WO2017186074A1 - Procédé de préparation de microparticules à libération prolongée, microparticules à libération prolongée et leur utilisation - Google Patents

Procédé de préparation de microparticules à libération prolongée, microparticules à libération prolongée et leur utilisation Download PDF

Info

Publication number
WO2017186074A1
WO2017186074A1 PCT/CN2017/081637 CN2017081637W WO2017186074A1 WO 2017186074 A1 WO2017186074 A1 WO 2017186074A1 CN 2017081637 W CN2017081637 W CN 2017081637W WO 2017186074 A1 WO2017186074 A1 WO 2017186074A1
Authority
WO
WIPO (PCT)
Prior art keywords
water
microparticles
solid dispersion
organic solvent
acid
Prior art date
Application number
PCT/CN2017/081637
Other languages
English (en)
Chinese (zh)
Inventor
刘锋
赖树挺
郑阳
曹付春
连远发
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 WO2017186074A1 publication Critical patent/WO2017186074A1/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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/095—Oxytocins; Vasopressins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/31—Somatostatins
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy

Definitions

  • the invention belongs to the field of water-soluble medicines, in particular to a preparation method of sustained-release microparticles, a preparation of sustained-release microparticles and sustained-release microparticles in an implantable sustained-release pharmaceutical composition.
  • DDS Drug Delivery System
  • microparticles there have been various methods for preparing microparticles, such as solvent evaporation, coacervation, spray drying, and spray freeze drying.
  • the solvent is used in the aqueous phase, which can be subdivided into a single emulsion method (Oil/Water, O/W; Water/Oil, W/O) and a double emulsion method (Water/Oil/Water, W). /O/W; Water/Oil/Oil, W/O/O).
  • An improved double emulsification method (such as CN102245210 A, CN1826170 B) directly suspends the polypeptide powder in an organic phase to form a suspension (S/O), and then disperses the suspension into the aqueous phase. In the middle, a complex emulsion of S/O/W is formed. Since the polypeptide powder is generally insoluble in the intermediate organic phase solvent, this method can avoid the diffusion of the internal aqueous phase to the outer aqueous phase in the W 1 /O/W 2 double emulsification method, thereby increasing the encapsulation efficiency.
  • the size of the pre-prepared active material particles is very important.
  • the diameter of the solid protein particles is increased from 5 micrometers to 20 micrometers, not only the initial release rate is doubled, but also the microencapsulation rate. From 80% to 20%.
  • the protein or polypeptide lyophilized powder generally obtained has an average particle diameter of 10 to 1000 ⁇ m.
  • a typical protein and polypeptide freeze-dried powder has an average particle diameter of about 10 to 500 ⁇ m.
  • the drug will not be well encapsulated, resulting in a result of Or the encapsulation efficiency is low, or the sustained release result is unsatisfactory (previous drug release is large, and the late drug release is insufficient), or the prepared microparticles are too large in particle size to be administered by injection; at the same time, the shape of the drug particles It also affects the shape of the particles.
  • the particle size of the prepared particles is slightly smaller than that of the particles (that is, the particle radius is much larger than the thickness of the polymer layer), and then each particle may be coated with only one or a few active material particles, thereby It leads to the release of very few drugs in the early stage, and the release of the drug in the late stage is released quickly, which does not achieve the sustained release effect.
  • An improved double emulsification method (CN102233129 B, CN 102871969 A, CN102266294 B, etc.), preparing a small particle size of an active substance with one or more additives (such as dextran, polyethylene glycol, sodium alginate, etc.)
  • additives such as dextran, polyethylene glycol, sodium alginate, etc.
  • the particles are then washed away with some or all of the additives with an organic solvent to obtain small particles of porous, semi-emptied or hollowed active material, which are then prepared by an S/O/hO process.
  • This method adds a more complicated step in the preparation of small particles and requires removal of the additives therein with an organic solvent.
  • additives are water-soluble substances, and if not completely removed, it is easy to affect the release effect, accelerate the release of active substances, or form a gel (such as high molecular weight dextran, sodium alginate), which may lead to particle breakage, drugs Delay in release or incomplete release.
  • a gel such as high molecular weight dextran, sodium alginate
  • a further optimized preparation method (U S 5556642), dissolving the water-soluble active substance and the polymer in a co-solvent, then removing the organic solvent by evaporation to obtain a solid dispersion, and then dissolving the solid dispersion in an organic solvent, passing O/ The W method prepares microparticles.
  • This method overcomes the shortcomings of the traditional S/O/W method without drug release in the early stage, and the rapid release of drug release in the later stage.
  • the process of preparing a solid by volatile organic solvent is not conducive to temperature-sensitive active materials, and it is easy to cause denaturation; if the organic solvent is volatilized at a lower temperature, the active substance is aggregated and precipitated when solidified due to slow evaporation of the solvent, drying.
  • the active material in the subsequent solid dispersion also exists in a large volume, such as a block, a ribbon, or a filament, which causes difficulty or waste to the subsequent process of preparing the microparticles, and also causes unstable release.
  • the object of the present invention is to provide a sustained-release composition prepared by an emulsification-solvent volatilization method without preparing a small-diameter drug powder in advance, which is simple in process and can ensure the biological activity of the active substance and an ideal encapsulation efficiency. And excellent method of sustained release effect.
  • the present invention provides a preparation method of sustained-release microparticles, which is prepared at a normal temperature or a low temperature throughout the whole process, and is very advantageous for a high-temperature sensitive drug, and can maintain the active material to the greatest extent. Biological activity.
  • the technical scheme adopted by the invention is: a preparation method of sustained-release particles, comprising the following steps:
  • the particles in the emulsion are solidified by solvent evaporation or solvent extraction, the particles are collected, washed several times with the organic solvent D, and then washed several times with ultrapure water to remove the surfactant attached to the surface of the particles, and then dried.
  • the sustained release microparticles are obtained; wherein the organic solvent D is incapable of dissolving a water-soluble drug and a poorly water-soluble polymer, which is miscible with the oil solution, and has good solubility to the surfactant.
  • the water-soluble drug comprises a basic substance having a molecular weight of less than about 3350 Da or a substance containing a basic group (such as an alkaloid, a short peptide, an antagonist, an antibiotic, a small molecule nucleic acid) and a salt thereof, and a molecular weight of more than about 3350 Da.
  • a basic substance or a substance containing a basic group and a salt thereof such as a polypeptide, a protein, a nucleic acid, an antibody, an antigen, an antibiotic, etc.
  • the water-soluble drug is at least one of a protein drug, a peptide drug, and a nucleic acid drug.
  • the water soluble drug has a molecular weight of less than about 3350 Da.
  • the protein includes a natural, synthetic, semi-synthetic or recombinant compound or protein, or a basic constituent structure comprising an alpha amino acid covalently linked by a peptide bond, or is functionally related.
  • globular proteins such as albumin, globulin, histone
  • fibrin such as collagen, elastin, keratin
  • compound proteins which may contain one or more non-peptide components, such as sugar
  • Proteins nuclear proteins, mucins, lipoproteins, metalloproteins
  • therapeutic proteins such as synthetic or recombinant antigens
  • viral surface proteins hormones and hormone analogues
  • antibodies such as At least one of a clone or polyclonal antibody, an enzyme, a Fab fragment, an interleukin and a derivative thereof, an interferon and a derivative thereof.
  • the nucleic acid refers to a naturally occurring, synthetic, semi-synthetic, or at least partially recombinant compound formed from two or more identical or different nucleotides, and may be single-stranded or double-stranded.
  • nucleic acids include oligonucleotides, antisense oligonucleotides, aptamers, polynucleotides, deoxyribonucleic acids, siRNAs, nucleotide constructs, single or double stranded segments, and precursors and Derivatives (such as glycosylation, hyperglycosylation, PEGylation, FITC labeling, nucleosides, and salts thereof).
  • the nucleic acid includes, but is not limited to, Mipomersen, Alicaforsen, Nusinersen, Volanesorsen, Custirsen, Apatorsen, Plazomicin, RG-012, RG-101, ATL1102, ATL1103, IONIS-HBV Rx , IONIS-HBV-L Rx , IONIS- GCGR Rx , IONIS-GCCR Rx , IONIS-HTT Rx , IONIS-TTR Rx , IONIS-PKK Rx , IONIS-FXI Rx , IONIS-APO(a)-L Rx , IONIS-ANGPTL3-L Rx , IONIS-AR-2.5 At least one of Rx , IONIS-DMPK-2.5 Rx , IONIS-STAT3-2.5 Rx , IONIS-SOD1 Rx , IONIS-GSK4-L Rx , IONIS-PTP
  • the water-soluble drug preferably contains at least one basic group of water-soluble substances (such as peptide drugs), including but not limited to adrenocorticotropic hormone (ACTH) and its derivatives, epidermal growth factor (EGF), platelet-derived growth Factor (TOGF), gonadotropin releasing hormone (LHRH) and its derivatives or analogues, calcitonin, insulin-like growth factor (IGF-I, IGF-II), cell growth factors (eg EGF, TGF- ⁇ , TGF- ⁇ , PDGF, FGF, basic FGF, etc.), glucagon-like peptides (such as GLP-1, GLP-2) and their derivatives or analogues, neurotrophic factors (such as NT-3, NT- 4.
  • adrenocorticotropic hormone ACTH
  • EGF epidermal growth factor
  • TOGF platelet-derived growth Factor
  • LHRH gonadotropin releasing hormone
  • calcitonin insulin-like growth factor
  • GLP-1 CNTF, GDNF, BDNF, etc.
  • colony stimulating factors e.g., CSF, GCSF, GMCSF, MCSF, etc.
  • Derivatives or analogs of GLP-1 include, but are not limited to, exendin-3 and exendin-4.
