WO2018223894A1 - Préparation pharmaceutique à libération lente à action prolongée et son procédé de préparation - Google Patents

Préparation pharmaceutique à libération lente à action prolongée et son procédé de préparation Download PDF

Info

Publication number
WO2018223894A1
WO2018223894A1 PCT/CN2018/089383 CN2018089383W WO2018223894A1 WO 2018223894 A1 WO2018223894 A1 WO 2018223894A1 CN 2018089383 W CN2018089383 W CN 2018089383W WO 2018223894 A1 WO2018223894 A1 WO 2018223894A1
Authority
WO
WIPO (PCT)
Prior art keywords
release
long
pharmaceutical preparation
lactide
acting sustained
Prior art date
Application number
PCT/CN2018/089383
Other languages
English (en)
Chinese (zh)
Inventor
赖树挺
郑阳
曹付春
连远发
刘锋
Original Assignee
广州帝奇医药技术有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 广州帝奇医药技术有限公司 filed Critical 广州帝奇医药技术有限公司
Publication of WO2018223894A1 publication Critical patent/WO2018223894A1/fr

Links

Images

Classifications

    • 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
    • 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
    • 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
    • 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)

Definitions

  • the invention belongs to the field of long-acting sustained-release pharmaceutical preparations, in particular to a long-acting sustained-release pharmaceutical preparation with fast onset, small difference in daytime release rate and small fluctuation range of blood drug concentration, and a preparation method thereof.
  • the blood concentration will gradually increase, and the stable and effective blood concentration will reach 4 to 5 half-lives.
  • the speed and the elimination speed are balanced, and the blood drug concentration is relatively stable at a certain level.
  • the blood concentration is called the steady state blood concentration, which is also called the ping value.
  • the effective blood concentration of the drug not only the effective blood concentration of the drug but also the range of effective blood drug concentrations should be considered.
  • the fluctuation of the steady-state blood concentration is greater, and the drug having a narrow therapeutic window (such as aminophylline, etc.) is more likely to have an adverse effect.
  • Increasing the number of doses can increase the steady-state blood concentration and reduce its fluctuation, but it can not accelerate the time to reach the steady-state blood concentration; increasing the dose can increase the steady-state blood concentration, but it can not accelerate the steady state.
  • a drug delivery system such as a slow-release preparation released at a specific rate reduces the number of medications, stabilizes the blood concentration, and avoids peaks and valleys. It is of great value in improving patient compliance, reducing side effects, and improving efficacy, especially for needs. Long-term administration of treatments (such as schizophrenia), long-acting drug delivery system can greatly reduce the probability of patients leaking, but how to reduce the fluctuation of blood concentration during a longer dosing interval, has a high Technically challenging.
  • Risperidal Consta (Hengde), a listed long-acting antipsychotic drug developed based on the technology disclosed in the patent CN1137756, uses PLGA with a molecular weight of about 150kDa as a carrier, and risperidone as an API. It is injected intramuscularly every 2 weeks, but only on the first day. A small amount of drug release, followed by a drug release stagnation period of about 3 weeks, so the patient needs to rely on oral administration of tablets to achieve therapeutic effect within 3 weeks after the injection of the microsphere, which is inconvenient for clinical use, and the patient complies with Poor sex.
  • the object of the present invention is to provide a delayed release or burst release without significant release after administration, which can quickly reach a steady state blood concentration, and can maintain a small fluctuation range in a few weeks or longer in a single administration.
  • the long-acting sustained-release pharmaceutical preparation of blood concentration has a fast onset of action and good patient compliance.
  • another object of the present invention is to provide a method for preparing the long-acting sustained-release pharmaceutical preparation.
  • the long-acting sustained-release pharmaceutical preparation is characterized in that, when administered in a single intramuscular injection, the ratio of the highest blood concentration to the lowest blood concentration during the main release period is less than 5, preferably less than 4.5, more preferably less than 4.
  • the main release period refers to a release period in which the blood drug concentration is higher than the minimum onset concentration.
  • the main release period is not less than 12 days, preferably not less than 14 days.
  • the long-acting sustained-release pharmaceutical preparation characterized in that, under in vitro simulated release conditions, the slope of the linear trend line of the cumulative release profile is less than 8, preferably less than 7, more preferably less than 6, and 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 of 37 ⁇ 0.5 ° C and a pH of 6.5-8.4, including PBS, HEPES, TEA, Tris-HCl, MOPS.
  • the simulated release medium is a buffer solution of 37 ⁇ 0.5° C. and a pH of 6.8-7.4, including PBS, HEPES, TEA, Tris-HCl, MOPS.
