CN103705466A - Flurbiprofen acetaminophen ester solid dispersion and preparation method thereof - Google Patents
Flurbiprofen acetaminophen ester solid dispersion and preparation method thereof Download PDFInfo
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- CN103705466A CN103705466A CN201310414840.8A CN201310414840A CN103705466A CN 103705466 A CN103705466 A CN 103705466A CN 201310414840 A CN201310414840 A CN 201310414840A CN 103705466 A CN103705466 A CN 103705466A
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Abstract
The present invention relates to a flurbiprofen acetaminophen ester solid dispersion and a preparation method thereof, wherein the main component of the anti-inflammatory and analgesic prodrug is a complete-new compound flurbiprofen acetaminophen ester. According to the present invention, a hydrophilic carrier material is added, a solvent method and a solvent-melting method are respectively adopted to prepare the flurbiprofen acetaminophen ester solid dispersion, and the flurbiprofen acetaminophen ester solid dispersion can further be mixed with suitable auxiliary materials so as to prepare oral tablets or capsules; and the dissolubility and the dissolution rate of the drug can be significantly increased, the dissolubility of the drug is increased by 10-100 times compared with the raw material drug, and the 45 min accumulation dissolution percentage in the dissolution medium is correspondingly and substantially increased so as to improve the oral absorbability of the drug.
Description
Technical field
The invention belongs to medical manufacture field, be specifically related to flurbiprofen medicament paracetamol containing carboxyl group solid dispersion and preparation method thereof.
Background technology
Nonsteroidal anti-inflammatory analgetic (NSAIDs) is the fastest medicine of global evolution, is widely used in treatment of arthritis, the various inflammatory pains that particularly osteoarthritis, rheumatoid arthritis etc. cause.Different types of NSAID has identical mechanism of action [Curr.Opin.Rheum.1996,8:169 – 175], all by suppressing the activity of Cycloxygenase, thereby suppress arachidonic acid and finally generate inflammatory reaction factor prostacyclin (PGI1), prostaglandin (PGE1, PGE2) and thromboxane A2 (TXA2).This type of medicine more easily causes gastrointestinal ulceration, hemorrhage, and even perforation waits side effect [Br J Pharmacol.1999Nov, 128 (6): 1121-32.].
Flurbiprofen is aryl propionic non-steroid anti-inflammation analgesis medicament, is non-selective COX-2 inhibitors, and COX-1 and COX-2 are all produced to inhibitory action.For osteoarthritis, rheumatic arthritis all has good therapeutic effect,, due to its good analgesic activity, applies clinically as the operation analgesic of a line meanwhile.Acetaminophen is different from general NSAID (non-steroidal anti-inflammatory drug), it is generally acknowledged that at present it plays the effect of antipyretic-antalgic [Proc Natl Acad Sci U S A.2002Oct15 by suppressing COX-3; 99 (21): 13371-3.].But, long-term or excessive use acetaminophen, metabolism is Radical Metabolism product N-acetyl-p Benzoquinone imines (NAPQI) that toxicity is larger in vivo, causes hepatic injury, even acute hepatic failure, seriously limits its clinical practice.
Flurbiprofen medicament paracetamol containing carboxyl group is the original new drug with independent intellectual property right of designing and developing based on drug synergism mechanism and prodrug design concept, there is clear and definite drug effect target spot and ADME target spot, thereby produce collaborative anti-inflammatory and antalgic and antipyretic pharmacodynamics effect.This prodrug is degraded limited in gastrointestinal tract, but can be discharged two active drug molecules (flurbiprofen and acetaminophen) that action target spot is different by liver esterase fast hydrolyzing after entering blood, and can bring into play collaborative anti-inflammatory and analgesic effect.This prodrug greatly reduces dosage and the gastrointestinal tract toxic and side effects of two bioactive molecule medicines, and safety is significantly improved.The structural formula of this brand-new compound is shown in Fig. 1.
Yet the water solublity of flurbiprofen medicament paracetamol containing carboxyl group is very poor, oral slow through gastrointestinal tract stripping, directly the oral absorption of administration is poor.Solid dispersion technology is the focus of studying this year; be successfully used in improving the dissolubility of insoluble drug; by hydrophilic carrier material and insoluble drug are mixed with to solid dispersion with molecular state; can significantly improve the In Vitro Dissolution situation of medicine, and then improve bioavailability [the Drug Discovery Today.2007. (12): 1068-1075 of oral drugs; Eur.J.Pharm.Biopharm.50,47 – 60].This problem, from market application reality, adopts workable solid dispersion technology, solves flurbiprofen medicament paracetamol containing carboxyl group due to the low problem of bioavailability in the poorly soluble body causing.
