WO2017186076A1 - Solid dispersion, preparation method for same, and applications thereof - Google Patents

Abstract

A solid dispersion and a preparation method therefor. The solid dispersion comprises a water-soluble medicament and a water-soluble polymer, the mass ratio of the two being 1 : (1-25), and the mass percent of the water-soluble medicament in the solid dispersion being 3.8-50%. The solid dispersion is applicable in preparing a solid implant, an in situ gel implant, and a sustained release particle.

Description

Solid dispersion and preparation method and application thereof Technical field

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.

Background technique

In recent years, a large number of biologically active substances such as oligopeptides, polypeptides and proteins have received much attention as drug candidates, and they play an important role in the treatment of severe conditions (diabetes, cancer, anemia, multiple sclerosis, hepatitis, etc.). However, these macromolecular active ingredients are fragile because of their poor stability in the gastrointestinal tract (degradation at low pH and proteolysis), short circulatory half-lives, and poor permeability through the intestinal wall, leading to organisms The degree of utilization is very low, so it is difficult to orally administer. Although it is possible to increase the permeability of peptides and proteins across the epithelial cell membrane, the bioavailability of oral administration is still as low as a few percent, which hinders the development of oral dosage forms of these active ingredients. The development of stable, effective and patient-acceptable dosage forms remains a formidable challenge, and injection or parenteral routes of administration are still preferred routes of administration for active ingredients such as polypeptides and proteins. Many preparations of peptides and proteins that can be injected by intravenous, intramuscular or subcutaneous routes have been marketed or under development, such as leuprolide slow release microparticles, goserelin sustained release implants, triptorelin sustained release microparticles, etc. .

For many peptide agents, particularly hormones, which require long-term continuous administration at a controlled rate, the systemic concentrations required to produce the desired effect on the target tissue or organ are high and require frequent injections of high doses. The concentration required in the therapeutic utility window often results in systemic toxicity that is detrimental to the patient. At the same time, the administration of the injection is painful, resulting in low compliance, poor efficacy and side effects. These problems can be solved by a polymer-based active ingredient, the Drug Delivery System (DDS), which is made into microcapsules by encapsulating the active ingredient in a biodegradable and biocompatible polymer matrix. In the form of microparticles or implants, the active ingredient is released stably for a long period of time, thereby achieving the purpose of sustained release and controlled release.

Most of the existing peptide or protein implants or sustained-release microparticles have sudden or delayed release, and the sustained release effect is not good, mainly because the active ingredients are dispersed unevenly. Therefore, how to control the burst release of the active ingredients, Delayed release, increased drug loading and sustained release are urgent problems to be solved.

Summary of the invention

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. Advantageous solid implants, in situ gel implants and sustained release microparticles; meanwhile, the present invention also discloses a method for preparing the solid dispersion.

In order to achieve the above object, 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).

As a preferred embodiment of the solid dispersion of the present invention, 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.

As a 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 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).

In the solid dispersion of the present invention, 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. 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.

In the above solid dispersion of the present invention, 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. Substance substances (such as polypeptides, proteins, nucleic acids, antibodies, antigens, antibiotics, etc.) and salts thereof.

In a preferred embodiment of the solid dispersion of the present invention, the water-soluble drug is at least one of a protein drug, a peptide drug, and a nucleic acid drug.

As a preferred embodiment of the solid dispersion of the present invention, 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, 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. Calcitonin, insulin-like growth factor (IGF-I, IGF-II), cell growth factors (such as EGF, TGF-α, TGF-β, 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). Specifically, 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-PTP1B _Rx , IONIS-FGFR4 _Rx , IONIS-DGAT2 _Rx . The above noun is the name or code of the nucleic acid drug.

As a preferred embodiment of the solid dispersion of the present invention, 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 (9 peptide), octreotide (8 peptide), lanreotide (8 peptide), Bremer wave (7 peptide), eptifibatide (7 peptide), sarsarelin (6 peptide), spleen pentapeptide (5 peptide), thymopentin (5 peptide), ecalcitonin (31 peptide), somaglutide (31 peptide), pancreatic high Glucagon-like peptide-1 (31 peptide), liraglutide (34 peptide), teriparatide (34 peptide), pramlintide (37 peptide), enfuvirtide (38 peptide), exenatide (39 peptide), adrenocorticotropic hormone (39 peptide), adrenocorticotropic hormone Hormone (41 peptide), temoline (44 peptide), lixisenatide (44 peptide), sputum stimulating hormone (118 peptide), duraglutide (274 peptide), albendide (645) At least one of peptides;

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 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. Sexual or may lack one or more functions. For example, glucagon peptide-1 (GLP-1), exendin-4, is the second position of glycine, while GLP-1 is the second position of alanine, and exendin-4 can interact with GLP-1 receptor. Binding and producing a cascade of cellular signaling.