  • the water-soluble drug containing at least one basic group is preferably at least one of a peptide substance, a derivative thereof, and the like, and the peptide substance includes, but is not limited to, calcitonin (31 peptide), Somaru Peptide (31 peptide), glucagon-like peptide-1 (31 peptide), liraglutide (34 peptide), teriparatide (34 peptide), pramlintide (37 peptide), enfuvirtide ( 38 peptide), Exendin (39 peptide), adrenocorticotropic hormone (39 peptide), corticotropin releasing hormone (41 peptide), temoline (44 peptide), lixisenatide (44 peptide) , follicle stimulating hormone (118 peptide), duraglutide (274 peptide), arbuturide (645 peptide), glucagon (29 peptide), mayrelin (29 peptide), adipine
  • the peptide material preferably has a short peptide or polypeptide of no more than 30 amino acid residues.
  • the derivative or analog of the peptide substance means that at least one of a polypeptide having not more than 30 amino acid residues and a variant or the like thereof is modified with a water-soluble or poorly water-soluble group or substance.
  • the peptide drug derivatives, analogs include at least one of a glucagon-like peptide (such as GLP-1, GLP-2) and derivatives, analogs thereof, including but not limited to exendin-3, exendin -4 and at least one of their variants and derivatives.
  • a glucagon-like peptide such as GLP-1, GLP-2
  • derivatives, analogs thereof including but not limited to exendin-3, exendin -4 and at least one of their variants and derivatives.
  • the analog refers to a peptide in which one or more amino acid residues of the amino acid sequence are substituted (or substituted), deleted, inserted, fused, truncated or any combination thereof, and the variant polypeptide may be fully functional.
  • GLP-1 (GLP-1) analogue exendin-4 is glycine at the second position, and GLP-1 is at the second position alanine, and exendin-4 can be associated with G LP-1.
  • the body binds and produces a cascade of cellular signaling.
  • the water-soluble or poorly water-soluble group or substance is selected from the group consisting of polyethylene glycol and derivatives thereof, cyclodextrin, hyaluronic acid, short peptide, albumin, amino acid sequence, nucleic acid, gene, antibody, phosphoric acid, sulfonate Acid, fluorescent dye, KLH, OVA, PVP, PEO, PVA, alkane, aromatic hydrocarbon, biotin, immunoglobulin, albumin, polyamino acid, gelatin, succinylated gelatin, acrylamide derivative, fatty acid, polysaccharide, lipid amino acid At least one of chitosan and dextran.
  • polyethylene glycol and/or its derivatives the structure of said polyethylene glycols and derivatives thereof It can be branched, straight, bifurcated or dumbbell shaped.
  • Derivatives of the polyethylene glycol include, but are not limited to, monomethoxypolyethylene glycol, methoxypolyethylene glycol propionate.
  • the polyethylene glycols and their derivatives are either commercially available or can be prepared by themselves by techniques well known to those skilled in the art.
  • the water-soluble or poorly water-soluble substance is modified to be a modifying agent with an activating group, and is coupled to the peptide substance derivative, and the activating group is selected from the group consisting of maleimide, halogen, and vinyl. At least one of a sulfone, a disulfide bond, a thiol group, an aldehyde group, a carbonyl group, an O-substituted hydroxylamine, an active ester, an alkenyl group, an alkynyl group, an azide group, and other groups having a high chemical reactivity; preferably,
  • the activating group is selected from at least one of a maleimide, a halogen, a vinyl sulfone, and a disulfide bond; more preferably a maleimide and/or a disulfide bond.
  • the number of activating groups carried on the polymer is one or more, and when the number of activating groups is more than one, the activating groups may
  • the one or more of the water-soluble or poorly water-soluble substances have a molecular weight of from 1 to 60 kDa, preferably from 2 to 50 kDa, more preferably from 5 to 40 kDa.
  • the modifying agent having an activating group can be coupled to the peptide or a variant thereof or the like by an amino group, a carboxyl group, a hydroxyl group or a thiol group on the amino acid sequence.
  • Such groups are typically located at amino acid residues such as Lys (lysine), Asp (aspartic acid), Glu (glutamic acid), Cys (cysteine), His (histidine), 4-mercapto Any one of valine, Trp (tryptophan), Arg (arginine), Ala (alanine), Gly (glycine), Ser (serine) or Thr (threonine) or their derivatives
  • the N-terminus, C-terminus, side chain or any site of the object is preferably a site containing a thiol group.
  • any cysteine residue site or other amino acid residue at 2, 14, 21, 25, 28, 35, 38 or any position is replaced with a cysteine.
  • the site of the residue is typically located at amino acid residues such
  • Modifications of the peptides and variants, analogs thereof are random modifications, localization modifications (specific modifications), single-site modifications or multi-point modifications, preferably single-site localization modifications.
  • the peptide, its variants and analogs are prepared by conventional polypeptide synthesis methods, including solid phase polypeptide synthesis methods, liquid phase polypeptide synthesis methods, solid phase-liquid phase polypeptide synthesis methods, and recombinant methods; peptides and variants thereof, and the like.
  • the reaction between the substance and the modifier is carried out in an aqueous solution or a buffered salt solution, and the pH of the reaction system is appropriately controlled, and the modified product is monitored by HPLC, GPC, etc., and separated and purified by ion exchange, gel chromatography, etc., concentrated and freeze-dried. Obtain the target product.
  • the water-soluble drug mentioned above may be in the form of a free form or a pharmaceutically acceptable salt, and the salt-forming acid may be selected from a mineral acid or an organic acid.
  • the inorganic acid includes hydrochloric acid, sulfuric acid, phosphoric acid, and the organic acid includes acetic acid, formic acid, propionic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, malonic acid, maleic acid, tartaric acid, aspartic acid, Benzoic acid, methanesulfonic acid, benzenesulfonic acid, citric acid, malic acid, oxalic acid, succinic acid, carbonic acid; preferably hydrochloric acid, acetic acid, fumaric acid, maleic acid; more preferably acetic acid.
  • the biodegradable and biocompatible water poorly soluble polymers include polyesters, polycarbonates, polyacetals, polyanhydrides, polyhydroxy fatty acids, and copolymers or blends thereof.
  • the biodegradable and biocompatible polymers are polylactide (PLA), polyglycolide (PGA), lactide-glycolide copolymer (PLGA) and their polycaprolactone (PCL) or polyethylene glycol (PEG) copolymer (such as PLA-PEG, PLGA-PEG, PLGA-PEG-PLGA, PLA-PEG-PLA, PEG-PCL, PCL-PLA-PCL, PCL-PLGA- PCL, PEG-PLA-PEG, PEG-PLGA-PEG), polycaprolactone and its copolymer with polyethylene glycol, polyhydroxybutyric acid, polyhydroxyvaleric acid, polydioxanone (PPDO) , chitosan, alginic acid and its salts, polycyan
  • the PLA, PLGA and their copolymers with PCL or PEG have a weight average molecular weight of 25,000 to 150,000 Da, preferably a molecular weight of 30,000 to 130,000 Da, more preferably a molecular weight of 35,000 to 110,000 Da.
  • the weight average molecular weight used in the present specification is a value obtained by gel permeation chromatography (GPC) measurement.
  • the viscosity of the PLA, PLGA and their copolymers with PCL or PEG (test conditions of -0.5% (w/v), CHCl3, 25 ° C) is 0.22-1.1 dL/g, preferably 0.27-1.0 dL/g. More preferably, it is 0.31-0.9 dL/g.
  • the molecular chains of the poorly water-soluble polymer may carry anionic or cationic groups or may not carry these groups.
  • the polymer has a terminal carboxyl group or a terminal ester group, more preferably a polymer having a terminal carboxyl group.
  • the polymer for preparing sustained-release fine particles of the present invention may be a single polymer or a mixture of a plurality of polymers, such as a combination of a ratio of a lactide to a glycolide and a PLGA having the same molecular weight but a different carrying group.
  • a combination of PLGA having different ratios of lactide to glycolide, a combination of PLGA and PLA and the like.
  • the organic solvent C does not dissolve the water-soluble drug, but dissolves the biodegradable and biocompatible water-insoluble polymer, has a boiling point lower than water and is insoluble or poorly soluble in water.
  • the organic solvent C may be a single organic solvent or a miscible two or more organic solvents.
  • the organic solvent C is selected from aliphatic hydrocarbons (molecular structure is linear, branched or cyclic, such as n-hexane, n-heptane, n-pentane, cyclohexane, petroleum ether, etc.), halogenated hydrocarbons (such as dichloro Methane, chloroform, ethyl chloride, tetrachloroethylene, trichloroethylene, dichloroethane, trichloroethane, carbon tetrachloride, fluorocarbons, chlorobenzene (mono, di, trisubstituted), trichlorofluoromethane Et,) fatty acid esters (such as ethyl acetate, butyl acetate, etc.), aromatic hydrocarbons (such as benzene, toluene, xylene, etc.), ethers (such as diethyl ether, diisopropyl ether,
  • the concentration of the poorly water-soluble polymer in the organic solvent C varies depending on the type of the polymer, the weight average molecular weight, and the type of the organic solvent; generally, the mass concentration (polymer mass / organic solvent C mass * 100%) is about 1 -18% (w/w), preferably about 2-15% (w/w), more preferably about 3-12% (w/w).
  • the organic solvent D does not dissolve the water-soluble drug and the biodegradable and biocompatible water-insoluble polymer at the same time, but is miscible with the oil solution while having good solubility to the surfactant.
  • the organic solvent D may be a single organic solvent or a miscible two or more organic solvents.
  • the organic solvent D is at least one selected from the group consisting of anhydrous diethyl ether, cyclohexane, n-hexane, n-heptane, and petroleum ether, preferably at least one of n-hexane, cyclohexane, and n-heptane.
  • the type and proportion of the solvent D are different depending on the surfactant and the oil solution, and are formulated according to actual conditions.
  • the organic solvent having a boiling point lower than water and insoluble or poorly soluble in water means an organic solvent which is only miscible with water in a volume ratio of ⁇ 5% by volume, and has a lower boiling point (less than or much less than 100 ° C) so that It is easily removed by, for example, lyophilization, evaporation, or blasting.
  • the internal oil phase is a low temperature, which is understood to be 20 ° C or below, preferably 15 ° C or below, more preferably 10 ° C or below.
  • the surfactant-containing oil solution (also referred to as the outer oil phase) is a low temperature, which is understood to be 18 ° C or below, preferably 12 ° C or below, more preferably 8 ° C.
  • the oil base of the surfactant-containing oil solution is at least one of any pharmaceutically acceptable polyol, vegetable oil, mineral oil, and other oils in the pharmaceutical arts.
