WO2017186076A1 - Dispersion solide, procédé de préparation et applications de ladite dispersion - Google Patents

Dispersion solide, procédé de préparation et applications de ladite dispersion Download PDF

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WO2017186076A1
WO2017186076A1 PCT/CN2017/081639 CN2017081639W WO2017186076A1 WO 2017186076 A1 WO2017186076 A1 WO 2017186076A1 CN 2017081639 W CN2017081639 W CN 2017081639W WO 2017186076 A1 WO2017186076 A1 WO 2017186076A1
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solid dispersion
water
acid
peptide
soluble
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PCT/CN2017/081639
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English (en)
Chinese (zh)
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刘锋
赖树挺
郑阳
曹付春
连远发
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广州帝奇医药技术有限公司
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Publication of WO2017186076A1 publication Critical patent/WO2017186076A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • 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
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • 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
    • A61K38/1767—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates
    • 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
    • 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
    • A61K38/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • A61K38/35—Corticotropin [ACTH]
    • 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
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)

Definitions

  • the invention relates to a water-soluble drug sustained-release composition and a preparation method thereof, in particular to a water-soluble drug solid dispersion and a preparation method thereof.
  • DDS Drug Delivery System
  • the object of the present invention is to provide a solid dispersion having high stability against the above-mentioned deficiencies of the prior art, which can be used for preparing a sustained release effect, a small burst release, a short delay period, and the like.
  • the technical solution adopted by the present invention is: a solid dispersion containing a water-soluble drug and a poorly water-soluble polymer, and the quality of the water-soluble drug in the solid dispersion The percentage is 3.8 to 50%, and the mass ratio of the water-soluble drug to the poorly water-soluble polymer is 1: (1 to 25).
  • the mass percentage of the water-soluble drug in the solid dispersion is The amount is from 6.25 to 45%; as a more preferred embodiment of the solid dispersion of the present invention, the water-soluble drug is contained in the solid dispersion in an amount of 10 to 40% by mass.
  • the mass ratio of the water-soluble drug to the water-insoluble polymer is 1: (1 to 20). As a more preferred embodiment of the solid dispersion of the present invention, the mass ratio of the water-soluble drug to the water-insoluble polymer is 1: (1 to 15). As a more preferred embodiment of the solid dispersion of the present invention, the mass ratio of the water-soluble drug to the water-insoluble polymer is 1: (1 to 12). As a more preferred embodiment of the solid dispersion of the present invention, the mass ratio of the water-soluble drug to the water-insoluble polymer is 1: (1 to 9).
  • the solid dispersion may be prepared by dissolving the poorly water-soluble polymer and the water-soluble drug in the organic solvent A sequentially or simultaneously; and injecting the solution into the organic solvent B. Or injecting the organic solution B into the above solution to produce a uniform fine precipitate, collecting the precipitate, washing with the organic solvent B, and finally removing the organic solvent to obtain a solid dispersion; wherein the organic solvent A is capable of simultaneously dissolving water. a poorly soluble polymer and a water-soluble drug; the solvent B cannot dissolve a poorly water-soluble polymer and a water-soluble drug.
  • the solid dispersion of the present invention has a lower glass transition temperature (Tg) and a viscous flow temperature (Tf) than a pure water poorly soluble polymer or a water-soluble pharmaceutically active ingredient, and thus is required for preparation of an implant.
  • Tg glass transition temperature
  • Tf viscous flow temperature
  • the temperature is significantly reduced and the operating temperature can be lowered without the addition of plasticizer.
  • the water-insoluble polymer is heated and the temperature rises to a certain level (ie, T>Tf). At this time, the polymer undergoes viscous flow under external force and is irreversible deformation. After the external force is removed, the deformation does not spontaneously recover.
  • the active ingredient is uniformly dispersed in the polymer, and can be used for rapidly preparing a solid implant by hot melt extrusion or hot press forming, and can reduce hot melt extrusion or hot press forming. Temperature and time, and the solid dispersion has high stability and excellent sustained release effect.
  • the water-soluble drug includes a basic substance having a molecular weight of less than 3,350 Da or a substance containing a basic group (such as an alkaloid, a short peptide, an antagonist, an antibiotic) and a salt thereof, and a basic substance having a molecular weight of more than 3,350 Da or containing a base.
  • a basic substance having a molecular weight of less than 3,350 Da or a substance containing a basic group such as an alkaloid, a short peptide, an antagonist, an antibiotic
  • Substance substances such as polypeptides, proteins, nucleic acids, antibodies, antigens, antibiotics, etc.
  • the water-soluble drug is at least one of a protein drug, a peptide drug, and a nucleic acid drug.
  • the protein comprises 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 Functionally related.
  • the protein drug comprises 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 glycoproteins).