In the derivative of the peptide, 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.

In the derivative of the peptide, 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. Imide, halogen, vinyl sulfone, disulfide, sulfhydryl, aldehyde, carbonyl, O-substituted hydroxyamine, active ester, alkenyl, alkynyl, azide or other groups with high chemical reactivity Preferably, 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. 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. For example, in Exendin-4 and its analogs, 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.

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.

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.

As a preferred embodiment of the solid dispersion of the present invention, 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.

As a preferred embodiment of the solid dispersion of the present invention, 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. As a more preferred embodiment of the solid dispersion of the present invention, 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, polyphosphates, and copolymers thereof / or a mixture; preferably PLA, PLGA, or copolymers thereof with PCL or PEG, and mixtures thereof; more preferably PLA, PLGA or mixtures thereof.

As a preferred embodiment of the solid dispersion of the present invention, when 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.

As a preferred embodiment of the solid dispersion of the present invention, 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. Preferably, 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 PLA, PLGA and their copolymers with PCL or PEG, wherein the ratio of lactide to glycolide is from 100:0 to 50:50, preferably from about 90:10 to 50:50, more preferably 85: 15 to 50:50.

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.

As a preferred embodiment of the solid dispersion of the present invention, 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%.

One or more 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. For some drugs that are particularly sensitive to temperature, 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. Preferred are 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. Specifically, including but not limited to calcium carbonate, calcium hydroxide, calcium myristate, calcium oleate, calcium palmitate, calcium stearate, calcium phosphate, calcium acetate, magnesium acetate, magnesium carbonate, magnesium hydroxide, phosphoric acid Magnesium, magnesium myristate, magnesium oleate, magnesium palmitate, magnesium stearate, zinc carbonate, zinc hydroxide, zinc oxide, zinc myristate, zinc oleate, zinc acetate, zinc chloride, zinc sulfate, Zinc hydrogen sulphate, zinc nitrate, zinc gluconate, zinc palmitate, zinc stearate, zinc phosphate, sodium carbonate, sodium hydrogencarbonate, sodium hydrogen sulfite, sodium thiosulfate, and any combination thereof. A zinc salt of an inorganic acid or an organic acid is preferred, and zinc chloride is more preferred. The buffering agent comprises from 0 to 4%, preferably from 0.01 to 3%, more preferably from 0.01 to 2% by mass of the solid dispersion.

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, ρ-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.

As a preferred embodiment of the method for producing a solid dispersion according to the present invention, 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. Usually, the mass concentration (water poorly soluble polymer mass / organic solvent mass * 100%) is 1-15% (w/w), preferably 2-12% (w/w), more preferably 3-10%. (w/w).

Finally, 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.

DRAWINGS

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.

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.

detailed description

The present invention will be further described with reference to specific embodiments in order to better illustrate the objects, aspects and advantages of the invention.

Example 1

An embodiment of the solid dispersion of the present invention, 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% .

Wherein 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:

(1) completely dissolving the poorly water-soluble polymer and the water-soluble drug in glacial acetic acid; wherein the poorly water-soluble polymer is 3% by mass of glacial acetic acid;

(2) Anhydrous diethyl ether (8 ° C) was injected to produce a white precipitate, and the precipitate was collected and extracted with anhydrous diethyl ether for 5 times. The precipitate was collected and dried in a vacuum oven for 24 h (10 ° C) to obtain a solid dispersion. .

Example 2

An embodiment of the solid dispersion of the present invention, 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%.

Wherein 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:

(1) completely dissolving the poorly water-soluble polymer, water-soluble drug and auxiliary agent in glacial acetic acid; wherein the poorly water-soluble polymer is 3.5% of the mass of glacial acetic acid;

(2) The solution of the step (1) was poured into anhydrous diethyl ether (6 ° C) to produce a white precipitate, and the precipitate was collected and extracted 5 times with anhydrous diethyl ether. The precipitate was collected and dried in a vacuum drying oven for 24 hours ( 10 ° C), a solid dispersion was obtained.

Example 3

An embodiment of the solid dispersion of the present invention, 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%.

Wherein 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:

(1) completely dissolving the poorly water-soluble polymer in glacial acetic acid, and then adding a water-soluble drug and an auxiliary agent to completely dissolve; wherein the poorly water-soluble polymer is 4% by mass of glacial acetic acid;

(2) Hexane (6 ° C) was injected to produce a white precipitate, and the precipitate was collected and extracted 5 times with hexane. The precipitate was collected and dried in a vacuum oven for 24 h (10 ° C) to obtain a solid dispersion.

