CN113133971A - Ibuprofen sustained-release microsphere and preparation method and application thereof - Google Patents
Ibuprofen sustained-release microsphere and preparation method and application thereof Download PDFInfo
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- CN113133971A CN113133971A CN202010052541.4A CN202010052541A CN113133971A CN 113133971 A CN113133971 A CN 113133971A CN 202010052541 A CN202010052541 A CN 202010052541A CN 113133971 A CN113133971 A CN 113133971A
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- ibuprofen
- isobutylphenyl
- propionyl
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- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 title claims abstract description 91
- 229960001680 ibuprofen Drugs 0.000 title claims abstract description 91
- 238000013268 sustained release Methods 0.000 title claims abstract description 76
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 76
- 239000004005 microsphere Substances 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- -1 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl Chemical group 0.000 claims abstract description 37
- QXVRLFIKHYCFJS-UHFFFAOYSA-N 2-[4-(2-methylpropyl)phenyl]propanoyl chloride Chemical compound CC(C)CC1=CC=C(C(C)C(Cl)=O)C=C1 QXVRLFIKHYCFJS-UHFFFAOYSA-N 0.000 claims abstract description 33
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 24
- 229920002818 (Hydroxyethyl)methacrylate Polymers 0.000 claims abstract description 22
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- STVZJERGLQHEKB-UHFFFAOYSA-N ethylene glycol dimethacrylate Substances CC(=C)C(=O)OCCOC(=O)C(C)=C STVZJERGLQHEKB-UHFFFAOYSA-N 0.000 claims abstract description 18
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- 239000002245 particle Substances 0.000 claims description 19
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 7
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- 238000003756 stirring Methods 0.000 description 10
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 150000001263 acyl chlorides Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
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- 239000000843 powder Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
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- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
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- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
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Images
Classifications
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/58—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/10—Esters
- C08F220/12—Esters of monohydric alcohols or phenols
- C08F220/14—Methyl esters, e.g. methyl (meth)acrylate
Abstract
The invention relates to the technical field of sustained-release medicines, in particular to ibuprofen sustained-release microspheres and a preparation method and application thereof. The preparation method of the ibuprofen sustained release microsphere provided by the invention comprises the following steps: mixing ibuprofen, thionyl chloride and a catalyst, and carrying out substitution reaction to obtain 2- (4-isobutylphenyl) propionyl chloride; mixing the 2- (4-isobutylphenyl) propionyl chloride and hydroxyethyl methacrylate for esterification reaction to obtain 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate; under the action of an emulsifier and an initiator, the 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate, methyl methacrylate and ethylene glycol dimethacrylate are subjected to polymerization reaction to obtain the ibuprofen sustained-release microsphere. The ibuprofen sustained-release microspheres prepared by the invention not only have a good sustained-release effect, but also can improve the bioavailability of ibuprofen.
Description
Technical Field
The invention relates to the technical field of sustained-release medicines, in particular to ibuprofen sustained-release microspheres and a preparation method and application thereof.
Background
Ibuprofen is an active drug with anti-inflammatory, analgesic and antipyretic effects, belongs to non-steroidal anti-inflammatory drugs, and is one of the best-tolerated drugs. But ibuprofen has large stimulation to gastric mucosa, and is easy to cause side effects such as gastric ulcer, gastrointestinal bleeding and abdominal pain; in addition, ibuprofen has a short biological half-life in humans (only 1-2 h) [ Biomaterials 2015,53,202-10.Nanotechnology 2018,29(22),225604 ]. For this reason, many ibuprofen preparations with sustained release function have been developed to improve the side effects and the administration frequency, such as: sustained release capsules, suspensions, sustained release gels, and the like.
The ibuprofen sustained-release capsules, ibuprofen sustained-release gels, ibuprofen suspensions and the like which are circulated in the market at present can be used for sustained release of ibuprofen, but still have certain side effects on gastrointestinal tracts, and the bioavailability of the drug is low.