Summary of the invention
The object of this invention is to provide a kind of flurbiprofen medicament paracetamol containing carboxyl group solid dispersion and preparation method thereof.
The invention provides flurbiprofen medicament paracetamol containing carboxyl group solid dispersion, this solid dispersion is comprised of flurbiprofen medicament paracetamol containing carboxyl group and carrier material; The ratio of the weight of flurbiprofen medicament paracetamol containing carboxyl group and carrier material is 1:1~1:20, this efficiently stripping of hydrophobic drug flurbiprofen medicament paracetamol containing carboxyl group; Described carrier material is one or more mixture of Polyethylene Glycol, polyvidone, PLURONICS F87, hydroxypropyl methylcellulose, acrylic resin apoplexy due to endogenous wind.
In the present invention, the preparation technology of the related collaborative prodrug flurbiprofen medicament paracetamol containing carboxyl group of NSAID (non-steroidal anti-inflammatory drug) anti-inflammatory and antalgic is simple, and favorable reproducibility, can complete by the following steps.First flurbiprofen is used under anhydrous condition to thionyl chloride chloride, obtained flurbiprofen acyl chlorides; Secondly by flurbiprofen acyl chlorides and acetaminophen in molar ratio 1:1 after mixing, carry out esterification.Finally, by dehydrated alcohol, synthetic product is carried out to recrystallization purifying.Refer to synthetic route chart (Fig. 2).Meanwhile, adopt infrared spectrum, nuclear magnetic resonance technique and high resolution mass spectrum further this compound to be carried out to structure verification, refer to infared spectrum, nuclear magnetic spectrum and high resolution mass spectrum figure (Fig. 3-Fig. 8).
The physical and chemical property determining of the brand-new compound flurbiprofen medicament paracetamol containing carboxyl group described in the present invention the results are shown in Table 1:
Table 1
This law is bright also provides the preparation method of described flurbiprofen medicament paracetamol containing carboxyl group solid dispersion, and this solid dispersion can adopt any one method preparation in hot-melt extruded method, solvent fusion method, solvent method.
The preparation method of flurbiprofen medicament paracetamol containing carboxyl group solid dispersion provided by the invention, described hot-melt extruded method technique is: flurbiprofen medicament paracetamol containing carboxyl group is mixed homogeneously by weight 1:1~1:20 with carrier material, be placed in hot-melt extruded machine, setting extrusion temperature is 120~180 ℃, after extrudate solidifies, pulverize, sieve, obtain solid dispersion.
The preparation method of flurbiprofen medicament paracetamol containing carboxyl group solid dispersion provided by the invention, described solvent fusion method technique is: get appropriate carrier material, in 80 ℃ of water-baths, heating makes its melting, flurbiprofen medicament paracetamol containing carboxyl group is dissolved in to appropriate organic solvent, and (organic solvent is methanol, ethanol, chloroform, one or more in dichloromethane) in, slowly drop in the carrier material of molten state, stir, after organic solvent volatilizes, a dislocation-20 ℃ refrigerator and cooled was frozen after 2~12 hours rapidly, be placed in vacuum drying oven dry, after dry thing is pulverized, obtain solid dispersion.
The preparation method of flurbiprofen medicament paracetamol containing carboxyl group solid dispersion provided by the invention, described solvent process is: get flurbiprofen medicament paracetamol containing carboxyl group and for 1:1~1:20, mix by weight with carrier material, (organic solvent is dehydrated alcohol to add organic solvent, methanol, one or more in dichloromethane) and a small amount of purified water, be stirred to dissolve, 40~60 ℃ of water-baths, after rotary evaporation majority of organic solvent, a dislocation-20 ℃ refrigerator and cooled was frozen after 2~12 hours rapidly, be placed in vacuum drying oven dry, after dry thing is pulverized, obtain solid dispersion.
The present invention also provides a kind of pharmaceutical preparation, and it comprises flurbiprofen medicament paracetamol containing carboxyl group solid dispersion claimed in claim 1; Described pharmaceutical preparation is multiple oral formulations, comprises tablet, capsule, can be conventional formulation, can be also oral disintegrated preparation, enteric coated preparation, slow/controlled release preparation.