Example 4

An embodiment of the solid dispersion of the present invention, 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%.

Wherein 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:

(1) completely dissolving the poorly water-soluble polymer in acetonitrile, and then adding a water-soluble drug and an auxiliary agent to completely dissolve; wherein the poorly water-soluble polymer is 4.5% by mass of acetonitrile;

(2) The solution of the step (1) was poured into anhydrous diethyl ether (8 ° C) to give a white precipitate, and the precipitate was collected and extracted 5 times with anhydrous diethyl ether. The precipitate was collected and dried in a vacuum oven for 24 hours ( 10 ° C), a solid dispersion was obtained.

Example 5

An embodiment of the solid dispersion of the present invention, 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%.

Wherein 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:

(1) completely dissolving the poorly water-soluble polymer in glacial acetic acid, and then adding a water-soluble drug and an auxiliary agent to completely dissolve; wherein the poorly water-soluble polymer is 5% by mass of glacial acetic acid;

(2) The solution of the step (1) was poured into anhydrous diethyl ether (8 ° C) to give a white precipitate, and the precipitate was collected and extracted 5 times with anhydrous diethyl ether. The precipitate was collected and dried in a vacuum oven for 24 hours ( 10 ° C), a solid dispersion was obtained.

Example 6

An embodiment of the solid dispersion of the present invention, 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%.

Wherein 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:

(1) completely dissolving the poorly water-soluble polymer in glacial acetic acid, and then adding a water-soluble drug and an auxiliary agent to completely dissolve; wherein the poorly water-soluble polymer is 5.5% of the mass of glacial acetic acid;

(2) Injecting n-heptane (6 ° C) to produce a white precipitate, collecting the precipitate, and extracting it with n-heptane 5 times, collecting the precipitate and drying in a vacuum oven for 24 h (10 ° C) to obtain a solid dispersion. .

Example 7

An embodiment of the solid dispersion of the present invention, 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%.

Wherein 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:

(1) completely dissolving the poorly water-soluble polymer in glacial acetic acid, and then adding a water-soluble drug and an auxiliary agent to completely dissolve; wherein the poorly water-soluble polymer is 6% of the mass of glacial acetic acid;

(2) Anhydrous diethyl ether (6 ° C) was injected to produce a white precipitate, and the precipitate was collected and extracted with anhydrous diethyl ether for 5 times. The precipitate was collected and dried in a vacuum oven for 24 h (10 ° C) to obtain a solid dispersion. .

Example 8

An embodiment of the solid dispersion of the present invention, 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%.

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:

(1) completely dissolving the poorly water-soluble polymer in trifluoroacetic acid, and then adding a water-soluble drug and an auxiliary agent to completely dissolve; wherein the poorly water-soluble polymer is 6.5% by mass of trifluoroacetic acid;

(2) The solution of the step (1) was poured into anhydrous diethyl ether (8 ° C) to give a white precipitate, and the precipitate was collected and extracted 5 times with anhydrous diethyl ether. The precipitate was collected and dried in a vacuum oven for 24 hours ( 10 ° C), a solid dispersion was obtained.

Example 9

An embodiment of the solid dispersion of the present invention, 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%.

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:

(1) completely dissolving the poorly water-soluble polymer in glacial acetic acid, and then adding a water-soluble drug and an auxiliary agent to completely dissolve; wherein the poorly water-soluble polymer is 7% by mass of glacial acetic acid;

(2) The solution of the step (1) was poured into anhydrous diethyl ether (6 ° C) to produce a white precipitate, and the precipitate was collected and extracted 5 times with anhydrous diethyl ether. The precipitate was collected and dried in a vacuum drying oven for 24 hours ( 10 ° C), a solid dispersion was obtained.

Example 10

An embodiment of the solid dispersion of the present invention, 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%.

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:

(1) completely dissolving the poorly water-soluble polymer in glacial acetic acid, and then adding a water-soluble drug and an auxiliary agent to completely dissolve; wherein the poorly water-soluble polymer is 8% by mass of glacial acetic acid;

(2) Anhydrous diethyl ether (6 ° C) was injected to produce a white precipitate, and the precipitate was collected and extracted with anhydrous diethyl ether for 5 times. The precipitate was collected and dried in a vacuum oven for 24 h (10 ° C) to obtain a solid dispersion. .

Example 11

An embodiment of the solid dispersion of the present invention, 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%.