  • the simulated release medium employs a buffer solution of 37 ⁇ 0.5 ° C, pH 7.4, including PBS, HEPES, TEA, Tris-HCl, MOPS.
  • the simulated release medium uses a buffer solution of 37 ⁇ 0.5° C. and a pH of 6.8, including PBS, HEPES, and MOPS.
  • the long-acting sustained release pharmaceutical preparation comprises a water-insoluble/slightly soluble drug and a high molecular polymer.
  • the water-insoluble/slightly soluble drug has a mass percentage of 25 to 60%, and the high molecular weight polymer has a mass percentage of 40 to 75%; preferably, The water-insoluble/slightly soluble drug has a mass percentage of 30 to 55%, and the high molecular weight polymer has a mass percentage of 45 to 70%; further preferably, the water-insoluble/slightly soluble drug The mass percentage is 35-50%, and the mass percentage of the high molecular polymer is 50-65%.
  • the high molecular polymer of the present invention is a biodegradable water-insoluble polymer selected from the group consisting of polylactide (PLA), polyglycolide (PGA), lactide-glycolide copolymer (PLGA), and poly Caprolactone (PCL), their copolymer with polyethylene glycol (such as PLA-PEG, PLGA-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, poly A composition of any one or more of phosphazene and polyphosphate, but is not limited to the above-described poorly water-soluble polymer.
  • PLA polylactide
  • PGA polyglycolide
  • PLGA lact
  • the high molecular polymer is at least one of polylactide (PLA), lactide-glycolide copolymer (PLGA), and a copolymer thereof with polyethylene glycol.
  • the poorly water-soluble polymer is in a polylactide (PLA) or a lactide-glycolide copolymer (PLGA). At least one.
  • the polylactide (PLA), lactide-glycolide copolymer (PLGA), and a copolymer of these and polyethylene glycol have a weight average molecular weight of 20,000 to 50,000 Da.
  • the polylactide (PLA), lactide-glycolide copolymer (PLGA), and copolymers thereof with polyethylene glycol have a weight average molecular weight of 23,000-45,000 Da.
  • the polylactide (PLA), lactide-glycolide copolymer (PLGA), and copolymers thereof with polyethylene glycol have a weight average molecular weight of 25,000 to 40,000 Da.
  • the molecular chain of the high molecular polymer carries an anionic or cationic group or does not carry an anionic or cationic group.
  • 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. Since the drug is a poorly water-soluble drug, it is more advantageous to eliminate or shorten the delayed release period by using a polymer having a certain hydrophilicity as a carrier.
  • the high molecular polymer is a polylactide (PLA), a lactide-glycolide copolymer (PLGA), a lactide in a copolymer thereof with polyethylene glycol, and
  • the molar ratio of glycolide is from 100:0 to 65:35; preferably, the high molecular polymer is polylactide (PLA), lactide-glycolide copolymer (PLGA), and they are combined with polyethylene glycol.
  • the molar ratio of lactide to glycolide in the copolymer of alcohol is from 100:0 to 70:30.
  • the high molecular polymer is polylactide (PLA), lactide-glycolide copolymer (PLGA), lactide and glycolide in their copolymer with polyethylene glycol.
  • the molar ratio is from 100:0 to 75:25.
  • the high-molecular polymer may be a single polymer or a mixture of a plurality of polymers.
  • the difference in the percentage of lactide is not more than 10%; the molecular weight, the carrier group and the combination of PLGA and PLA which are different in the molar ratio of lactide to glycolide, and the difference in molecular weight is not more than 10 kDa, and the difference in the difference in the
  • the above molecular weight is a weight average molecular weight and is a value obtained by gel permeation chromatography (GPC) detection.
  • the poorly water-soluble polymer is at least one of polylactide (PLA), lactide-glycolide copolymer (PLGA), and a copolymer thereof with polyethylene glycol.
  • the polylactide (PLA), lactide-glycolide copolymer (PLGA), and their copolymers with polyethylene glycol have a viscosity of 0.25-0.52 dL/g (test condition is 0.5-1). % (w/v), 25 ° C), preferably 0.27-0.47 dL/g, more preferably 0.30-0.42 dL/g.
  • the water-insoluble/slightly soluble drug includes, but is not limited to, risperidone, paliperidone, aripiprazole, iloperidone, epiliperazole, ziprasidone, At least one of anastrozole, donepezil, olanzapine, naltrexone, haloperidol, entecavir, and derivatives of the above drugs.
  • the water-insoluble/slightly soluble drug includes, but is not limited to, risperidone, paliperidone, aripiprazole, iloperidone, entecavir, epidazole, and the like. At least one of the derivatives.
  • the derivative includes, but is not limited to, paliperidone palmitate, aripiprazole lauroyl, haloperidol citrate, olanzapine pamoate, ziprasidone mesylate.
  • the water-insoluble/slightly soluble drug includes, but is not limited to, at least one of risperidone, paliperidone, and paliperidone palmitate.
  • the water-insoluble/slightly soluble drug is risperidone, paliperidone or paliperidone palmitate
  • the high molecular polymer is lactide.
  • a glycolide copolymer PLGA having a weight average molecular weight of 22,000 to 30,000 Da, a molar ratio of lactide to glycolide of 72:28 to 78:22, and an intrinsic viscosity of 0.25 to 0.36 dL/g.