  • nuclear proteins nuclear proteins, mucins, lipoproteins, metalloproteins), therapeutic proteins, fusion proteins, receptors, antigens (such as synthetic or recombinant antigens), viral surface proteins, hormones, hormone analogues, antibodies (such as monoclonal Or a polyclonal antibody), an enzyme, a Fab fragment, an interleukin and a derivative thereof, at least one of an interferon and a derivative thereof;
  • the peptide drug comprises adrenocorticotropic hormone (ACTH) and its derivatives, epidermal growth factor (EGF), platelet-derived growth factor (TOGF), gonadotropin releasing hormone (LHRH) and derivatives or analogs thereof.
  • ACTH adrenocorticotropic hormone
  • EGF epidermal growth factor
  • TOGF platelet-derived growth factor
  • LHRH gonadotropin releasing hormone
  • IGF-I insulin-like growth factor
  • IGF-II insulin-like growth factor
  • cell growth factors such as EGF, TGF- ⁇ , TGF- ⁇ , PDGF, FGF, basic FGF, etc.
  • glucagon-like peptide Such as GLP-1, GLP-2) and its derivatives or analogues, neurotrophic factors (such as NT-3, NT-4, CNTF, GDNF, BDNF, etc.), colony stimulating factors (such as CSF, GCSF, GMCSF, MCSF Etc.) and their synthetic analogues, modifications and drugs
  • At least one of the active fragments; the derivative or analog of GLP-1 includes, but is not limited to, exendin-3 and exendin-4.
  • 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.
  • the nucleic acid drug is an oligonucleotide, an antisense oligonucleotide, an aptamer, a polynucleotide, a deoxyribonucleic acid, an siRNA, a nucleotide construct, a single-stranded or double-stranded segment, and a precursor and At least one of its 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 peptide drug includes derivatives of peptides and peptides; wherein the peptides include, but are not limited to, glucagon (29 peptide), shemerilin (29) Peptide), adiformil (28 peptide), secretin (27 peptide), ziconotide (25 peptide), ticocarp (24 peptide), bivalirudin (20 peptide), somatostatin (14 peptide), terlipressin (12 peptide), goserelin (10 peptide), triptorelin (10 peptide), nafarelin (10 peptide), gonarelin (10 peptide) , cetrorelix (10 peptide), degarelix (10 peptide), antipeptide (10 peptide), angiotensin (6-10 peptide), leuprolide (9 peptide), alarin ( 9 peptide), buserelin (9 peptide), desherrin
  • Derivatives of the peptide are products of peptides or variants, analogs thereof which are modified by water-soluble or poorly water-soluble groups or substances.
  • the derivative of the peptide drug refers to a product in which these peptides or variants or analogs thereof are appropriately modified by water-soluble or poorly water-soluble substances, which have higher biological and pharmacological activities, stability, or new functions. Or attribute.
  • Derivatives of the peptide drug include derivatives of glucagon-like peptides (such as GLP-1, GLP-2) and derivatives or analogs thereof, including but not limited to exendin-3 and exendin-4 or their A variant of a variant.
  • 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 glucagon peptide-1
  • exendin-4 is the second position of glycine
  • GLP-1 is the second position of alanine
  • exendin-4 can interact with GLP-1 receptor. Binding and producing a cascade of cellular signaling.
  • the water-soluble or poorly water-soluble group or substance comprises polyethylene glycol and a derivative thereof, cyclodextrin, hyaluronic acid, short peptide, albumin, amino acid sequence, nucleic acid, Genes, antibodies, phosphoric acid, sulfonic acid, fluorescent dyes, KLH, OVA, PVP, PEO, PVA, alkanes, aromatic hydrocarbons, biotin, immunoglobulins, albumin, polyamino acids, gelatin, succinylated gelatin, acrylamide derivatives, Fatty acids, polysaccharides, lipid amino acids, chitosan and dextran.
  • Polyethylene glycol and derivatives thereof are preferred, and the structure of the polyethylene glycol and its derivatives may be branched, linear, bifurcated or dumbbell-shaped.
  • Derivatives of the polyethylene glycol include, but are not limited to, monomethoxypolyethylene glycol, methoxypolyethylene glycol propionate.
  • the polyethylene glycol and its derivatives are commercially available or are known to those skilled in the art. Prepared by yourself.
  • the water-soluble or poorly water-soluble substance is modified to be a modifying agent having an activating group, and is coupled to the peptide substance derivative, and the activating group is selected from a horse.
  • the activating group is selected from the group consisting of maleimide, halogen, vinyl sulfone and disulfide bonds; more preferably maleimide and disulfide bonds.
  • the number of activating groups carried on the polymer is one or more, and when the number of the activating groups is 2 or more, the activating group may be one or more.
  • 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 or analog thereof by an amino group, a carboxyl group, a hydroxyl group and/or a thiol group on the amino acid sequence.
  • 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
  • the modification of the peptide analog is a random modification, a localization modification (specific modification), a single point modification or a multi-point modification, preferably a single point localization modification.
  • the peptide, its variants and analogs are prepared by a conventional polypeptide synthesis method, including a solid phase polypeptide synthesis method, a liquid phase polypeptide synthesis method, a solid phase-liquid phase polypeptide synthesis method, and a recombinant method; the reaction of the peptide with the modifier is The pH of the reaction system is appropriately controlled in an aqueous solution or a buffered saline solution, and the modified product is monitored by HPLC, GPC, etc., and purified by ion exchange and gel chromatography, concentrated, and freeze-dried to obtain a target product.
