CN108524446B - Functional pharmaceutical composition - Google Patents
Functional pharmaceutical composition Download PDFInfo
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- CN108524446B CN108524446B CN201810568412.3A CN201810568412A CN108524446B CN 108524446 B CN108524446 B CN 108524446B CN 201810568412 A CN201810568412 A CN 201810568412A CN 108524446 B CN108524446 B CN 108524446B
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 33
- 239000003814 drug Substances 0.000 claims abstract description 59
- 229940079593 drug Drugs 0.000 claims abstract description 51
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 52
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 238000003756 stirring Methods 0.000 claims description 34
- -1 2, 6-difluoro-3- (1H-pyrrol-1-yl) phenyl Chemical group 0.000 claims description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 33
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical group O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 28
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- 229910019142 PO4 Inorganic materials 0.000 claims description 10
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- 238000002390 rotary evaporation Methods 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- WQABAGNOIRGXHH-WHFBIAKZSA-N (2r)-2-amino-3-[[(2r)-2-amino-3-methoxy-3-oxopropyl]disulfanyl]propanoic acid Chemical compound COC(=O)[C@@H](N)CSSC[C@H](N)C(O)=O WQABAGNOIRGXHH-WHFBIAKZSA-N 0.000 claims description 3
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- OTXKQKKLEDBPAD-LURJTMIESA-N ethyl (2s)-2,5-diaminopentanoate Chemical compound CCOC(=O)[C@@H](N)CCCN OTXKQKKLEDBPAD-LURJTMIESA-N 0.000 claims description 3
- 229960001592 paclitaxel Drugs 0.000 claims description 3
- IBUIVNCCBFLEJL-UHFFFAOYSA-M sodium;phosphoric acid;chloride Chemical group [Na+].[Cl-].OP(O)(O)=O IBUIVNCCBFLEJL-UHFFFAOYSA-M 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 3
- NAALWFYYHHJEFQ-ZASNTINBSA-N (2s,5r,6r)-6-[[(2r)-2-[[6-[4-[bis(2-hydroxyethyl)sulfamoyl]phenyl]-2-oxo-1h-pyridine-3-carbonyl]amino]-2-(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC(O)=CC=1)C(=O)C(C(N1)=O)=CC=C1C1=CC=C(S(=O)(=O)N(CCO)CCO)C=C1 NAALWFYYHHJEFQ-ZASNTINBSA-N 0.000 claims description 2
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 claims description 2
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 claims description 2
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 claims description 2
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- 229960001467 bortezomib Drugs 0.000 claims description 2
- 229960003109 daunorubicin hydrochloride Drugs 0.000 claims description 2
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 claims description 2
- 239000008363 phosphate buffer Substances 0.000 claims description 2
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- 239000005977 Ethylene Substances 0.000 claims 1
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- NHWZQIYTQZEOSJ-UHFFFAOYSA-N carbonic acid;phosphoric acid Chemical group OC(O)=O.OP(O)(O)=O NHWZQIYTQZEOSJ-UHFFFAOYSA-N 0.000 abstract description 3
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
- C08G81/02—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers at least one of the polymers being obtained by reactions involving only carbon-to-carbon unsaturated bonds
- C08G81/024—Block or graft polymers containing sequences of polymers of C08C or C08F and of polymers of C08G
- C08G81/028—Block or graft polymers containing sequences of polymers of C08C or C08F and of polymers of C08G containing polyamide sequences
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/722—Chitin, chitosan
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- 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
- A61K38/05—Dipeptides
Abstract
The invention discloses a functional pharmaceutical composition, which utilizes respective active groups to polymerize an acrylic acid unit, a phosphate-carbonate unit and an amino acid unit to obtain a carrier; and finally, self-assembling the hydrophobic anticancer drug and the carrier molecule in the solution, and fixing the volume according to actual needs to obtain the acid-sensitive functional pharmaceutical composition. In the functional pharmaceutical composition disclosed by the invention, the carrier has good biocompatibility and biodegradability; the chemical cross-linking structure effectively prolongs the circulation time in vivo, releases the encapsulated drug after entering the cancer part, and can be used as a high-efficiency controllable drug release system; particularly, the functional pharmaceutical composition also has a slow release function, solves the defect of over-quick release of the existing pharmaceutical system, and has good application value in the fields of biological materials and biomedicines.
