivery system can greatly reduce the probability of missed drug administration of patients, but has high technical challenge on how to reduce the fluctuation range of the blood concentration at a long drug administration interval.
The marketed long-acting antipsychotic Risperidal Consta (Hengde), which is developed based on the technology disclosed in patent CN1137756, uses PLGA with a molecular weight of about 150kDa as a carrier and risperidone as API, and is injected intramuscularly once every 2 weeks, but only a small amount of drug is released in the first day, and then a drug release lag period of about 3 weeks occurs, so that patients need to rely on oral administration tablets within 3 weeks after the injection of the microspheres to achieve the treatment effect, the clinical use is inconvenient, and the compliance of patients is poor. Therefore, the development is accelerated, the delayed release period is avoided, the administration interval time is long (such as 2 weeks, 4 weeks and more), the steady-state blood concentration can be quickly achieved, and the long-acting or ultra-long-acting sustained-release pharmaceutical preparation with small fluctuation range of the blood concentration can meet the urgent needs of the market.
Disclosure of Invention
The invention aims to provide a long-acting sustained-release pharmaceutical preparation which has no obvious release delay period or burst release phenomenon after administration, can quickly reach steady-state blood concentration, can maintain the blood concentration with smaller fluctuation range within a plurality of weeks or longer by single administration, and has quick response speed and good patient compliance. Meanwhile, the invention also aims to provide a preparation method of the long-acting sustained-release pharmaceutical preparation.
The long-acting sustained-release pharmaceutical preparation is characterized in that the ratio of the highest blood concentration to the lowest blood concentration in the main release period is less than 5, preferably less than 4.5, and more preferably less than 4 in a single intramuscular injection administration.
The main release period refers to a release period in which the blood concentration is higher than the lowest effective concentration. The main release period is not less than 12 days, preferably not less than 14 days.
The long-acting sustained-release pharmaceutical preparation is characterized in that under in vitro simulated release conditions, the slope of a linear trend line of an accumulated release curve is less than 8, preferably less than 7, and more preferably less than 6; the daily release is less than 8.5%, preferably less than 8%, more preferably less than 7.5%.
The simulated release medium is a buffer solution with the temperature of 37 +/-0.5 ℃ and the pH value of 6.5-8.4, and comprises PBS, HEPES, TEA, Tris-HCl and MOPS.
To further approach the practical situation, it is preferable that the simulated release medium is a buffer solution with a pH of 6.8-7.4 at 37 + -0.5 deg.C, including PBS, HEPES, TEA, Tris-HCl, MOPS.
In one embodiment, the simulated release medium is a buffer solution with a pH of 7.4 at 37 + -0.5 deg.C, including PBS, HEPES, TEA, Tris-HCl, MOPS.
Since the body fluid pH will decrease during activity or exercise, the present invention in another embodiment uses a buffer solution with a pH of 6.8 at 37 + -0.5 deg.C, including PBS, HEPES, MOPS for the simulated release medium.
The long-acting sustained-release pharmaceutical preparation comprises a poorly water-soluble/slightly soluble drug and a high molecular polymer.
In the long-acting sustained-release medicinal preparation, the mass percentage of the water-insoluble/slightly soluble medicament is 25-60%, and the mass percentage of the high molecular polymer is 40-75%; preferably, the mass percentage of the water-insoluble/slightly soluble drug is 30-55%, and the mass percentage of the high molecular polymer is 45-70%; further preferably, the mass percentage of the water-insoluble/slightly soluble drug is 35-50%, and the mass percentage of the high molecular polymer is 50-65%.
The high molecular polymer is a biodegradable water-insoluble polymer, and is selected from Polylactide (PLA), Polyglycolide (PGA), poly (lactide-co-glycolide) (PLGA), Polycaprolactone (PCL), and copolymers thereof with polyethylene glycol (such as PLA-PEG, PLGA-PEG-PLGA, PLA-PEG-PLA, PEG-PCL, PCL-PEG-PCL, PEG-PLA-PEG, PEG-PLGA-PEG), polyhydroxybutyric acid, polyhydroxyvaleric acid, polydioxanone (PPDO), polycyanoacrylate, polyanhydride, polyorthoester, polyamide, polyphosphazene, and polyphosphoester, but is not limited to the above water-insoluble polymers.
In a preferred embodiment of the present invention, the high molecular polymer is at least one of Polylactide (PLA), poly (lactide-co-glycolide) (PLGA), and a copolymer of these with polyethylene glycol. As a preferable embodiment of the poorly water soluble/slightly soluble drug sustained-release composition of the present invention, the poorly water soluble polymer is at least one of Polylactide (PLA) and poly (lactide-co-glycolide) (PLGA).
As a preferred embodiment of the present invention, the weight average molecular weight of the Polylactide (PLA), the poly (lactide-co-glycolide) (PLGA) and the copolymer thereof with polyethylene glycol is 20000-50000 Da. Preferably, the weight average molecular weight of the Polylactide (PLA), the lactide-glycolide copolymer (PLGA) and the copolymer of the Polylactide (PLA), the lactide-glycolide copolymer (PLGA) and the polyethylene glycol is 23000-45000 Da. More preferably, the weight average molecular weight of the Polylactide (PLA), the poly (lactide-co-glycolide) (PLGA) and the copolymer thereof with polyethylene glycol are both 25000-40000 Da.
As a preferred embodiment of the present invention, the molecular chain of the high molecular polymer carries an anionic or cationic group, or does not carry an anionic or cationic group. Preferably, the high molecular polymer has a terminal carboxyl group or a terminal ester group. More preferably, the poorly water soluble polymer has a terminal carboxyl group. Because the medicine is a water-insoluble medicine, the high molecular polymer with certain hydrophilicity is used as a carrier, which is more beneficial to eliminating or shortening the delayed release period.