  • a conventional polypeptide synthesis method including a solid phase polypeptide synthesis method, a liquid phase polypeptide synthesis method, a solid phase-liquid phase polypeptide synthesis method, and a recombinant method; the reaction of the peptide with the modifier is The pH of the reaction system is appropriately controlled in an aqueous solution or a buffered saline solution, and the modified
  • the above-mentioned protein, peptide, nucleic acid drug 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 poorly water-soluble polymer is a biodegradable, biocompatible water-insoluble polymer.
  • the poorly water-soluble polymer is polylactide, polyglycolide, lactide-glycolide copolymer and copolymers thereof with polycaprolactone or polyethylene glycol, polycaprolactone and Copolymer of ethylene glycol, polyhydroxybutyric acid, polyhydroxyvaleric acid, polydioxanone, chitosan, alginic acid and salts thereof, polycyanoacrylate, polyanhydride, polyorthoester, poly At least one of an amide, a polyphosphazene, a polyphosphate, and copolymers and/or mixtures thereof.
  • the poorly water-soluble polymer is a polylactide, a lactide-glycolide copolymer or a copolymer thereof with polycaprolactone or polyethylene glycol. At least one of them.
  • the poorly water-soluble polymer is polylactide (PLA), polyglycolide (PGA), lactide-glycolide copolymer (PLGA), and They are copolymers with polycaprolactone (PCL) or polyethylene glycol (PEG) (eg 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, polydioxane Cyclohexanone (PPDO), chitosan, alginic acid and its salts, polycyanoacrylates, polyanhydrides, polyorthoesters, polyamides, polyphosphazenes, polyphosphate
  • PCL polycaprolactone
  • PEG polyethylene glyco
  • the poorly water-soluble polymer is PLA, PLGA and a copolymer thereof with PCL or PEG
  • the PLA, PLGA and copolymers thereof with PCL or PEG The weight average molecular weight is from 25,000 to 150,000 Da, preferably the weight average molecular weight is from 30,000 to 130,000 Da, and more preferably the weight average molecular weight is from 35,000 to 110,000 Da.
  • the weight average molecular weight described above is a value obtained by gel permeation chromatography (GPC) measurement.
  • the water-insoluble polymer is PLA, PLGA and a copolymer thereof with PCL or PEG, the PLA, PLGA and copolymer thereof with PCL or PEG
  • the viscosity (test conditions of -0.5% (w/v), CHCl 3 , 25 ° C) is 0.22-1.1 dL/g, preferably the viscosity is 0.27-1.0 dL/g, more preferably the viscosity is 0.31-0.9 dL/g.
  • the water-insoluble polymer molecular chains may all carry anionic or cationic groups or may not carry these groups.
  • the poorly water-soluble polymer has a terminal hydroxyl group, a terminal carboxyl group or a terminal ester group, and more preferably, the poorly water-soluble polymer is a polymer having a terminal carboxyl group.
  • the poorly water-soluble polymer described in the present invention may be a single polymer or a mixture of a plurality of polymers, such as a ratio of lactide to glycolide and a PLGA having the same molecular weight but different carrying groups.
  • the combination, molecular weight, and carrier group of PLGA in combination, ratio of lactide to glycolide, and combination of PLGA having the same carrier group but different molecular weights, molecular weight and the same carrier group but different ratio of lactide to glycolide The combination of PLGA, PLGA and PLA, etc., which are different in the ratio of the group and the lactide to the glycol.
  • the solid dispersion further contains an auxiliary agent which is at least one of an amino acid, an antioxidant, a buffer, a saccharide, a fatty acid, and an alcohol;
  • the mass percentage of the adjuvant in the solid dispersion is from 0.5 to 10%.
  • auxiliaries may be included in the solid dispersion of the invention.
  • the adjuvant may impart additional characteristics to the active drug or composition, such as increasing the stability of the microparticles, active drug or carrier, promoting controlled release of the active drug from the microparticles, or modulating the biological tissue permeability of the active drug.
  • an appropriate amount of additives can further reduce the glass transition temperature (Tg) and viscosity temperature (Tf) of the solid dispersion.
  • Suitable additives include, but are not limited to, amino acids, antioxidants, buffers. , sugars, fatty acids and alcohols.
  • the mass percentage of these auxiliaries in the solid dispersion is from 0.01 to 10%, preferably from 0.1 to 8.5%, more preferably from 0.5 to 7.5%.
  • the saccharides include monosaccharides, oligosaccharides, polysaccharides, sugar alcohols, and 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, poloxamer, chondroitin sulfate and its salts, heparin, inulin, chitin and its derivatives, dextrin, Portuguese Glycans and alginic acid and salts thereof, or any combination thereof.
  • sucrose mannitol, xylitol, and any combination thereof.
  • the saccharide builder comprises from 0.1 to 8.5%, preferably from 0.5 to 8.5%, more preferably from 1 to 7.5% by mass of the solid dispersion.