  • the ratio of the highest blood drug concentration to the lowest blood drug concentration of the long-acting sustained-release pharmaceutical preparation during the main release period of a single administration is less than 5, preferably less than 4.5, more preferably less than 4.
  • the slope of the linear trend line of the cumulative release profile of the long-acting sustained release pharmaceutical formulation is less than 6.5, preferably less than 6, more preferably less than 5.5; the daily release is less than 8.5%, preferably less than 8%, more It is 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.
  • the long-acting sustained-release pharmaceutical preparation has a ratio of the highest blood concentration to the lowest blood concentration of less than 2 during the first to the 14th day of the single administration.
  • the water-insoluble/slightly soluble drug is risperidone, paliperidone or paliperidone palmitate
  • the high molecular polymer is lactide.
  • a glycolide copolymer PLGA having a weight average molecular weight of 22,000 to 30,000 Da, a molar ratio of lactide to glycolide of 82:18 to 88:12, and an intrinsic viscosity of 0.25 to 0.36 dL/g.
  • the ratio of the highest blood drug concentration to the lowest blood drug concentration of the long-acting sustained-release pharmaceutical preparation during the main release period of a single administration is less than 5, preferably less than 4.5, more preferably less than 4.
  • the linear trend line of the cumulative release profile of the long-acting sustained release pharmaceutical formulation has a slope of less than 5, preferably less than 4.5, more preferably less than 4, in an in vitro simulated release condition; a daily release of less than 5.5%, preferably less than 5%, more It is preferably less than 4.5%.
  • the long-acting sustained-release pharmaceutical preparation has a main release period of not less than 26 days, preferably not less than 28 days.
  • the long-acting sustained-release pharmaceutical preparation has a ratio of the highest blood concentration to the lowest blood concentration of less than 2 during the first 28th day of the single administration.
  • the water-insoluble/slightly soluble drug is risperidone
  • the high molecular polymer is lactide-glycolide copolymer (PLGA)
  • PLGA lactide-glycolide copolymer
  • the molecular weight is about 25,000 Da
  • the molar ratio of lactide to glycolide is about 76:24
  • the intrinsic viscosity is about 0.30 dL/g.
  • the ratio of the highest blood concentration to the lowest blood concentration of the long-acting sustained-release pharmaceutical preparation during the main release period of a single administration is about 3.6.
  • the slope of the linear trend line of the cumulative release profile of the long-acting sustained release pharmaceutical formulation was about 5.7; the daily release was less than 7.3%.
  • the main release period of the long-acting sustained-release pharmaceutical preparation is about 14-18 days.
  • the ratio of the highest blood concentration to the lowest blood concentration during the first to the 14th day of the single administration of the long-acting sustained-release pharmaceutical preparation is about 1.7.
  • the water-insoluble/slightly soluble drug is risperidone
  • the high molecular polymer is lactide-glycolide copolymer (PLGA)
  • PLGA lactide-glycolide copolymer
  • the molecular weight is about 24000 Da
  • the molar ratio of lactide to glycolide is about 85:15
  • the intrinsic viscosity is about 0.29 dL/g.
  • the ratio of the highest blood concentration to the lowest blood concentration of the long-acting sustained-release pharmaceutical preparation during the main release period of a single administration is about 2.5.
  • the slope of the linear trend line of the cumulative release profile of the long-acting sustained release pharmaceutical formulation was about 2.84; the daily release was less than 3.25%.
  • the main release period of the long-acting sustained-release pharmaceutical preparation is about 28-35 days.
  • the long-acting sustained-release pharmaceutical preparation has a ratio of the highest blood concentration to the lowest blood concentration of about 1.6 during the first 28th day of the single administration.
  • the water-insoluble/slightly soluble drug is risperidone
  • the high molecular polymer is lactide-glycolide copolymer (PLGA)
  • PLGA lactide-glycolide copolymer
  • the molecular weight is about 28,000 Da
  • the molar ratio of lactide to glycolide is about 75:25
  • the intrinsic viscosity is about 0.34 dL/g.
  • the ratio of the highest blood concentration to the lowest blood concentration of the long-acting sustained-release pharmaceutical preparation during the main release period of a single administration is about 3.5.
  • the slope of the linear trend line of the cumulative release profile of the long-acting sustained release pharmaceutical formulation was about 5.7; the daily release was less than 7.3%.
  • the main release period of the long-acting sustained-release pharmaceutical preparation is about 14-18 days.
  • the long-acting sustained-release pharmaceutical preparation has a ratio of the highest blood concentration to the lowest blood concentration of about 1.6 during the first to the 14th day of a single administration.
  • the water-insoluble/slightly soluble drug is risperidone
  • the high molecular polymer is lactide-glycolide copolymer (PLGA)