As a preferred embodiment of the invention, the high molecular polymer is Polylactide (PLA), lactide-glycolide copolymer (PLGA), and the molar ratio of lactide to glycolide in the copolymer of the PLA and the PLGA and polyethylene glycol is 100: 0-65: 35; preferably, the high molecular polymer is Polylactide (PLA), lactide-glycolide copolymer (PLGA), and the molar ratio of lactide to glycolide in the copolymer of the PLA and the PLGA and polyethylene glycol is 100: 0-70: 30. More preferably, the high molecular polymer is Polylactide (PLA), lactide-glycolide copolymer (PLGA), and the molar ratio of lactide to glycolide in the copolymer of the PLA and the PLGA and polyethylene glycol is 100: 0-75: 25.
In the long-acting sustained-release pharmaceutical preparation, the high molecular polymer can be a single polymer or a mixture of multiple polymers. E.g., a combination of PLGA and or PLA with the same ratio and molecular weight of Lactide (LA) to Glycolide (GA) but different carrying groups; the molar ratio of Lactide (LA) to Glycolide (GA) and the combination of PLGA and/or PLA which carry the same groups but have different molecular weights, and the difference of the molecular weights is not more than 10 kDa; a combination of PLGA and or PLA of the same molecular weight and carrying groups but different molar ratios of lactide to glycolide, and with the percentage difference of glycolide being no more than 10%; a combination of PLGA and or PLA having different molecular weights, carrying groups and molar ratios of lactide to glycolide, and having a molecular weight difference of no more than 10kDa and a percentage of glycolide difference of no more than 10%.
The molecular weight is a weight average molecular weight, which is a value obtained by detection with a Gel Permeation Chromatograph (GPC).
In a preferred embodiment of the present invention, when the poorly water-soluble polymer is at least one of Polylactide (PLA), a poly (lactide-co-glycolide) (PLGA) and a copolymer thereof with polyethylene glycol, the viscosity of the Polylactide (PLA), the poly (lactide-co-glycolide) (PLGA) and the copolymer thereof with polyethylene glycol is 0.25 to 0.52dL/g (test conditions of 0.5 to 1% (w/v), 25 ℃), preferably 0.27 to 0.47dL/g, and more preferably 0.30 to 0.42 dL/g.
As a preferred embodiment of the present invention, the poorly water soluble/sparingly water soluble drug includes, but is not limited to, at least one of risperidone, paliperidone, aripiprazole, iloperidone, ipiprazole, ziprasidone, anastrozole, donepezil, olanzapine, naltrexone, haloperidol, entecavir, and derivatives thereof.
As a preferred embodiment of the present invention, the poorly water soluble/slightly soluble drug includes, but is not limited to, at least one of risperidone, paliperidone, aripiprazole, iloperidone, entecavir, ipiprazole, and derivatives of the above drugs.
Wherein, the derivatives include but are not limited to paliperidone palmitate, lauroyl aripiprazole, haloperidol decanoate, olanzapine pamoate, ziprasidone mesylate.
More preferably, the poorly water soluble/slightly soluble drug includes, but is not limited to, at least one of risperidone, paliperidone, and paliperidone palmitate.
In some embodiments, in the long-acting sustained-release pharmaceutical preparation, the poorly water soluble/slightly soluble drug is risperidone, paliperidone or paliperidone palmitate, the high molecular polymer is poly (lactide-co-glycolide) (PLGA), the weight average molecular weight is 22000-30000Da, the molar ratio of lactide to glycolide is 72: 28-78: 22, and the intrinsic viscosity is 0.25-0.36 dL/g. The ratio of the maximum blood concentration to the minimum blood concentration of the long-acting sustained-release pharmaceutical preparation in the main release period of a single administration is less than 5, preferably less than 4.5, and more preferably less than 4. Under in vitro simulated release conditions, the slope of the linear trend line of the cumulative release curve of the long-acting sustained-release pharmaceutical preparation is less than 6.5, preferably less than 6, and more preferably less than 5.5; the daily release is less than 8.5%, preferably less than 8%, more preferably less than 7.5%. The main release period of the long-acting sustained-release pharmaceutical preparation is not less than 12 days, preferably not less than 14 days. Preferably, the ratio of the maximum blood concentration to the minimum blood concentration of the long-acting sustained-release pharmaceutical preparation is less than 2 during the 1 st to 14 th days of single administration.
In some embodiments, in the long-acting sustained-release pharmaceutical preparation, the poorly water soluble/slightly soluble drug is risperidone, paliperidone or paliperidone palmitate, the high molecular polymer is poly (lactide-co-glycolide) (PLGA), the weight average molecular weight is 22000-30000Da, the molar ratio of lactide to glycolide is 82: 18-88: 12, and the intrinsic viscosity is 0.25-0.36 dL/g. The ratio of the maximum blood concentration to the minimum blood concentration of the long-acting sustained-release pharmaceutical preparation in the main release period of a single administration is less than 5, preferably less than 4.5, and more preferably less than 4. Under in vitro simulated release conditions, the slope of the linear trend line of the cumulative release curve of the long-acting sustained-release pharmaceutical preparation is less than 5, preferably less than 4.5, and more preferably less than 4; the daily release is less than 5.5%, preferably less than 5%, more preferably less than 4.5%. Preferably, the main release period of the long-acting sustained-release pharmaceutical formulation is not less than 26 days, preferably not less than 28 days. Preferably, the ratio of the maximum blood concentration to the minimum blood concentration of the long-acting sustained-release pharmaceutical preparation is less than 2 during the 1 st to 28 th days of single administration.
In some embodiments, the poorly water soluble/slightly soluble drug is risperidone, the high molecular polymer is poly (lactide-co-glycolide) (PLGA) having a weight average molecular weight of about 25000Da, a molar ratio of lactide to glycolide of about 76:24, and an intrinsic viscosity of about 0.30 dL/g. The ratio of the maximum blood concentration to the minimum blood concentration of the long-acting sustained-release pharmaceutical preparation in the main release period of single administration is about 3.6. Under in vitro simulated release conditions, the slope of the linear trend line of the cumulative release curve of the long-acting sustained-release pharmaceutical preparation is about 5.7; the daily release amount is less than 7.3%. The main release period of the long-acting sustained-release drug preparation is about 14 to 18 days. Preferably, the ratio of the maximum blood concentration to the minimum blood concentration of the long-acting sustained-release pharmaceutical preparation is about 1.7 during the 1 st to 14 th days of a single administration.