Description
The invention relates to a functional pharmaceutical composition and a preparation method thereof, which is a divisional application with application number of 201610348663.1 invention at 2016, 05 and 23 days, and belongs to the technical part of products.
Technical Field
The invention belongs to the field of biomedical high polymer materials, and particularly relates to an acid-sensitive functional pharmaceutical composition based on polyphosphate ester-carbonate.
Background
As is known, most anticancer drugs have strong hydrophobicity, while the micelle of the core-shell structure formed by self-assembly of the amphiphilic copolymer has a hydrophobic inner core and can be used for encapsulating the hydrophobic anticancer drugs, and the hydrophilic outer shell can play a role in stabilizing the micelle and increasing the water solubility of the drugs and greatly improve the circulation time of the drug-loaded micelle in vivo. There are two main ways of micelle crosslinking: "Physical cross-linking" and "chemical cross-linking". Physically cross-linked micelles are formed primarily by non-covalent interactions, such as: electrostatic interaction, hydrogen bonding, coordination bonding, hydrophobic interaction, supramolecular complexation and the like; the chemically crosslinked micelle is mainly formed by covalent bond interaction, namely, the mutual reaction between the molecular chains of the functional copolymer or the chemical reaction between the functional micromolecule crosslinking agent and the copolymer chain is added. According to the difference of the cross-linking position of the micelle, the cross-linked micelle can be divided into a Core cross-linked micelle (Core cross-linked micelle) and a Shell cross-linked micelle (Shell cross-linked micelle), and the cross-linked micelle can be stably existed in the in vivo circulation process as a drug carrier. The amphiphilic copolymer generally consists of hydrophilic and hydrophobic chain segments, and can be self-assembled into nano particles with various shapes in aqueous solution, such as micelles, vesicles, nano rods, sheets and the like, so that the amphiphilic copolymer has wide application prospects in the fields of biomedicine, supermolecules, nanotechnology and the like.
The existing amphiphilic copolymer drug-loaded micelle has certain thermodynamic instability, and in the in vivo circulation process, the anticancer drug is easy to diffuse out of the micelle, so that the enrichment degree of the drug at the cancerous tissue part is low, and the treatment effect is seriously influenced. Meanwhile, the toxicity of the medicine causes many adverse reactions to human bodies. Biodegradable polymers have very unique properties, for example, they generally have good biocompatibility and are degraded in vivo, and degradation products can be absorbed by the human body or excreted out of the body through the normal physiological pathways of the human body, so that they are widely used in various fields of biomedicine, such as surgical sutures, bone fixation instruments, scaffold materials for biological tissue engineering, and drug controlled release carriers. However, the existing biodegradable polymers such as PTMC, PCL, PLA, PLGA, etc. have a single structure, lack functional groups for modification, and are often difficult to provide a drug nanocarrier with stable circulation or a stable surface modification coating. The ideal drug carrier should have good biocompatibility and biodegradability, and, as a carrier of antitumor drugs, should also be able to efficiently enter cancer cells by active or passive targeting. Therefore, there is a need to develop new pharmaceutical carriers for the preparation of pharmaceutical compositions.
Disclosure of Invention
The object of the present invention is to provide a pharmaceutical composition based on polyphosphate-carbonate.