  • PLGA lactide-glycolide copolymer
  • the molecular weight is about 27,000 Da
  • the molar ratio of lactide to glycolide is about 84:16
  • the intrinsic viscosity is about 0.32 dL/g.
  • the ratio of the highest blood concentration to the lowest blood concentration of the long-acting sustained-release pharmaceutical preparation during the main release period of a single administration is about 3.0.
  • the slope of the linear trend line of the cumulative release profile of the long-acting sustained release pharmaceutical formulation was about 2.84; the daily release was less than 4.0%.
  • the main release period of the long-acting sustained-release pharmaceutical preparation is about 28-35 days.
  • the long-acting sustained-release pharmaceutical preparation has a ratio of the highest blood concentration to the lowest blood concentration of about 1.5 during the first 28th day of the single administration.
  • the non-solvent-type preparation raw material of the long-acting sustained-release pharmaceutical preparation further comprises an excipient having a mass percentage of 0 to 8%.
  • the excipient comprises a buffer and an antioxidant.
  • the buffering agent includes, but is not limited to, mineral acids and organic acid salts, such as salts of carbonic acid, acetic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid, including calcium carbonate, calcium hydroxide, calcium myristate, calcium oleate, palm.
  • mineral acids and organic acid salts such as salts of carbonic acid, acetic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid, including calcium carbonate, calcium hydroxide, calcium myristate, calcium oleate, palm.
  • the buffering agent is present in an amount of from 0 to 5% by mass in the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition.
  • the antioxidants are tert-butyl-p-hydroxyanisole, dibutylphenol, tocopherol, isopropyl myristate, tocopheryl daacetate, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butyl Hydroxyguanidine, hydroxycoumarin, butylated hydroxytoluene, decanoic acid fatty acid ester, propyl hydroxybenzoate, hydroxybutanone, vitamin E, vitamin E-TPGS, ⁇ -hydroxybenzoate At least one of the antioxidants; the antioxidant is in a non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition in a mass percentage of 0 to 1%.
  • the long-acting sustained-release pharmaceutical preparation of the present invention is a microsphere, and the microsphere preferably has a geometric particle diameter of less than 200 ⁇ m. Typically, it is about 10 to 200 ⁇ m, preferably 15 to 150 ⁇ m, more preferably about 20 to 120 ⁇ m.
  • the particle size of the microspheres is measured by a dynamic light scattering method (for example, laser diffraction method) or a microscopic technique (such as scanning electron microscopy).
  • the present invention also provides a preparation method of the long-acting sustained-release pharmaceutical preparation as described above, and in order to achieve the object, the technical solution adopted by the present invention is:
  • the non-solvent-type preparation raw material in the step (1) includes a water-insoluble/slightly soluble drug and a high molecular polymer.
  • the non-solvent-type preparation raw material further contains an excipient.
  • the mass percentage of the poorly water-soluble polymer and the organic solvent in the step (1) is 7 to 12%, preferably; the step (2)
  • the mass percentage of the surfactant in the outer aqueous phase is from 1 to 5%; in the step (3), the volume of the outer aqueous phase is more than 60 times the volume of the inner oil phase.
  • the organic solvent in the step (1) can simultaneously dissolve a water-insoluble/slightly soluble polymer, a water-insoluble/slightly soluble drug.
  • the solvent may be a single organic solvent or a miscible two or more organic solvents.
  • the organic solvent is at least one of a halogenated hydrocarbon, a fatty acid ester, and an aromatic hydrocarbon;
  • the halogenated hydrocarbon includes dichloromethane, chloroform, ethyl chloride, tetrachloroethylene, trichloroethylene, dichloroethane, Trichloroethane, carbon tetrachloride, fluorocarbon, chlorobenzene (mono, di, trisubstituted), trichlorofluoromethane;
  • the fatty acid ester comprises ethyl acetate, butyl acetate;
  • the aromatic hydrocarbon comprises benzene , toluene, xylene, benzyl alcohol.
  • a halogenated aliphatic hydrocarbon solvent is preferred, and at least one of dichloromethane and chloroform is more preferred.
  • the proportion of the organic solvent is different according to different drugs, and is formulated according to actual conditions.
  • the outer aqueous phase of the step (2) contains a surfactant, the surfactant can increase the wetting property of the organic phase, and improve the small liquid bead during the emulsification process.
  • the stability and shape avoids the re-polymerization of small droplets and reduces the number of unencapsulated or partially encapsulated pellets, thereby reducing the initial burst release of the drug during release.
  • the surfactant is a nonionic surfactant, preferably a poloxamer, a polyvinyl alcohol, a polysorbate, a polyvinylpyrrolidone and a polysaccharide, preferably a polyvinyl alcohol.