In some embodiments, the poorly water soluble/slightly soluble drug is risperidone, the high molecular polymer is poly (lactide-co-glycolide) (PLGA), the weight average molecular weight is about 24000Da, the molar ratio of lactide to glycolide is about 85:15, and the intrinsic viscosity is about 0.29 dL/g. The ratio of the maximum blood concentration to the minimum blood concentration of the long-acting sustained-release pharmaceutical preparation in the main release period of single administration is about 2.5. Under in vitro simulated release conditions, the slope of the linear trend line of the cumulative release curve of the long-acting sustained-release drug preparation is about 2.84; the daily release amount is less than 3.25%. Preferably, the major release period of the long-acting sustained-release pharmaceutical formulation is about 28 to 35 days. Preferably, the ratio of the maximum blood concentration to the minimum blood concentration of the long-acting sustained-release pharmaceutical preparation is about 1.6 during the 1 st to 28 th days of a single administration.
In some embodiments, the poorly water soluble/slightly soluble drug is risperidone, the high molecular polymer is poly (lactide-co-glycolide) (PLGA) having a weight average molecular weight of about 28000Da, a molar ratio of lactide to glycolide of about 75:25, and an intrinsic viscosity of about 0.34 dL/g. The ratio of the maximum blood concentration to the minimum blood concentration of the long-acting sustained-release pharmaceutical preparation in the main release period of single administration is about 3.5. Under in vitro simulated release conditions, the slope of the linear trend line of the cumulative release curve of the long-acting sustained-release pharmaceutical preparation is about 5.7; the daily release amount is less than 7.3%. The main release period of the long-acting sustained-release drug preparation is about 14 to 18 days. Preferably, the ratio of the maximum blood concentration to the minimum blood concentration of the long-acting sustained-release pharmaceutical preparation is about 1.6 during the 1 st to 14 th days of a single administration.
In some embodiments, the poorly water soluble/slightly soluble drug is risperidone, the high molecular polymer is poly (lactide-co-glycolide) (PLGA), the weight average molecular weight is about 27000Da, the molar ratio of lactide to glycolide is about 84:16, and the intrinsic viscosity is about 0.32 dL/g. The ratio of the maximum blood concentration to the minimum blood concentration of the long-acting sustained-release pharmaceutical preparation in the main release period of single administration is about 3.0. Under in vitro simulated release conditions, the slope of the linear trend line of the cumulative release curve of the long-acting sustained-release drug preparation is about 2.84; the daily release amount is less than 4.0%. Preferably, the major release period of the long-acting sustained-release pharmaceutical formulation is about 28 to 35 days. Preferably, the ratio of the maximum blood concentration to the minimum blood concentration of the long-acting sustained-release pharmaceutical preparation is about 1.5 during the 1 st to 28 th days of a single administration.
In a preferred embodiment of the invention, the non-solvent type preparation raw material of the long-acting slow-release pharmaceutical preparation further comprises an excipient with a mass percentage of 0-8%. As a preferred embodiment of the present invention, the excipients include a buffer and an antioxidant.
The buffering agents include, but are not limited to, inorganic and organic acid salts, such as salts of carbonic, acetic, oxalic, citric, phosphoric, hydrochloric acids, including calcium carbonate, calcium hydroxide, calcium croquette fringed pink, calcium oleate, calcium palmitate, calcium stearate, calcium phosphate, calcium acetate, magnesium carbonate, magnesium hydroxide, magnesium phosphate, magnesium myristate, magnesium oleate, magnesium palmitate, magnesium stearate, zinc carbonate, zinc hydroxide, zinc oxide, zinc croquette fringed pink, zinc oleate, zinc acetate, zinc chloride, zinc sulfate, zinc bisulfate, zinc carbonate, zinc nitrate, zinc gluconate, zinc palmitate, zinc stearate, zinc phosphate, sodium carbonate, sodium bicarbonate, sodium bisulfite, sodium thiosulfate, sodium acetate-acetate buffer salts, and combinations thereof. Zinc salts of inorganic and organic acids are preferred. The mass percentage of the buffering agent in the non-solvent preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition is 0-5%.
The antioxidant is at least one of t-butyl p-hydroxyanisole, dibutylphenol, tocopherol, isopropyl myristate, d-a tocopherol acetate, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxyquinone, hydroxycoumarin, butylated hydroxytoluene, fatty acid esters, propylhydroxybenzoate, trihydroxy phenylbutanone, vitamin E-TPGS, rho-hydroxybenzoate; the mass percentage of the antioxidant in the non-solvent preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition is 0-1%.
The long-acting sustained-release pharmaceutical preparation of the present invention is a microsphere, preferably having a geometric particle size of less than 200 μm. Typically, it is about 10 to 200 μm, preferably 15 to 150 μm, and more preferably about 20 to 120 μm. The microsphere particle size is measured by dynamic light scattering methods (e.g., laser diffraction methods), or microscopic techniques (e.g., scanning electron microscopy).
In addition, the invention also provides a preparation method of the long-acting sustained-release medicinal preparation, and in order to realize the purpose, the technical scheme adopted by the invention is as follows:
(1) dissolving a non-solvent preparation raw material in an organic solvent to form an internal oil phase;
(2) dissolving a surfactant in water to form an external aqueous phase;
(3) and (2) mixing the inner oil phase obtained in the step (1) with the outer water phase obtained in the step (2) to prepare emulsion, then hardening the particles in the solution through solvent evaporation or solvent extraction, collecting the particles, washing and drying to obtain the long-acting slow release microspheres of the water-insoluble/slightly soluble drug.
The solvent-free preparation raw material in the step (1) comprises a water-insoluble/slightly soluble drug and a high molecular polymer. In a preferred embodiment of the present invention, the non-solvent type preparation raw material further contains an excipient.
