CN102871952A - 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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- CN102871952A CN102871952A CN 201210375632 CN201210375632A CN102871952A CN 102871952 A CN102871952 A CN 102871952A CN 201210375632 CN201210375632 CN 201210375632 CN 201210375632 A CN201210375632 A CN 201210375632A CN 102871952 A CN102871952 A CN 102871952A
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Abstract
The invention relates to flurbiprofen acetaminophen ester solid dispersion and a preparation method thereof. Anti-inflammatory and analgesic prodrugs mainly comprise brand new compounds of flurbiprofen acetaminophen ester, and the flurbiprofen acetaminophen ester solid dispersion is prepared by adding hydrophilic carrier materials and by respectively adopting a solvent method, a solvent-melting method and a melting method and can be further prepared into oral tablets or capsules by being mixed with proper adjuvants. By the flurbiprofen acetaminophen ester solid dispersion and the preparation method thereof, solubility and dissolving-out speed of drugs can be obviously increased, the solubility of the drugs in water is increased by 10-100 times as compared with that of crude drugs, cumulative dissolving-out percentage of the drugs in dissolving-out media in 45 minutes is substantially increased accordingly, and finally oral absorbability of the drugs is improved.
Description
Technical field
The invention belongs to medical manufacturing 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, particularly the various inflammatory pains that cause such as osteoarthritis, rheumatoid arthritis.Different types of NSAID has identical mechanism of action [Curr.Opin.Rheum.1996,8:169 – 175], all be 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, and is hemorrhage, even the side effect [Br J Pharmacol.1999 Nov, 128 (6): 1121-32.] such as perforation.
Flurbiprofen is the aryl propionic non-steroid anti-inflammation analgesis medicament, is non-selective COX-2 inhibitors, and COX-1 and COX-2 are all produced inhibitory action.For osteoarthritis, rheumatic arthritis all has good therapeutic effect, simultaneously, because its analgesic activity is preferably used as the operation analgesic of a line clinically.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 is Oct15 A.2002 by suppressing COX-3; 99 (21): 13371-3.].But, long-term or excessive use acetaminophen, metabolism is the larger Radical Metabolism product N-acetyl of toxicity-p Benzoquinone imines (NAPQI) in vivo, causes hepatic injury, even acute hepatic failure, seriously limits its clinical practice.
The flurbiprofen medicament paracetamol containing carboxyl group is based on the original new drug with independent intellectual property right that drug synergism mechanism and prodrug design concept are designed and developed, have clear and definite drug effect target spot and ADME target spot, thereby produce collaborative anti-inflammatory and antalgic and analgesic 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 the 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 chemical compound is seen Fig. 1.
Yet the water solublity of flurbiprofen medicament paracetamol containing carboxyl group is very poor, and is oral slow through the gastrointestinal tract stripping, and directly the oral absorption of administration is relatively 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 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 is used reality from market, adopt workable solid dispersion technology, solves the flurbiprofen medicament paracetamol containing carboxyl group because the interior low problem of bioavailability of the poorly soluble body that causes.
Summary of the invention
The purpose 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.
The bright preparation method that described flurbiprofen medicament paracetamol containing carboxyl group solid dispersion also is provided of this law, this solid dispersion can adopt any one method preparation in hot-melt extruded method, solvent fusion method, the 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: with flurbiprofen medicament paracetamol containing carboxyl group and carrier material by weight 1:1 ~ 1:20 mix homogeneously, place the hot-melt extruded machine, setting extrusion temperature is 120 ~ 180 ℃, after extrudate solidifies, pulverize, sieve, namely get 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 an amount of carrier material, heating makes its melting in 80 ℃ of water-baths, the flurbiprofen medicament paracetamol containing carboxyl group is dissolved in an amount of organic solvent, and (organic solvent is methanol, ethanol, chloroform, in the dichloromethane one or more) in, slowly drop in the carrier material of molten state, stir, after organic solvent volatilizes, after dislocation-20 a ℃ refrigerator and cooled is frozen 2 ~ 12 hours rapidly, place vacuum drying oven dry, after dry thing is pulverized, namely get solid dispersion.
The preparation method of flurbiprofen medicament paracetamol containing carboxyl group solid dispersion provided by the invention, described solvent process is: get the flurbiprofen medicament paracetamol containing carboxyl group and mix for 1:1 ~ 1:20 by weight with carrier material, (organic solvent is dehydrated alcohol to add organic solvent, methanol, in the dichloromethane one or more) and a small amount of purified water, stirring makes dissolving, 40 ~ 60 ℃ of water-baths, behind the rotary evaporation majority of organic solvent, after dislocation-20 a ℃ refrigerator and cooled is frozen 2 ~ 12 hours rapidly, place vacuum drying oven dry, dry thing namely gets solid dispersion after pulverizing.