Disclosure of Invention
The particle size of the ibuprofen sustained-release microsphere prepared by the invention is 385.00-927.65 nm, so that the sustained-release microsphere is beneficial to permeation of the sustained-release microsphere to organisms, and the bioavailability of ibuprofen can be improved.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of ibuprofen sustained-release microspheres, which comprises the following steps:
(1) mixing ibuprofen, thionyl chloride and a catalyst, and carrying out substitution reaction to obtain 2- (4-isobutylphenyl) propionyl chloride;
(2) mixing the 2- (4-isobutylphenyl) propionyl chloride and hydroxyethyl methacrylate for esterification reaction to obtain 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate;
(3) under the action of an emulsifier and an initiator, carrying out polymerization reaction on the 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate, methyl methacrylate and ethylene glycol dimethacrylate to obtain the ibuprofen sustained-release microsphere; the dosage ratio of the emulsifier to 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate is (0.5-5) g: 6 mL; the dosage ratio of the initiator to 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate is (0.1-1) g: 6 mL.
Preferably, the molar ratio of the ibuprofen to the thionyl chloride in the step (1) is 1 (1-1.4).
Preferably, the temperature of the substitution reaction in the step (1) is 75-85 ℃ and the time is 2-4 h.
Preferably, the molar ratio of the 2- (4-isobutylphenyl) propionyl chloride to the hydroxyethyl methacrylate in the step (2) is (1.2-1.5): 1.
Preferably, the esterification reaction in the step (2) is carried out at the temperature of 20-30 ℃ for 24-36 h.
Preferably, the volume ratio of the 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate to the methyl methacrylate to the ethylene glycol dimethacrylate in the step (3) is (0.6-2.0): (2-4): (0.5 to 1).
Preferably, the emulsifier in step (3) is sodium lauryl sulfate; the initiator is azobisisobutyronitrile.
Preferably, the temperature of the polymerization reaction in the step (3) is 70-80 ℃, and the time is 10-15 h.
The invention also provides ibuprofen sustained-release microspheres prepared by the preparation method in the technical scheme, wherein the particle size is 385.00-927.65 nm, and the polydispersity is 0.122-0.739.
The invention also provides the application of the ibuprofen sustained release microspheres in the technical scheme in the preparation of ibuprofen sustained release drugs.
The invention provides a preparation method of ibuprofen sustained-release microspheres, which comprises the following steps: (1) mixing ibuprofen, thionyl chloride and a catalyst, and carrying out substitution reaction to obtain 2- (4-isobutylphenyl) propionyl chloride; (2) mixing the 2- (4-isobutylphenyl) propionyl chloride and hydroxyethyl methacrylate for esterification reaction to obtain 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate; (3) under the action of an emulsifier and an initiator, carrying out polymerization reaction on the 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate, methyl methacrylate and ethylene glycol dimethacrylate to obtain the ibuprofen sustained-release microsphere; the dosage ratio of the emulsifier to 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate is (0.5-5) g: 6 mL; the dosage ratio of the initiator to 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate is (0.1-1) g: 6 mL. The invention makes the carboxyl on the ibuprofen substituted by acyl chloride through substitution reaction to obtain 2- (4-isobutyl phenyl) propionyl chloride; then 2- (4-isobutylphenyl) propionyl chloride and hydroxyethyl methacrylate are subjected to esterification reaction, so that ibuprofen and hydroxyethyl methacrylate are connected by ester bonds, and the sustained-release effect of ibuprofen can be improved; according to the invention, methyl methacrylate is used as a main material, ethylene glycol dimethacrylate is used as a cross-linking agent, and the ibuprofen sustained-release microspheres with the particle size of 385.00-927.65 nm are obtained through polymerization by controlling the dosage of an emulsifier and an initiator, so that the sustained-release microspheres can permeate organisms and the bioavailability of ibuprofen can be improved.
In addition, the preparation method provided by the invention has the advantages of wide and easily available raw materials, simple and convenient method and suitability for industrial production.