  • the fatty acids include C12-C24 alkanoic acids and derivatives thereof, including, but not limited to, oleic acid, stearic acid, lauric acid, myristic acid, palmitic acid, arachidic acid, behenic acid, lignin acid, and any combination thereof. Preferred are stearic acid, behenic acid, palmitic acid, and any combination thereof.
  • the fatty acid builder comprises from 0 to 5%, preferably from 0.01 to 3%, more preferably from 0.05 to 2% by mass of the solid dispersion.
  • the alcohols include, but are not limited to, polyethylene glycol (PEG) such as PEG400, PEG600, PEG2000, PEG4000, PEG6000. PEG having a molecular weight of 400 to 3000 Da is preferred.
  • the alcohol adjuvant comprises from 0 to 4%, preferably from 0.01 to 3%, more preferably from 0.05 to 2% by mass of the solid dispersion.
  • the buffering agent includes a salt of an inorganic acid or an organic acid such as a salt of carbonic acid, acetic acid, oxalic acid, citric acid, phosphoric acid, or hydrochloric acid.
  • a salt of an inorganic acid or an organic acid such as a salt of carbonic acid, acetic acid, oxalic acid, citric acid, phosphoric acid, or hydrochloric acid.
  • a salt of an inorganic acid or an organic acid such as a salt of carbonic acid, acetic acid, oxalic acid, citric acid, phosphoric acid, or hydrochloric acid.
  • a salt of an inorganic acid or an organic acid such as a salt of carbonic acid, acetic acid, oxalic acid, citric acid, phosphoric acid, or hydrochloric acid.
  • 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, hydroxy coumarin, butylated hydroxytoluene, propyl hydroxybenzoate, trihydroxy phenyl ketone, vitamin E, vitamin E-TPGS, ⁇ -hydroxybenzoate (such as Ester, ethyl ester, propyl ester, butyl ester), or any combination thereof.
  • the antioxidant can effectively remove free radicals or peroxides from the composition.
  • the antioxidant builder comprises from 0 to 1%, preferably from 0 to 0.5%, more preferably from 0 to 0.1% by mass of the solid dispersion.
  • the amino acids include glycine, alanine, serine, aspartic acid, glutamic acid, threonine, tryptophan, lysine, hydroxylysine, histidine, arginine, cystine At least one of cysteine, methionine, phenylalanine, leucine, isoleucine, and the like, and derivatives thereof, preferably basic amino acids such as arginine, histidine, Lysine, or any combination thereof.
  • the amino acid builder comprises from 0 to 3%, preferably from 0 to 2%, more preferably from 0.01 to 1% by mass of the solid dispersion.
  • the present invention also provides a method for producing a solid dispersion as described above, which comprises the steps of: completely or completely dissolving or dispersing the water-insoluble polymer or other substances contained in the solid dispersion in the organic solvent A. Injecting the above solution into the organic solvent B or injecting the organic solution B into the above solution to produce a uniform fine precipitate, collecting the precipitate, washing with the organic solvent B, and finally removing the organic solvent to obtain a solid dispersion; wherein the organic
  • the solvent A can simultaneously dissolve the water-insoluble polymer and the water-soluble drug, and the solvent B cannot dissolve the water-insoluble polymer and the water-soluble drug.
  • the solid dispersion prepared by the method described above, the active ingredient is uniformly dispersed in the polymer, can be used for preparing the sustained-release fine particles, or the implant is prepared by hot melt extrusion or hot press forming, and the hot melt extrusion can be reduced. Or the temperature of hot press forming, and the sustained release fine particles and the implant have high stability and excellent sustained release effect.
  • the organic solvent A is at least one of glacial acetic acid, acetonitrile, trifluoroacetic acid, and dimethyl sulfoxide; and the organic solvent B is anhydrous. At least one of diethyl ether, hexane, and n-heptane.
  • 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 selected from the group consisting of glacial acetic acid, acetonitrile, trifluoroacetic acid, dimethyl sulfoxide, or a mixture of two or more thereof, preferably glacial acetic acid, acetonitrile, more preferably glacial acetic acid.
  • the proportion of the organic solvent in the mixture varies according to different drugs, 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, hexane (including cyclohexane, n-hexane), n-heptane, or a mixture of two or more thereof, preferably anhydrous diethyl ether, hexane (including cyclohexane, N-hexane), more preferably anhydrous diethyl ether.
  • the proportion of the organic solvent in the mixture varies according to different drugs, 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 be below normal temperature or low temperature, and the normal temperature is generally understood to be 15 ° C, preferably 10 ° C; the low temperature is generally understood to be 10 ° C or lower, preferably 4 ° C or lower; the organic solvent A is more than the organic solvent B
  • the temperature is 0-10 ° C higher, preferably 3-8 ° C.
  • the concentration of the poorly water-soluble polymer in the organic solvent A varies depending on the type of the poorly water-soluble polymer, the weight average molecular weight, and the type of the organic solvent.
