CN102600108A - Flurbiprofen sustained release capsules and preparation method thereof - Google Patents
Flurbiprofen sustained release capsules and preparation method thereof Download PDFInfo
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- CN102600108A CN102600108A CN2012100209893A CN201210020989A CN102600108A CN 102600108 A CN102600108 A CN 102600108A CN 2012100209893 A CN2012100209893 A CN 2012100209893A CN 201210020989 A CN201210020989 A CN 201210020989A CN 102600108 A CN102600108 A CN 102600108A
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Abstract
The invention discloses flurbiprofen sustained release capsules and a preparation method of the flurbiprofen sustained release capsules. The flurbiprofen sustained release capsules consist of sustained release pellets and hollow capsules; and each sustained release pellet consists of the following raw materials by weight: 75-97% of drug-containing core and 3-25% of a sustained release coating layer. The flurbiprofen sustained release capsules consist of hundreds of sustained release pellets with uniform particle sizes, and errors or defects appearing in the preparation method of some pellets are unlikely to have serious influence on drug release of the whole preparation, so that the flurbiprofen sustained release capsules are safer than that of the sustained release tablets, have little irritation to gastrointestinal tract, have more stable plasma concentration and higher bioavailability and can continuously release drug to relieve inflammation and pain for 24 hours by administration once in a day. The preparation method provided by the invention adopts a extrusion-spheronization method to prepare the drug-containing cores and adopts a fluidized bed to wrap the sustained release coat layers; and the flurbiprofen sustained release capsules have simple process and are easy for industrial production.
Description
Technical field
The present invention relates to the technical field of flurbiprofen slow releasing preparation, relate in particular to a kind of flurbiprofen slow releasing capsule and preparation method thereof.It belongs to a kind of non-steroidal anti-inflammatory analgesics slow releasing preparation.
Background technology
(rheumatoidarthritis is the not clear as yet chronic heterogeneous systemic disease of a kind of cause of disease RA) to rheumatoid arthritis, belongs to autoimmune disease.Maybe be relevant with multiple factors such as infection, heredity and disorders of immune mechanism.Mainly show as symmetric multi-joint chronic nonspecific inflammation on every side; Can be with abarticular systematicness infringement; For example cause multiple pathological changes such as subcutaneous rheumatoid nodules, pericarditis, myocarditis, pulmonary fibrosis, pleuritis, splenomegaly, renal amyloidosis, peripheral neuritis, arteritis; Sometimes also possibly invade eyes, scleritis, iritis take place.The prevalence of RA increases with advancing age and gradually, and the research of most colonies shows that prevalence is the highest among old peoples' (over-65s or more than 70 years old).In elderly population, the prevalence of those schoolings junior RA is the highest, and the women is a little more than the male.China never has nationwide definite data about the arthritic epidemic data of rheumatoid property, has only the epidemic data of some areas.According to relevant report, the prevalence of China's rheumatoid arthritis is approximately 0.32%-0.36%.
The nonsteroidal anti-inflammatory immune substance is a line medication of treatment rheumatoid arthritis disease, and this type medicine has pain relieving and antiphlogistic characteristic, thereby can alleviate arthralgia and swelling, but can not change disease process or stop destruction of joint, therefore can not use separately.This type of medicine gets final product onset in the general a few days, expresses one's gratification again and does medication.Slowly doing medication as yet not during onset, using that NSAIIDs is beneficial to patient's function of joint and quality of life improves as early as possible.
Flurbiprofen (Flurbiprofen) is an aryl propionic non-steroid antiphlogistic, is one of outstanding kind in the non-steroidal anti-inflammatory analgesic, is used to treat rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, wound pain and other pain clinically.This medicine is oral effectively, better tolerance, and life-time service neither promotes also not suppress self metabolism.Thereby flurbiprofen plays the effect of anti-inflammatory analgesic through the activity that suppresses the prostaglandin synthetase epoxidase; In molecular structure, introduced a fluorine atom; The special performance that is caused by fluorine atom acts on it in similar medicine stronger; Therapeutic dose is little, thereby possesses powerful antiinflammatory, pain relieving and the function of bringing down a fever, and side effect is minimized.These article reach the clinical observation in 4 years through 21 treatment 1396 patients of unit of Britain, do not see obvious toxic and side effects.
The about 0.038mg/ml of the dissolubility of flurbiprofen in water is low dissolving high osmosis (ClassII class) medicine, and dissolubility increases under alkali condition.Half-life is about 6 hours, absorbs basically fully after oral, and the influence of unable to take food thing, the blood plasma combination rate is about 90%, and its biopharmaceutics characteristic shows the suitable slow releasing preparation that is developed as.