As a preferred embodiment of the preparation method of the long-acting sustained-release pharmaceutical preparation, the mass percentage of the water-insoluble polymer and the organic solvent in the step (1) is 7-12%, preferably; in the step (2), the mass percentage of the surfactant in the external water phase is 1-5%; in the step (3), the volume of the external aqueous phase is 60 times or more the volume of the internal oil phase.
The organic solvent in the step (1) can simultaneously dissolve the water-insoluble/slightly-soluble polymer and the water-insoluble/slightly-soluble drug. The solvent may be a single organic solvent, or two or more organic solvents that are miscible.
The organic solvent is at least one of halogenated hydrocarbon, fatty acid ester and aromatic hydrocarbon; the halogenated hydrocarbon comprises dichloromethane, chloroform, chloroethane, tetrachloroethylene, trichloroethylene, dichloroethane, trichloroethane, carbon tetrachloride, fluorocarbon, chlorobenzene (mono-, di-or tri-substituted), trichlorofluoromethane; the fatty acid ester comprises ethyl acetate and butyl acetate; the aromatic hydrocarbon comprises benzene, toluene, xylene and benzyl alcohol.
Among the organic solvents, halogenated aliphatic hydrocarbon solvents are preferable, and at least one of dichloromethane and chloroform is more preferable. In the inner oil phase, the dosage proportion of the organic solvent is different according to different medicines and is prepared according to actual conditions.
In the preparation method of the long-acting sustained-release pharmaceutical preparation, the external water phase in the step (2) contains the surfactant, and the surfactant can increase the wetting property of an organic phase, improve the stability and the shape of the globule in the emulsification process, avoid the reunion of the globule, reduce the number of the non-encapsulated or partially encapsulated globule particles, and further reduce the initial burst release of the drug in the release process.
The surfactant is a nonionic surfactant, preferably poloxamer, polyvinyl alcohol, polysorbate, polyvinylpyrrolidone and polysaccharide, preferably polyvinyl alcohol.
As a preferred embodiment of the preparation method according to the present invention, the emulsion is prepared in the step (3) by using a device generating high shear force (e.g., a magnetic stirrer, a mechanical stirrer, a high-speed homogenizer, an ultrasonic instrument, a membrane emulsifier, a rotor-stator mixer, a static mixer, a high-pressure homogenizer, etc.) and mixing the organic internal phase and the aqueous external phase to form a homogeneous emulsion.
In the preferred embodiment of the present invention, in the step (3) of the method for preparing a long-acting sustained-release pharmaceutical preparation, the internal oil phase and the external water phase are mixed by using an inline high-speed homogenizer to prepare an emulsion. Wherein, the inner oil phase is fed by a peristaltic pump, and the rotating speed of the peristaltic pump is 50-100 rpm; the external water phase is fed by a screw pump, and the linear velocity of the medium is 2-8 m/s.
When the long-acting sustained-release pharmaceutical formulation is administered as a suspension, it may be formulated with a suitable dispersion medium into a suspension formulation.
The dispersion medium comprises nonionic surfactant (or stabilizer), polyoxyethylene castor oil derivative, cellulose thickener, sodium alginate, hyaluronic acid, dextrin, and starch. Or alternatively, it can be combined with other excipients such as isotonic agent (such as sodium chloride, mannitol, glycerol, sorbitol, lactose, xylitol, maltose, galactose, sucrose, glucose, etc.), pH regulator (such as carbonic acid, acetic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid or salts of these acids, such as sodium carbonate, sodium bicarbonate, etc.), antiseptic (such as p-hydroxybenzoate, propyl p-hydroxybenzoate, benzyl alcohol, chlorobutanol, sorbic acid, boric acid, etc.), etc., made into aqueous solution, solidified by freeze drying, drying under reduced pressure, spray drying, etc., and dissolved in water for injection to obtain dispersion medium for dispersing microspheres before use.
In addition, the sustained-release injection can also be obtained by the following method: microparticles or microspheres are dispersed in vegetable oils (such as sesame oil and corn oil) or vegetable oils added with phospholipids (such as lecithin), or in medium chain triglycerides to obtain an oily suspension.
The microspheres obtained by the present invention can be used in the form of granules, suspensions, implants, injections, adhesives, etc., and can be administered orally or parenterally (intramuscular injection, subcutaneous injection, transdermal administration, mucosal administration (buccal, vaginal, rectal, etc.).
The long acting sustained release pharmaceutical formulations of the present invention may be released over a sustained period of weeks, such as up to about 2 weeks, such as up to about 4 weeks, such as up to about 8 weeks, such as up to about 12 weeks, such as up to about 24 weeks, such as up to about 48 weeks, or longer, and may be adjusted according to the particular pharmaceutical characteristics or therapeutic needs.
The invention aims to provide a long-acting sustained-release medicinal preparation which has no obvious release delay period or burst release phenomenon after administration, can quickly reach steady-state blood concentration, can maintain the blood concentration with smaller fluctuation range within a plurality of weeks or longer by single administration, and has the advantages of quick response speed and good patient compliance. The long-acting sustained-release medicinal preparation is a water-insoluble/slightly soluble medicinal sustained-release composition. The preparation method of the long-acting sustained-release medicinal preparation can quickly and efficiently prepare the long-acting sustained-release medicinal preparation.
The long-acting sustained-release pharmaceutical preparation is suitable for treating acute and chronic schizophrenia and other obvious positive symptoms and negative symptoms of various psychotic states, emotional symptoms related to schizophrenia, Alzheimer disease, viruses, relapse after drug withdrawal, breast cancer and other diseases.
When the slightly water-soluble/slightly water-soluble drug is risperidone, paliperidone or paliperidone palmitate, the long-acting sustained-release pharmaceutical preparation is suitable for treating acute and chronic schizophrenia and other obvious positive symptoms and negative symptoms of various psychotic states and affective symptoms related to schizophrenia.
Drawings
FIGS. 1 to 14 are graphs of cumulative in vitro release curves and linear trend curves of the sustained-release microspheres prepared in examples 1 to 14, respectively;
FIG. 15 is a graph of the in vitro cumulative release curve and linear trend of Hedgel microspheres.