  • the apparatus for preparing the emulsion in the step (3) employs a device for generating high shear force (such as a magnetic stirrer, a mechanical stirrer, a high-speed homogenizer, an ultrasound system, Membrane emulsifier, rotor-stator mixer, static mixer, high pressure homogenizer, etc.), the organic internal phase is mixed with the aqueous external phase to form a uniform emulsion.
  • a device for generating high shear force such as a magnetic stirrer, a mechanical stirrer, a high-speed homogenizer, an ultrasound system, Membrane emulsifier, rotor-stator mixer, static mixer, high pressure homogenizer, etc.
  • the inner oil phase and the outer aqueous phase are mixed to form an emulsion using a line type high-speed homogenizer.
  • the inner oil phase is fed by a peristaltic pump, the peristaltic pump speed is 50-100 rpm; the outer water phase is fed by a screw pump, and the medium linear velocity is 2-8 m/s.
  • the long-acting sustained-release pharmaceutical preparation When administered as a suspension, it can be in the form of a suspension preparation with a suitable dispersion medium.
  • the dispersion medium includes a nonionic surfactant (or stabilizer), a polyoxyethylene castor oil derivative, a cellulose thickener, sodium alginate, hyaluronic acid, dextrin, and starch. Alternatively, it may be combined with other excipients such as isotonic agents (such as sodium chloride, mannitol, glycerol, sorbitol, lactose, xylitol, maltose, galactose, sucrose, glucose, etc.), pH adjusters.
  • preservatives eg, parabens, propylparaben, benzyl alcohol
  • chlorobutanol e.g., chlorobutanol
  • sorbic acid boric acid, etc., etc.
  • a dispersion medium that disperses the microspheres.
  • sustained-release injections can also be obtained by dispersing microparticles or microspheres in vegetable oils such as sesame oil and corn oil or vegetable oils supplemented with phospholipids such as lecithin, or in medium chain triglycerides. To obtain an oily suspension.
  • microspheres obtained by the 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, menstrual injection). Dermal administration, mucosal administration (intracrine, intravaginal, rectal, etc.).
  • the long-acting sustained release pharmaceutical formulation of the present invention can be sustained for several weeks or more, 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. For example, up to about 48 weeks, or longer, can be adjusted to specific drug characteristics or treatment needs.
  • the object of the present invention is to provide a delayed release or burst release without significant release after administration, which can quickly reach a steady state blood concentration, and can maintain a small fluctuation range in a few weeks or longer in a single administration.
  • the long-acting sustained-release drug preparation of blood concentration has a fast onset and good patient compliance.
  • the long-acting sustained-release pharmaceutical preparation is a water-insoluble/slightly soluble drug sustained-release composition.
  • the preparation method of the long-acting sustained-release pharmaceutical preparation of the invention can quickly and efficiently prepare the long-acting sustained-release pharmaceutical preparation of the invention.
  • the long-acting sustained-release pharmaceutical preparation is suitable for acute and chronic schizophrenia as well as obvious positive symptoms and obvious negative symptoms of various psychiatric states, emotional symptoms associated with schizophrenia, Alzheimer's disease, Treatment of diseases such as viruses, relapse after detoxification, and breast cancer.
  • the long-acting sustained-release pharmaceutical preparation is suitable for acute and chronic schizophrenia and various other mental diseases when the water-insoluble/slightly soluble drug is risperidone, paliperidone or paliperidone palmitate Significant positive symptoms of sexual status and significant negative symptoms, treatment of emotional symptoms associated with schizophrenia.
  • 1 to 14 are cumulative release curves and linear trend lines of the long-acting sustained-release microspheres prepared in Examples 1-14, respectively;
  • Figure 15 is an in vitro cumulative release curve and a linear trend line graph of Hengde microspheres.
  • the inner oil phase obtained in the step (1) is injected into the outer aqueous phase of the step (2) to form an emulsion by a membrane emulsifier (average pore diameter of about 50 ⁇ m), and then the mixture is stirred for 10 hours to harden the particles, and the particles are collected by filtration to be ultrapure. After washing with water and freeze-drying for 50 h, a long-acting sustained-release entecavir microsphere with a drug loading rate of 22.59% and a geometric particle size of 28-105 ⁇ m was obtained.
  • a membrane emulsifier average pore diameter of about 50 ⁇ m
  • microspheres were tested for their drug loading rate (HPLC) and geometric particle size (laser particle size analyzer) by the usual methods, the same below.
  • the cells were washed with ultrapure water and lyophilized for 50 hours to obtain long-acting sustained-release anastrozole microspheres with a drug loading rate of 27.11% and a geometric particle size of 32-110 ⁇ m.
  • step (3) The inner oil phase obtained by the step (1) (peristaltic pump 70 rpm) and the outer water phase of the step (2) (screw pump 4 m/s) are mixed by an in-line homogenizer to prepare an emulsion, and then the stirring is continued for 10 hours to make the particles.