  • the oil base may be a single component or a mixture of two or more components.
  • the vegetable oil includes, but is not limited to, soybean oil, cottonseed oil, rapeseed oil, peanut oil, safflower oil, sesame oil, rice bran oil, corn germ oil, sunflower oil, poppy oil, olive oil, corn oil, cottonseed oil, coconut oil, flax.
  • At least one of a seed oil, castor oil, and palm oil, and at least one of soybean oil, peanut oil, and castor oil is preferably used in the vegetable oil, more preferably peanut oil; and the mineral oil includes, but not limited to, silicone oil, liquid paraffin; other oil These include oils obtained by partial hydrogenation of vegetable oils (such as hydrogenated castor oil) and liquid saturated fatty acids (such as caproic acid, caprylic acid, etc.); the polyols include glycerin, polyethylene glycol.
  • the oil base is preferably a vegetable oil and/or a mineral oil, more preferably a vegetable oil.
  • the surfactant can increase the wetting property of the organic phase, improve the stability and shape of the small liquid bead during the emulsification process, avoid re-polymerization of the small liquid bead, and reduce the number of unencapsulated or partially encapsulated small spherical particles, thereby avoiding The initial burst of the drug during release.
  • the surfactant is a compound such as an anionic surfactant, a zwitterionic surfactant, a nonionic surfactant or a surface active biomolecule, preferably an anionic surfactant, a nonionic surfactant, more preferably an anionic surfactant. Agent.
  • the nonionic surfactant includes, but is not limited to, at least one of sorbitan ester (Span), glyceryl monostearate, cetyl alcohol, octadecyl alcohol, stearyl alcohol .
  • sorbitan ester Span
  • glyceryl monostearate cetyl alcohol
  • cetyl alcohol octadecyl alcohol
  • stearyl alcohol sorbitan ester
  • the anionic surfactants include, but are not limited to, phospholipids and derivatives thereof, glycerides, fatty acid esters, fatty alcohols, and other bile acids (eg, bile acid, deoxycholic acid, glycocholic acid, taurocholic acid, glycine deoxygenation). At least one of cholic acid).
  • the anionic surfactant is preferably a phospholipid and a derivative thereof, including but not limited to phosphatidylcholine (lecithin), phosphatidylethanolamine (cephalin), phosphatidylserine, phosphatidylinositol, Phosphatidylglycerol, diphosphatidylglycerol (cardiolipin), glycerophosphatidic acid, lysophospholipid, soybean phospholipid, dipalmitoyl-phosphatidylcholine, dioleoylphosphatidyl-ethanolamine, dioleoylphosphatidylcholine and two flesh Myristoyl-phosphatidylglycerol, and mixtures thereof.
  • phosphatidylcholine lecithin
  • phosphatidylethanolamine cephalin
  • phosphatidylserine phosphatidylinositol
  • Phosphatidylglycerol di
  • the phospholipids may be salified or non-salted, hydrogenated or partially hydrogenated, natural, semi-synthetic or fully synthetic.
  • the phospholipid and its derivative are preferably phosphatidylcholine, soybean phospholipid, phosphatidylglycerol, more preferably soybean phospholipid.
  • the mass percentage of the surfactant (or stabilizer) in the oil base is generally from 0.05 to 10%, preferably from 0.25 to 8%, more preferably from 0.5 to 5%.
  • the amount of the external oil phase used is usually about 50 times by volume or more, preferably about 70 times by volume or more, and particularly preferably about 100 times by volume or more.
  • the method of forming a uniform emulsion is the same as the well-known emulsification method, using a device that generates high shear force (such as a magnetic stirrer, a mechanical stirrer, a high speed homogenizer, an ultrasound machine, a membrane emulsifier, a rotor-stator mixer). , static mixer, high pressure homogenizer, etc.)
  • a device that generates high shear force such as a magnetic stirrer, a mechanical stirrer, a high speed homogenizer, an ultrasound machine, a membrane emulsifier, a rotor-stator mixer.
  • static mixer high pressure homogenizer, etc.
  • the gas stream blows the surface of the liquid, and controls the contact area of the liquid phase with the gas phase, the rate of emulsion agitation and circulation (such as JP-A-9-221418) to accelerate the volatilization of the organic solvent, preferably the dry gas;
  • the organic solvent for example, W00183594
  • W00183594 is quickly removed by a hollow fiber membrane
  • the hollow fiber membrane is preferably a silicone rubber pervaporation film, particularly a pervaporation film prepared from polydimethylsiloxane.
  • microparticles obtained in the step 4) are separated by centrifugation, sieving or filtration.
  • the temperature of the ultrapure water used for washing the microparticles in the step 4) is a low temperature, which is understood to be 12 ° C or less, preferably 9 ° C or less, more preferably 6 ° C or less.
  • the ultrapure water used for washing in the step 4) may further contain an inorganic salt (such as a zinc salt) to reduce the infiltration of the water-soluble active substance into the aqueous phase during the washing process, thereby improving the encapsulation efficiency of the drug, and the mechanism is to improve the external phase.
  • an inorganic salt such as a zinc salt
  • the osmotic pressure or the solubility of the active substance in the external phase For active substances such as peptides, proteins, nucleic acids, antibodies, antigens, antibiotics, etc., zinc ion-containing compounds are ideal, including but not limited to zinc acetate, zinc chloride, zinc sulfate, zinc hydrogen sulfate, zinc nitrate, gluconic acid. Zinc, zinc carbonate or any mixture thereof.
  • the mass concentration of the inorganic salt in the ultrapure water is from 0 to 3%, preferably from 0.01 to 1.5%, more preferably from 0.01 to 1%.
  • the step 1) is carried out by the following steps:
  • the organic solvent A can simultaneously dissolve a water-soluble drug and a biodegradable, biocompatible water-insoluble polymer.
  • the organic solvent A may be a single organic solvent or a miscible two or more organic solvents.
  • the organic solvent A is at least one selected from the group consisting of glacial acetic acid, acetonitrile, trifluoroacetic acid, and dimethyl sulfoxide, preferably glacial acetic acid and/or acetonitrile, more preferably glacial acetic acid.
  • the kind and proportion of the organic solvent in the mixture vary according to different drugs and polymers, and can be formulated according to actual conditions.
  • the organic solvent B does not dissolve the water-soluble drug and the biodegradable, biocompatible water-insoluble polymer at the same time.
  • the organic solvent B may be a single organic solvent or a miscible two or more organic solvents.
  • the organic solvent B is selected from the group consisting of anhydrous diethyl ether, At least one of hexane (including cyclohexane, n-hexane) and n-heptane is preferably at least one of anhydrous diethyl ether and hexane (including cyclohexane, n-hexane), more preferably anhydrous diethyl ether.
  • the kind and proportion of the organic solvent in the mixture vary according to different drugs and polymers, and can be formulated according to actual conditions.
  • the organic solvent A is controlled to be below normal temperature or low temperature, and the normal temperature is generally understood to be 20 ° C, preferably 10-15 ° C; the low temperature is generally understood to be 10 ° C or lower, preferably 4-6 ° C or below;
  • the organic solvent B is controlled to a low temperature, which is generally understood to be 15 ° C or lower, preferably 10 ° C or lower, more preferably 6 ° C or lower; the organic solvent A is 0 to 10 ° C higher than the temperature of the organic solvent B, preferably 3 8 ° C.
  • the mass ratio of the water-soluble drug to the biodegradable and biocompatible water-insoluble polymer is from 1:1 to 1:99, preferably from 2:3 to 3:97, more preferably 7:13. ⁇ 1:19.
  • the concentration of the water-insoluble polymer in the organic solvent A varies depending on the type of the polymer, the weight average molecular weight, and the type of the organic solvent. Usually, the mass concentration (polymer mass / organic solvent A mass * 100%) is 1-18% (w/w), preferably 2-15% (w/w), more preferably 3-12% (w) /w).
  • the step of removing the organic solvent B is carried out below normal temperature or at a low temperature, which is generally understood to be 20-30 ° C, preferably 20-25 ° C; the low temperature is generally understood to be 15 ° C or less, preferably 10 ° C and the following.
  • Methods of removing organic solvents include, but are not limited to, vacuum drying, freeze drying, and fluidized drying.
  • the sustained release microparticles of the present invention may contain one or more auxiliary agents.
  • the preparation method of the sustained-release fine particles of the present invention further comprises the step of adding an auxiliary agent, which is added during the step of preparing the solid dispersion in the step 1), or added during the preparation of the solid dispersion emulsion in the step 2); It is added at the time of preparing the solid dispersion emulsion in the step 2).
  • the adjuvant is dissolved or suspended in the inner oil phase.
  • the auxiliary agent may be a very fine powder having a particle diameter of less than 0.5 ⁇ m, preferably a particle diameter of less than 0.1 ⁇ m, more preferably a particle diameter of less than 0.05 ⁇ m.
  • the adjuvant may impart additional characteristics to the active drug or microparticles, such as increasing the stability of the microparticles, active drug or polymer, promoting controlled release of the active drug from the microparticles, or modulating the biological tissue permeability of the active drug.
  • the auxiliary agent is 0.01 to 10%, preferably 0.1 to 8%, more preferably 0.5 to 8% by mass of the sum of the mass of the water-soluble drug and the poorly water-soluble polymer.
  • the adjuvant includes, but is not limited to, at least one of a saccharide, an amino acid, a fatty acid, an alcohol, an antioxidant, and a buffer.
  • the buffering agents include, but are not limited to, mineral or organic acid salts such as salts of carbonic acid, acetic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid.
  • mineral or organic acid salts such as salts of carbonic acid, acetic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid.
  • a zinc salt of an inorganic acid or an organic acid is preferred, and zinc chloride is more preferred.
  • the buffering agent is 0-5%, preferably 0.01-3%, more preferably 0.01-2%, of the sum of the mass of the water-soluble drug and the poorly water-soluble polymer.