In order to achieve the aim, the invention adopts the technical scheme that the preparation method of the functional pharmaceutical composition comprises the following steps:
(1) adding ethylene glycol dimethacrylate, lauryl methacrylate and pentaerythritol tetraacrylate into butane, stirring for 5 minutes, adding diisopropylethylamine, stirring for 15 minutes at 60 ℃, adding copper N, N-di-N-butyl dithiocarbamate, stirring for 10 minutes, cooling to room temperature, adding bis (2, 6-difluoro-3- (1H-pyrrol-1-yl) phenyl) titanocene and ethanol, stirring, and carrying out illumination reaction for 8 hours; after the reaction is finished, adding the reaction solution into water, and taking the upper layer solution as an acrylic prepolymer solution;
(2) adding a phosphate ester monomer into tetrahydrofuran in a nitrogen atmosphere, stirring for 15 minutes, adding isopropanol, stirring for 30 minutes, then adding trimethylene cyclic carbonate, stirring for 5 minutes, adding 1, 8-diazabicyclo [5.4.0] undec-7-ene, and reacting for 10 minutes at 70 ℃; concentrating the reaction product by rotary evaporation, dropping the concentrated solution into a methanol/ether mixed solution for precipitation, removing the supernatant, dissolving the residue in methanol, transferring the methanol solution into a dialysis bag, dialyzing the solution in deionized water for 50 hours, and freeze-drying the solution to obtain a phosphate-carbonate copolymer; the chemical structural formula of the phosphate ester monomer is as follows:
(3) dissolving an amino compound in dimethylformamide, placing the mixture in a closed reactor, dropwise adding a dimethylformamide solution of gamma-oligo (ethylene glycol) -L-glutamic acid-N-carboxyl internal anhydride in a nitrogen environment, and reacting for 2 hours at 40 ℃; after the reaction is finished, precipitating the reaction solution by using glacial ethyl ether, centrifuging, and drying in vacuum to obtain an amino acid polymer; the amino compound is ornithine ethyl ester or cystine methyl ester;
(4) respectively adding the phosphate-carbonate copolymer and the amino acid polymer into dichloromethane to obtain a dichloromethane solution of the phosphate-carbonate copolymer and a dichloromethane solution of the amino acid polymer; then simultaneously dripping a methylene dichloride solution of the phosphate-carbonate copolymer and a methylene dichloride solution of the amino acid polymer into an acrylic prepolymer solution; after the dropwise addition is finished, adding polyethylene glycol and zinc phthalocyanine; reacting at 50 ℃ for 20 hours; then using glacial acetic acid to terminate the reaction, using ethyl acetate to precipitate reaction liquid, filtering, drying filter cake to obtain carrier;
(5) dissolving a drug in DMSO to obtain a drug solution; dissolving a carrier in N, N-dimethylformamide to obtain a carrier solution; under stirring, dripping the medicine solution into the carrier solution, uniformly mixing, then adding secondary water and 1, 4-dithio-D with the mass of 0.05 percent of the carrier, stirring for 30 minutes, and dialyzing primary water; then adding buffer solution to fix the volume to obtain the targeted medicine composition.
In the step (1), the molar ratio of ethylene glycol dimethacrylate, lauryl methacrylate, pentaerythritol tetraacrylate, diisopropylethylamine, copper N, N-di-N-butyldithiocarbamate and bis (2, 6-difluoro-3- (1H-pyrrol-1-yl) phenyl) titanocene is 1: 0.8: 0.4: 0.1: 0.01: 0.005.
In the step (2), the molar ratio of the phosphate ester monomer, isopropanol, trimethylene cyclic carbonate and 1, 8-diazabicyclo [5.4.0] undec-7-ene is 1: 0.3: 2: 0.008.
In the step (3), the molar ratio of the amino compound to the gamma-oligo (ethylene glycol) -L-glutamic acid-N-carboxyanhydride is 1: 5.
In the invention, the molar ratio of ethylene glycol dimethacrylate, trimethylene cyclic carbonate, gamma-oligo (ethylene glycol) -L-glutamic acid-N-carboxyl internal anhydride, polyethylene glycol and zinc phthalocyanine is 3: 6: 1: 0.02: 0.0008. The acrylic acid unit, the phosphate-carbonate unit and the amino acid unit in the obtained carrier polymer are reasonably distributed, and the improvement of the drug loading rate and the release rate when the polymer is used as a drug carrier is facilitated.