  • the mass concentration water poorly soluble polymer mass / organic solvent mass * 100%
  • the mass concentration is 1-15% (w/w), preferably 2-12% (w/w), more preferably 3-10%. (w/w).
  • the invention also provides the use of the solid dispersion described above in solid implants, in situ gel implants and sustained release microparticles.
  • the solid dispersion of the invention can be directly used for preparing a solid implant, an in situ gel implant and a sustained release microparticle, and the prepared solid implant, in situ gel implant and sustained release microparticle have higher Good stability and excellent sustained release.
  • the solid dispersion active ingredient of the invention is uniformly dispersed, and provides a new choice for preparing a solid implant, an in situ gel implant and a sustained release microparticle with high stability and sustained release effect.
  • the preparation method of the solid dispersion of the invention has simple process and is easy to realize industrial scale production.
  • Example 1 is a graph showing serum testosterone concentration-time of rats administered with leuprolide slow-release microparticles or triptorelin sustained-release microparticles prepared in Example 25.
  • Example 2 is a graph showing the mean HbA 1c value-time curve of diabetic model mice administered with Exenatide sustained-release microparticles or liraglutide sustained-release microparticles prepared in Example 25.
  • the solid implant according to the embodiment contains the following components by mass percent: water-soluble drug: 50% of salicillin acetate, poorly water-soluble polymer: PLGA 50% .
  • the PLGA has a molecular weight of 150 kDa, wherein the ratio of lactide to glycolide is 50/50, and the PLGA has a terminal carboxyl group.
  • the solid dispersion described in this example was prepared by the following method:
  • the solid dispersion of the present embodiment contains the following components by mass: water soluble Drugs: Bremer Langdan 45%, poorly water-soluble polymer: PLGA 49.49%, adjuvant: sucrose 0.5%, PEG 30000.01%, magnesium carbonate 3%, lysine 2%.
  • the PLGA has a molecular weight of 130 kDa, wherein the ratio of lactide to glycolide is 50/50, and the PLGA has a terminal carboxyl group.
  • the solid dispersion described in this example was prepared by the following method:
  • the solid dispersion of the present embodiment contains the following components by mass: water-soluble drug: octreotide acetate 40%, water-insoluble polymer: PLGA 55.8%, auxiliary: Mannitol 3%, behenic acid 0.1%, zinc chloride 2%, vitamin E-TPGS 0.1%.
  • the PLGA has a molecular weight of 110 kDa, wherein the ratio of lactide to glycolide is 60/40, and the PLGA has a terminal carboxyl group.
  • the solid dispersion described in this example was prepared by the following method:
  • the solid dispersion of the present embodiment contains the following components by mass: water-soluble drug: triprolin acetate 35%, water poorly soluble polymer: PLGA 55.9%, Additives: xylitol 8.5%, PEG 20000.1%, zinc chloride 0.5%.
  • the PLGA has a molecular weight of 90 kDa, wherein the ratio of lactide to glycolide is 65/35, and the PLGA has a terminal carboxyl group.
  • the solid dispersion described in this example was prepared by the following method:
  • the solid dispersion of the present embodiment contains the following components by mass: water-soluble drug: leuprolide acetate 30%, water poorly soluble polymer: PLGA 67%, Additives: xylitol 1%, stearic acid 2%.
  • the PLGA has a molecular weight of 70 kDa, wherein the ratio of lactide to glycolide is 70/30, and the PLGA has a terminal carboxyl.
  • the solid dispersion described in this example was prepared by the following method:
  • the solid dispersion of the present embodiment contains the following components by mass: water-soluble drug: 25% acetic acid tickcopeptide, water poorly soluble polymer: PLGA 74.4%, Additives: sorbitol 0.05%, PEG 10000.5%, zinc chloride 0.05%.
  • the PLGA has a molecular weight of 65 kDa, wherein the ratio of lactide to glycolide is 75/25, and the PLGA has a terminal carboxyl group.
  • the solid dispersion described in this example was prepared by the following method:
  • the solid dispersion of the present embodiment contains the following components by mass: water-soluble drug: 6.25% acetic acid somaglutide, poorly water-soluble polymer: PLGA88.75% Additives: sucrose 2%, lignin 3%.
  • the PLGA has a molecular weight of 60 kDa, wherein the ratio of lactide to glycolide is 50/50, and the PLGA has a terminal carboxyl group.
  • the solid dispersion described in this example was prepared by the following method:
  • the solid dispersion of the present embodiment contains the following components by mass: water-soluble drug: liraglutide acetate 20%, water-insoluble polymer: PLGA 79.5% , additives: xylitol 0.5%.
  • 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.
  • the solid dispersion described in this example was prepared by the following method:
  • the solid dispersion of the present embodiment contains the following components by mass: water-soluble drug: exenatide acetate 15%, water-insoluble polymer: PLGA 84%, help Agent: xylitol 1%.
  • 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.
  • the solid dispersion described in this example was prepared by the following method:
  • the solid dispersion of the present embodiment contains the following components by mass: water-soluble drug: lixisenatide 20%, water-insoluble polymer: PLGA 76%, Additive: xylitol 4%.