Wherein 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:

(1) completely dissolving the poorly water-soluble polymer in glacial acetic acid, and then adding a water-soluble drug and an auxiliary agent to completely dissolve; wherein the water-insoluble polymer is 9% of the mass of glacial acetic acid;

(2) Anhydrous diethyl ether (8 ° C) was injected to produce a white precipitate, and the precipitate was collected and extracted with anhydrous diethyl ether for 5 times. The precipitate was collected and dried in a vacuum oven for 24 h (10 ° C) to obtain a solid dispersion. .

Example 12

An embodiment of the solid dispersion of the present invention, 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%.

Wherein 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:

(1) completely dissolving the poorly water-soluble polymer in glacial acetic acid, and then adding a water-soluble drug and an auxiliary agent to completely dissolve; wherein the poorly water-soluble polymer is 10% of the mass of glacial acetic acid;

(2) Anhydrous diethyl ether (6 ° C) was injected to produce a white precipitate, and the precipitate was collected and extracted with anhydrous diethyl ether for 5 times. The precipitate was collected and dried in a vacuum oven for 24 h (10 ° C) to obtain a solid dispersion. .

Example 13

In one embodiment of the solid dispersion of the present invention, 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%.

Wherein 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:

(1) completely dissolving the poorly water-soluble polymer in dimethyl sulfoxide, and then adding a water-soluble drug and an auxiliary agent to completely dissolve; wherein the poorly water-soluble polymer is 7.5% by mass of dimethyl sulfoxide;

(2) Anhydrous diethyl ether (6 ° C) was injected to produce a white precipitate, and the precipitate was collected and extracted with anhydrous diethyl ether for 5 times. The precipitate was collected and dried in a vacuum oven for 24 h (10 ° C) to obtain a solid dispersion. .

Example 14

In one embodiment of the solid dispersion of the present invention, 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%;

Wherein 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:

(1) completely dissolving the poorly water-soluble polymer in acetonitrile, and then adding a water-soluble drug and an auxiliary agent to completely dissolve; wherein the poorly water-soluble polymer is 6.5% of the mass of acetonitrile;

(2) Anhydrous diethyl ether (8 ° C) was injected to produce a white precipitate, and the precipitate was collected and extracted with anhydrous diethyl ether for 5 times. The precipitate was collected and dried in a vacuum oven for 24 h (10 ° C) to obtain a solid dispersion. .

Example 15

In one embodiment of the solid dispersion of the present invention, 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%;

Wherein 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:

(1) completely dissolving the poorly water-soluble polymer in trifluoroacetic acid, and then adding a water-soluble drug and an auxiliary agent to completely dissolve; wherein the poorly water-soluble polymer is 12% by mass of trifluoroacetic acid;

(2) Anhydrous diethyl ether (6 ° C) was injected to produce a white precipitate, and the precipitate was collected and extracted with anhydrous diethyl ether for 5 times. The precipitate was collected and dried in a vacuum oven for 24 h (10 ° C) to obtain a solid dispersion. .

Example 16

In one embodiment of the solid dispersion of the present invention, 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:

(1) A 10 kDa PEG-NHS ester was prepared, which was then reacted with asparagine at position 28 in Exendin-4 in PBS buffer, purified by ion exchange, gel chromatography, concentrated, and lyophilized to obtain an Exendin-4 derivative.

(2) completely dissolving the poorly water-soluble polymer in glacial acetic acid, and then adding a water-soluble drug and an auxiliary agent to completely dissolve; wherein the poorly water-soluble polymer is 6.5% of the mass of glacial acetic acid;

(3) Anhydrous diethyl ether (6 ° C) was injected to produce a white precipitate, and the precipitate was collected and extracted with anhydrous diethyl ether for 5 times. The precipitate was collected and dried in a vacuum oven for 24 h (10 ° C) to obtain a solid dispersion. .

Example 17

In one embodiment of the solid dispersion of the present invention, 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:

(1) Preparation of 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.

(2) completely dissolving the poorly water-soluble polymer in glacial acetic acid, and then adding a water-soluble drug and an auxiliary agent to completely dissolve; wherein the poorly water-soluble polymer is 6.5% of the mass of glacial acetic acid;

(3) Anhydrous diethyl ether (6 ° C) was injected to produce a white precipitate, and the precipitate was collected and extracted with anhydrous diethyl ether for 5 times. The precipitate was collected and dried in a vacuum oven for 24 h (10 ° C) to obtain a solid dispersion. .

Example 18

In one embodiment of the solid dispersion of the present invention, 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:

(1) Preparation of exendin-4 variant of arginine at position 20 in Exendin-4 by cysteine by solid phase peptide synthesis, followed by 5kDa monomethoxypolyethylene glycol in PBS buffer- The maleimide reaction is purified by ion exchange, gel chromatography, concentrated, and lyophilized to obtain an Exendin-4 derivative.