Pharmaceutical preparation provided by the invention, the preparation method of described tablet or capsule is solid dispersion after pulverizing, and adds suitable adjuvant, carries out direct compression or fill and becomes capsule; Described adjuvant is one or more mixture in (20%~80%) microcrystalline Cellulose, lactose, mannitol, magnesium stearate, micropowder silica gel, Pulvis Talci, carboxymethyl starch sodium, pregelatinized Starch, polyvinylpolypyrrolidone.
The invention provides solid dispersion preparation technology, can guarantee stripping the absorption rapidly in intestinal of the collaborative prodrug flurbiprofen medicament paracetamol containing carboxyl group of slightly solubility, via liver esterase, be hydrolyzed to two active drug molecules and enter body circulation, the collaborative anti-inflammatory and analgesic effect of performance.
The present invention adopts dissolution in vitro test to investigate drug-eluting situation, through test, confirm, compare with undressed crude drug, flurbiprofen medicament paracetamol containing carboxyl group preparation of the present invention can improve in medicine water 10~100 times of dissolubility, the dissolution in vitro of medicine is significantly improved, and in dissolution medium, 45min accumulation stripping percentage rate improves greatly.Result is as follows:
1, dissolution in vitro experimental condition, measures by 2010 editions appendix dissolution method XC the 3rd methods of Chinese Pharmacopoeia (little agar diffusion method).Dissolution medium is 0.5%SDS aqueous solution, and rotating speed 50~100 turns.
2, with crude drug in contrast, measure the In Vitro Dissolution situation of flurbiprofen medicament paracetamol containing carboxyl group oral formulations.Result shows, crude drug is in 45min, and Cumulated released percent in vitro is in 30% left and right, and solid dispersion preparation reaches 75.3%~102.8% at 45min cumulative in vitro stripping percentage rate, compares and is significantly increased with crude drug.
Accompanying drawing explanation
Fig. 1 is the chemical structural formula of flurbiprofen medicament paracetamol containing carboxyl group;
The synthetic route of Fig. 2 flurbiprofen medicament paracetamol containing carboxyl group;
The infared spectrum of Fig. 3 flurbiprofen medicament paracetamol containing carboxyl group;
Fig. 4 flurbiprofen medicament paracetamol containing carboxyl group
1h NMR nuclear magnetic spectrum;
Fig. 5 flurbiprofen medicament paracetamol containing carboxyl group
13c NMR nuclear magnetic spectrum;
The HMBC nuclear magnetic spectrum of Fig. 6 flurbiprofen medicament paracetamol containing carboxyl group;
The HSQC nuclear magnetic spectrum of Fig. 7 flurbiprofen medicament paracetamol containing carboxyl group;
The high resolution mass spectrum figure of Fig. 8 flurbiprofen medicament paracetamol containing carboxyl group;
Solid dispersion In Vitro Dissolution curve of the present invention prepared by Fig. 9 different carriers material;
Figure 10 is the In Vitro Dissolution curve of preparation of the present invention.
The specific embodiment
Below in conjunction with embodiment, the present invention is further described, but not thereby limiting the invention.
Embodiment 1: the preparation of flurbiprofen medicament paracetamol containing carboxyl group
Taking 100g(410mmol) flurbiprofen is placed in round-bottomed flask, under condition of ice bath, dripping while stirring dichloromethane to flurbiprofen dissolves completely, slowly drip subsequently last 45mL(614mmol) thionyl chloride, after normal-temperature reaction 6 hours, steaming desolventizes, and obtains 105.5g flurbiprofen acyl chlorides, productive rate 98%.Taking 73g(792mmol) acetaminophen is placed in round-bottomed flask, dichloromethane solvent, under condition of ice bath, slowly drip 112mL(803mmol) triethylamine, then the flurbiprofen acyl chlorides being dissolved by dichloromethane is slowly added drop-wise in the middle of the solution of acetaminophen.Remove ice bath reaction 6 hours.
After completion of the reaction, three times (200mL * 3) of water extraction, three times (200mL * 3) of sodium bicarbonate solution extraction, organic facies is used anhydrous magnesium sulfate drying 4 hours, and sucking filtration is removed magnesium sulfate, is spin-dried for organic facies, obtains faint yellow crude product 145g, productive rate 95.7%.
In 80 ℃, use anhydrous alcohol solution product, add 50g active carbon and stir.Sucking filtration while hot after 2 hours, constantly stirs filtrate, makes its slow cooling in air, good to guarantee recrystallization crystal formation.Room temperature to be down to, is placed in ice bath and continues to stir 1 hour, and sucking filtration is collected filter cake, is dried to obtain white sterling flurbiprofen medicament paracetamol containing carboxyl group 134.1g, total recovery 86.8%.