  • the antioxidants include, but are not limited to, tert-butyl-p-hydroxyanisole, dibutylphenol, tocopherol, isopropyl myristate, tocopheryl daacetate, ascorbic acid, ascorbyl palmitate, butylated hydroxybenzoic acid Ether, butylated hydroxy hydrazine, hydroxycoumarin, butylated hydroxytoluene, decanoic acid fatty acid ester (such as ethyl ester, propyl ester, octyl ester, lauryl ester), propyl hydroxybenzoate, trihydroxy phenyl butyl At least one of a ketone, a vitamin E, a vitamin E-TPGS, and a p-hydroxybenzoic acid ester (such as a methyl ester, an ethyl ester, a propyl ester, or a butyl ester).
  • the antioxidant can effectively remove free radicals or peroxides in the sustained release microparticles.
  • the antioxidant is 0-1%, preferably 0-0.5%, more preferably 0-0.1%, of the sum of the mass of the water-soluble drug and the poorly water-soluble polymer.
  • Such saccharides include, but are not limited to, monosaccharides, oligosaccharides, and polysaccharides, as well as derivatives thereof. Specifically, including but not limited to trehalose, glucose, sucrose, glycerol, erythritol, arabitol, xylitol, sorbitol, mannitol, glucuronic acid, iduronic acid, nervous amino acid, Galacturonic acid, gluconic acid, mannuronic acid, hyaluronic acid and its salts, chondroitin sulfate and its salts, heparin, inulin, chitin and its derivatives, dextrin, dextran and alginic acid At least one of its salts.
  • sucrose mannitol, xylitol, or any combination thereof.
  • the saccharide is 0.01 to 10%, preferably 0.1 to 8%, more preferably 0.5 to 6%, based on the sum of the mass of the water-soluble drug and the water-insoluble polymer.
  • the amino acids include, but are not limited to, glycine, alanine, serine, aspartic acid, glutamic acid, threonine, tryptophan, lysine, hydroxylysine, histidine, arginine, cyst At least one of amino acid, cysteine, methionine, phenylalanine, leucine, isoleucine, and derivatives thereof; preferably a basic amino acid, including but not limited to arginine, At least one of histidine and lysine.
  • the amino acid is 0-4%, preferably 0-2%, more preferably 0.01-1%, of the sum of the mass of the water-soluble drug and the poorly water-soluble polymer.
  • the fatty acid includes 12-24 alkanoic acid and its derivatives including, but not limited to, oleic acid, stearic acid, lauric acid, myristic acid, palmitic acid, arachidic acid, behenic acid, lignin acid, preferably stearic acid. At least one of behenic acid and palmitic acid.
  • the fatty acid is 0 to 5%, preferably 0.01 to 4%, more preferably 0.05 to 3%, of the sum of the mass of the water-soluble drug and the water-insoluble polymer.
  • the alcohols include, but are not limited to, polyethylene glycol.
  • the polyethylene glycol has a molecular weight of from 400 to 6000 Da, preferably from 400 to 4000 Da, more preferably from 400 to 2000 Da.
  • the alcohol is 0 to 5%, preferably 0.01 to 4%, more preferably 0.05 to 3%, of the sum of the mass of the water-soluble drug and the water-insoluble polymer.
  • Formulations for injection require sterility, and specific sterilization methods are within the ordinary knowledge and skill of those skilled in the art, such as aseptic processing, hot pressing, ethylene oxide or gamma radiation to assure sterility of the formulation.
  • the preparation of the sustained-release microparticles of the present invention is preferably aseptic operation, such as filtering the outer phase aqueous solution with a cellulose acetate membrane, filtering the PLGA acetic acid solution with a polyethersulfone membrane, filtering the dichloromethane with a polytetrafluoroethylene membrane, and all the equipment is easily sealed. It is equipped with an organic solvent recovery unit to prevent bacterial contamination and the diffusion of organic solvents into the air.
  • the present invention also provides sustained release microparticles prepared according to the method for preparing sustained release microparticles.
  • the sustained release microparticles prepared by the present invention preferably have an average geometric particle size of less than 200 ⁇ m.
  • the sustained-release fine particles have a particle diameter of 10 to 200 ⁇ m, preferably 10 to 150 ⁇ m, more preferably 20 to 150 ⁇ m.
  • the particle size of the sustained release particles is measured by a dynamic light scattering method (for example, laser diffraction method) or a microscopic technique (such as scanning electron microscopy).
  • the sustained-release microparticles of the present invention may encapsulate a large amount of active ingredients, and the dosage may depend on the type and content of the active ingredient, the dosage form, the duration of release, the subject to be administered, the route of administration, the purpose of administration, the target disease and symptoms, and the like. Choose as appropriate. However, the dosage can be considered satisfactory as long as the active ingredient can be maintained in the active concentration of the drug for the desired duration in vivo.
  • the water-soluble drug has a mass content percentage of about 1 to 40%, preferably 3 to 35%, more preferably 5 to 30%.
  • the present invention also provides a suspension formulation comprising the sustained release microparticles and a dispersion medium.
  • microparticles When the microparticles are administered as a suspension, they can be formulated as a suspension with a suitable dispersion medium.
  • the dispersion medium includes at least one of a nonionic surfactant, a polyoxyethylene castor oil derivative, a cellulose thickener, sodium alginate, hyaluronic acid, dextrin, and starch.
  • a nonionic surfactant such as sodium chloride, mannitol, glycerol, sorbitol, lactose, xylitol, maltose, galactose, sucrose, glucose, etc.
  • pH adjusters For example, carbonic acid, acetic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid or salts of these acids, such as sodium carbonate, sodium hydrogencarbonate, etc.
  • preservatives for example, parabens, propylparaben, benzyl alcohol, Chlorobutanol, sorbic acid, boric acid, etc. are combined to form an aqueous solution, or subsequently cured by freeze drying,
  • the sustained release injection can also be obtained by dispersing the sustained release microparticles in a vegetable oil such as sesame oil and corn oil or a vegetable oil to which a phospholipid such as lecithin is added, or dispersed in a medium chain triglyceride, Obtain an oily suspension.
  • a vegetable oil such as sesame oil and corn oil or a vegetable oil to which a phospholipid such as lecithin is added
  • a medium chain triglyceride Obtain an oily suspension.
  • the present invention also provides the use of the solid dispersion, sustained release microparticles in an implantable sustained release pharmaceutical composition.
  • the water-soluble drug sustained-release pharmaceutical composition prepared by the present invention may also be a stick or a sheet. Further, the present invention also provides an implantable type.
  • a method for preparing a sustained release pharmaceutical composition comprising the steps of:
  • the solid dispersion prepared in the step 1 is heated and then molded by a molding method, and the implanted sustained-release pharmaceutical composition is prepared by cooling.
  • the molding method is not limited herein, and molding methods well known to those skilled in the art can be used, such as compression molding, extrusion molding, and the sustained-release composition can be formed into a rod shape or a sheet shape.
  • the sustained-release pharmaceutical composition for preparing a water-soluble drug, particularly a protein, a peptide drug, and a nucleic acid of the present invention is a rod-shaped or sheet-like implant.
  • a method for preparing an implantable sustained release pharmaceutical composition comprises the following steps:
  • the sustained release microparticles obtained in step 1' are prepared into an implantable sustained release pharmaceutical composition by a molding method well known to those skilled in the art.
  • the sustained release pharmaceutical composition can be formed into a rod shape or a sheet shape.
  • the sustained-release microparticles obtained by the present invention can be used in the form of granules, suspensions, implants, injections, adhesive preparations, and the like, and can be administered orally or parenterally (intramuscular injection, subcutaneous injection). , transdermal administration, mucosal administration (intracrine, intravaginal, rectal, etc.)).
  • the implant of the invention is based on a biodegradable and biocompatible material, and has a thin rod shape, a round rod shape or a sheet shape (disc shape), and can be implanted into the body by injection or surgery, and the drug is completely released. No need to remove it by surgery.
  • the advantage of the implant is that it is easy to obtain high encapsulation rate and drug loading rate, low burst release rate, and can continuously release the therapeutic dose of the active drug at a stable rate for one month to several months, greatly reducing medical treatment. Cost to improve patient compliance.
  • the preparation of the sustained-release microparticles is normal or low temperature throughout the whole process, and is highly advantageous for the preparation of the polymer matrix for drugs sensitive to high temperatures, particularly proteins, nucleic acids and peptide drugs.
  • the technology can maintain the biological activity of the active substance to the greatest extent in the whole process; at the same time, the prepared sustained-release particles have an excellent sustained release effect close to zero order, and the drug concentration is stable during the release, which solves the traditional advance
  • the S/O/W process for preparing the fine particles of the drug has no drug release in the early stage, and has the disadvantage of rapid release of the drug in the later stage; further, the sustained release particles have a higher drug loading rate and drug encapsulation efficiency.
  • active substances such as proteins, peptides, nucleic acids, and alkaloids can be continuously transported in the body for a period of time, and the release period is as long as several weeks or several months.
  • microparticles in the following examples are also “sustained release microparticles”; the “sustained release implant” is also an implantable sustained release pharmaceutical composition.
  • the solid dispersion obtained in the step I was uniformly dispersed in about 5.50 g of dichloromethane to obtain an internal oil phase, and then the inner oil phase was poured into 200 mL of 0.05% (w/w) lecithin/peanut oil which had been previously thermostated to about 10 ° C.
  • the S/O/O emulsion was prepared by emulsification in a solution using a wheel-type homomixer (running speed of about 7000 rpm, 5 min).
  • the S/O/O emulsion was transferred to a sealed glass flask and mechanical stirring was continued for about 3 hours (500 rpm) to solidify the microparticles, and then the microparticles were collected by centrifugation (about 2500 rpm, 5 min) using a centrifuge. After washing the particles with n-heptane about 5 times, The mixture was again dispersed in ultrapure water (5 ° C) for about 2 times, then collected by centrifugation, and lyophilized in a freeze dryer to obtain fine particles. The content of glucagon in the obtained microparticles was measured to be 0.93%, and the particle diameter of the microparticles was 42 to 100 ⁇ m.