Drawings
FIG. 1 is a NMR spectrum of 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate prepared in example 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance spectrum of ibuprofen sustained release microspheres prepared in example 2 of the present invention;
FIG. 3 is a chart of the infrared spectra of MMA, Ibu @ HEMA and Ibu @ PMMA in example 2 of the present invention;
FIG. 4 is a graph showing the particle size and polydispersity of Ibu @ PMMA prepared in example 2 of the present invention;
FIG. 5 is a scanning electron micrograph of Ibu @ PMMA prepared according to example 2 of the present invention;
FIG. 6 is a graph showing the particle size and polydispersity index of Ibu @ PMMA prepared in example 3 of the present invention;
FIG. 7 is a scanning electron micrograph of Ibu @ PMMA prepared according to example 3 of the present invention;
FIG. 8 is a graph comparing the sustained release profiles of Ibu @ PMMA and ibuprofen prepared in example 3 of the present invention in phosphate buffered saline.
Detailed Description
The invention provides a preparation method of ibuprofen sustained-release microspheres, which comprises the following steps:
(1) mixing ibuprofen, thionyl chloride and a catalyst, and carrying out substitution reaction to obtain 2- (4-isobutylphenyl) propionyl chloride;
(2) mixing the 2- (4-isobutylphenyl) propionyl chloride and hydroxyethyl methacrylate for esterification reaction to obtain 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate;
(3) under the action of an emulsifier and an initiator, carrying out polymerization reaction on the 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate, methyl methacrylate and ethylene glycol dimethacrylate to obtain the ibuprofen sustained-release microsphere; the dosage ratio of the emulsifier to the 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate is (0.5-5.0) g: 6 mL; the dosage ratio of the initiator to 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate is (0.1-1.0) g: 6 mL.
The invention mixes ibuprofen, thionyl chloride and catalyst for substitution reaction to obtain 2- (4-isobutylphenyl) propionyl chloride. In the invention, the molar ratio of ibuprofen to thionyl chloride is preferably 1 (1-1.4), and more preferably 1 (1.2-1.3). In the invention, the catalyst is preferably N, N-dimethylformamide, and the dosage ratio of the catalyst to ibuprofen is preferably 0.3-0.7 mL: 5g of the total weight. In the invention, the mixing mode of the ibuprofen, the thionyl chloride and the catalyst is preferably as follows: mixing ibuprofen and thionyl chloride at low temperature, and then adding a catalyst. In the invention, the temperature of the low-temperature condition is preferably-5 ℃, and more preferably 0 ℃. The mixing effect of the invention at low temperature is that a large amount of heat is generated after the thionyl chloride is added, and the byproduct generated by excessive heat accumulation is prevented.
In the invention, the temperature of the substitution reaction is preferably 75-85 ℃, and more preferably 80-82 ℃; the time of the substitution reaction is preferably 2-4 h, and more preferably 3 h. In the present invention, the substitution reaction is preferably performed under reflux conditions, and during the substitution reaction, the carboxyl group on ibuprofen is substituted by acyl chloride to obtain 2- (4-isobutylphenyl) propionyl chloride. In the present invention, the 2- (4-isobutylphenyl) propionyl chloride is a yellow oily liquid.
After the 2- (4-isobutylphenyl) propionyl chloride is obtained, the 2- (4-isobutylphenyl) propionyl chloride and hydroxyethyl methacrylate are mixed for esterification reaction to obtain the 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate. In the invention, the molar ratio of the 2- (4-isobutylphenyl) propionyl chloride to the hydroxyethyl methacrylate is preferably (1.2-1.5): 1, and is preferably (1.3-1.4): 1.