Detailed Description
The above-mentioned contents of the present invention are further described in detail by way of the following examples, but it should not be construed that the scope of the above-mentioned subject matter of the present invention is limited to the following examples, and any technique realized based on the above-mentioned contents of the present invention falls within the scope of the present invention.
Example 1
(1) Dissolving 7.5g of PLGA (20000Da, 0.22dL/g, lactide/glycolide 100/0, COOH, COOH represents a terminal carboxyl group, the same below) in 30mL of dichloromethane, and adding 2.5g of entecavir into the PLGA solution for dissolving to obtain an inner oil phase;
(2) dissolving polyvinyl alcohol in purified water with the concentration of 1% and the volume of 2.4L, and then cooling to 4-8 ℃ to obtain an external water phase;
(3) and (2) injecting the inner oil phase obtained in the step (1) into the outer water phase obtained in the step (2) through a membrane emulsifier (the average pore diameter is about 50 mu m) to prepare emulsion, then stirring for 10 hours to harden the particles, filtering and collecting the particles, washing with ultrapure water, and freeze-drying for 50 hours to obtain the long-acting slow-release entecavir microspheres with the drug loading rate of 22.59% and the geometric particle size of 28-105 mu m.
The drug loading rate (HPLC) and the geometric particle size (laser particle size analyzer) of the obtained microspheres were measured by a conventional method, as follows.
Example 2
(1) Dissolving 7g of PLGA (23000Da, 0.27dL/g, 90/10, COOH) in 31.5mL of dichloromethane, and then adding 3g of anastrozole into the PLGA solution for dissolving to obtain an inner oil phase;
(2) dissolving polyvinyl alcohol in purified water with the concentration of 1% and the volume of 2.5L, and then cooling to 4-8 ℃ to obtain an external water phase;
(3) and (3) mixing the inner oil phase obtained in the step (1) with the outer water phase obtained in the step (2) by using a static mixer (L/D is 30-50) to prepare emulsion, then stirring for 10 hours to harden the particles, filtering and collecting the particles, washing with ultrapure water, and freeze-drying for 50 hours to obtain the long-acting slow-release anastrozole microspheres with the drug loading rate of 27.11 percent and the geometric particle size of 32-110 mu m.
Example 3
(1) Dissolving 6.5g PLGA (22000Da, 0.25dL/g, 88/12, COOH) in 42mL dichloromethane, then adding 3.5g paliperidone into the PLGA solution for dissolving to obtain an inner oil phase;
(2) dissolving polyvinyl alcohol in purified water with concentration of 1.5% and volume of 3.4L, and cooling to 4-8 deg.C to obtain external water phase;
(3) and (3) mixing the inner oil phase (peristaltic pump 70rpm) obtained in the step (1) and the outer water phase (screw pump 4m/s) obtained in the step (2) by using a pipeline type homogenizer to prepare emulsion, then continuously stirring for 10 hours to harden the particles, filtering and collecting the particles, washing with ultrapure water, and freeze-drying for 50 hours to obtain the long-acting slow-release paliperidone microspheres with the drug loading rate of 32.08 percent and the geometric particle size of 25-95 microns.
Example 4
(1) 6.2g of PLGA (24000Da, 0.29dL/g, 85/15, COOH) is dissolved in 38mL of dichloromethane, and then 3.8g of risperidone is added into the PLGA solution to be dissolved, so as to obtain an inner oil phase;
(2) dissolving polyvinyl alcohol in purified water with concentration of 2.0% and volume of 3.0L, and cooling to 4-8 deg.C to obtain external water phase;
(3) and (2) mixing the inner oil phase (60 rpm of a peristaltic pump) obtained in the step (1) and the outer water phase (3 m/s of a screw pump) obtained in the step (2) by using a pipeline type homogenizer to prepare emulsion, then stirring for 10 hours to harden the particles, filtering and collecting the particles, washing with ultrapure water, and freeze-drying for 50 hours to obtain the long-acting sustained-release risperidone microspheres with the drug loading rate of 35.00% and the geometric particle size of 27-112 microns.
Example 5
(1) 6.0g of PLGA (27000Da, 0.32dL/g, 84/16, COOH) is dissolved in 38mL of dichloromethane, and then 4.0g of risperidone is added into the PLGA solution to be dissolved, so as to obtain an inner oil phase;
(2) dissolving polyvinyl alcohol in purified water with concentration of 2.5% and volume of 3.0L, and cooling to 4-8 deg.C to obtain external water phase;
(3) and (2) mixing the internal oil phase obtained in the step (1) and the external water phase obtained in the step (2) by mechanical stirring (1300rpm) to prepare emulsion, then stirring for 10 hours to harden the particles, filtering and collecting the particles, washing with ultrapure water, and freeze-drying for 50 hours to obtain the long-acting sustained-release risperidone microspheres with the drug loading rate of 36.85% and the geometric particle size of 30-122 microns.
Example 6
(1) Dissolving 5.5g PLGA (30000Da, 0.36dL/g, 80/20, COOH) in 41mL dichloromethane, and then adding 4.5g paliperidone palmitate into the PLGA solution for dissolving to obtain an inner oil phase;
(2) dissolving polyvinyl alcohol in purified water with the concentration of 3.0% and the volume of 3.2L, and then cooling to 4-8 ℃ to obtain an external water phase;
(3) and (2) mixing the inner oil phase (80 rpm of a peristaltic pump) obtained in the step (1) and the outer water phase (6 m/s of a screw pump) obtained in the step (2) by using a pipeline type homogenizer to prepare emulsion, then stirring for 10 hours to harden the particles, filtering and collecting the particles, washing with ultrapure water, and freeze-drying for 50 hours to obtain the long-acting slow-release paliperidone palmitate microsphere with the drug loading rate of 40.26 percent and the geometric particle size of 35-132 mu m.