  • the solid dispersion obtained in the step I was uniformly dispersed in about 5.39 g of chloroform to obtain an internal oil phase, and then the inner oil phase was poured into 290 mL of a 0.1% (w/w) lecithin/liquid paraffin solution which had been previously thermostated to about 8 °C.
  • the S/O/O emulsion (rotor speed about 5000 rpm, 5 min) was prepared using a high speed homogenizer.
  • the S/O/O emulsion was mechanically stirred for about 3.5 hours (500 rpm) to solidify the microparticles, and then the microparticles were collected by centrifugation (about 3500 rpm, 5 min) using a centrifuge.
  • microparticles were washed with n-hexane for about 5 times, they were again dispersed in ultrapure water (5 ° C) for about 2 times, then collected by centrifugation, and freeze-dried in a freeze dryer to obtain microparticles.
  • the content of ziconotide in the obtained microparticles was determined to be 2.81%, and the particle diameter of the microparticles was 19-91 ⁇ m.
  • the solid dispersion obtained in the step I was uniformly dispersed in about 6.33 g of tetrachloroethylene to obtain an internal oil phase, and then the inner oil phase was injected into 480 mL of 0.25% (w/w) lecithin/corn which had been previously thermostated to about 6 °C.
  • An S/O/O emulsion (film pore size 20-50 ⁇ m, cycle 3 times) was prepared in an oil solution using a SPG membrane emulsifier. The S/O/O emulsion was mechanically stirred for about 3.5 hours (500 rpm) to solidify the microparticles, and then the microparticles were collected by centrifugation (about 3500 rpm, 5 min) using a centrifuge.
  • microparticles had a content of tink peptide of 4.57% and a particle diameter of 39-80 ⁇ m.
  • PLGA molecular weight 35 kDa, monomer ratio 75/25, terminal carboxyl group
  • the solid dispersion obtained in the step I was uniformly dispersed in a mixture of about 7.50 g of dichloromethane and chloroform to obtain an internal oil phase, and then the inner oil phase was injected into 450 mL of 0.5% which had been previously thermostated to about 5 ° C (w/w).
  • a S/O/O emulsion was prepared using a static mixer (rotation speed 5000 rpm, 3 cycles).
  • the S/O/O emulsion was transferred to a sealed glass flask and mechanical stirring was continued for about 3.5 hours (500 rpm) to solidify the microparticles, and then the microparticles were collected by centrifugation (about 3500 rpm, 5 min) using a centrifuge. After the microparticles were washed about 5 times with a mixture of n-heptane and n-hexane, they were again dispersed in ultrapure water (5 ° C) for about 2 times, then collected by centrifugation, and lyophilized in a freeze dryer to obtain fine particles. The obtained microparticles were found to have a somatostatin content of 9.35% and a particle diameter of 39 to 84 ⁇ m.
  • PLGA molecular weight 40 KDa, monomer ratio 65/35, terminal carboxyl group
  • the solid dispersion obtained in the step I was uniformly dispersed in about 8.50 g of trichlorobenzene to obtain an internal oil phase, and then the inner oil phase was injected into 580 mL of 0.75% (w/w) lecithin which had been previously thermostated to about 5 ° C /
  • the S/O/O emulsion (1200 rpm, 3 min) was prepared in a castor oil solution by mechanical stirring.
  • the S/O/O emulsion was mechanically stirred for about 3.5 hours (500 rpm) to solidify the microparticles, and then the microparticles were collected by centrifugation (about 3000 rpm, 5 min) using a centrifuge.
  • the particles were washed with petroleum ether for about 5 times, they were again dispersed in ultrapure water (5 ° C) for about 2 times, then collected by centrifugation, and lyophilized in a freeze dryer to obtain fine particles.
  • the content of terlipressin in the obtained fine particles was measured to be 14.20%, and the particle diameter was 20-83 ⁇ m.
  • the solid dispersion obtained in the step I was uniformly dispersed in about 6.42 g of dichloromethane to obtain an internal oil phase, and then the inner oil phase was injected into 440 mL of 1% (w/w) lecithin/peanut oil which had been previously thermostated to about 6 ° C.
  • the S/O/O emulsion 1000 rpm, 5 min
  • the S/O/O emulsion was mechanically stirred for about 3.5 hours (500 rpm) to solidify the microparticles, and then the microparticles were collected by centrifugation (about 3000 rpm, 5 min) using a centrifuge.
  • microparticles were washed with anhydrous diethyl ether for about 5 times, they were again dispersed in ultrapure water (5 ° C) for about 2 times, then collected by centrifugation, and lyophilized in a freeze dryer to obtain microparticles.
  • the content of goserelin in the obtained fine particles was measured to be 3.48%, and the particle diameter of the fine particles was 27-123 ⁇ m.
  • the solid dispersion obtained in the step I was uniformly dispersed in about 7.71 g of dichloromethane to obtain an internal oil phase, and then the inner oil phase was injected into 470 mL of 1.25% (w/w) lecithin/peanut oil which had been previously thermostated to about 7 ° C.
  • the S/O/O emulsion 1000 rpm, 5 min
  • the S/O/O emulsion was mechanically stirred for about 4 hours (500 rpm) to solidify the particles for use, and then the machine was centrifuged (about 3000 rpm, 5 min) to collect the particles.
  • the particles were washed with n-heptane for about 5 times, they were again dispersed in ultrapure water (5 ° C) for about 2 times, then collected by centrifugation, and lyophilized in a freeze dryer to obtain fine particles.
  • the content of leuprolide in the obtained fine particles was measured to be 7.10%, and the particle diameter of the fine particles was 21 to 80 ⁇ m.
  • the solid dispersion obtained in Step I was uniformly dispersed in about 8.50 g of dichloromethane to obtain an internal oil phase, and then the inner oil phase was injected into 640 mL of 1.5% (w/w) lecithin/peanut oil which had been previously thermostated to about 8 °C.
  • the S/O/O emulsion (1300 rpm, 5 min) was prepared in solution and by mechanical stirring.
  • the S/O/O emulsion was mechanically stirred for about 4 hours (500 rpm) to solidify the microparticles, and then the microparticles were collected by centrifugation (about 3000 rpm, 5 min) using a centrifuge.
  • the particles were washed with n-heptane for about 5 times, they were again dispersed in ultrapure water (5 ° C) for about 2 times, then collected by centrifugation, and lyophilized in a freeze dryer to obtain fine particles.
  • the content of triptorelin in the obtained microparticles was measured to be 13.57%, and the particle diameter of the microparticles was 23-79 ⁇ m.
  • PLGA molecular weight 50 kDa, monomer ratio 50/50, terminal carboxyl group
  • 0.20 g of leuprolide acetate was added, dissolved under vortex, and then slowly infused without stirring.
  • a white precipitate was obtained in water diethyl ether (6 ° C).
  • the white precipitate was collected and extracted with anhydrous diethyl ether for about 5 times.
  • the precipitate was collected and dried in a vacuum oven for 24 h (10 ° C) to give a solid dispersion.
  • the solid dispersion obtained in Step I was uniformly dispersed in about 10.00 g of dichloromethane to obtain an internal oil phase, and then the inner oil phase was injected into 900 mL of 2% (w/w) lecithin/peanut oil which had been previously thermostated to about 10 °C.
  • the S/O/O emulsion (1200 rpm, 5 min) was prepared in solution and mechanically agitated.
  • the S/O/O emulsion was mechanically stirred for about 4 hours (600 rpm) to solidify the microparticles, and then the microparticles were collected by centrifugation (about 4000 rpm, 5 min) using a centrifuge.
  • the particles were washed with n-heptane for about 5 times, they were again dispersed in ultrapure water (5 ° C) for about 2 times, then collected by centrifugation, and lyophilized in a freeze dryer to obtain fine particles.
  • the content of leuprolide in the obtained fine particles was measured to be 19.11%, and the particle diameter was 36-112 ⁇ m.
  • the solid dispersion obtained in the step I was uniformly dispersed in about 11.71 g of dichloromethane to obtain an internal oil phase, and then the inner oil phase was injected into 700 mL of 2% (w/w) lecithin/peanut oil which had been previously thermostated to about 10 ° C.
  • the S/O/O emulsion (900 rpm, 5 min) was prepared in solution and by mechanical stirring.
  • the S/O/O emulsion was mechanically stirred for about 4 hours (400 rpm) to solidify the microparticles, and then the microparticles were collected by centrifugation (about 4000 rpm, 5 min) using a centrifuge.
  • microparticles had an antipeptide content of 17.30% and a particle diameter of 20-94 ⁇ m.
  • PLGA molecular weight 65 kDa, monomer ratio 65/35, terminal carboxyl group
  • 0.20 g of nafarelin acetate, 0.05 g of sucrose and 0.01 g of stearic acid were added, and vortexed. Dissolved, and then slowly poured into anhydrous diethyl ether (6 ° C) under stirring to give a white precipitate. The white precipitate was collected and extracted with anhydrous diethyl ether for about 5 times. The precipitate was collected and dried in a vacuum oven for 24 h (10) °C), a solid dispersion was obtained.
  • the solid dispersion obtained in the step I was uniformly dispersed in about 13.33 g of dichloromethane to obtain an internal oil phase, and then the inner oil phase was injected into 900 mL of 3% (w/w) lecithin/peanut oil which had been previously thermostated to about 10 ° C.
  • the S/O/O emulsion (1300 rpm, 5 min) was prepared in solution and by mechanical stirring.
  • the S/O/O emulsion was mechanically stirred for about 4 hours (400 rpm) to solidify the microparticles, and then the microparticles were collected by centrifugation (about 3500 rpm, 5 min) using a centrifuge.
  • the particles were washed with n-heptane for about 5 times, they were again dispersed in ultrapure water (5 ° C) for about 2 times, then collected by centrifugation, and lyophilized in a freeze dryer to obtain fine particles.
  • the content of nafarelin in the obtained fine particles was measured to be 18.95%, and the particle diameter was 27-101 ⁇ m.
  • the solid dispersion obtained in Step I was uniformly dispersed in about 15.00 g of dichloromethane to obtain an internal oil phase, and then the inner oil phase was injected into 1.1 L of 4% (w/w) lecithin which had been previously thermostated to about 13 ° C/
  • the S/O/O emulsion (1400 rpm, 5 min) was prepared in a peanut oil solution by mechanical stirring.
  • the S/O/O emulsion was mechanically stirred for about 4 hours (400 rpm) to solidify the microparticles, and then the microparticles were collected by centrifugation (about 3000 rpm, 5 min) using a centrifuge.