  • 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.
  • the solid dispersion described in this example was prepared by the following method:
  • the solid dispersion of the present embodiment contains the following components by mass: water-soluble drug: 15% of duraglutide acetate, poorly water-soluble polymer: PLGA 80%, help Agent: xylitol 5%.
  • the PLGA has a molecular weight of 35 kDa, wherein the ratio of lactide to glycolide is 50/50, and the PLGA has a terminal carboxyl group.
  • the solid dispersion described in this example was prepared by the following method:
  • the solid dispersion of the present embodiment contains the following components by mass: water-soluble drug: abiprodide acetate 10%, water-insoluble polymer: PLGA 82.5%, Auxiliary: xylitol 7.5%.
  • the PLGA has a molecular weight of 25 kDa, wherein the ratio of lactide to glycolide is 50/50, and the PLGA has a terminal carboxyl group.
  • the solid dispersion described in this example was prepared by the following method:
  • the solid dispersion of the present embodiment contains the following components by mass: water-soluble drug: lanreotide 40%, water-insoluble polymer: PLGA 50%, help Agent: mannitol 3.5%, behenic acid 5%, magnesium hydroxide 1%, tocopherol 0.5%.
  • the PLGA has a molecular weight of 65 kDa, wherein the ratio of lactide to glycolide is 90/10, and the PLGA has a terminal carboxyl group.
  • the solid dispersion described in this example was prepared by the following method:
  • the solid dispersion of the present embodiment contains the following components by mass percent: water-soluble drug: bracelin acetate 35%, water poorly soluble polymer: PLGA 56.5%, Additives: xylitol 2.5%, PEG 6003%, histidine 3%;
  • the PLGA has a molecular weight of 80 kDa, wherein the ratio of lactide to glycolide is 85/15, and the PLGA has a terminal carboxyl group.
  • the solid dispersion described in this example was prepared by the following method:
  • the solid dispersion of the present embodiment contains the following components by mass percent: water-soluble drug: chicorroin acetate 3.8%, water-insoluble polymer: PLGA 95.6%, Additives: sorbitol 0.1%, PEG 4000.05%, zinc phosphate 0.01%, arginine 1%;
  • the PLA has a molecular weight of 25 kDa and the PLA has a terminal carboxyl group.
  • the solid dispersion described in this example was prepared by the following method:
  • the solid dispersion of the present embodiment contains the following components by mass percent: water-soluble drug: Exendin-4 derivative 20%, water-insoluble polymer: PLGA 78%, help Agent: xylitol 2%; 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.
  • the solid dispersion described in this example was prepared by the following method:
  • the solid dispersion of the present embodiment contains the following components by mass percent: water-soluble drug: Exendin-4 derivative 15%, water-insoluble polymer: PLGA 82%, help Agent: xylitol 3%; 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.
  • the solid dispersion described in this example was prepared by the following method:
  • Exendin-4 variant of asparagine at position 28 in Exendin-4 by cysteine by solid phase peptide synthesis followed by 10kDa Y-type monomethoxypolyethylene in PBS buffer
  • the alcohol-maleimide reaction is purified by ion exchange, gel chromatography, concentrated, and lyophilized to obtain an Exendin-4 derivative.
  • the solid dispersion of the present embodiment contains the following components by mass: water-soluble drug: Exendin-4 derivative 20%, water-insoluble polymer: PLGA 76%, help Agent: sorbitol 4%; 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.
  • the solid dispersion described in this example was prepared by the following method:
  • the solid dispersion of the present embodiment contains the following components by mass: water-soluble drug: Exendin-4 derivative 16%, water-insoluble polymer: PLGA 81%, help Agent: xylitol 3%; wherein the PLGA has a molecular weight of 45 kDa, wherein the ratio of lactide to glycolide is 50/50, and the PLGA has a terminal carboxyl group.
  • the solid dispersion described in this example was prepared by the following method:
  • the solid dispersion of the present embodiment contains the following components by mass percent: water-soluble drug: Exendin-4 derivative 12%, water-insoluble polymer: PLGA 82%, help Agent: xylitol 6%; 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.
  • the solid dispersion described in this example was prepared by the following method:
  • the solid dispersion of the present embodiment contains the following components by mass: water-soluble drug: Mipomersen sodium 20%, water-insoluble polymer: PLGA 76%, auxiliary: xylose Alcohol 4%.
  • the PLGA has a molecular weight of 30 kDa, wherein the ratio of lactide to glycolide is 50/50, and the PLGA has a terminal carboxyl group.
  • the solid dispersion described in this example was prepared by the following method:
  • the solid dispersion of the present embodiment contains the following components by mass: water-soluble drug: interleukin 18%, poorly water-soluble polymer: PLGA 77%, auxiliary: xylose Alcohol 5%.
  • the PLGA has a molecular weight of 30 kDa, wherein the ratio of lactide to glycolide is 50/50, and the PLGA has a terminal carboxyl group.