Refer to synthetic route chart (Fig. 2).Meanwhile, adopt infrared spectrum, nuclear magnetic resonance technique and high resolution mass spectrum further this compound to be carried out to structure verification, refer to infared spectrum, nuclear magnetic spectrum and high resolution mass spectrum figure (Fig. 3-Fig. 8).
Nuclear magnetic data ownership is in Table 2.
Table 2
Note:
*do not determine
Get flurbiprofen medicament paracetamol containing carboxyl group 5g, be dissolved in alcoholic solution, PEG400020g is heated to 80 ℃ and forms molten state, flurbiprofen medicament paracetamol containing carboxyl group alcoholic solution is slowly added dropwise in carrier material, stir, volatilize ethanol, move to rapidly-20 ℃ of curing 4h.Taking-up gains are pulverized, dry.Obtain solid dispersion powder.The solid dispersion of this invented technology is in 45min, and cumulative in vitro dissolution is 93.5 ± 3.1%(n=6).6 samples of parallel assay.
Get flurbiprofen medicament paracetamol containing carboxyl group 5g, after suitable dissolve with ethanol, PVP-S630 is dissolved in ethanol, is placed in 60 ℃ of heating, by above-mentioned two kinds of solution mix homogeneously, stirs 2h, volatilizes ethanol, moves to rapidly-20 ℃ of curing 8h.Taking-up gains are pulverized, dry, obtain solid dispersion powder.The solid dispersion of this invented technology is in 45min, and cumulative in vitro dissolution is 94.4 ± 3.6%(n=6).6 samples of parallel assay.
Get flurbiprofen medicament paracetamol containing carboxyl group 5g, kollidon VA6420g, mix homogeneously melt extrudes at 160 ℃, and medicine fully mixes in extruder with the mixture of carrier, disperses, and after solidifying, pulverizes and sieves and obtains solid dispersion.The solid dispersion of this invented technology is in 45min, and cumulative in vitro dissolution is 88.4 ± 2.8%(n=6).6 samples of parallel assay.
Get flurbiprofen medicament paracetamol containing carboxyl group 5g, be dissolved in alcoholic solution, 30g PLURONICS F87 is heated to 80 ℃ and forms molten state, flurbiprofen medicament paracetamol containing carboxyl group alcoholic solution is slowly added dropwise in carrier material, stir, volatilize ethanol, move to rapidly-20 ℃ of curing 12h.Taking-up gains are pulverized, dry.Obtain solid dispersion powder.The solid dispersion of this invented technology is in 45min, and cumulative in vitro dissolution is 95.5 ± 3.1%(n=6).6 samples of parallel assay.
Solid dispersion in embodiment 2~5, the 40-60 order that sieves, mixes the granule of screening with the weight ratio of microcrystalline Cellulose and pregelatinized Starch (2:1), add polyvinylpolypyrrolidone (2~10%) as disintegrating agent, magnesium stearate is as lubricant, mix homogeneously, and direct pressing becomes tablet.The tablet of this invented technology is in 45min, and cumulative in vitro dissolution is 90.4 ± 2.5%(n=6).6 samples of parallel assay.
Embodiment 7
Clathrate in embodiment 2~5 or solid dispersion, add magnesium stearate and micropowder silica gel (1:1), accounts for middle recipe quantity 1~3%, adds microcrystalline Cellulose, starch, and lactose, accounts for recipe quantity 30%, filled capsules.Embodiment 2-7 In Vitro Dissolution curve is as follows: the capsule of this invented technology is in 45min, and cumulative in vitro dissolution is 92.5 ± 4.1%(n=6).6 samples of parallel assay.
Claims (9)
1. flurbiprofen medicament paracetamol containing carboxyl group solid dispersion, is characterized in that: this solid dispersion is comprised of flurbiprofen medicament paracetamol containing carboxyl group and carrier material;
The ratio of the weight of flurbiprofen medicament paracetamol containing carboxyl group and carrier material is 1:1~1:20;
Described carrier material is one or more mixture of Polyethylene Glycol, polyvidone, PLURONICS F87, hydroxypropyl methylcellulose, acrylic resin apoplexy due to endogenous wind.
2. the preparation method of flurbiprofen medicament paracetamol containing carboxyl group solid dispersion claimed in claim 1, is characterized in that: the preparation method of this solid dispersion is a kind of in hot-melt extruded method, solvent fusion method, solvent method.