  • the particles were washed with n-heptane for about 5 times, they were again dispersed in ultrapure water (5 ° C) for about 2 times, then collected by centrifugation, and lyophilized in a freeze dryer to obtain fine particles.
  • the content of nafarelin in the obtained microparticles was measured to be 23.56%, and the particle diameter was 26-111 ⁇ m.
  • the solid dispersion obtained in Step I was uniformly dispersed in about 17.50 g of dichloromethane to obtain an internal oil phase, and then the inner oil phase was injected into 1.3 L of 5% (w/w) lecithin which had been previously thermostated to about 10 ° C/ S/O/O emulsion (1500 rpm, 5 min) was prepared in a peanut oil solution by mechanical stirring.
  • the S/O/O emulsion was mechanically stirred for about 4 hours (400 rpm) to solidify the microparticles, and then the microparticles were collected by centrifugation (about 3000 rpm, 5 min) using a centrifuge.
  • the particles were washed with n-heptane for about 5 times, they were again dispersed in ultrapure water (5 ° C) for about 2 times, then collected by centrifugation, and lyophilized in a freeze dryer to obtain fine particles.
  • the content of alarillin in the obtained fine particles was 27.00%, and the particle diameter was 19-116 ⁇ m.
  • the solid dispersion obtained in Step I was uniformly dispersed in about 21.67 g of dichloromethane to obtain an internal oil phase, and then the inner oil phase was injected into 1.6 L of 6% (w/w) lecithin which had been previously thermostated to about 8 ° C/
  • the S/O/O emulsion (1800 rpm, 5 min) was prepared in a peanut oil solution by mechanical stirring.
  • the S/O/O emulsion was mechanically stirred for about 5 hours (700 rpm) to solidify the microparticles, and then the microparticles were collected by centrifugation (about 3000 rpm, 5 min) using a centrifuge.
  • the particles were washed with n-heptane for about 5 times, they were again dispersed in ultrapure water (5 ° C) for about 2 times, then collected by centrifugation, and lyophilized in a freeze dryer to obtain fine particles.
  • the content of octreotide in the obtained microparticles was measured to be 32.71%, and the particle diameter of the microparticles was 17-89 ⁇ m.
  • the solid dispersion obtained in Step I was uniformly dispersed in about 30.00 g of dichloromethane to obtain an internal oil phase, and then the inner oil phase was injected into 2 L of 8% (w/w) lecithin/glycerol which had been previously thermostated to about 8 ° C.
  • the S/O/O emulsion 2000 rpm, 5 min
  • the S/O/O emulsion was mechanically stirred for about 5 hours (700 rpm) to solidify the microparticles, and then the microparticles were collected by centrifugation (about 3000 rpm, 5 min) using a centrifuge.
  • the particles were washed with n-heptane for about 5 times, they were again dispersed in ultrapure water (5 ° C) for about 2 times, then collected by centrifugation, and lyophilized in a freeze dryer to obtain fine particles.
  • the content of Bremerwave was 36.52% in the obtained microparticles, and the particle diameter was 22-85 ⁇ m.
  • the solid dispersion obtained in Step I was uniformly dispersed in about 50.00 g of dichloromethane to obtain an internal oil phase, and then the inner oil phase was injected into 2.6 L of 10% (w/w) lecithin which had been previously thermostated to about 8 °C.
  • the S/O/O emulsion was prepared by emulsification in a peanut oil solution using a wheel-type homomixer (running speed of about 7000 rpm, 5 min).
  • the S/O/O emulsion was transferred to a sealed glass flask and mechanical stirring was continued for about 5 hours (800 rpm) to solidify the microparticles, and then the microparticles were collected by centrifugation (about 4000 rpm, 5 min) using a centrifuge. After the particles were washed with n-heptane for about 5 times, they were again dispersed in ultrapure water (5 ° C) for about 2 times, then collected by centrifugation, and lyophilized in a freeze dryer to obtain fine particles. The content of the hazelurin in the obtained fine particles was measured to be 44.00%, and the particle diameter was 26-98 ⁇ m.
  • the solid dispersion contains the following components in mass percent: water-soluble drug: Exendin-4 derivative 20%, poorly water-soluble polymer: PLGA 79.5%, adjuvant: xylitol 0.5%; wherein the molecular weight of the PLGA It is 50 kDa in which the ratio of lactide to glycolide is 50/50, and the PLGA has a terminal carboxyl group.
  • Exendin-4 derivative Preparation of 10kDa PEG-NHS ester, then reacted with asparagine at position 28 in Exendin-4 in PBS buffer, purified by ion exchange, gel chromatography, concentrated and freeze-dried Obtained the Exendin-4 derivative.
  • the solid dispersion obtained in the step I was uniformly dispersed in about 12 times of dichloromethane to obtain an internal oil phase, and then the inner oil phase was injected into 1 L of 2% (w/w) lecithin which had been previously thermostated to about 5 ° C /
  • the S/O/O emulsion (1400 rpm, 5 min) was prepared in a peanut oil solution by mechanical stirring.
  • the S/O/O emulsion was mechanically stirred for about 4 hours (600 rpm) to solidify the microparticles, and then the microparticles were collected by centrifugation (about 3500 rpm, 5 min) using a centrifuge.
  • the particles were washed with n-heptane for about 5 times, they were again dispersed in ultrapure water (5 ° C) for about 2 times, then collected by centrifugation, and lyophilized in a freeze dryer to obtain fine particles.
  • the content of the Exendin-4 derivative in the obtained fine particles was measured to be 18.40%, and the particle diameter was 27-109 ⁇ m.
  • the solid dispersion contains the following components by mass: water-soluble drug: Exendin-4 derivative 15%, poorly water-soluble polymer: PLGA 84%, adjuvant: xylitol 1%; wherein the PLGA has a molecular weight of 50 kDa Wherein the ratio of lactide to glycolide is 50/50 and the PLGA has a terminal carboxyl group.
  • Exendin-4 derivative Exendin-4 variant in which asparagine at position 28 in Exendin-4 was replaced with cysteine by solid phase peptide synthesis method, and then in 10 kbD with PBS buffer The monomethoxypolyethylene glycol-maleimide reaction was purified by ion exchange, gel chromatography, concentrated, and lyophilized to obtain an Exendin-4 derivative.
  • the solid dispersion obtained in the step I was uniformly dispersed in about 13 times of dichloromethane to obtain an internal oil phase, and then the inner oil phase was injected into 970 mL of 1.75% (w/w) lecithin which had been previously thermostated to about 5 °C.
  • the S/O/O emulsion (1400 rpm, 5 min) was prepared in a peanut oil solution by mechanical stirring.
  • the S/O/O emulsion was mechanically stirred for about 4 hours (500 rpm) to solidify the microparticles, and then the microparticles were collected by centrifugation (about 3500 rpm, 5 min) using a centrifuge.
  • the particles were washed with n-heptane for about 5 times, they were again dispersed in ultrapure water (5 ° C) for about 2 times, then collected by centrifugation, and lyophilized in a freeze dryer to obtain fine particles.
  • the content of the Exendin-4 derivative in the obtained fine particles was 13.25%, and the particle diameter was 30-113 ⁇ m.
  • the solid dispersion contains the following components in mass percent: water-soluble drug: Exendin-4 derivative 20%, poorly water-soluble polymer: PLGA 78%, adjuvant: sorbitol 2%; wherein the PLGA has a molecular weight of 55 kDa, Wherein the ratio of lactide to glycolide is 50/50, and the PLGA has a terminal carboxyl group.
  • Exendin-4 derivative Exendin-4 variant in which arginine at position 20 in Exendin-4 was replaced with cysteine by solid phase peptide synthesis method, and then 5kDa in PBS buffer
  • the oxypolyethylene glycol-maleimide reaction is purified by ion exchange, gel chromatography, concentrated, and lyophilized to obtain an Exendin-4 derivative.
  • the solid dispersion obtained in the step I was uniformly dispersed in about 14 times of dichloromethane to obtain an internal oil phase, and then the inner oil phase was injected into 1 L of 1.5% (w/w) lecithin which had been previously thermostated to about 5 ° C /
  • the S/O/O emulsion (1400 rpm, 5 min) was prepared in a peanut oil solution by mechanical stirring.
  • the S/O/O emulsion was mechanically stirred for about 4 hours (500 rpm) to solidify the microparticles, and then the microparticles were collected by centrifugation (about 3500 rpm, 5 min) using a centrifuge.
  • the particles were washed with n-heptane for about 5 times, they were again dispersed in ultrapure water (5 ° C) for about 2 times, then collected by centrifugation, and lyophilized in a freeze dryer to obtain fine particles.
  • the content of the Exendin-4 derivative in the obtained fine particles was measured to be 18.31%, and the particle diameter was 32-126 ⁇ m.
  • the solid dispersion contains the following components in mass percent: water-soluble drug: 16% of the aralelin derivative, poorly water-soluble polymer: PLGA 81%, adjuvant: xylitol 3%; wherein the molecular weight of the PLGA is 45 kDa Wherein the ratio of lactide to glycolide is 50/50 and the PLGA has a terminal carboxyl group.
  • the solid dispersion obtained in Step I was uniformly dispersed in about 11 times of dichloromethane to obtain an internal oil phase, and then the internal oil phase was injected into 970 mL of 1.25% (w/w) lecithin which had been previously thermostated to about 5 °C.
  • S/O/O emulsion (1300 rpm, 5 min) was prepared in a peanut oil solution and mechanically agitated. The S/O/O emulsion was mechanically stirred for about 4 hours (500 rpm) to solidify the microparticles, and then the microparticles were collected by centrifugation (about 3500 rpm, 5 min) using a centrifuge.
  • the particles were washed with n-heptane for about 5 times, they were again dispersed in ultrapure water (5 ° C) for about 2 times, then collected by centrifugation, and lyophilized in a freeze dryer to obtain fine particles.
  • the content of the aralilin derivative in the obtained fine particles was measured to be 13.74%, and the particle diameter of the fine particles was 32 to 128 ⁇ m.
  • the solid dispersion contains the following components in mass percent: water-soluble drug: thymopentin derivative 12%, poorly water-soluble polymer: PLGA 84%, adjuvant: xylitol 4%; wherein the PLGA has a molecular weight of 40 kDa Wherein the ratio of lactide to glycolide is 50/50 and the PLGA has a terminal carboxyl group.
  • thymopentin derivatives Preparation of 10kDa PEG-NHS ester, followed by reaction with lysine at position 2 in thymopentin in PBS buffer, separation and purification by ion exchange, gel chromatography, concentration and freeze-drying A thymopentin derivative is obtained.
  • the solid dispersion obtained in the step I was uniformly dispersed in about 10 times of dichloromethane to obtain an internal oil phase, and then the inner oil phase was injected into 970 mL of 1% (w/w) lecithin which had been previously thermostated to about 5 ° C /