  • the solid dispersion described in this example was prepared by the following method:
  • test groups 1 to 22 are used, and the test groups 1 to 22 respectively use the solid dispersion prepared in Examples 1 to 22 to prepare a solid implant, and the preparation of the solid implant Methods as below:
  • the solid dispersion is prepared by hot melt extrusion or hot press molding to obtain a solid implant
  • the specific operation steps of the hot melt extrusion are: placing the solid dispersion in a hot melt extruder, adjusting the temperature of the cavity, extruding the melt into strips or ribbons; and then cutting into rods, The solid implant;
  • the specific operation steps of the hot press forming are: placing the solid dispersion in a mold, heating the mold, pressing and forming the material in the mold under a certain pressure, controlling temperature, pressure and holding time, and then externally cooling The mold is taken out of the mold to obtain the solid implant.
  • the preparation method of the solid implant according to Test Groups 1 to 22 is hot melt extrusion or hot press molding.
  • the in vitro release effects of the solid implants in Test Groups 1 to 22 were tested separately.
  • the test method was: accurately weigh 10 mg of the solid implant into a 15 ml centrifuge tube, and a phosphate buffer solution of pH 7.4 (containing 0.02%). Sodium azide as a bacteriostatic agent was used as a release medium and placed in a constant temperature air bath shaker.
  • the in vitro release of the solid implant was measured at an oscillation speed of 100 rpm and a temperature of 37 ° C ⁇ 0.5 ° C. All the release media were taken out at 1 day, 2 days, 7 days, 14 days, 21 days, 28 days, 40 days, 50 days and 60 days, and the same amount of new release medium was added.
  • the drug release amount was determined by high performance liquid chromatography. The measurement method is:
  • Test group 3 0.83% 1.75% 6.45% 13.31% 22.25% 35.57% 66.19% 82.64% 91.50%
  • the solid implant prepared by using the solid dispersion of the present invention has no burst phenomenon or obvious delayed release, and the whole release tendency is close to zero-order release.
  • some samples have an in vitro release period of 50-60 days, and most of the samples have an in vitro release period of more than 60 days, which has an excellent sustained release effect.
  • test groups 1 to 22 which are test groups 1 to 22, respectively, which use the solid dispersion prepared in Examples 1 to 22 for in situ gel implant application, are provided.
  • the solid dispersion is dissolved in an organic solvent to obtain an in situ gel implant.
  • the organic solvent is at least one of an organic solvent insoluble in water or low in water solubility and/or a water-soluble organic solvent.
  • the water-insoluble or low-water-soluble organic solvent is selected from the group consisting of aromatic alcohols such as benzyl alcohol; lower alkyl esters and aralkyl esters of benzoic acid, such as benzoic acid hexyl ester, alkyl benzyl phthalate, Benzyl benzoate, ethyl benzoate; (C3-C15) esters of mono-, di- and tricarboxylic acids and short Alkyl esters such as methyl acetate, ethyl acetate, dimethyl citrate, triethyl citrate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl phthalate; lactone For example, caprolactone and butyrolactone, or a mixture thereof. At least one of benzyl alcohol, benzyl benzoate, phthalic acid ester and short-chain alkyl carboxylic acid ester is preferred; at least one
  • the water-soluble organic solvent is selected from the group consisting of dimethyl sulfoxide, N-methyl-2-pyrrolidone, 2-pyrrolidone, tetrahydrofuran; (C1-C15) alcohol, diol, triol and Tetrahydrins such as ethanol, glycerol and propylene glycol; (C3-C15) alkyl ketones such as acetone, diethyl ketone and methyl ethyl ketone; (C1-C15) amides such as dimethylformamide, dimethyl Acetamide, caprolactam, amine acetate, propionamide and butanamide, or mixtures thereof.
  • the in vitro release effects of the in situ gel implants described in Test Groups 1-22 were tested separately.
  • the test method was as follows: take 2 mL of the in situ gel implant in a 5 mL dialysis tube with a pipette, and then place the dialysis tube In 50 mL of pH 7.4 phosphate buffer (containing 0.02% sodium azide as bacteriostatic agent), placed in a constant temperature air bath shaker, in situ at an oscillation speed of 100 rpm and a temperature of 37 ° C ⁇ 0.5 ° C In vitro release assay of gel implants. All the release media were taken out at 1 day, 2 days, 7 days, 14 days, 21 days, 28 days, 40 days, 50 days and 60 days, and the same amount of new release medium was added. The drug release amount was determined by high performance liquid chromatography. The measurement method is:
  • Test group 13 1.86% 2.66% 4.14% 8.74% 14.27% 22.28% 32.43% 47.00% 70.97% Test group 14 1.92% 2.58% 4.16% 8.73% 16.19% 25.19% 37.65% 54.07% 83.23% Test group 15 1.70% 2.57% 5.65% 12.09% 24.28% 35.95% 52.03% 61.18% 83.45% Test group 16 1.77% 2.54% 8.20% 17.83% 31.08% 46.21% 67.96% 80.08% 94.82% Test group 17 1.80% 2.62% 8.15% 18.30% 32.84% 48.37% 69.50% 83.16% 96.50% Test group 18 1.88% 2.26% 13.00% 27.15% 42.08% 59.36% 74.90% 86.00% 97.08% Test group 19 1.67% 2.81% 12.24% 23.05% 40.55% 55.63% 72.15% 84.90% 95.80% Test group 20 1.35% 2.60% 13.82% 28.15% 43.60% 58.22% 83.20% 95.24% 100.00% Test group 21 1.14% 2.78%
  • the in situ gel implant prepared by using the solid dispersion of the present invention has no burst phenomenon or obvious delayed release, and the whole release tendency is close to zero-order release.