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, also can be oral disintegrated preparation, enteric coated preparation, slow/controlled release preparation.
Pharmaceutical preparation provided by the invention, the preparation method of described tablet or capsule are after the solid dispersion process is pulverized, to add suitable adjuvant, carry out direct compression or fill and become 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, the polyvinylpolypyrrolidone.
The invention provides solid dispersion preparation technology, can guarantee rapidly stripping and the absorption in intestinal of the collaborative prodrug flurbiprofen medicament paracetamol containing carboxyl group of slightly solubility, be hydrolyzed to two active drug molecules via liver esterase and enter the body circulation, the collaborative anti-inflammatory and analgesic effect of performance.
The present invention adopts the dissolution in vitro test to investigate the drug-eluting situation, confirm through test, compare with undressed crude drug, flurbiprofen medicament paracetamol containing carboxyl group preparation of the present invention can improve in the medicine water 10 ~ 100 times of dissolubility, the dissolution in vitro of medicine is significantly improved, and 45min accumulation stripping percentage rate improves greatly in the dissolution medium.The result is as follows:
1, dissolution in vitro experimental condition is pressed 2010 editions appendix dissolution methods of Chinese Pharmacopoeia XC three therapeutic methods of traditional Chinese medicine (little agar diffusion method) and is measured.Dissolution medium is the 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.The result shows, crude drug is in 45min, and Cumulated released percent in vitro is about 30%, and solid dispersion preparation reaches 75.3% ~ 102.8% at 45min cumulative in vitro stripping percentage rate, compares with crude drug to be significantly increased.
Description of drawings
Fig. 1 is the chemical structural formula of flurbiprofen medicament paracetamol containing carboxyl group;
Fig. 2 is the solid dispersion In Vitro Dissolution curve of the present invention of different carriers material preparation;
Fig. 3 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
Get flurbiprofen medicament paracetamol containing carboxyl group 5g, be dissolved in the alcoholic solution, PEG4000 20g is heated to 80 ℃ and forms molten state, slowly be added dropwise to flurbiprofen medicament paracetamol containing carboxyl group alcoholic solution in the carrier material, stir, volatilize ethanol, move to rapidly-20 ℃ and solidify 4h.The taking-up gains are pulverized, drying.Namely get the solid dispersion powder.The solid dispersion of this invented technology is in 45min, and the cumulative in vitro dissolution is 93.5 ± 3.1%(n=6).6 samples of parallel assay.
Embodiment 2
Get flurbiprofen medicament paracetamol containing carboxyl group 5g, behind the suitable dissolve with ethanol, PVP-S630 is dissolved in the ethanol, places 60 ℃ of heating, with above-mentioned two kinds of solution mix homogeneously, stirs 2h, volatilizes ethanol, moves to rapidly-20 ℃ and solidifies 8h.The taking-up gains are pulverized, and drying namely gets the solid dispersion powder.The solid dispersion of this invented technology is in 45min, and the cumulative in vitro dissolution is 94.4 ± 3.6%(n=6).6 samples of parallel assay.
Embodiment 3
Get flurbiprofen medicament paracetamol containing carboxyl group 5g, kollidon VA64 20g, mix homogeneously melt extrudes under 160 ℃, and medicine fully mixes in extruder with the mixture of carrier, disperses, and after the curing, crushing screening namely gets solid dispersion.The solid dispersion of this invented technology is in 45min, and the cumulative in vitro dissolution is 88.4 ± 2.8%(n=6).6 samples of parallel assay.
Embodiment 4
Get flurbiprofen medicament paracetamol containing carboxyl group 5g, be dissolved in the alcoholic solution, the 30g PLURONICS F87 is heated to 80 ℃ and forms molten state, slowly be added dropwise to flurbiprofen medicament paracetamol containing carboxyl group alcoholic solution in the carrier material, stir, volatilize ethanol, move to rapidly-20 ℃ and solidify 12h.The taking-up gains are pulverized, drying.Namely get the solid dispersion powder.The solid dispersion of this invented technology is in 45min, and the cumulative in vitro dissolution is 95.5 ± 3.1%(n=6).6 samples of parallel assay.
Embodiment 5
Solid dispersion among the embodiment 1 ~ 4, the 40-60 order that sieves mixes the granule that screens 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 the cumulative in vitro dissolution is 90.4 ± 2.5%(n=6).6 samples of parallel assay.