  • the cells were hardened, collected by filtration, washed with ultrapure water, and lyophilized for 50 hours to obtain long-acting sustained-release paliperidone microspheres having a drug loading rate of 32.08% and a geometric particle size of 25-95 ⁇ m.
  • step (3) The internal oil phase obtained by the step (1) (peristaltic pump 60 rpm) and the external aqueous phase of the step (2) (screw pump 3 m/s) are mixed into an emulsion by a line homogenizer, and then the mixture is stirred for 10 hours to harden the particles.
  • the microparticles were collected by filtration, washed with ultrapure water, and lyophilized for 50 h to obtain long-acting sustained-release risperidone microspheres having a drug loading rate of 35.00% and a geometric particle size of 27-112 ⁇ m.
  • step (3) The internal oil phase obtained by the step (1) (peristaltic pump 80 rpm) and the external aqueous phase of the step (2) (screw pump 6 m/s) are mixed into an emulsion by a line homogenizer, and then stirred for 10 hours to harden the particles.
  • the microparticles were collected by filtration, washed with ultrapure water, and lyophilized for 50 h to obtain a long-acting sustained-release palmiticin paliperone microsphere having a drug loading rate of 40.26% and a geometric particle size of 35-132 ⁇ m.
  • step (3) The inner oil phase obtained by the step (1) (peristaltic pump 50 rpm) and the outer water phase of the step (2) (screw pump 2 m/s) are mixed into an emulsion by a line homogenizer, and then the stirring is continued for 10 hours to make the particles.
  • the cells were hardened, collected by filtration, washed with ultrapure water, and lyophilized for 50 hours to obtain long-acting sustained-release paliperidone microspheres having a drug loading rate of 31.55% and a geometric particle size of 30-117 ⁇ m.
  • step (3) The internal oil phase obtained by the step (1) (peristaltic pump 60 rpm) and the external aqueous phase of the step (2) (screw pump 3 m/s) are mixed into an emulsion by a line homogenizer, and then the mixture is stirred for 10 hours to harden the particles.
  • the microparticles were collected by filtration, washed with ultrapure water, and lyophilized for 50 h to obtain long-acting sustained-release risperidone microspheres having a drug loading rate of 34.08% and a geometric particle size of 22-98 ⁇ m.
  • step (3) mixing the inner oil phase obtained in the step (1) with the outer water phase in the step (2) to form an emulsion by a high-speed homogenizer (5000 rpm, rotor radius 2.5-3 cm), and then stirring for 10 hours to harden the particles, and collecting by filtration.
  • the microparticles were washed with ultrapure water and lyophilized for 50 h to obtain long-acting sustained-release aripiprazole microspheres with a drug loading rate of 50.32% and a geometric particle size of 34-127 ⁇ m.
  • step (3) mixing the inner oil phase obtained in step (1) with the outer water phase in step (2) to form an emulsion by a high-pressure homogenizer (700 bar), and then stirring for 10 hours to harden the particles, and collecting the particles by filtration to obtain ultrapure water. After washing and freeze-drying for 50 hours, a long-acting sustained-release donepezil microsphere with a drug loading rate of 55.19% and a geometric particle size of 38-110 ⁇ m was obtained.
  • a high-pressure homogenizer 700 bar
  • Test method Precision weighed the microspheres of Examples 1-14 and 20mg of the commercially available Hengde microspheres in a 200mL Erlenmeyer flask (3 samples in parallel), and added PBS buffer pH 7.4 (0.05%) Tween 80, 0.05% sodium azide) 100 mL, placed in a 37 ⁇ 0.5 ° C, 100 rpm constant temperature water bath shaker, take 2 mL of release solution at a preset time point (1 day, 2 days, then every 2 days after sampling) After adding an equal amount of fresh medium, it was placed in a constant temperature water bath oscillator to continue the release test. The extract was detected by high performance liquid chromatography (HPLC), and then the cumulative release curve (including the linear trend line) was calculated, and the daily release rate (averaged every 2 days) was calculated. The results are shown in Figures 1-14. And Table 1.
  • HPLC high performance liquid chromatography
  • Example 2 Example 3
  • Example 4 Example 5
  • Example 6 Example 7
  • Example 8 1 0.40 0.60 1.10 0.90 1.20 1.70 1.30 1.42 2 1.10 1.60 1.30 1.20 2.10 2.40 2.20 2.15 3/4 1.00 1.95 1.15 1.65 2.85 3.05 3.40 3.62 5/6 1.15 2.15 0.90 2.00 3.30 3.40 3.45 4.00 7/8 1.30 2.15 1.50 2.55 3.40 3.55 3.95 5.25 9/10 1.70 2.10 1.75 2.85 3.70 3.95 4.55 6.30 11/12 1.75 2.15 2.25 2.45 3.85 4.00 5.15 7.30 13/14 1.80 2.10 2.65 2.70 4.00 4.35 5.40 7.25 15/16 1.80 2.10 2.60 2.85 3.20 3.90 5.55 6.60 17/18 1.80 2.30 2.75 2.85 2.80 3.75 4.95 5.70 19/20 2.10 2.15 2.85 3.15 2.80 3.85 4.70 2.10 21/22 1.50 2.00 2.65 3.15 2.45 3.40 3.30 - 23/24 1.50 1.70 2.55 3.15 2.50 3.05 2.75
  • Example 10 Example 11
  • Example 12 Example 13
  • Example 14 Hengde 1 1.90 1.70 1.26 1.12 1.70 1.86 0.75 2 2.42 2.90 2.44 1.97 2.80 3.37 0.27 3/4 3.59 4.05 1.80 4.36 4.30 4.89 0.19 5/6 4.70 4.60 1.80 5.35 5.60 5.00 0.09 7/8 5.40 6.00 1.75 6.55 6.60 4.75 0.16 9/10 6.80 7.30 2.65 7.20 7.90 4.40 0.26 11/12 7.10 7.50 2.65 7.10 7.95 3.65 0.59 13/14 7.30 7.33 2.75 6.60 6.80 2.70 0.60 15/16 6.65 5.92 2.75 4.30 4.60 3.55 0.71 17/18 5.05 3.75 2.75 3.50 2.15 4.20 0.95 19/20 1.30 1.25 2.90 2.15 1.65 2.85 0.48 21/22 - - 2.25 1.15 - 2.30 1.21 23/24 - - 1.75 - 2.05 3.92