In the present invention, the specific method for mixing the 2- (4-isobutylphenyl) propionyl chloride and the hydroxyethyl methacrylate is preferably: respectively dissolving 2- (4-isobutylphenyl) propionyl chloride and hydroxyethyl methacrylate in an organic solvent to obtain a 2- (4-isobutylphenyl) propionyl chloride solution and a hydroxyethyl methacrylate solution; then mixing the 2- (4-isobutyl phenyl) propionyl chloride solution with an acid-binding agent at low temperature to obtain a mixed solution; and then adding a hydroxyethyl methacrylate solution into the mixed solution. In the present invention, the organic solvent is preferably tetrahydrofuran, and the volume ratio of the 2- (4-isobutylphenyl) propionyl chloride to the organic solvent is preferably 1: (5-6); the volume ratio of the hydroxyethyl methacrylate to the organic solvent is preferably 1: (10-12). In the invention, the temperature of the low-temperature condition is preferably-5 ℃, and more preferably 0 ℃. In the present invention, the acid scavenger is preferably pyridine; the volume ratio of the 2- (4-isobutyl phenyl) propionyl chloride to the acid-binding agent is preferably 1: (1.5-2.0). The acid-binding agent can neutralize acidic substances released in the esterification reaction process, so that the esterification reaction is carried out in the positive direction. In the invention, the adding speed of the hydroxyethyl methacrylate is preferably 1-1.5 mL/min; the hydroxyethyl methacrylate is preferably added to the mixed solution by a constant-pressure low-liquid funnel. In the invention, the reaction of 2- (4-isobutylphenyl) propionyl chloride and hydroxyethyl methacrylate is very violent and is accompanied with a large amount of heat generation, and the slow addition of the hydroxyethyl methacrylate can ensure the safe experiment, ensure the complete esterification reaction and reduce the side reaction caused by the release of local heat.
In the invention, the esterification reaction is preferably carried out at room temperature, specifically 20-30 ℃ for 24-36 h, and more preferably carried out for 24h after the hydroxyethyl methacrylate is added. In the present invention, the esterification reaction is preferably carried out under a nitrogen atmosphere.
After the esterification reaction is finished, the reaction liquid obtained by the esterification reaction is preferably dissolved, washed, separated and purified in sequence. In the invention, the solvent for dissolving is preferably dichloromethane, and the reaction solution is dissolved in dichloromethane and then washed, separated and purified, so that the product yield can be improved. In the present invention, the washing mode is particularly preferably: washing a dichloromethane solution of a reaction solution by using an ethanol solution to be neutral, and then collecting an organic phase; the organic phase was washed with saturated sodium chloride solution and the dichloromethane was evaporated to give the crude product. In the present invention, the mass fraction of the sodium bicarbonate solution is preferably 5%; the sodium chloride solution is a saturated solution. In the present invention, the method for separation and purification is preferably: the crude product was isolated and purified by silica gel column using petroleum ether and ethyl acetate as mobile phases to give 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate. In the present invention, the volume ratio of the petroleum ether to the ethyl acetate is preferably 100: 1.
in the present invention, the 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate has the structural formula shown in formula I:
after obtaining 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate, under the action of an emulsifier and an initiator, carrying out polymerization reaction on the 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate, methyl methacrylate and ethylene glycol dimethacrylate to obtain the ibuprofen sustained release microsphere.
In the invention, the dosage ratio of the emulsifier to the 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate is (0.5-5) g: 6mL, preferably (1-4.5) g: 6mL, more preferably (1.5 to 4) g: 6mL, particularly preferably 0.5 g: 6mL, 1 g: 6mL, 1.5 g: 6mL, 2 g: 6mL, 2.5 g: 6mL, 3 g: 6mL, 3.5 g: 6mL, 4 g: 6mL, 4.5 g: 6mL or 5 g: 6 mL; the emulsifier is preferably sodium lauryl sulfate.
In the invention, the dosage ratio of the initiator to the 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate is (0.1-1) g: 6mL, preferably (0.2-0.9) g: 6mL, more preferably (0.3 to 0.8) g: 6mL, more preferably 0.1 g: 6mL, 0.2 g: 6mL, 0.3 g: 6mL, 0.4 g: 6mL, 0.5 g: 6mL, 0.6 g: 6mL, 0.7 g: 6mL, 0.8 g: 6mL, 0.9 g: 6mL or 1 g: 6 mL; the initiator is preferably azobisisobutyronitrile. The particle size of the ibuprofen sustained release microspheres can be regulated and controlled by controlling the addition of the emulsifier and the initiator, and is specifically shown in table 3.