  • the S/O/O emulsion (1400 rpm, 5 min) was prepared in a peanut oil solution by mechanical stirring.
  • the S/O/O emulsion was mechanically stirred for about 4 hours (500 rpm) to solidify the microparticles, and then the microparticles were collected by centrifugation (about 3500 rpm, 5 min) using a centrifuge.
  • the particles were washed with n-heptane for about 5 times, they were again dispersed in ultrapure water (5 ° C) for about 2 times, then collected by centrifugation, and lyophilized in a freeze dryer to obtain fine particles.
  • the content of the thymopentin derivative in the obtained microparticles was measured to be 10.68%, and the particle diameter was 35-132 ⁇ m.
  • PLGA molecular weight 30 kDa, monomer ratio 50/50, terminal carboxyl group
  • the solid dispersion obtained in the step I was uniformly dispersed in about 6.53 g of tetrachloroethylene to obtain an internal oil phase, and then the inner oil phase was injected with 500 mL of 1% (w/w) lecithin/peanut oil which had been previously thermostated to about 6 ° C.
  • the S/O/O emulsion 1000 rpm, 5 min
  • the S/O/O emulsion was mechanically stirred for about 3.5 hours (500 rpm) to solidify the microparticles, and then the microparticles were collected by centrifugation (about 3500 rpm, 5 min) using a centrifuge.
  • the particles were washed with cyclohexane for about 5 times, they were again dispersed in ultrapure water (5 ° C) for about 2 times, then collected by centrifugation, and lyophilized in a freeze dryer to obtain fine particles.
  • the content of Mipomersen in the obtained fine particles was measured to be 18.10%, and the particle diameter was 32-109 ⁇ m.
  • the solid dispersion obtained in the step I was uniformly dispersed in a mixture of about 6.12 g of dichloromethane and chloroform to obtain an internal oil phase, and then the inner oil phase was injected into 500 mL of 0.5% (w/w which had been previously thermostated to about 5 ° C).
  • an S/O/O emulsion 1000 rpm, 5 min was prepared by mechanical stirring.
  • the S/O/O emulsion was transferred to a sealed glass flask and mechanical stirring was continued for about 4 hours (500 rpm) to solidify the microparticles, and then the microparticles were collected by centrifugation (about 3500 rpm, 5 min) using a centrifuge. After the microparticles were washed about 5 times with a mixture of n-heptane and n-hexane, they were again dispersed in ultrapure water (5 ° C) for about 2 times, then collected by centrifugation, and lyophilized in a freeze dryer to obtain fine particles. The content of interleukin in the obtained fine particles was 16.36%, and the particle diameter was 31-114 ⁇ m.
  • the dried solid mixture prepared in the step I of Example 9 was fed into a hot melt extruder, hot melt extruded into a strip having a diameter of about 1 mm, and after cooling, it was cut to obtain a leuprolide having a length of about 5 mm. Release the implant. The content of leuprolide in the obtained implant was measured to be 19.32%.
  • the fine particles obtained in the step II of Example 9 were filled in a mold of 1 mm * 10 mm (the inner cavity was cylindrical, the diameter of the round bottom was 1 mm, and the depth was about 10 mm), and the temperature was raised to about 43 ° C, and then compression molding was performed to obtain a columnar shape ( 1mm*4.98mm) leuprolide slow release implant.
  • the content of leuprolide in the obtained implant was measured to be 19.05%.
  • the method for analyzing the drug loading rate and the drug encapsulation efficiency of the microparticles or implants in the above embodiments is as follows: taking 5 mg of microparticles or an implant, dissolving in 50 mL of acetonitrile (ACN), and then adding 0.1 ⁇ of TFA 500 ⁇ L, and after thoroughly mixing, The supernatant was centrifuged, and the concentration of the drug was analyzed by high performance liquid chromatography. The ratio of the mass of the drug encapsulated in the microparticle (or implant) to the dose of the drug is the encapsulation efficiency of the drug, and the ratio of the mass of the drug encapsulated in the microparticle (or implant) to the mass of the microparticle is the drug-loaded drug. rate. All experiments were repeated more than 3 times.
  • the particle size analysis method of the microparticles prepared in the above examples was as follows: about 10 mg of the microparticles were dispersed in liquid paraffin, ultrasonically dispersed for about 30 s, and measured using a Beckman Coulter laser particle size analyzer.
  • the sustained-release microparticles and the implant prepared in the above examples were subjected to the burst release and in vitro release curves, and the measurement method was as follows: accurately weigh the drug-containing microparticles or the implant 20 mg into a 15 mL centrifuge tube, and the pH was 7.4. Buffer (containing 0.02% sodium azide as bacteriostatic agent) as release medium, placed in a constant temperature air bath shaker, and in vitro release of microparticles or implants at an oscillation speed of 100 rpm and a temperature of 37 °C ⁇ 0.5 °C. Degree determination.
  • the drug release amount was determined by high performance liquid chromatography. The measurement method is:
  • Example 1 0.90% 1.86% 6.08% 13.09% 23.28% 38.15% 52.01% 66.85% 83.45%
  • Example 2 1.04% 2.08% 5.59% 12.73% 21.19% 32.39% 48.63% 62.74% 80.64%
  • Example 3 1.0% 2.16% 5.63% 11.60% 15.27% 25.48% 36.41% 52.67% 75.97%
  • Example 4 0.82% 1.81% 6.06% 11.76% 19.28% 32.61% 51.82% 68.52% 85.20%
  • Example 5 1.05% 1.98% 7.41% 16.83% 29.43% 45.80% 69.94% 83.91% 94.92%
  • Example 6 1.05% 2.12% 5.31% 10.79% 22.30% 37.27% 58.57% 76.65% 90.50%
  • Example 7 0.79% 1.88% 5.89% 12.86% 23.19% 42.35% 67.81% 79.61% 90.23%
  • Example 8 1.68% 4.16% 11.10% 21.25% 33.24% 52.61% 78.2
  • Example 20 0.94% 1.83% 8.59% 16.91% 28.81% 42.50% 63.72% 80.76% 91.50%
  • Example 21 1.20% 2.14% 10.10% 20.36% 30.64% 48.80% 65.56% 83.37% 95.95%
  • Example 22 1.44% 2.48% 11.34% 24.68% 38.00% 46.80% 64.34% 79.21% 91.05%
  • Example 23 1.06% 2.20% 10.05% 22.80% 31.95% 43.34% 65.76% 81.50% 93.14%
  • Example 24 0.89% 1.73% 11.09% 22.81% 43.81% 59.64% 77.22% 90.00% 100.00%
  • Example 25 1.19% 2.34% 14.81% 29.75% 45.00% 61.56% 78.14% 91.26% 100.00%
  • the sustained release microparticles prepared by using the solid dispersion of the present invention and the prepared implant have no burst phenomenon or obvious delayed release, and the whole release tendency is close to zero.
  • Level release Among them, some samples have an in vitro release period of 40-50 days, some samples have an in vitro release period of 50-60 days, and some samples have an in vitro release period of more than 60 days, which has an excellent sustained release effect.
  • Approximately 20 mg of the microparticle sample was suspended in 2 mL of diluent (3% carboxymethylcellulose, 0.9% NaCl), and then inhaled into a syringe and injected into a commercially available 1 kg weight of the hind leg (muscle) through a 24-30 G injection needle. )in. Each injection was carried out for 20 seconds or less, and no obstruction and smooth needle pushing were observed. The results are shown in Table 2.
  • the residual amounts of the organic solvent A, the organic solvent B, the organic solvent C, and the organic solvent D in the solid dispersion and the sustained-release fine particles prepared in Examples 1 to 23 of the present invention are measured, and the measurement method is a well-known measurement method.
  • the measurement results are shown in Table 3.
  • the residual amount of the organic solvent in Table 3 it can be seen from the results of the residual amount of the organic solvent in Table 3 that in the solid dispersion and the sustained-release fine particles prepared by the present invention, the residual amount of the organic solvent is low, or is not detected, or the residual amount is lower than the detectable range, and the drug is administered. After the patient has no side effects caused by organic solvents, it is also beneficial to maintain the stability of the particles and extend the shelf life.
  • Blood was taken from the tail vein at the same time on the 0th, 0.5d, 1d, 2d, 3d, 4d, 5d, 6d, 7d, 14d, 21d, 28d, 35d, 42d, 49d, 56d, 63d, 70d administration.
  • concentration of testosterone in serum was determined by radioimmunoassay, and then a curve of serum testosterone concentration-time was prepared. The results are shown in Fig. 1.
  • the prepared Goserelin microparticles of Example 6, the leuprolide microparticles of Example 7, the triptorelin microparticles of Example 8, and the buserelin of Example 12 of the present invention can well control serum testosterone concentrations within 70 days after administration, and the serum testosterone concentration is less than 5 ng/mL during the 4-63 days after administration, and the serum testosterone concentration within 7-50 days is less than about 4 ng/mL.
  • the goserelin microparticles, leuprolide microparticles, triptorelin microparticles and buserelin microparticles of the present invention can release the active drug for a long time after administration, and achieve the desired treatment.
  • the effect can reduce the frequency of administration and is beneficial to improve patient compliance.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Zoology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un procédé de préparation de microparticules à libération prolongée, comprenant les étapes suivantes : 1) préparation d'une dispersion solide d'un médicament soluble dans l'eau et d'un polymère insoluble dans l'eau biodégradable et biocompatible ; 2) dissolution de la dispersion solide préparée dans un solvant organique pour former une émulsion de la dispersion solide ; 3) injection de l'émulsion de la dispersion solide obtenue dans une solution d'huile avec des tensioactifs pour former une émulsion homogène ; et 4) durcissement des microparticules dans l'émulsion par évaporation ou extraction par solvant, et recueil, lavage et séchage des microparticules pour obtenir les microparticules à libération prolongée. L'invention concerne également des microparticules à libération prolongée préparées par ce procédé de préparation de microparticules à libération prolongée, ainsi que l'utilisation de ces microparticules à libération prolongée dans une composition pharmaceutique implantable à libération prolongée. Le procédé de préparation de microparticules à libération prolongée est mis en œuvre, dans son intégralité, à température normale ou à basse température. Les microparticules à libération prolongée préparées ont un effet de libération prolongée proche du niveau zéro, et le médicament est stable en concentration au cours de la période de libération prolongée.
PCT/CN2017/081637 2016-04-26 2017-04-24 Procédé de préparation de microparticules à libération prolongée, microparticules à libération prolongée et leur utilisation WO2017186074A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610268762.9A CN105878190B (zh) 2016-04-26 2016-04-26 缓释微粒的制备方法、制得的缓释微粒及其应用
CN201610268762.9 2016-04-26