(2) completely dissolving the poorly water-soluble polymer in glacial acetic acid, and then adding a water-soluble drug and an auxiliary agent to completely dissolve; wherein the poorly water-soluble polymer is 6% of the mass of glacial acetic acid;

(3) Anhydrous diethyl ether (6 ° C) was injected to produce a white precipitate, and the precipitate was collected and extracted with anhydrous diethyl ether for 5 times. The precipitate was collected and dried in a vacuum oven for 24 h (10 ° C) to obtain a solid dispersion. .

Example 19

In one embodiment of the solid dispersion of the present invention, 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:

(1) Preparation of exendin-4 variant of hemyanine at position 14 in exendin-4 with cysteine by solid phase peptide synthesis, followed by 20kDa monomethoxypolyethylene glycol in PBS buffer - Maleimide reaction, purified by ion exchange, gel chromatography, concentrated and lyophilized to obtain Exendin-4 derivative.

(2) completely dissolving the poorly water-soluble polymer in glacial acetic acid, and then adding a water-soluble drug and an auxiliary agent to completely dissolve; wherein the poorly water-soluble polymer is 7% of the mass of glacial acetic acid;

(3) Anhydrous diethyl ether (6 ° C) was injected to produce a white precipitate, and the precipitate was collected and extracted with anhydrous diethyl ether for 5 times. The precipitate was collected and dried in a vacuum oven for 24 h (10 ° C) to obtain a solid dispersion. .

Example 20

In one embodiment of the solid dispersion of the present invention, 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:

(1) Preparation of exendin-4 variant of glycine at position 2 in Exendin-4 by cysteine by solid phase peptide synthesis, followed by 40 kDa monomethoxypolyethylene glycol-Malay in PBS buffer The imide reaction was purified by ion exchange, gel chromatography, concentrated, and lyophilized to obtain an Exendin-4 derivative.

(2) completely dissolving the poorly water-soluble polymer in glacial acetic acid, and then adding a water-soluble drug and an auxiliary agent to completely dissolve; wherein the poorly water-soluble polymer is 7% of the mass of glacial acetic acid;

(3) Anhydrous diethyl ether (6 ° C) was injected to produce a white precipitate, and the precipitate was collected and extracted with anhydrous diethyl ether for 5 times. The precipitate was collected and dried in a vacuum oven for 24 h (10 ° C) to obtain a solid dispersion. .

Example 21

An embodiment of the solid dispersion of the present invention, 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%.

Wherein 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:

(1) completely dissolving the poorly water-soluble polymer in glacial acetic acid, and then adding a water-soluble drug and an auxiliary agent to completely dissolve; The poorly water-soluble polymer is 9% of the mass of glacial acetic acid;

(2) Anhydrous diethyl ether (8 ° C) was injected to produce a white precipitate, and the precipitate was collected and extracted with anhydrous diethyl ether for 5 times. The precipitate was collected and dried in a vacuum oven for 24 h (10 ° C) to obtain a solid dispersion. .

Example 22

An embodiment of the solid dispersion of the present invention, 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%.

Wherein 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:

(1) completely dissolving the poorly water-soluble polymer in glacial acetic acid, and then adding a water-soluble drug and an auxiliary agent to completely dissolve; wherein the water-insoluble polymer is 9% of the mass of glacial acetic acid;

(2) Anhydrous diethyl ether (8 ° C) was injected to produce a white precipitate, and the precipitate was collected and extracted with anhydrous diethyl ether for 5 times. The precipitate was collected and dried in a vacuum oven for 24 h (10 ° C) to obtain a solid dispersion. .

Example 23

Test of solid dispersion of the invention for preparing solid implants

In this embodiment, a total of 22 test groups, 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 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:

Liquid chromatograph: Agilent 1260;

Chromatographic conditions: column: Phenomenex Gemini NX 5u C184.6 × 150mm;

Mobile phase: triethylamine solution - acetonitrile-propanol;

Flow rate: 1 mL/min;

Detection wavelength: 280 nm.

The test results are shown in Table 1.