In the present invention, the volume ratio of the 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate, the methyl methacrylate and the ethylene glycol dimethacrylate is preferably (0.6 to 2.0): (2-4): (0.5 to 1), more preferably (1.2 to 2.0): 4: 1, most preferably 1.2: 4: 1. in the invention, ethylene glycol dimethacrylate is a cross-linking agent with biocompatibility, and can enable monomers to be cross-linked to form a polymer network during polymerization, thereby being beneficial to the formation of microspheres; meanwhile, the network structure of the polymer can slow down the release speed of ibuprofen. In the present invention, polymethylmethacrylate is a non-toxic, non-teratogenic polymer in the bulk portion of the drug delivery system.
In the specific embodiment of the present invention, it is preferable that the first mixing of the emulsifier aqueous solution with 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate, methyl methacrylate, and ethylene glycol dimethacrylate is performed to obtain an emulsion; and then mixing the emulsion and an initiator ethanol solution for the second time, and heating for polymerization reaction to obtain the ibuprofen slow-release microspheres. In the invention, the concentration of the emulsifier aqueous solution is preferably 0.5-5 g/L. In the invention, the first mixing is preferably carried out at room temperature, and the specific room temperature is preferably 20-30 ℃; the first mixing is preferably carried out under stirring conditions, and the stirring speed is preferably 600 to 800r/min, and more preferably 650 to 750 r/min. In the invention, the concentration of the initiator ethanol solution is preferably 1-10 g/L. In the present invention, the second mixing mode is preferably to drop the initiator ethanol solution into the emulsion, the dropping speed is preferably 2mL/min, and the initiator can be uniformly dispersed in the system by dropping.
In the invention, the temperature of the polymerization reaction is preferably 70-80 ℃, and more preferably 70-72 ℃; the time is preferably 10-15 h, and more preferably 12 h. In the present invention, the polymerization reaction is preferably carried out under a nitrogen atmosphere. In the invention, the polymerization reaction is preferably carried out under the condition of stirring, and the stirring speed is preferably 360-460 r/min, and more preferably 400 r/min.
In the present invention, the reaction formula of the polymerization reaction is shown in formula II:
after the polymerization reaction is finished, the solid-liquid separation is preferably carried out on the obtained system, and then the obtained solid matters are sequentially washed and dried to obtain the ibuprofen sustained-release microspheres. In the invention, the solid-liquid separation mode is preferably centrifugation, and the rotation speed of the centrifugation is preferably 8000-12000 r/min, and more preferably 8000 r/min; the centrifugation time is preferably 4-10 min, and more preferably 5 min; the solid material obtained by the centrifugation is preferably a white solid. In the present invention, the washing preferably includes water washing and ethanol washing performed in this order. In the invention, the drying is preferably vacuum drying, the vacuum degree of the vacuum drying is preferably-0.08 to-0.1 MPa, the temperature is preferably 35 to 45 ℃, and more preferably 40 ℃; the vacuum drying time is preferably 15-30 h, and more preferably 24 h. The invention removes unreacted monomers, soluble impurities and emulsifying agents through solid-liquid separation and washing processes.
In the invention, the particle size of the ibuprofen sustained-release microsphere is 385.00-927.65 nm, preferably 385-615.1 nm; the polydispersity is 0.122 to 0.739, preferably 0.122 to 0.362. The ibuprofen sustained-release microsphere provided by the invention has the advantages of small particle size, uniform particle size distribution and good biocompatibility, is favorable for permeation of the sustained-release microsphere to organisms, and can improve the bioavailability of ibuprofen.