Publications (1)

Publication Number Publication Date
WO2017186074A1 true WO2017186074A1 (fr) 2017-11-02

Family

ID=56704744

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/081637 WO2017186074A1 (fr) 2016-04-26 2017-04-24 Procédé de préparation de microparticules à libération prolongée, microparticules à libération prolongée et leur utilisation

Country Status (2)

Country Link
CN (1) CN105878190B (fr)
WO (1) WO2017186074A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112450316A (zh) * 2020-12-02 2021-03-09 通化承诚药业有限公司 小牛胸腺肽粉制备方法
CN113717706A (zh) * 2021-08-05 2021-11-30 西安交通大学 一种可完全降解固体缓蚀剂的制备方法

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105878190B (zh) * 2016-04-26 2021-01-22 广州帝奇医药技术有限公司 缓释微粒的制备方法、制得的缓释微粒及其应用
CN110101846B (zh) * 2018-02-01 2022-09-23 齐鲁制药有限公司 一种低突释率的索玛鲁肽微球及其制备方法
CN114569564B (zh) * 2022-03-21 2024-02-23 浙江圣兆药物科技股份有限公司 戈舍瑞林缓释微球组合物

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5556642A (en) * 1992-07-16 1996-09-17 Tanabe Seiyaku Co., Ltd. Method for producing sustained release microsphere preparation
CN1524516A (zh) * 2003-09-18 2004-09-01 中国人民解放军第二军医大学 胰高血糖素样肽－1缓释微球制剂及其用途
CN1754570A (zh) * 2004-09-28 2006-04-05 中国人民解放军军事医学科学院毒物药物研究所 含干扰素或其类似物的注射用缓释微球及其制备方法
CN1754572A (zh) * 2004-09-27 2006-04-05 中国人民解放军军事医学科学院毒物药物研究所 含干扰素α－1b的注射用缓释微球及其制备方法
CN1965809A (zh) * 2005-11-16 2007-05-23 中国人民解放军军事医学科学院毒物药物研究所 Lhrh拮抗剂类物质的注射用缓释微球及其制备方法
CN102233129A (zh) * 2010-04-29 2011-11-09 上海交通大学 一种预防或治疗视网膜损伤的长效缓释制剂及其制备方法
US20160083345A1 (en) * 2014-09-19 2016-03-24 Cadila Healthcare Limited Polymorphic forms of lomitapide and its salts and processes for their preparation
CN105878190A (zh) * 2016-04-26 2016-08-24 广州帝奇医药技术有限公司 缓释微粒的制备方法、制得的缓释微粒及其应用

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001083594A1 (fr) * 2000-04-28 2001-11-08 Tanabe Seiyaku Co., Ltd. Procede de preparation d'une microsphere
US20140128431A1 (en) * 2012-04-03 2014-05-08 Hoffmann-Laroche Inc. Pharmaceutical composition with improved bioavailability, safety and tolerability
CN105168137A (zh) * 2014-06-23 2015-12-23 天津金耀集团有限公司 一种乳糖塞来昔布药物组合物
PT107846B (pt) * 2014-08-01 2019-03-22 Hovione Farm S A Produção de nano- partículas de dispersões sólidas amorfas por co-precipitação controlada

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5556642A (en) * 1992-07-16 1996-09-17 Tanabe Seiyaku Co., Ltd. Method for producing sustained release microsphere preparation
CN1524516A (zh) * 2003-09-18 2004-09-01 中国人民解放军第二军医大学 胰高血糖素样肽－1缓释微球制剂及其用途
CN1754572A (zh) * 2004-09-27 2006-04-05 中国人民解放军军事医学科学院毒物药物研究所 含干扰素α－1b的注射用缓释微球及其制备方法
CN1754570A (zh) * 2004-09-28 2006-04-05 中国人民解放军军事医学科学院毒物药物研究所 含干扰素或其类似物的注射用缓释微球及其制备方法
CN1965809A (zh) * 2005-11-16 2007-05-23 中国人民解放军军事医学科学院毒物药物研究所 Lhrh拮抗剂类物质的注射用缓释微球及其制备方法
CN102233129A (zh) * 2010-04-29 2011-11-09 上海交通大学 一种预防或治疗视网膜损伤的长效缓释制剂及其制备方法
US20160083345A1 (en) * 2014-09-19 2016-03-24 Cadila Healthcare Limited Polymorphic forms of lomitapide and its salts and processes for their preparation
CN105878190A (zh) * 2016-04-26 2016-08-24 广州帝奇医药技术有限公司 缓释微粒的制备方法、制得的缓释微粒及其应用

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112450316A (zh) * 2020-12-02 2021-03-09 通化承诚药业有限公司 小牛胸腺肽粉制备方法
CN113717706A (zh) * 2021-08-05 2021-11-30 西安交通大学 一种可完全降解固体缓蚀剂的制备方法
CN113717706B (zh) * 2021-08-05 2022-08-09 西安交通大学 一种可完全降解固体缓蚀剂的制备方法

Also Published As

Publication number Publication date
CN105878190A (zh) 2016-08-24
CN105878190B (zh) 2021-01-22

Similar Documents

Publication Publication Date Title
WO2017186073A1 (fr) Procédé de préparation de microparticules à libération prolongée, microparticules à libération prolongée et leur utilisation
WO2017186077A1 (fr) Procédé de préparation de microparticules à libération prolongée
Molavi et al. Polyester based polymeric nano and microparticles for pharmaceutical purposes: A review on formulation approaches
WO2017186075A1 (fr) Procédé de préparation de microgranules à libération prolongée
WO2017186074A1 (fr) Procédé de préparation de microparticules à libération prolongée, microparticules à libération prolongée et leur utilisation
Lee et al. Poly (lactic‐co‐glycolic acid) devices: Production and applications for sustained protein delivery
Sinha et al. Biodegradable microspheres for protein delivery
Meinel et al. Stabilizing insulin-like growth factor-I in poly (D, L-lactide-co-glycolide) microspheres
US9877922B2 (en) Process of preparing microspheres for sustained release having improved dispersibility and syringeability
AU2003217367B2 (en) Polymer-based compositions for sustained release
Choi et al. G-CSF loaded biodegradable PLGA nanoparticles prepared by a single oil-in-water emulsion method
JP2014533740A (ja) 疎水性薬物送達材料、その製造方法および薬物送達組成物の送達方法
BRPI0715469A2 (pt) composiÇÕes farmacÊuticas para a liberaÇço sustentada de peptÍdeos
JP2008528698A (ja) 埋め込み可能なインターフェロン含有デバイス
WO2017186076A1 (fr) Dispersion solide, procédé de préparation et applications de ladite dispersion
US20220133630A1 (en) Preparation method of sustained-release microparticles
Mok et al. Water-free microencapsulation of proteins within PLGA microparticles by spray drying using PEG-assisted protein solubilization technique in organic solvent
JP2018510883A (ja) タンパク質またはペプチド伝達用の溶解性マイクロニドル
KR20140097541A (ko) 폴리머 약물-전달 물질, 이의 제조 방법 및 약물-전달 조성물을 전달하는 방법
US20210154147A1 (en) Preparation method of sustained-release microparticles
KR100486028B1 (ko) 단백질 함유 서방성 리피드 임플란트 및 이의 제조방법
Shim et al. Fabrication of hollow porous PLGA microspheres using sucrose for controlled dual delivery of dexamethasone and BMP2
EP2696856B1 (fr) Formulation à libération contrôlée comprenant hcg
Rhodes et al. Formulation of Depot Delivery Systems
Sax Twin-screw extruded lipid implants for controlled protein drug delivery

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

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

Ref document number: 17788726

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 17788726

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 17788726

Country of ref document: EP

Kind code of ref document: A1