In the invention, the medicine is adriamycin, paclitaxel, bortezomib, aclarubicin, pirarubicin, daunorubicin hydrochloride, semustine or plicamycin; the concentration of the drug solution was 5.0 mg/mL.
In the invention, the buffer solution is a saturated sodium chloride phosphate buffer solution; the pH is generally 10.
The invention further discloses a functional pharmaceutical composition prepared by the preparation method of the functional pharmaceutical composition; the drug is coated by a carrier polymer, has excellent stability in vivo circulation, can slowly release the drug when reaching a focus, achieves an effective treatment effect, can reduce the administration times and the side effect of the drug, and is beneficial to the health of a patient.
The invention further discloses application of the functional pharmaceutical composition in preparing anticancer drugs.
The invention combines ring-opening polymerization and photoinitiated free radical reaction to synthesize the acid-sensitive biodegradable amphiphilic polymer carrier. Firstly, by using a simple photocatalytic free radical polymerization method, taking an acrylic monomer as a raw material, and fully mixing the monomer and other components by gradually adding raw material components, an acrylic prepolymer is effectively prepared, and particularly, by combining heating and photocatalysis, taking photocatalytic polymerization as a main part, the compatibility and reactivity of each component are increased by heating assistance, so that the uniformity of the reaction of the acrylic monomer is facilitated; then, taking small molecular alcohol as an initiator, and carrying out ring-opening polymerization on the cyclic phosphate ester monomer and the carbonate ester monomer to obtain an amphiphilic polyphosphate ester-carbonate ester copolymer; modifying glutamic acid by using amino micromolecules to obtain an amphiphilic polymer with an amino group at the end group; then, utilizing respective active groups to polymerize an acrylic acid unit, a phosphate-carbonate unit and an amino acid unit to obtain a carrier; and finally, self-assembling the hydrophobic anticancer drug and the carrier molecule in the solution, and fixing the volume according to actual needs to obtain the acid-sensitive functional pharmaceutical composition.
In the functional pharmaceutical composition disclosed by the invention, the amphiphilic copolymer carrier has good biocompatibility and biodegradability, contains hydrophilic and hydrophobic chain segments, and can entrap hydrophobic anticancer drugs through self-assembly; the formed drug-loaded polymer has a stable structure, in the in-vivo circulation process, the chemical cross-linking structure effectively prolongs the in-vivo circulation time, after entering a cancer part, the chemical cross-linking points of the drug-loaded micelle are destroyed, in the presence of hydrolase in the lysosome, polyphosphate is partially hydrolyzed, so that the carrier structure is destroyed, the encapsulated drug is released, and the drug-loaded polymer can be used as a high-efficiency controllable drug release system; particularly, the functional pharmaceutical composition also has a slow release function, solves the defect of over-quick release of the existing pharmaceutical system, and has good application value in the fields of biological materials and biomedicines.