The invention also provides the application of the ibuprofen sustained release microspheres in the technical scheme in the preparation of ibuprofen sustained release medicines, and preferably ibuprofen sustained release microspheres provided by the invention are used as raw materials to prepare ibuprofen sustained release capsules or ibuprofen sustained release solution.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
The preparation method of the 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate comprises the following steps:
adding 10.0g of ibuprofen into a double-mouth flask, adding 9.0g of thionyl chloride at 0 ℃, stirring until the mixture is dissolved, slowly dripping 1mLN, N-dimethylformamide into the mixture, raising the temperature to 80 ℃ to enable the reaction liquid to reflux, reacting for 3 hours, removing the thionyl chloride to obtain 2- (4-isobutylphenyl) propionyl chloride, wherein the obtained 2- (4-isobutylphenyl) propionyl chloride is yellow oily liquid;
under the nitrogen atmosphere, slowly adding (the specific adding speed is about 5mL/min)20mL tetrahydrofuran into the 2- (4-isobutylphenyl) propionyl chloride, stirring, and slowly dropping (the specific adding speed is about 5mL/min) 15-20 mL pyridine at the temperature of 0 ℃ for reacting for half an hour; then, 40mL of a tetrahydrofuran solution of hydroxyethyl methacrylate (the concentration of the solution is 0.85mol/L) is slowly added by using a constant-pressure low-liquid funnel; after the addition, slowly returning to the room temperature, and carrying out esterification reaction for 24 h; adding 100mL of dichloromethane into the obtained reaction solution, and washing the solution to be neutral by using a sodium bicarbonate solution (the mass fraction is 5%); collecting an organic phase, washing the organic phase by using a saturated sodium chloride solution, and evaporating to remove dichloromethane to obtain a crude product; separating and purifying the crude product by a silica gel column by using petroleum ether and ethyl acetate (the ratio of the petroleum ether to the ethyl acetate is 100: 1) as mobile phases to obtain 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate, wherein the nuclear magnetic resonance spectrogram of the obtained 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate is shown in figure 1;
the nuclear magnetic data are:1H NMR(400MHz,CDCl3)δ7.21-7.19(d,J＝8.0Hz,2H),7.09-7.07(d,J＝8.0Hz,2H),6.04(s,1H),5.54-5.53(t,J1＝2.8,1.6Hz,1H),4.36–4.26(m,J＝8.0Hz,4H),3.72(q,J＝7.1Hz,1H),2.44(d,J＝7.2Hz,2H),1.89(s,3H),1.84(dt,J＝13.5,6.7Hz,1H),1.49(d,J＝7.2Hz,3H),0.90(d,J＝6.7Hz,6H)。
example 2
Sodium Dodecyl Sulfate (SDS) was dissolved in water (H)2O) to this mixture was added Methyl Methacrylate (MMA), 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate (Ibu @ HEMA) prepared in example 1 andethylene Glycol Dimethacrylate (EGDMA), and is rapidly stirred for 5min at the stirring speed of 700r/min to form emulsion;
dissolving Azobisisobutyronitrile (AIBN) in ethanol (EtOH) to obtain an ethanol solution of azobisisobutyronitrile; then dropwise adding the azodiisobutyronitrile ethanol solution (the dropwise adding speed is 2mL/min) into the emulsion, stirring at the speed of 400r/min under the nitrogen atmosphere, heating to 70-72 ℃, and carrying out polymerization reaction for 12 h;
after the polymerization reaction is finished, slowly restoring the system to room temperature, centrifuging for 5min at the speed of 8000r/min to obtain a white solid, washing the solid by using water and ethanol respectively until an emulsifier and unreacted substances are completely removed, and finally drying in vacuum for 24h at the temperature of 40 ℃ to obtain white solid powder, namely the ibuprofen sustained-release microspheres (Ibu @ PMMA);
wherein, SDS and H2The amounts of O, MMA, Ibu @ HEMA, EGDMA, AIBN and EtOH are shown in Table 1;
table 1 amount of raw materials used in example 2
Test example 1
The nuclear magnetic resonance spectrum of the ibuprofen sustained release microspheres prepared by the sample 1-1 in the example 2 is shown in fig. 2, compared with fig. 1, Ibu @ HEMA in fig. 1 has a chemical shift of 6.04, two hydrogens of 5.54-5.53 belong to two hydrogens on a carbon-carbon double bond, and a peak is obviously not shown in fig. 2, which indicates that Ibu @ HEMA carbon-carbon double bond is polymerized to form the ibuprofen sustained release microspheres; furthermore, in FIG. 1, at the 7.21-7.19 and 7.09-7.07 shifts are the hydrogens of both chemical positions in the phenyl ring; similar peaks appear at similar positions in fig. 2, which indicates that a benzene ring structure exists in the ibuprofen sustained release microspheres, and simultaneously proves that the sustained release microspheres loaded with ibuprofen are formed.