Embodiment 6
Clathrate among the embodiment 1 ~ 4 or solid dispersion add magnesium stearate and micropowder silica gel (1:1), account for middle recipe quantity 1 ~ 3%, add microcrystalline Cellulose, starch, and lactose accounts for recipe quantity 30%, filled capsules.Embodiment 1-6 In Vitro Dissolution curve is as follows: the capsule of this invented technology is in 45min, and the 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, it 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, the 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, with flurbiprofen medicament paracetamol containing carboxyl group and carrier material by weight 1:1 ~ 1:20, mix homogeneously places the hot-melt extruded machine, and setting extrusion temperature is 50 ~ 180 ℃, after extrudate solidifies, pulverize, sieve, namely get 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 an amount of carrier material, heating and melting in 40 ~ 80 ℃ of water-baths is dissolved in the flurbiprofen medicament paracetamol containing carboxyl group in an amount of organic solvent, slowly drop in the carrier material of molten state, stir, after organic solvent volatilizes, move to rapidly freezing curing and dry in the cryogenic refrigerator, after dry thing is pulverized, namely get solid dispersion.
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, getting the flurbiprofen medicament paracetamol containing carboxyl group mixes for 1:1 ~ 1:20 by weight with carrier material, add organic solvent and a small amount of purified water, 40 ~ 80 ℃ of water-baths, stir, behind the rotary evaporation majority of organic solvent, rapidly in the dislocation cryogenic refrigerator after freezing 1 ~ 48 hour, place vacuum drying oven dry, after dry thing is pulverized, namely get solid dispersion.
6. according to the preparation method of claim 4 or 5 described flurbiprofen medicament paracetamol containing carboxyl group solid dispersion, it is characterized in that: described organic solvent is one or more in methanol, ethanol, chloroform, the dichloromethane.
7. 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 adds suitable adjuvant for after solid dispersion is pulverized, and 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, the polyvinylpolypyrrolidone.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201210375632 CN102871952A (en) | 2012-09-29 | 2012-09-29 | Flurbiprofen acetaminophen ester solid dispersion and preparation method thereof |
| CN201310414840.8A CN103705466B (en) | 2012-09-29 | 2013-09-12 | flurbiprofen acetaminophen ester solid dispersion and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 201210375632 CN102871952A (en) | 2012-09-29 | 2012-09-29 | Flurbiprofen acetaminophen ester solid dispersion and preparation method thereof |
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| CN102871952A true CN102871952A (en) | 2013-01-16 |
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| CN 201210375632 Pending CN102871952A (en) | 2012-09-29 | 2012-09-29 | Flurbiprofen acetaminophen ester solid dispersion and preparation method thereof |
| CN201310414840.8A Expired - Fee Related CN103705466B (en) | 2012-09-29 | 2013-09-12 | flurbiprofen acetaminophen ester solid dispersion and preparation method thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103211799A (en) * | 2013-03-11 | 2013-07-24 | 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 |
| CN110585156A (en) * | 2019-10-24 | 2019-12-20 | 中国人民解放军军事科学院军事医学研究院 | Acetaminophen sustained-release preparation and 3D printing preparation method thereof |
| WO2020000831A1 (en) * | 2018-06-29 | 2020-01-02 | 山东新时代药业有限公司 | Ketorolac tromethamine tablet |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101011374A (en) * | 2006-12-15 | 2007-08-08 | 陈文展 | Non-steroidal analgesic-antipyretic medicament paracetamol containing carboxyl group |
-
2012
- 2012-09-29 CN CN 201210375632 patent/CN102871952A/en active Pending
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2013
- 2013-09-12 CN CN201310414840.8A patent/CN103705466B/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103211799A (en) * | 2013-03-11 | 2013-07-24 | 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 |
| WO2020000831A1 (en) * | 2018-06-29 | 2020-01-02 | 山东新时代药业有限公司 | Ketorolac tromethamine tablet |
| CN110585156A (en) * | 2019-10-24 | 2019-12-20 | 中国人民解放军军事科学院军事医学研究院 | Acetaminophen sustained-release preparation and 3D printing preparation method thereof |
| CN110585156B (en) * | 2019-10-24 | 2021-09-28 | 中国人民解放军军事科学院军事医学研究院 | Acetaminophen sustained-release preparation and 3D printing preparation method thereof |
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| Publication number | Publication date |
|---|---|
| CN103705466A (en) | 2014-04-09 |
| CN103705466B (en) | 2016-01-06 |
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Application publication date: 20130116 |