  • 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.
  • test groups 1 to 22 which are test groups 1 to 22, respectively, are used, and the test groups 1 to 22 respectively use the solid dispersion prepared in Examples 1 to 22 to prepare sustained-release microparticles, and the sustained-release microparticles are used now. It is prepared by the emulsification-solvent evaporation method (S/O/W) which is commonly used in technology.
  • S/O/W emulsification-solvent evaporation method
  • the in vitro release effects of the sustained release microparticles of the test groups 1 to 22 were respectively tested.
  • the test method was as follows: accurately weigh 20 mg of the sustained release microparticles in a 15 ml centrifuge tube, and a phosphate buffer solution having a pH of 7.4 (containing 0.02% azide).
  • the sodium is used as a bacteriostatic agent as a release medium, and placed in a constant temperature air bath shaker, and the in vitro release of the particles is measured at an oscillation speed of 100 rpm and a temperature of 37 ° C ⁇ 0.5 ° C.
  • the drug release amount was determined by high performance liquid chromatography. The measurement method is:
  • Test group 4 1.98% 4.16% 8.36% 16.25% 27.24% 41.61% 78.25% 93.75% 99.96% Test group 5 1.05% 2.12% 4.31% 10.79% 22.16% 35.27% 58.57% 76.13% 90.34% Test group 6 0.96% 1.81% 4.06% 8.76% 19.28% 32.61% 51.82% 70.52% 85.20% Test group 7 0.79% 1.88% 5.37% 12.86% 23.19% 42.35% 67.81% 89.61% 100.00% Test group 8 0.91% 1.88% 7.41% 16.83% 29.08% 45.46% 69.94% 83.91% 94.92% Test group 9 1.02% 2.12% 8.46% 19.78% 34.21% 52.57% 76.98% 90.03% 100.00% Test group 10 1.69% 2.98% 15.81% 31.25% 50.53% 70.36% 88.64% 100.00% 100.00% Test group 11 1.14% 2.23% 9.77% 24.31% 45.81% 70.64% 92.72% 100.00% 100.00% Test
  • the sustained release microparticles prepared by using the solid dispersion of the present invention have no burst release phenomenon or obvious delayed release, and the whole release tendency is close to zero-order release.
  • 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.
  • the solid dispersion organic solvent A or B prepared by the present invention has a low residual amount, or is not detected, or the residual amount is lower than the detectable range, and the solid dispersion is
  • the prepared solid implant, the sustained-release microparticles have no residual organic solvent A or B or the residual amount of the organic solvent A or B is lower than the detectable range, and the patient has no side effects due to the organic solvent after administration, and is also beneficial for maintaining The stability of the particles, extending 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 leuprolide sustained-release microparticles and the triptorelin sustained-release microparticles prepared by the present invention can well control the serum testosterone concentration within 70 days after administration, and the fourth after administration.
  • Serum testosterone concentration within -63 days is less than 5ng/mL
  • serum testosterone within 7-50 days The ketone concentration is less than about 4 ng/mL, which is significantly lower than that of the blank group, indicating that the leuprolide slow-release microparticles and the triptorelin sustained-release 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.
  • mice Twenty-four diabetic mice were selected, weighing 20 ⁇ 5g, male and female, and each group was randomly divided into the drug-administered group (group 2) and the blank group (group 1). The mice in the drug-administered group were injected subcutaneously into the neck.
  • the blank group was subcutaneously injected with the same volume of physiological saline.
  • the exenatide sustained-release microparticles or liraglutide sustained-release microparticles prepared by the present invention can well control the HbA 1c value within 70 days after administration, and 7th after administration.
  • the HbA 1c value within -70 days is between 5 and 6.5, which is significantly lower than that of the blank group, indicating that the active drug of the present invention can be released for a long time after administration of the exenatide sustained-release microparticles or the liraglutide sustained-release microparticles.
  • the desired therapeutic effect can reduce the frequency of administration, and help to improve patient compliance.

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Abstract

La présente invention concerne une dispersion solide et un procédé de préparation de ladite dispersion. Cette dispersion solide comprend un médicament soluble dans l'eau et un polymère soluble dans l'eau, le rapport de masse médicament-polymère étant de 1/(1-25), et le pourcentage en masse du médicament soluble dans l'eau dans la dispersion solide étant de 3,8 à 50 %. Ladite dispersion solide peut être utilisée pour préparer un implant solide, un implant de gel in situ et une particule à libération prolongée.
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