The infrared spectra of MMA, Ibu @ HEMA and Ibu @ PMMA (ibuprofen sustained release microspheres prepared in samples 1-1) in example 2 are shown in FIG. 3, and as can be seen from FIG. 3, 3100--1In the range of MMA, Ibu @ HEMA and Ibu @ PMMAStretching vibration and stretching vibration of unsaturated hydrocarbon; at 1710cm-1Nearby stretching vibration of carbon-oxygen double bonds in MMA, Ibu @ HEMA and Ibu @ PMMA; at 1640cm-1In the vicinity of the polymer monomers MMA and Ibu @ HEMA, stretching vibration of the carbon-carbon double bond on the olefin; in addition, in Ibu @ HEMA and Ibu @ PMMA, due to the presence of a benzene ring, at 1600--1Multiple groups of peaks appear in the range, which belongs to the stretching vibration of the skeleton of the benzene ring; and at 1100cm-1The absorption peak at (A) is ascribed to the asymmetric stretching vibration of C-O-C in the ether bond.
The ibuprofen sustained release microsphere sample (2-3 mg) prepared in example 2 is dispersed into 5mL of ethanol, and the particle size distribution and the polydispersity index (PDI) of the sample are tested by using a dynamic light scattering technology (DLS), and the test results are shown in fig. 4 and table 3. As can be seen from fig. 4 and table 3, as the proportion of the emulsifier is increased, the particle size of the ibuprofen sustained release microspheres is reduced from 615.1nm to 385nm, and the PDI is reduced from 0.739 to 0.122; particularly, after the addition of the emulsifier reaches more than 0.20g, the particle size is obviously reduced and the particle size distribution is more uniform, because micelles in the emulsion are unchanged and continuously increased along with the increase of the proportion of the emulsifier (the critical micelle concentration value of the sodium dodecyl sulfate is about 0.23g/L), so that the particle size of the obtained ibuprofen sustained-release microspheres is reduced and the distribution is more uniform; meanwhile, the same result can be obtained from the scanning electron microscope (figure 5) of the ibuprofen sustained-release microspheres (samples 1-1, 1-3, 1-5, 1-7, 1-9); in addition, it can be seen from fig. 5 that the ibuprofen sustained release microspheres are regularly spherical.
Example 3
Sodium Dodecyl Sulfate (SDS) was dissolved in water (H)2O), Methyl Methacrylate (MMA), 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate (Ibu @ HEMA) prepared in example 1 and Ethylene Glycol Dimethacrylate (EGDMA) were added thereto, and stirred rapidly at a stirring speed of 700r/min for 5min to form an emulsion;
dissolving Azobisisobutyronitrile (AIBN) in ethanol (EtOH) to obtain an ethanol solution of azobisisobutyronitrile; then dropwise adding the azodiisobutyronitrile ethanol solution (the dropwise adding speed is 2mL/min) into the emulsion, stirring at the speed of 400r/min under the nitrogen atmosphere, heating to 70-72 ℃, and carrying out polymerization reaction for 12 h;
after the polymerization reaction is finished, slowly restoring the system to room temperature, centrifuging for 5min at the speed of 8000r/min to obtain a white solid, washing the solid by using water and ethanol respectively until an emulsifier and unreacted substances are completely removed, and finally drying in vacuum for 24h at the temperature of 40 ℃ to obtain white solid powder, namely the ibuprofen sustained-release microspheres (Ibu @ PMMA);
wherein, SDS and H2The amounts of O, MMA, Ibu @ HEMA, EGDMA, AIBN and EtOH are shown in Table 2;
table 2 amounts of raw materials used in example 3
Test example 2
The ibuprofen sustained release microsphere sample (1-3 mg) prepared in example 3 is dispersed in 5mL of ethanol, and the particle size and polydispersity index (PDI) of the sample are tested by using a Dynamic Light Scattering (DLS) technique, and the test results are shown in fig. 6 and table 3. As can be seen from fig. 6 and table 3, as the addition amount of the initiator AIBN is increased from 0.01g to 0.10g, the particle size of the ibuprofen sustained release microsphere is reduced from 927.65nm to 385.00nm, and PDI is reduced from 0.362 to 0.122, because the more the amount of the initiator is added, the more the free radicals are formed after heating, the chain initiation and chain termination can occur in the micelle, the polymerization of the monomer droplets in the dispersion system is reduced, and the particle size of the ibuprofen sustained release microsphere is reduced; meanwhile, the same result can be obtained from the scanning electron microscope image (figure 7) of the ibuprofen sustained-release microspheres (samples 2-2, 2-4, 2-6, 2-8, 2-10); in addition, it can be seen from fig. 7 that the ibuprofen sustained release microspheres are regularly spherical.