Detailed Description
Example a method of preparing a support, comprising the steps of:
(1) adding 3mmol of ethylene glycol dimethacrylate, 2.4mmol of lauryl methacrylate and 1.2mmol of pentaerythritol tetraacrylate into butane, stirring for 5 minutes, adding 0.3mmol of diisopropylethylamine, stirring for 15 minutes at 60 ℃, adding 0.03mmol of copper N, N-di-N-butyldithiocarbamate, stirring for 10 minutes, cooling to room temperature, adding 0.015mmol of bis (2, 6-difluoro-3- (1H-pyrrol-1-yl) phenyl) titanocene and ethanol, stirring, and carrying out illumination reaction for 8 hours; after the reaction is finished, adding the reaction solution into water, and taking the upper layer solution as an acrylic prepolymer solution;
(2) adding 3mmol of phosphate ester monomer into tetrahydrofuran in nitrogen atmosphere, stirring for 15 minutes, adding 0.9mmol of isopropanol, stirring for 30 minutes, adding 6mmol of trimethylene cyclic carbonate, stirring for 5 minutes, adding 0.024mmol of 1, 8-diazabicyclo [5.4.0] undec-7-ene, and reacting at 70 ℃ for 10 minutes; concentrating the reaction product by rotary evaporation, dropping the concentrated solution into a methanol/ether mixed solution for precipitation, removing the supernatant, dissolving the residue in methanol, transferring the methanol solution into a dialysis bag, dialyzing the solution in deionized water for 50 hours, and freeze-drying the solution to obtain a phosphate-carbonate copolymer; the chemical structural formula of the phosphate ester monomer is as follows:
(3) dissolving 0.2mmol of ornithine ethyl ester in dimethylformamide, placing the mixture in a closed reactor, dropwise adding 1mmol of gamma-oligo (ethylene glycol) -L-glutamic acid-N-carboxyl internal anhydride dimethylformamide solution in a nitrogen environment, and then reacting for 2 hours at 40 ℃; after the reaction is finished, precipitating the reaction solution by using glacial ethyl ether, centrifuging, and drying in vacuum to obtain an amino acid polymer;
(4) respectively adding the phosphate-carbonate copolymer and the amino acid polymer into dichloromethane to obtain a dichloromethane solution of the phosphate-carbonate copolymer and a dichloromethane solution of the amino acid polymer; then simultaneously dripping a methylene dichloride solution of the phosphate-carbonate copolymer and a methylene dichloride solution of the amino acid polymer into an acrylic prepolymer solution; after the dropwise addition is finished, 0.02mmol of polyethylene glycol and 0.0008mmol of zinc phthalocyanine are added; reacting at 50 ℃ for 20 hours; then using glacial acetic acid to terminate the reaction, using ethyl acetate to precipitate reaction liquid, filtering, drying filter cake to obtain the carrier.
Example two methods of preparing a support, comprising the steps of:
(1) adding 3mmol of ethylene glycol dimethacrylate, 2.4mmol of lauryl methacrylate and 1.2mmol of pentaerythritol tetraacrylate into butane, stirring for 5 minutes, adding 0.3mmol of diisopropylethylamine, stirring for 15 minutes at 60 ℃, adding 0.03mmol of copper N, N-di-N-butyldithiocarbamate, stirring for 10 minutes, cooling to room temperature, adding 0.015mmol of bis (2, 6-difluoro-3- (1H-pyrrol-1-yl) phenyl) titanocene and ethanol, stirring, and carrying out illumination reaction for 8 hours; after the reaction is finished, adding the reaction solution into water, and taking the upper layer solution as an acrylic prepolymer solution;
(2) adding 3mmol of phosphate ester monomer into tetrahydrofuran in nitrogen atmosphere, stirring for 15 minutes, adding 0.9mmol of isopropanol, stirring for 30 minutes, adding 6mmol of trimethylene cyclic carbonate, stirring for 5 minutes, adding 0.024mmol of 1, 8-diazabicyclo [5.4.0] undec-7-ene, and reacting at 70 ℃ for 10 minutes; concentrating the reaction product by rotary evaporation, dropping the concentrated solution into a methanol/ether mixed solution for precipitation, removing the supernatant, dissolving the residue in methanol, transferring the methanol solution into a dialysis bag, dialyzing the solution in deionized water for 50 hours, and freeze-drying the solution to obtain a phosphate-carbonate copolymer;
(3) dissolving 0.2mmol of cystine methyl ester in dimethylformamide, placing the mixture in a closed reactor, dropwise adding 1mmol of a dimethylformamide solution of gamma-oligo (ethylene glycol) -L-glutamic acid-N-carboxyl internal anhydride under a nitrogen environment, and then reacting for 2 hours at 40 ℃; after the reaction is finished, precipitating the reaction solution by using glacial ethyl ether, centrifuging, and drying in vacuum to obtain an amino acid polymer;
(4) respectively adding the phosphate-carbonate copolymer and the amino acid polymer into dichloromethane to obtain a dichloromethane solution of the phosphate-carbonate copolymer and a dichloromethane solution of the amino acid polymer; then simultaneously dripping a methylene dichloride solution of the phosphate-carbonate copolymer and a methylene dichloride solution of the amino acid polymer into an acrylic prepolymer solution; after the dropwise addition is finished, 0.02mmol of polyethylene glycol and 0.0008mmol of zinc phthalocyanine are added; reacting at 50 ℃ for 20 hours; then using glacial acetic acid to terminate the reaction, using ethyl acetate to precipitate reaction liquid, filtering, drying filter cake to obtain the carrier.