Example 7
(1) 6.5g PLGA (22000Da, 0.25dL/g, 78/22, COOH) is dissolved in 37mL dichloromethane, then 3.5g paliperidone is added into the PLGA solution to be dissolved, and an inner oil phase is obtained;
(2) dissolving polyvinyl alcohol in purified water with the concentration of 1.5% and the volume of 3L, and then cooling to 4-8 ℃ to obtain an external water phase;
(3) and (2) mixing the inner oil phase (50 rpm of a peristaltic pump) obtained in the step (1) and the outer water phase (2 m/s of a screw pump) obtained in the step (2) by using a pipeline type homogenizer to prepare emulsion, then continuously stirring for 10 hours to harden the particles, filtering and collecting the particles, washing with ultrapure water, and freeze-drying for 50 hours to obtain the long-acting slow-release paliperidone microspheres with the drug loading rate of 31.55 percent and the geometric particle size of 30-117 microns.
Example 8
(1) Dissolving 6.2g PLGA (25000Da, 0.30dL/g, 76/24, COOH) in 38mL dichloromethane, and then adding 3.8g risperidone into the PLGA solution for dissolving to obtain an inner oil phase;
(2) dissolving polyvinyl alcohol in purified water with concentration of 2.0% and volume of 3.0L, and cooling to 4-8 deg.C to obtain external water phase;
(3) and (2) mixing the inner oil phase (60 rpm of a peristaltic pump) obtained in the step (1) and the outer water phase (3 m/s of a screw pump) obtained in the step (2) by using a pipeline type homogenizer to prepare emulsion, then stirring for 10 hours to harden the particles, filtering and collecting the particles, washing with ultrapure water, and freeze-drying for 50 hours to obtain the long-acting sustained-release risperidone microspheres with the drug loading rate of 34.08 percent and the geometric particle size of 22-98 mu m.
Example 9
(1) Dissolving 6.0g of PLGA (28000Da, 0.34dL/g, 75/25, COOH) in 36mL of dichloromethane, and then adding 4.0g of risperidone into the PLGA solution for dissolving to obtain an inner oil phase;
(2) dissolving polyvinyl alcohol in purified water with the concentration of 3.0% and the volume of 2.9L, and then cooling to 4-8 ℃ to obtain an external water phase;
(3) and (2) mixing the internal oil phase obtained in the step (1) and the external water phase obtained in the step (2) by mechanical stirring (1500rpm) to prepare emulsion, then stirring for 10 hours to harden the particles, filtering and collecting the particles, washing with ultrapure water, and freeze-drying for 50 hours to obtain the long-acting sustained-release risperidone microspheres with the drug loading rate of 35.85% and the geometric particle size of 38-125 microns.
Example 10
(1) Dissolving 5.5g PLGA (30000Da, 0.36dL/g, 72/28, COOH) in 38mL dichloromethane, and adding 4.5g paliperidone palmitate into the PLGA solution for dissolving to obtain an inner oil phase;
(2) dissolving polyvinyl alcohol in purified water with the concentration of 3.5% and the volume of 3.1L, and then cooling to 4-8 ℃ to obtain an external water phase;
(3) and (2) mixing the inner oil phase (peristaltic pump 100rpm) obtained in the step (1) and the outer water phase (screw pump 8m/s) obtained in the step (2) by using an in-line homogenizer to prepare emulsion, then stirring for 10 hours to harden the particles, filtering and collecting the particles, washing with ultrapure water, and freeze-drying for 50 hours to obtain the long-acting slow-release paliperidone palmitate microsphere with the drug loading rate of 40.88% and the geometric particle size of 31-130 microns.
Example 11
(1) Dissolving 5.5g of PLGA (35000Da, 0.39dL/g, 85/15, COOH) in 41mL of dichloromethane, and then adding 4.5g of ipiprazole into the PLGA solution for dissolving to obtain an inner oil phase;
(2) dissolving polyvinyl alcohol in purified water with the concentration of 3.0% and the volume of 3.3L, and then cooling to 4-8 ℃ to obtain an external water phase;
(3) and (2) mixing the inner oil phase obtained in the step (1) and the outer water phase obtained in the step (2) by mechanical stirring (1500rpm) to prepare emulsion, then continuing stirring for 10 hours to harden the particles, filtering and collecting the particles, washing with ultrapure water, and freeze-drying for 50 hours to obtain the long-acting slow-release epipiprazole microspheres with the drug loading rate of 41.56% and the geometric particle size of 28-122 microns.
Example 12
(1) Dissolving 5.0g of PLGA (40000Da, 0.42dL/g, 75/25, COOH) in 40mL of dichloromethane, and then adding 5.0g of iloperidone into the PLGA solution for dissolving to obtain an inner oil phase;
(2) dissolving polyvinyl alcohol in purified water with the concentration of 3.5% and the volume of 3.2L, and then cooling to 4-8 ℃ to obtain an external water phase;
(3) and (2) mixing the internal oil phase obtained in the step (1) and the external water phase obtained in the step (2) by mechanical stirring (1400rpm) to prepare emulsion, then continuing stirring for 10 hours to harden the particles, filtering and collecting the particles, washing with ultrapure water, and freeze-drying for 50 hours to obtain the long-acting sustained-release iloperidone microspheres with the drug loading rate of 46.30% and the geometric particle size of 35-133 m.
Example 13
(1) Dissolving 4.5g PLGA (40000Da, 0.47dL/g, 70/30, COOH) in 44mL dichloromethane, and then adding 5.5g aripiprazole into the PLGA solution for dissolving to obtain an inner oil phase;
(2) dissolving polyvinyl alcohol in purified water with concentration of 4% and volume of 3.5L, and cooling to 4-8 deg.C to obtain external water phase;
(3) mixing the inner oil phase obtained in the step (1) and the outer water phase obtained in the step (2) by using a high-speed homogenizer (5000rpm, the radius of a rotor is 2.5-3cm) to prepare emulsion, then continuously stirring for 10 hours to harden the particles, filtering and collecting the particles, washing with ultrapure water, and freeze-drying for 50 hours to obtain the long-acting sustained-release aripiprazole microspheres with the drug loading rate of 50.32% and the geometric particle size of 34-127 mu m.