Table 1 cumulative release results of in vitro release of solid implants

Group	1 day	2 days	7 days	14 days	21 days	28 days	40 days	50 days	60 days
Test group 1	1.31%	2.39%	7.42%	16.37%	26.02%	39.37%	73.76%	92.30%	100.00%
Test group 2	1.29%	2.21%	7.37%	14.32%	24.13%	37.49%	70.74%	86.36%	91.47%
Test group 3	0.83%	1.75%	6.45%	13.31%	22.25%	35.57%	66.19%	82.64%	91.50%
Test group 4	1.28%	2.16%	7.36%	14.75%	25.24%	38.61%	73.75%	87.75%	91.46%
Test group 5	0.85%	1.72%	3.31%	9.29%	20.16%	32.27%	54.07%	70.13%	81.84%
Test group 6	0.66%	1.21%	3.06%	7.26%	17.28%	29.61%	47.32%	64.52%	76.70%
Test group 7	0.59%	1.08%	4.37%	11.36%	21.19%	39.35%	63.31%	83.61%	91.50%
Test group 8	0.61%	1.18%	6.41%	15.33%	27.08%	42.46%	65.44%	77.91%	86.42%
Test group 9	0.82%	1.72%	7.46%	18.28%	32.21%	49.57%	72.48%	84.03%	91.50%
Test group 10	1.19%	2.28%	14.81%	29.75%	45.00%	61.26%	78.14%	94.26%	100.00%
Test group 11	0.84%	1.73%	8.77%	22.81%	43.81%	59.64%	77.22%	94.00%	100.00%
Test group 12	0.65%	1.24%	12.90%	26.84%	41.64%	60.42%	81.06%	93.96%	100.00%
Test group 13	0.86%	1.86%	3.37%	8.24%	13.27%	21.48%	31.91%	46.67%	62.47%
Test group 14	0.72%	1.68%	3.39%	8.23%	15.19%	24.39%	37.13%	53.74%	71.50%
Test group 15	0.47%	1.07%	4.88%	11.59%	23.28%	35.15%	51.51%	60.85%	74.95%
Test group 16	0.55%	1.03%	6.50%	15.33%	29.58%	45.87%	66.31%	79.94%	92.00%
Test group 17	0.78%	1.48%	7.12%	18.28%	30.20%	43.15%	60.40%	74.27%	89.56%
Test group 18	1.00%	1.97%	12.26%	24.02%	37.30%	52.11%	70.31%	88.54%	98.61%
Test group 19	0.48%	1.03%	6.70%	16.98%	31.76%	46.84%	64.29%	81.33%	90.70%
Test group 20	0.60%	1.31%	10.13%	22.25%	30.70%	48.12%	70.21%	83.96%	93.22%
Test group 21	0.82%	1.46%	7.62%	17.33%	30.05%	42.67%	59.50%	73.89%	89.38%
Test group 22	0.75%	1.35%	7.38%	15.98%	28.42%	40.34%	60.32%	77.50%	91.20%

It can be seen from the in vitro release results of Table 1 that 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. Among them, 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.

Example 24

Application of solid dispersion of the invention for in situ gel implant

In this embodiment, a total of 22 test groups, 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 of short-chain alkyl carboxylic acid esters is more preferred.

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. Preferably, at least one of ethanol, acetone, dimethyl sulfoxide, N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide; more preferably ethanol, acetone, dimethyl sulfoxide At least one of them.

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:

Liquid chromatograph: Agilent 1260;

Chromatographic conditions: column: Phenomenex Gemini NX 5u C184.6 × 150mm;

Mobile phase: triethylamine solution - acetonitrile-propanol;

Flow rate: 1 mL/min;

Detection wavelength: 280 nm.

The test results are shown in Table 2.

Table 2 cumulative release results of in situ gel implants in vitro

Group	1 day	2 days	7 days	14 days	21 days	28 days	40 days	50 days	60 days
Test group 1	2.61%	4.39%	8.19%	16.87%	27.02%	40.17%	74.28%	92.63%	100.00%
Test group 2	2.49%	4.11%	8.14%	14.82%	25.13%	38.29%	71.26%	86.69%	100.00%
Test group 3	2.33%	3.95%	7.22%	13.81%	23.25%	36.37%	66.71%	82.97%	100.00%
Test group 4	2.78%	4.66%	8.13%	15.25%	26.24%	39.41%	74.27%	88.08%	100.00%
Test group 5	1.85%	2.62%	4.08%	9.79%	21.16%	33.07%	54.59%	70.46%	90.34%
Test group 6	1.76%	2.31%	3.83%	7.76%	18.28%	30.41%	47.84%	64.85%	85.20%
Test group 7	1.59%	2.38%	5.14%	11.86%	22.19%	40.15%	63.83%	83.94%	100.00%
Test group 8	1.71%	2.38%	7.18%	15.83%	28.08%	43.26%	65.96%	78.24%	94.92%
Test group 9	1.82%	2.62%	8.23%	18.78%	33.21%	50.37%	73.00%	84.36%	100.00%
Test group 10	2.49%	3.48%	15.58%	30.25%	46.00%	62.06%	78.66%	94.59%	100.00%
Test group 11	1.94%	2.73%	9.54%	23.31%	44.81%	60.44%	77.74%	94.33%	100.00%
Test group 12	1.75%	2.74%	13.67%	27.34%	42.64%	58.22%	81.58%	94.29%	100.00%

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%	10.88%	19.60%	31.45%	43.36%	61.38%	74.30%	88.72%
Test group 22	1.05%	2.30%	9.65%	18.08%	30.60%	44.52%	64.17%	75.55%	90.17%

It can be seen from the in vitro release results of Table 2 that 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. Among them, 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.