TABLE 3 particle size and polydispersity index of ibuprofen sustained release microspheres
Test example 3
Respectively taking the ibuprofen sustained-release microspheres prepared by the samples 2-2, 2-6 and 2-10 in the example 3 and 50mg of ibuprofen into a dialysis bag (molecular weight cut-off 3500), placing the dialysis bag into 150mL of phosphate buffer solution (PBS, pH 7.4) and shaking at 37 ℃ (200r/min) to obtain a sustained-release solution;
respectively taking 3mL of sustained-release solution in each system at 1h, 5h, 12h, 1 day, 2 days, 3 days, 4 days, 5 days and 6 days, and supplementing the same amount of phosphate buffer solution in each sustained-release solution; the absorbance at 273nm of each sustained release solution was measured to obtain the sustained release ibuprofen content, as shown in fig. 8. As can be seen from figure 8, after 12 hours, the pure ibuprofen is released by 99.14%, while the ibuprofen sustained-release microspheres prepared by the invention release only 4.68% at most, which shows that the ibuprofen sustained-release microspheres prepared by the invention have obvious sustained-release effect on ibuprofen.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. A preparation method of ibuprofen sustained-release microspheres comprises the following steps:
(1) mixing ibuprofen, thionyl chloride and a catalyst, and carrying out substitution reaction to obtain 2- (4-isobutylphenyl) propionyl chloride;
(2) mixing the 2- (4-isobutylphenyl) propionyl chloride and hydroxyethyl methacrylate for esterification reaction to obtain 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate;
(3) under the action of an emulsifier and an initiator, carrying out polymerization reaction on the 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate, methyl methacrylate and ethylene glycol dimethacrylate to obtain the ibuprofen sustained-release microsphere; the dosage ratio of the emulsifier to 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate is (0.5-5) g: 6 mL; the dosage ratio of the initiator to 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate is (0.1-1) g: 6 mL.
2. The preparation method of claim 1, wherein the molar ratio of ibuprofen to thionyl chloride in step (1) is 1 (1-1.4).
3. The preparation method according to claim 1 or 2, wherein the temperature of the substitution reaction in the step (1) is 75-85 ℃ and the time is 2-4 h.
4. The preparation method according to claim 1, wherein the molar ratio of the 2- (4-isobutylphenyl) propionyl chloride and the hydroxyethyl methacrylate in the step (2) is (1.2-1.5): 1.
5. The preparation method according to claim 1 or 4, wherein the esterification reaction in the step (2) is carried out at a temperature of 20-30 ℃ for 24-36 h.
6. The method according to claim 1, wherein the volume ratio of 2- ((2- (4-isobutylphenyl) propionyl) oxy) ethyl methacrylate, methyl methacrylate and ethylene glycol dimethacrylate in the step (3) is (0.6-2.0): (2-4): (0.5 to 1).
7. The method according to claim 1, wherein the emulsifier in step (3) is sodium lauryl sulfate; the initiator is azobisisobutyronitrile.
8. The preparation method of claim 1, wherein the polymerization reaction in step (3) is carried out at a temperature of 70-80 ℃ for 10-15 hours.
9. The ibuprofen sustained-release microspheres prepared by the preparation method of any one of claims 1 to 8 have the particle size of 385.00-927.65 nm and the polydispersity of 0.122-0.739.
10. Use of ibuprofen sustained release microspheres in accordance with claim 9 for the preparation of ibuprofen sustained release medicament.
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