EXAMPLE triple Carrier toxicity
The L929 cells were cultured in DMEM medium containing 10% Fetal Bovine Serum (FBS) at 37 deg.C and 5% CO, and the target was human fibroblast (L929) and human nasopharyngeal carcinoma (KB)2And culturing in an incubator with relative humidity of 90%. Selecting cells in an active growth phase, inoculating the cells into a 96-well plate containing 100 mu L of DMEM medium in each well, and culturing for 24 hours; KB cells were cultured in RPMI-1640(-) FA medium for more than two weeks. Preparing a carrier solution of 1200 mg. L-1, adding the carrier solution into a 96-well plate, and continuously culturing for 48 hours; subsequently, 25. mu.L of MTT reagent was added, and after further incubation for 4 hours, the corresponding absorbance was measured at 570 nm with a microplate reader (Bio-Rad 680). Cell viability was calculated according to the following formula: cell viability (cellmediability) (%) ═ a]test/[A]In the control X100 formula, [ A ]]test is the absorbance measured with the sample to be measured added, [ A ]]control is the pipette measured under blank control conditions without sample additionAnd (4) luminosity. Each sample was tested five times and averaged.
The 48-hour test result shows that the cell survival rates of the carriers of the first example and the second example on L929 cells and KB cells are respectively greater than 92% and 88%, and the result shows that the polymer carrier has lower toxicity and good biocompatibility.
EXAMPLE four preparation of pharmaceutical compositions
Dissolving adriamycin in DMSO to obtain 5mg/L drug solution; dissolving a carrier in N, N-dimethylformamide to obtain a carrier solution; under stirring, dripping the medicine solution into the carrier solution, uniformly mixing, then adding secondary water and 1, 4-dithio-D with the mass of 0.05 percent of the carrier, stirring for 30 minutes, and dialyzing primary water; then adding saturated sodium chloride phosphate buffer solution with the pH value of 10 to fix the volume to obtain the pharmaceutical composition; the results of transmission electron microscopy and dynamic light scattering show that the pharmaceutical composition is in a circular structure in aqueous solution, and the particle size is about 210 nanometers.
Example five drug loading rates and encapsulation efficiencies
Taking a certain amount of medicinal composition solution, firstly removing water in the solution by a freeze drying method, then adding 1mL of formamide for ultrasonic treatment for 0.4h, taking 20mL of the solution, adding 3mL of formamide, and calculating the encapsulation efficiency and the drug loading rate by a fluorescence test in combination with a standard curve of adriamycin.
The encapsulation efficiency (mass of doxorubicin in the drug/mass of doxorubicin dosed) × 100%
The drug loading rate (mass of doxorubicin in the drug/total mass of doxorubicin in the drug and the amount of doxorubicin added) × 100%
When the theoretical drug loading is 30%, the encapsulation efficiency and the actual drug loading of the carrier of the first example and the carrier of the second example on the adriamycin are respectively 61.5%, 24%, 60.8% and 23%.
The results for the other drugs are shown in table 1.