Example 25

Test of solid dispersion of the invention for preparing sustained release microparticles

In this embodiment, a total of 22 test groups, 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.

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. 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:

Liquid chromatograph: Agilent 1260;

Chromatographic conditions: column: Phenomenex Gemini NX 5u C184.6 × 150mm;

Mobile phase: triethylamine solution - acetonitrile-propanol;

Flow rate: 1 mL/min;

Detection wavelength: 280 nm.

The test results are shown in Table 3.

Table 3 cumulative release results of sustained release microparticles in vitro

Group	1 day	2 days	7 days	14 days	21 days	28 days	40 days	50 days	60 days
Test group 1	1.81%	3.89%	8.42%	17.87%	28.02%	42.37%	78.26%	98.00%	100.00%
Test group 2	1.69%	3.61%	8.37%	15.82%	26.13%	40.49%	75.24%	92.36%	99.97%
Test group 3	1.53%	3.45%	7.45%	14.81%	24.25%	38.57%	70.69%	88.64%	100.00%

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 group 12	0.95%	2.24%	13.90%	28.34%	43.64%	68.82%	85.56%	99.96%	99.95%
Test group 13	1.06%	2.16%	4.37%	9.74%	15.27%	24.48%	36.41%	52.67%	70.97%
Test group 14	1.12%	2.08%	4.39%	9.73%	21.19%	32.39%	49.63%	62.74%	80.64%
Test group 15	0.90%	2.07%	5.88%	13.09%	25.28%	38.15%	56.01%	66.85%	83.45%
Test group 16	0.80%	1.52%	7.12%	16.03%	28.05%	40.50%	60.78%	78.42%	89.95%
Test group 17	0.92%	1.64%	7.46%	15.78%	28.21%	41.17%	61.48%	80.03%	91.20%
Test group 18	1.37%	2.15%	13.70%	26.25%	44.83%	58.66%	71.50%	85.00%	98.10%
Test group 19	0.94%	1.83%	8.59%	16.91%	28.81%	44.67%	62.72%	80.10%	90.50%
Test group 20	0.85%	1.94%	9.10%	17.36%	30.64%	48.80%	65.56%	83.37%	95.95%
Test group 21	1.14%	2.15%	11.34%	24.68%	38.00%	42.67%	64.34%	79.21%	91.05%
Test group 22	0.98%	1.97%	10.05%	22.80%	31.95%	40.34%	65.76%	81.50%	93.14%

It can be seen from the in vitro release results of Table 3 that 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. 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.

Example 26

The solid dispersion prepared in Examples 1-22 of the present invention and the prepared solid implant, the residual amount of the organic solvent A and the organic solvent B in the sustained-release fine particles are measured, and the measurement method is a well-known measurement method. The measurement results are shown in Table 4.

Table 4 Determination of residual amount of organic solvent

Note: - indicates no detection or content below the detection limit.

It can be seen from the residual results of the organic solvents in Table 4 that 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.

Example 27

Animal experiment of sustained release microparticles prepared by solid dispersion of the invention

(1) Twenty-four healthy male Sprague-Dawley rats, weighing 250±20g, were randomly divided into the drug-administered group (group 2) and the blank group (group 1). The rats in the drug-administered group were injected subcutaneously into the preparation of Example 25. The leuprolide slow-release microparticles and the triptorelin sustained-release microparticles were suspended with a diluent containing 3% carboxymethylcellulose and 0.9% NaCl. Each dose of the rats in the drug-administered group was injected at a dose of 200 μg/kg, and the blank group was subcutaneously injected with the same volume of physiological saline. 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. The 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.

As can be seen from the graph of 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.

(2) 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 exenatide sustained-release microparticles and the liraglutide sustained-release microparticles prepared in Example 25 were suspended with a diluent containing 3% carboxymethylcellulose and 0.9% NaCl, and the dose of each mouse in the administration group was injected. For the exenatide 2 mg/kg or liraglutide 10 mg/kg, the blank group was subcutaneously injected with the same volume of physiological saline. Blood samples were taken from the tail vein at the same time on the 0th, 0.5d, 1d, 3d, 7d, 14d, 21d, 28d, 35d, 42d, 49d, 56d, 63d, 70d administration, and the average HbA _{1c was prepared.} A plot of the values (% of glycated hemoglobin as a percentage of total hemoglobin, %) and time (d) is shown in Figure 2.