  • the sustained release microspheres of the present invention have no burst effect relative to the commercially available product (Hengde), and there is no significant delayed release period, and the first day release rate does not exceed 2%, and can be released in a near-zero trend within 66 days, the drug release rate is small, showing a superior sustained release effect.
  • the early release is slow and the late release is intensified, overcoming the shortcomings of the commercially available products, so that the patient can avoid the inconvenience caused by taking the oral preparation after the injection, significantly increasing the compliance and convenience of administration.
  • the present invention simultaneously tested the release behavior of the microspheres of Examples 1-14 and commercially available Hengde microspheres in HEPES buffer (0.05% Tween 80, 0.05% sodium azide) at pH 6.8, and the results were tested. It shows that under the condition of pH 6.8, although the release is slightly faster, there is still no burst effect, and there is no obvious delayed release period. The first day release rate does not exceed 2-4%, and it can be close to zero within 14-60 days. The level of trend release, the difference in drug release rate is small, showing superior sustained release effect.
  • Test method New Zealand white rabbits weighing 2.0kg-3.0kg, each group of 6 (randomized groups), male and female, each group were intramuscularly injected with risper prepared in Examples 4, 5, 8, and 9. a suspension of 1.2 mL of a physiological saline solution containing 0.5% CMC-Na of ketone microspheres and Hengde microspheres, and the drug content of the sustained release microspheres in each suspension of the suspension is 18 mg, respectively at 0.04d. 0.5 mL, 1d, 2d, 7d, 14d, 21d, 28d, 35d, 42d, 49d, 56d, 63d, 77d and 84d were taken 5 mL from the rabbit ear vein.
  • 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 twenty one 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
  • the long-acting sustained-release risperidone microsphere of the present invention exhibits a superior sustained-release effect relative to a commercially available product, and is rapidly increased after administration.
  • the blood concentration of the drug within 21 days does not reach the treatment window, and the long-acting sustained-release risperidone microsphere of the present invention can be in the treatment window from the first day after administration, and the blood concentration continues.
  • Maintaining in the range of 5-20 ng/mL can last for more than 14 days, even up to 35 days, twice as much as commercially available products.
  • the fluctuation of blood concentration is significantly higher than that of the commercially available product.
  • the blood concentration of the long-acting sustained-release risperidone microsphere of the present invention fluctuates less than 57% of the commercially available product, and the action period is longer, the long-term effect of the present invention
  • the blood concentration of sustained-release risperidone microspheres fluctuated even less, even less than 48% of commercially available products. It can be seen that the long-acting sustained-release microsphere of the present invention has a superior sustained-release effect and is more competitive than a commercially available product.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Optics & Photonics (AREA)
  • Nanotechnology (AREA)
  • Biomedical Technology (AREA)
  • Physics & Mathematics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une préparation pharmaceutique à libération lente à action prolongée. La préparation pharmaceutique contient 25 % à 60 % d'un médicament insoluble dans l'eau ou peu soluble et 40 % à 75 % d'un polymère à poids moléculaire élevé. Après que la préparation pharmaceutique est soumise à un temps d'administration par injection intramusculaire, le rapport d'une concentration plasmatique maximale à une concentration plasmatique minimale dans une période de libération principale est inférieur à 5; la pente d'une ligne de tendance linéaire d'une courbe de libération cumulative est inférieure à 8 dans une condition de libération simulée in vitro; la quantité de libération quotidienne est inférieure à 8,5 %; et la condition de libération simulée est une solution tampon ayant la température de 37±0.5°C et le pH de 6,5 à 8,4. La préparation pharmaceutique à libération lente à action prolongée préparée dans la présente invention a les effets bénéfiques qu'une période de retard de libération évidente ou phénomène de libération initiale rapide à très court terme (également bien connu sous l'anglicisme « burst release ») sont évités après l'administration, une concentration plasmatique à l'état stable peut être obtenue rapidement, la concentration plasmatique avec une plage de fluctuation relativement petite peut être maintenue pendant plusieurs semaines ou plus après une administration unique, et la préparation pharmaceutique peut prendre un effet rapidement et présente une bonne conformité avec un patient.
PCT/CN2018/089383 2017-06-07 2018-05-31 Préparation pharmaceutique à libération lente à action prolongée et son procédé de préparation WO2018223894A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710425540.8A CN107213136B (zh) 2017-06-07 2017-06-07 一种长效缓释药物制剂及其制备方法
CN201710425540.8 2017-06-07