TABLE 1 encapsulation efficiency and drug loading
EXAMPLE six Release of pharmaceutical compositions
The pharmaceutical composition of the adriamycin was placed in a 50mL centrifuge tube, phosphate buffer solutions (10mL) of different pH values were added, and the centrifuge tube was placed in a 37 ℃ constant temperature shaker for release experiments with deionized water as a control. Dialyzing at intervals with 5mL of solution (molecular weight cutoff 10000-15000 g.mol)-1) 5mL of buffer solution with the same pH value is supplemented at the same time, and the content of released adriamycin is detected by adopting a fluorescence spectrophotometer, so that the result shows that the release rate of the drug under the condition of pH 5.5 is obviously higher than that of pH 7.5, and at the same time, the release rates of the drug in the control sample are 16% and 17% in the carrier of the first embodiment and the carrier of the second embodiment in the stage of 20 hours, which indicates that the drug composition has acid sensitivity and can achieve the effect of controllable release of the drug; example one carrier drug release rates of 2.5%, 16.9%, 39.4%, 69.4%, 80.9% at pH 5.5 over 1 hour, 3 hours, 8 hours, 12 hours, 20 hours; example two carrier drugs release 2%, 18.1%, 39.1%, 67.5%, 81.2% of drug at pH 5.5 over 1 hour, 3 hours, 8 hours, 12 hours, 20 hours; the pharmaceutical composition has a sustained-release effect, can reduce medication and avoid side effects of the medicine.
The adriamycin is replaced by other medicines, and the release rate is 35-40% in 8 hours and 80-83% in 20 hours under the condition of pH 5.5.
EXAMPLE toxicity of the pharmaceutical compositions
Preparing a drug solution, wherein the drug concentration is 3 mg/L; toxicity was tested on human nasopharyngeal carcinoma cells (KB), human brain glioma cells (U87MG) according to the method of example three, with 3mg/L free drug as reference; table 2 shows the toxicity results.
TABLE 2 results of cell viability for pharmaceutical compositions (48 hours)
The result shows that the drug composition has strong capability of killing cancer cells, and the drug-loaded composition has stronger capability of killing cancer cells than free drugs under the same drug concentration.
Example eight mice cycling results
9 nude mice weighing about 20g at about 6 weeks of age were randomly divided into three groups, and each group was administered caudal vein separately (example one adriamycin pharmaceutical composition, example two paclitaxel pharmaceutical composition, free DOX) at a dose of 18 mg/kg. And (3) taking 8 mu L of blood at the tail of each time point of 5min, 30min, 1h, 2h, 5h, 8h, 12h and 24h after administration, weighing the blood sample after the blood taking is finished, dissolving the blood sample in 100 mu L of 1% triton solution, adding 1mL of 0.75mol/L isopropanol hydrochloride solution, standing overnight at minus 20 ℃ in the dark, centrifuging, and taking the supernatant for fluorescence test.
% ID/g ═ FL sample x (V triton + V hydrochloric acid))/(M blood x FL standard x V standard x dilution of standard) x 100%. The results show that: the pharmaceutical composition has good stability, can realize long circulation in mice, can detect about 20% in 8h, and almost cannot detect the free drug in the blood of the mice after 2 h.