Example 14
(1) Dissolving 4.0g of PLGA (50000Da, 0.52dL/g, 65/35, COOH) in 40mL of dichloromethane, and then adding 6.0g of donepezil into the PLGA solution for dissolving to obtain an inner oil phase;
(2) dissolving polyvinyl alcohol in purified water with the concentration of 5.0% and the volume of 3.8L, and then cooling to 4-8 ℃ to obtain an external water phase;
(3) and (2) mixing the internal oil phase obtained in the step (1) and the external water phase obtained in the step (2) by using a high-pressure homogenizer (700bar) to prepare emulsion, then continuously stirring for 10 hours to harden the particles, filtering and collecting the particles, washing with ultrapure water, and freeze-drying for 50 hours to obtain the long-acting sustained-release donepezil microspheres with the drug loading rate of 55.19% and the geometric particle size of 38-110 microns.
Example 15
In vitro simulated release
The test method comprises the following steps: the microspheres of examples 1 to 14 and commercially available Hedgel microspheres, each 20mg, were precisely weighed and placed in 200mL Erlenmeyer flasks (3 samples in parallel), 100mL of PBS buffer (containing 0.05% Tween 80 and 0.05% sodium azide) at pH 7.4 was added, the mixture was placed in a constant temperature water bath shaker at 37. + -. 0.5 ℃ and 100rpm, 2mL of the release solution was taken out at predetermined time points (1 day, 2 days, and then samples were taken every 2 days), and the mixture was supplemented with an equal amount of fresh medium and placed in the constant temperature water bath shaker to continue the release test. The drug release amount of the extract was measured by High Performance Liquid Chromatography (HPLC), then a cumulative release curve (containing a linear trend line) was prepared, and the daily release rate was calculated (averaged every 2 days of sampling), with the results shown in fig. 1 to 14 and table 1.
TABLE 1 in vitro daily Release Rate (%)
TABLE 2 gradient of in vitro release trend line and maximum daily release rate of the sustained-release microspheres
As can be seen from tables 1-2 and FIGS. 1-15, compared with the commercial product (Hengde), the sustained release microspheres of the invention have no burst release effect and no obvious delayed release period, the first day release rate is not more than 2%, the microspheres can be released in 66 days in a nearly zero-order trend, the difference of the drug release rates is small, and the excellent sustained release effect is shown. The phenomenon of slow early-stage release and aggravated later-stage release is avoided, the defects of products sold on the market are overcome, the inconvenience caused by the fact that patients still need to take common preparations orally after injection and taking medicines is avoided, and the medication compliance and convenience are obviously improved.
The invention simultaneously tests the release behaviors of the microspheres of examples 1 to 14 and commercially available Hedgel microspheres in HEPES buffer solution (containing 0.05% Tween 80 and 0.05% sodium azide) with pH 6.8, and the results show that under the condition of pH 6.8, the release is slightly accelerated, but the release has no burst effect, no obvious delayed release period exists, the release rate in the first day is not more than 2-4%, the release can be carried out in 14-60 days with a nearly zero-order trend, the difference of the drug release rates is small, and the excellent slow release effect is shown.
Example 16
Animal testing
The test method comprises the following steps: new Zealand big-ear white rabbits (2.0 kg-3.0 kg) were collected, 6 rabbits in each group (randomly grouped) and half of the male and female rabbits, and 1.2mL of a physiological saline solution containing 0.5% CMC-Na containing suspension containing risperidone microspheres and Hedgel microspheres prepared in examples 4, 5, 8 and 9 was intramuscularly injected into each group, and 5mL of blood was collected from the marginal veins of the rabbits at 0.04d, 0.5d, 1d, 2d, 7d, 14d, 21d, 28d, 35d, 42d, 49d, 56d, 63d, 77d and 84d, respectively, wherein the drug content of the sustained-release microspheres in each dose of the suspension was 18 mg. All collected blood samples were centrifuged at 8000rpm for 10min, the supernatants were frozen at-70 ℃ and the plasma concentrations in all the blood samples were determined by methods known in the art and averaged. The results are shown in Table 3.
TABLE 3 concentration of Long-acting sustained-release risperidone microspheres after administration (ng/mL)
| Time/d | Example 4 | Example 5 | Example 8 | Example 9 | Hengde |
| 0.04 | 1.68 | 1.08 | 1.42 | 1.87 | 2.72 |
| 0.5 | 5.15 | 4.84 | 5.32 | 5.85 | 9.88 |
| 1 | 8.35 | 9.89 | 11.27 | 12.45 | 5.04 |
| 2 | 10.54 | 11.39 | 14.25 | 15.37 | 3.26 |
| 7 | 11.68 | 13.87 | 19.15 | 20.36 | 1.56 |
| 14 | 10.85 | 14.46 | 11.27 | 10.52 | 2.50 |
| 21 | 12.95 | 13.42 | 2.86 | 2.56 | 5.12 |
| 28 | 11.84 | 9.64 | 0.35 | 0.44 | 32.20 |
| 35 | 6.74 | 4.87 | 0 | 0 | 12.50 |
| 42 | 2.16 | 1.02 | - | - | 4.33 |
| 49 | 0.51 | 0.15 | 0.97 | ||
| 56 | 0 | 0 | 0.18 | ||
| 63 | - | - | 0 |
TABLE 4 maximum and minimum blood concentrations and ratios
| Item | Example 4 | Example 5 | Example 8 | Example 9 | Hengde |
| Max(ng/mL) | 12.95 | 14.46 | 19.15 | 20.36 | 32.20 |
| Min(ng/mL) | 5.15 | 4.84 | 5.32 | 5.85 | 5.12 |
| Ratio of | 2.51 | 2.99 | 3.60 | 3.48 | 6.29 |