Publications (1)

Publication Number Publication Date
WO2018223894A1 true WO2018223894A1 (fr) 2018-12-13

Family

ID=59947846

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/089383 WO2018223894A1 (fr) 2017-06-07 2018-05-31 Préparation pharmaceutique à libération lente à action prolongée et son procédé de préparation

Country Status (2)

Country Link
CN (1) CN107213136B (fr)
WO (1) WO2018223894A1 (fr)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106727358A (zh) * 2017-01-24 2017-05-31 广州帝奇医药技术有限公司 阿立哌唑及其衍生物的缓释组合物与该缓释组合物的制备方法
CN107213136B (zh) * 2017-06-07 2021-06-01 广州帝奇医药技术有限公司 一种长效缓释药物制剂及其制备方法
US20200101054A1 (en) * 2017-11-30 2020-04-02 G2Gbio, Inc. Sustained-release injection preparation containing donepezil and preparation method therefor
CN108498456B (zh) * 2018-05-16 2021-01-01 丽珠医药集团股份有限公司 一种阿立哌唑缓释微球及其制备方法
CN108815138B (zh) * 2018-06-27 2024-05-03 珠海市丽珠微球科技有限公司 利培酮或其衍生物缓释微球、其制备方法及用途
CN111617043B (zh) * 2020-06-17 2022-05-06 山东谷雨春生物科技有限公司 一种治疗精神分裂症的长效药物组合物及其制备方法和装置
CN112587505A (zh) * 2020-10-16 2021-04-02 长春斯菲尔生物科技有限公司 一种奥氮平双羟萘酸盐缓释微粒制剂及其制备方法
CN113081952A (zh) * 2021-04-12 2021-07-09 山东谷雨春生物科技有限公司 一种含有恩替卡韦的长效注射凝胶
CN115184496A (zh) * 2022-07-11 2022-10-14 烟台大学 测定阿立哌唑长效干混悬注射剂的释放度的方法
CN115212174B (zh) * 2022-07-18 2024-02-20 辉粒药业(苏州)有限公司 一种载阿立哌唑长效缓释微球及其制备方法
CN116650497A (zh) * 2022-09-30 2023-08-29 广州帝奇医药技术有限公司 一种抗病毒药物组合物及其制备工艺与应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106727358A (zh) * 2017-01-24 2017-05-31 广州帝奇医药技术有限公司 阿立哌唑及其衍生物的缓释组合物与该缓释组合物的制备方法
CN106727589A (zh) * 2017-01-24 2017-05-31 广州帝奇医药技术有限公司 帕利哌酮及其衍生物的缓释组合物与该缓释组合物的制备方法
CN107213136A (zh) * 2017-06-07 2017-09-29 广州帝奇医药技术有限公司 一种长效缓释药物制剂及其制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101653422B (zh) * 2008-08-20 2013-03-20 山东绿叶制药有限公司 利培酮缓释微球、其制备方法和用途
CN101584652B (zh) * 2009-06-19 2012-06-20 上海医药集团股份有限公司 利培酮缓释凝胶注射剂及其制备方法
HUE032310T2 (hu) * 2011-04-25 2017-09-28 Shandong luye pharmaceutical co ltd Nyújtott risperidon-leadású mikrogömb kompozíció
CN106580868B (zh) * 2017-01-24 2020-06-16 广州帝奇医药技术有限公司 一种植入剂及其制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106727358A (zh) * 2017-01-24 2017-05-31 广州帝奇医药技术有限公司 阿立哌唑及其衍生物的缓释组合物与该缓释组合物的制备方法
CN106727589A (zh) * 2017-01-24 2017-05-31 广州帝奇医药技术有限公司 帕利哌酮及其衍生物的缓释组合物与该缓释组合物的制备方法
CN107213136A (zh) * 2017-06-07 2017-09-29 广州帝奇医药技术有限公司 一种长效缓释药物制剂及其制备方法

Also Published As

Publication number Publication date
CN107213136A (zh) 2017-09-29
CN107213136B (zh) 2021-06-01

Similar Documents

Publication Publication Date Title
WO2018223894A1 (fr) Préparation pharmaceutique à libération lente à action prolongée et son procédé de préparation
WO2018137631A1 (fr) Composition à libération prolongée de médicament peu soluble dans l'eau ou légèrement soluble dans l'eau et son procédé de préparation
WO2018166502A1 (fr) Composition pharmaceutique à libération prolongée faiblement/légèrement soluble dans l'eau
WO2018137627A1 (fr) Composition à libération prolongée d'aripiprazole et d'un dérivé correspondant, et procédé de préparation correspondant
Giri et al. Prospects of pharmaceuticals and biopharmaceuticals loaded microparticles prepared by double emulsion technique for controlled delivery
RU2449785C2 (ru) Мицеллярная композиция амфифильного блок-сополимера, содержащая таксан, и способ ее получения
JP5345141B2 (ja) コア／シェル構造を有するマイクロスフェア
JP5165239B2 (ja) 制御放出処方物の調製のための方法
Zhang et al. Design of controlled release PLGA microspheres for hydrophobic fenretinide
EP2866797B1 (fr) Composition pharmaceutique injectable stable d'antagoniste des récepteurs à la neurokinine 1 et procédé de préparation associé
JP2010505819A (ja) デポ型注射剤組成物とその調製方法
WO2018137629A1 (fr) Composition à libération prolongée de rispéridone, et procédé de préparation de cette dernière
KR20180131077A (ko) 방출제어가 용이한 서방성 약물 미립자의 제조방법
US20040097419A1 (en) Organic compounds
US20230062487A1 (en) Sustained-release matrices for adventitial or periadventitial neural ablation and uses thereof
WO2018137628A1 (fr) Composition à libération prolongée de palipéridone et son dérivé et procédé de préparation
CN112972388A (zh) 卡利拉嗪释放制剂
JP2016527308A (ja) エンテカビル微小球及びこれを含む非経口投与用医薬組成物
US11154504B2 (en) Sustained release cyclosporine-loaded microparticles
Martinez-Sancho et al. Poly (D, L-lactide-co-glycolide) microspheres for long-term intravitreal delivery of aciclovir: influence of fatty and non-fatty additives
WO2018137630A1 (fr) Composition à libération prolongée de rispéridone et son procédé de préparation
WO2023274414A1 (fr) Microsphère pour la libération stable de fulvestrant, et son procédé de préparation
KR20190125940A (ko) 약물 함유 plga 미립구 및 그의 제조방법
US11992559B2 (en) Microsphere formulations comprising lurasidone and methods for making and using the same
CN101254169A (zh) 含抗结核病药物的缓释剂

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18813458

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 08/04/2020)

122 Ep: pct application non-entry in european phase

Ref document number: 18813458

Country of ref document: EP

Kind code of ref document: A1