As can be seen from the graph of Fig. 2, 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. And to achieve the desired therapeutic effect, can reduce the frequency of administration, and help to improve patient compliance.

It should be noted that the above embodiments are only intended to illustrate the technical solutions of the present invention and are not intended to limit the scope of the present invention, although the present invention will be described in detail with reference to the preferred embodiments, The technical solutions of the present invention may be modified or equivalently substituted without departing from the spirit and scope of the technical solutions of the present invention.

Claims (11)

1. A solid dispersion comprising a water-soluble drug and a poorly water-soluble polymer, and the water-soluble drug is present in the solid dispersion in a mass percentage of 3.8 to 50%, The mass ratio of the water-soluble drug to the poorly water-soluble polymer is 1: (1 to 25).
2. The solid dispersion according to claim 1, wherein the water-soluble drug is at least one of a protein drug, a peptide drug, and a nucleic acid drug.
3. The solid dispersion according to claim 2, wherein the protein drug comprises globular protein, fibrin, compound protein, therapeutic protein, fusion protein, receptor, antigen, viral surface protein, hormone, hormone similar At least one of a substance, an antibody, an enzyme, a Fab fragment, an interleukin and a derivative thereof, 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. At least one of calcitonin, insulin-like growth factor, cell growth factor, glucagon-like peptide and derivatives or analogs thereof, neurotrophic factor, colony stimulating factor, and synthetic analogs, modifications thereof, and pharmaceutically active fragments thereof Species

   The nucleic acid drug comprises 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.
4. The solid dispersion according to claim 3, wherein said peptide drug comprises a peptide and a derivative of a peptide; wherein said peptide comprises glucagon, shemerilin, adipidal, pancreatic Secretin, ziconotide, teicopeptide, somatostatin, terlipressin, goserelin, leuprolide, triptorelin, nafarelin, gonarlin, xiqu Rick, degarelix, anticitrine, bivalirudin, angiotensin, alarin, buserelin, deserreline, octreotide, lanreotide, Bremerhad, eptifibat Peptide, samuralin, spleen pentapeptide, thymopentin, ecalcitonin, samaglutide, glucagon-like peptide-1, liraglutide, teriparatide, pramlintide, enfu At least one of Weidi, Exenatide, adrenocorticotropic hormone, corticotropin releasing hormone, temoline, lixisenatide, follicle stimulating hormone, duraglutide, and abiglutide;

   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.
5. The solid dispersion according to claim 4, wherein in the derivative of the peptide, the water-soluble or poorly water-soluble group or substance is polyethylene glycol and a derivative thereof.
6. The solid dispersion according to any one of claims 1 to 5, wherein the poorly water-soluble polymer is a polylactide, a polyglycolide, a lactide-glycolide copolymer, and the same Copolymer of caprolactone or polyethylene glycol, polycaprolactone and copolymer thereof with polyethylene glycol, polyhydroxybutyric acid, polyhydroxyvaleric acid, polydioxanone, chitosan, seaweed At least one of an acid and a salt thereof, a polycyanoacrylate, a polyanhydride, a polyorthoester, a polyamide, a polyphosphazene, a polyphosphate, and copolymers and/or mixtures thereof.
7. The solid dispersion according to claim 6, wherein the poorly water-soluble polymer is polylactide, lactide-B At least one of a lactide copolymer or a copolymer thereof with polycaprolactone or polyethylene glycol.
8. The solid dispersion according to any one of claims 1 to 7, wherein the solid dispersion further contains an auxiliary agent comprising an amino acid, an antioxidant, a buffer, a sugar, a fatty acid, an alcohol At least one of the additives; the auxiliary agent in the solid dispersion has a mass percentage of 0.01 to 10%.
9. A method for producing a solid dispersion according to any one of claims 1 to 8, which comprises the step of completely dissolving or dispersing the water-insoluble polymer or other substances contained in the solid dispersion in sequence or simultaneously. 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 solvent A can dissolve both the poorly water-soluble polymer and the water-soluble drug; the solvent B cannot dissolve the water-insoluble polymer and the water-soluble drug.
10. The method of preparing a solid dispersion according to claim 9, wherein the organic solvent A is at least one of glacial acetic acid, acetonitrile, trifluoroacetic acid, and dimethyl sulfoxide; and the organic solvent B is At least one of water diethyl ether, hexane, and n-heptane.
11. Use of a solid dispersion according to any one of claims 1 to 8 in solid implants, in situ gel implants and sustained release microparticles.

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