As can be seen from Table 3, even in the case of a single administration, the long-acting sustained-release risperidone microspheres of the present invention showed superior sustained-release effect to the commercially available products, increasing the blood concentration (about 5ng/mL as a reference value) soon after the administration, whereas the commercially available products required as much as 2-3 weeks to reach 5ng/mL or more except for the stress phenomenon at the first day of the administration. The blood concentration of the commercial product after administration reaches an untreated window within about 21 days, but the blood concentration of the long-acting slow-release risperidone microsphere can be within the treated window from the first day after administration, and the blood concentration can be continuously maintained within the range of 5-20ng/mL for more than 14 days, even 35 days, which is 2 times that of the commercial product. As can be seen from table 4, during the main release period (about 5ng/mL is used as the base limit), after a single administration, the blood concentration fluctuation range of the long-acting slow-release risperidone microsphere of the present invention is significantly smaller than that of the commercially available product, and under the condition of the same action cycle, the blood concentration fluctuation range of the long-acting slow-release risperidone microsphere of the present invention is less than 57% of that of the commercially available product, and under the condition of longer action cycle, the blood concentration fluctuation range of the long-acting slow-release risperidone microsphere of the present invention is smaller, even less than 48% of that of the commercially available product. Therefore, the long-acting sustained-release microspheres have more excellent sustained-release effect and are more competitive with the commercial products.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (8)
1. A long-acting sustained-release pharmaceutical preparation comprises 25-60% of a poorly water-soluble or slightly soluble drug and 40-75% of a high polymer, and is characterized in that the high polymer is a lactide-glycolide copolymer (PLGA), the weight average molecular weight is 22000-35000Da, the molar ratio of lactide to glycolide is 100: 0-75: 25, and the intrinsic viscosity is 0.25-0.39dL/g, wherein the long-acting sustained-release pharmaceutical preparation is microspheres, the particle size of the microspheres is 20-150 mu m, and the poorly water-soluble/slightly soluble drug is risperidone, paliperidone or paliperidone palmitate; the microsphere is prepared by the following method:
(1) dissolving a non-solvent type preparation raw material in an organic solvent to form an inner oil phase, wherein the non-solvent type preparation raw material comprises a water-insoluble or slightly soluble drug and a high molecular polymer;
(2) dissolving a surfactant in water to form an external aqueous phase;
(3) mixing the inner oil phase obtained in the step (1) and the outer water phase obtained in the step (2) to prepare emulsion, then hardening the particles in the solution through solvent evaporation or solvent extraction, collecting the particles, washing and drying to obtain the long-acting slow-release microspheres of the water-insoluble/slightly soluble drug,
wherein the mass percentage of the water-insoluble polymer and the organic solvent in the step (1) is 7-12%; in the step (2), the mass percentage of the surfactant in the external water phase is 1-5%; in the step (3), the volume of the external water phase is more than 60 times of the volume of the internal oil phase; the surfactant is a nonionic surfactant, and the nonionic surfactant is polyvinyl alcohol.
2. The long-acting sustained-release pharmaceutical preparation according to claim 1, wherein the high molecular polymer is poly (lactide-co-glycolide) (PLGA), the weight average molecular weight is 22000-30000Da, the molar ratio of lactide to glycolide is 72: 28-78: 22, and the intrinsic viscosity is 0.25-0.36 dL/g.
3. The long-acting sustained-release pharmaceutical preparation according to claim 1, wherein the high molecular polymer is a poly (lactide-co-glycolide) (PLGA), the weight average molecular weight is 22000-30000Da, the molar ratio of lactide to glycolide is 82: 18-88: 12, and the intrinsic viscosity is 0.25-0.36 dL/g.
4. The long-acting sustained-release pharmaceutical formulation according to claim 1, wherein the poorly water-soluble/slightly soluble drug is risperidone, the high molecular polymer is poly (lactide-co-glycolide) (PLGA), the weight average molecular weight is 25000Da, the molar ratio of lactide to glycolide is 76:24, and the intrinsic viscosity is 0.30 dL/g.
5. The long-acting sustained-release pharmaceutical formulation according to claim 2, wherein the poorly water-soluble/slightly soluble drug is risperidone, the high molecular polymer is poly (lactide-co-glycolide) (PLGA), the weight average molecular weight is 24000Da, the molar ratio of lactide to glycolide is 85:15, and the intrinsic viscosity is 0.29 dL/g.
6. The long-acting sustained-release pharmaceutical formulation according to claim 1, wherein the poorly water-soluble/slightly soluble drug is risperidone, the high molecular polymer is poly (lactide-co-glycolide) (PLGA), the weight average molecular weight is 28000Da, the molar ratio of lactide to glycolide is 75:25, and the intrinsic viscosity is 0.34 dL/g.
7. The long-acting sustained-release pharmaceutical formulation according to claim 1, wherein the poorly water-soluble/slightly soluble drug is risperidone, the high molecular polymer is a poly (lactide-co-glycolide) (PLGA) having a weight average molecular weight of 27000Da, a molar ratio of lactide to glycolide of 84:16, and an intrinsic viscosity of 0.32 dL/g.
8. Use of a long acting sustained release pharmaceutical formulation according to any one of claims 1 to 7 in the manufacture of a medicament for the treatment of acute and chronic schizophrenia as well as other positive and negative overt symptoms of various psychotic states, affective symptoms associated with schizophrenia.
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| RU2731489C1 (en) * | 2017-11-30 | 2020-09-03 | Джи2Джибио, Инк. | Preparation for injection with delayed release containing donepezil and method for obtaining said preparation |
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| CN108815138A (en) * | 2018-06-27 | 2018-11-16 | 丽珠医药集团股份有限公司 | Risperidone or derivatives thereof sustained-release micro-spheres, preparation method and the usage |
| CN111617043B (en) * | 2020-06-17 | 2022-05-06 | 山东谷雨春生物科技有限公司 | Long-acting pharmaceutical composition for treating schizophrenia and preparation method and device thereof |
| CN112587505A (en) * | 2020-10-16 | 2021-04-02 | 长春斯菲尔生物科技有限公司 | Olanzapine pamoate sustained-release microparticle preparation and preparation method thereof |
| CN113081952A (en) * | 2021-04-12 | 2021-07-09 | 山东谷雨春生物科技有限公司 | Long-acting injection gel containing entecavir |
| CN115184496A (en) * | 2022-07-11 | 2022-10-14 | 烟台大学 | Method for measuring release rate of aripiprazole long-acting dry suspension injection |
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