Claims (3)
1. A functional pharmaceutical composition, wherein the preparation method of the functional pharmaceutical composition comprises the following steps:
(1) adding ethylene glycol dimethacrylate, lauryl methacrylate and pentaerythritol tetraacrylate into butane, stirring for 5 minutes, adding diisopropylethylamine, stirring for 15 minutes at 60 ℃, adding copper N, N-di-N-butyl dithiocarbamate, stirring for 10 minutes, cooling to room temperature, adding bis (2, 6-difluoro-3- (1H-pyrrol-1-yl) phenyl) titanocene and ethanol, stirring, and carrying out illumination reaction for 8 hours; after the reaction is finished, adding the reaction solution into water, and taking the upper layer solution as an acrylic prepolymer solution;
(2) adding a phosphate ester monomer into tetrahydrofuran in a nitrogen atmosphere, stirring for 15 minutes, adding isopropanol, stirring for 30 minutes, then adding trimethylene cyclic carbonate, stirring for 5 minutes, adding 1, 8-diazabicyclo [5.4.0] undec-7-ene, and reacting for 10 minutes at 70 ℃; concentrating the reaction product by rotary evaporation, dropping the concentrated solution into a methanol/ether mixed solution for precipitation, removing the supernatant, dissolving the residue in methanol, transferring the methanol solution into a dialysis bag, dialyzing the solution in deionized water for 50 hours, and freeze-drying the solution to obtain a phosphate-carbonate copolymer; the chemical structural formula of the phosphate ester monomer is as follows:
(3) dissolving an amino compound in dimethylformamide, placing the mixture in a closed reactor, dropwise adding a dimethylformamide solution of gamma-oligo (ethylene glycol) -L-glutamic acid-N-carboxyl internal anhydride in a nitrogen environment, and reacting for 2 hours at 40 ℃; after the reaction is finished, precipitating the reaction solution by using glacial ethyl ether, centrifuging, and drying in vacuum to obtain an amino acid polymer; the amino compound is ornithine ethyl ester or cystine methyl ester;
(4) respectively adding the phosphate-carbonate copolymer and the amino acid polymer into dichloromethane to obtain a dichloromethane solution of the phosphate-carbonate copolymer and a dichloromethane solution of the amino acid polymer; then simultaneously dripping a methylene dichloride solution of the phosphate-carbonate copolymer and a methylene dichloride solution of the amino acid polymer into an acrylic prepolymer solution; after the dropwise addition is finished, adding polyethylene glycol and zinc phthalocyanine; reacting at 50 ℃ for 20 hours; then using glacial acetic acid to terminate the reaction, using ethyl acetate to precipitate reaction liquid, filtering, drying filter cake to obtain carrier;
(5) dissolving a drug in DMSO to obtain a drug solution; dissolving a carrier in N, N-dimethylformamide to obtain a carrier solution; under stirring, dripping the medicine solution into the carrier solution, uniformly mixing, then adding secondary water and 1, 4-dithio-D with the mass of 0.05 percent of the carrier, stirring for 30 minutes, and dialyzing primary water; then adding buffer solution to fix the volume to obtain the targeted pharmaceutical composition;
in the step (1), the molar ratio of ethylene glycol dimethacrylate, lauryl methacrylate, pentaerythritol tetraacrylate, diisopropylethylamine, copper N, N-di-N-butyldithiocarbamate and bis (2, 6-difluoro-3- (1H-pyrrol-1-yl) phenyl) titanocene is 1: 0.8: 0.4: 0.1: 0.01: 0.005;
in the step (2), the molar ratio of the phosphate ester monomer, the isopropanol, the trimethylene cyclic carbonate and the 1, 8-diazabicyclo [5.4.0] undec-7-ene is 1: 0.3: 2: 0.008;
in the step (3), the mol ratio of the amino compound to the gamma-oligo (ethylene glycol) -L-glutamic acid-N-carboxyl internal anhydride is 1: 5;
the mol ratio of ethylene glycol dimethacrylate, trimethylene cyclic carbonate, gamma-oligo-ethylene glycol-L-glutamic acid-N-carboxyl internal anhydride, polyethylene glycol and zinc phthalocyanine is 3: 6: 1: 0.02: 0.0008;
the medicine is adriamycin, paclitaxel, bortezomib, aclarubicin, pirarubicin, daunorubicin hydrochloride, semustine or plicamycin.
2. The functional pharmaceutical composition of claim 1, wherein: the concentration of the drug solution was 5.0 mg/mL.
3. The functional pharmaceutical composition of claim 1, wherein: the buffer is saturated sodium chloride phosphate buffer.
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| Publication number | Publication date |
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| CN105997867A (en) | 2016-10-12 |
| CN108542882B (en) | 2020-04-17 |
| CN105997867B (en) | 2019-03-05 |
| CN108524446A (en) | 2018-09-14 |
| CN108542882A (en) | 2018-09-18 |
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