3. according to the preparation method of flurbiprofen medicament paracetamol containing carboxyl group solid dispersion claimed in claim 2, it is characterized in that: described hot-melt extruded method technique is: by flurbiprofen medicament paracetamol containing carboxyl group and carrier material by weight 1:1~1:20, mix homogeneously, be placed in hot-melt extruded machine, setting extrusion temperature is 50~180 ℃, after extrudate solidifies, pulverizes, sieve, obtain solid dispersion.
4. according to the preparation method of flurbiprofen medicament paracetamol containing carboxyl group solid dispersion claimed in claim 2, it is characterized in that: described solvent fusion method technique is: get appropriate carrier material, heating and melting in 40~80 ℃ of water-baths, flurbiprofen medicament paracetamol containing carboxyl group is dissolved in appropriate organic solvent, slowly drops in the carrier material of molten state, stir, after organic solvent volatilizes, move to rapidly and freezingly in cryogenic refrigerator solidify and be dried, dry thing obtains solid dispersion after pulverizing.
5. according to the preparation method of flurbiprofen medicament paracetamol containing carboxyl group solid dispersion claimed in claim 2, it is characterized in that: described solvent process is: get flurbiprofen medicament paracetamol containing carboxyl group and for 1:1~1:20, mix by weight with carrier material, add organic solvent and a small amount of purified water, 40~80 ℃ of water-baths, stir, after rotary evaporation majority of organic solvent, rapidly in dislocation cryogenic refrigerator after freezing 1~48 hour, be placed in vacuum drying oven dry, dry thing obtains solid dispersion after pulverizing.
6. according to the preparation method of the flurbiprofen medicament paracetamol containing carboxyl group solid dispersion described in claim 4 or 5, it is characterized in that: described organic solvent is one or more in methanol, ethanol, chloroform, dichloromethane.
7. a pharmaceutical preparation, it comprises flurbiprofen medicament paracetamol containing carboxyl group solid dispersion claimed in claim 1.
8. according to pharmaceutical preparation claimed in claim 7, it is characterized in that: described pharmaceutical preparation is tablet, capsule, oral disintegrated preparation, enteric coated preparation, slow/controlled release preparation.
9. according to pharmaceutical preparation claimed in claim 8, it is characterized in that: the preparation method of described tablet or capsule, for after solid dispersion is pulverized, adds suitable adjuvant, then carries out direct compression or fill and becomes capsule;
Described adjuvant is one or more mixture in microcrystalline Cellulose, lactose, mannitol, magnesium stearate, micropowder silica gel, Pulvis Talci, carboxymethyl starch sodium, pregelatinized Starch, polyvinylpolypyrrolidone.
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CN108451909A (en) * | 2018-06-29 | 2018-08-28 | 鲁南制药集团股份有限公司 | A kind of ketorolac tromethamine tablet |
WO2021077889A1 (en) * | 2019-10-24 | 2021-04-29 | 中国人民解放军军事科学院军事医学研究院 | Paracetamol sustained-release preparation and 3d printing preparation method therefor |
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CN103211799B (en) * | 2013-03-11 | 2015-02-11 | 无锡艾德美特生物科技有限公司 | Flurbiprofen paracetamol ester external use slow release transdermal patch and preparation method thereof |
CN106880845A (en) * | 2015-12-10 | 2017-06-23 | 贵州益佰制药股份有限公司 | A kind of dabigatran etcxilate solid dispersions enteric coated preparations and preparation method thereof |
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CN101011374A (en) * | 2006-12-15 | 2007-08-08 | 陈文展 | Non-steroidal analgesic-antipyretic medicament paracetamol containing carboxyl group |
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CN101011374A (en) * | 2006-12-15 | 2007-08-08 | 陈文展 | Non-steroidal analgesic-antipyretic medicament paracetamol containing carboxyl group |
Non-Patent Citations (2)
Title |
---|
崔福德: "《药剂学》", 31 August 2002, 中国医药科技出版社 * |
李延昌等: "扑热息痛固体分散体的研究", 《河北医学院学报》 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN108451909A (en) * | 2018-06-29 | 2018-08-28 | 鲁南制药集团股份有限公司 | A kind of ketorolac tromethamine tablet |
CN108451909B (en) * | 2018-06-29 | 2020-06-12 | 鲁南制药集团股份有限公司 | Ketorolac tromethamine tablet |
WO2021077889A1 (en) * | 2019-10-24 | 2021-04-29 | 中国人民解放军军事科学院军事医学研究院 | Paracetamol sustained-release preparation and 3d printing preparation method therefor |
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