Controlled release flurbiprofen and muscle relaxant composition of medicine (patent No.: EP2074990, US20090175938; SANOVEL ILAC SANAYIVE TICARET); Describe be once a day, flurbiprofen and the muscle relaxant tizanidine controlled release double-layer tablet and the preparation technology thereof of release in 24 hours; Medicine nand function property adjuvant and slow release material mixing are processed granule, be pressed into double-layer tablet, belong to matrix sustained release tablet; Slow releasing tablet partial breakage and defective when producing can cause the prominent of total formulation to release generation, so safety is relatively poor.
Flurbiprofen slow releasing capsule (trade name: Froben SR) go on the market in European Union's approval in calendar year 2001 by the production of Abbott company; Listing is produced at present domestic existing flurbiprofen slow releasing tablet approval; Temporarily no flurbiprofen slow releasing capsule produces listing and registration is declared, and the flurbiprofen slow releasing capsule that develop once a day, 24 hours discharges has the good clinical application advantage.
Summary of the invention
The objective of the invention is to overcome the shortcoming and defect of prior art, a kind of have persistent, medicining times is few, blood drug level is steady, safety is higher flurbiprofen slow releasing capsule are provided.Based on this, the present invention also provides a kind of method for preparing of flurbiprofen slow releasing capsule.
The diameter that micropill is made up of medicine and adjuvant is about the miniature spherical entity of 1mm; According to different therapeutic doses and requirement; Micropill is that the medicine with dose is dispersed in 1,100 miniature spherical compartments; Error or the defective of indivedual micropills in preparation is unlikely to the drug release behavior of whole preparation is affected greatly, and significantly reduced the prominent generation of releasing of medicine.There is bigger contact surface the oral back of micropill with the gastrointestinal tract surface, and absorption is good and little to partial zest, and simultaneously, micropill is different with tablet, and the former does not receive the gastric emptying factor affecting basically, so the infiltration rate of medicine is even, individual bioavailability difference is also little.Micropill has advantages such as particle diameter is even, good fluidity, difficult crushing; Particularly the fine pellet core surface coatings, to process location, sustained-release preparation, technology simple; Can avoid coatings such as other solid preparations such as tablet inhomogeneous, may cause that the medicine sky is released, the risk of pulse.By the slow releasing capsule that the micropill of different pharmaceutical is formed, can increase advantages such as stability of drug, raising curative effect, reduction poisonous side effect of medicine.
For solving above technical problem, technical scheme of the present invention is:
A kind of slow releasing capsule of flurbiprofen is made up of slow-release micro-pill and Capsules two parts, counts by weight percentage, and said slow-release micro-pill is made up of 75～97% the sustained release coating layer that contains pill core and 3～25%, wherein:
Containing pill core comprises: 40～65% flurbiprofen and 22～56.5% excipient, 3～8% binding agent and 0.5～5% solubilizing agent, more than the percentage by weight of each component all to contain the total weight of pill core;
The sustained release coating layer comprises: 3～25% slow-release material, 15～80% antiplastering aid, 10～30% plasticizer and 3～30% porogen; More than in each component; The percentage by weight of slow-release material to be containing the total weight of pill core, and the percentage by weight of antiplastering aid, plasticizer and porogen is all with the total weight of slow-release material.
Preferably, said excipient is one or more the mixture in lactose, microcrystalline Cellulose, mannitol, starch, dextrin, the sucrose.
Preferably, said binding agent is one or more the mixture in polyvinylpyrrolidone, hydroxypropyl emthylcellulose, the carboxymethyl cellulose.
Preferably, said solubilizing agent is one or more the mixture in sodium lauryl sulphate, tween, the Polyethylene Glycol.
Said slow-release material is methacrylic resin polymer or ethyl cellulose; Preferably; The methacrylic resin polymer is one or more the mixture among Eudragit NE30D, Eudragit RS30D, Eudragit RL30D, Eudragit RS, the Eudragit RL, and ethyl cellulose is Surelease or Aquacoat.
Preferably, said antiplastering aid is one or more the mixture in Pulvis Talci, magnesium stearate, silicon dioxide, the titanium dioxide.
Preferably, said plasticizer is one or more the mixture in diethyl phthalate, dibutyl phthalate, triethyl citrate, ATBC, dibutyl sebacate, the glycerol.
Preferably, said porogen is one or more the mixture in lactose, polyvinylpyrrolidone, polyethylene glycols, the hydroxypropyl emthylcellulose.
The release in vitro degree of the flurbiprofen slow releasing capsule that above-mentioned optimizing prescriptions makes is: 2 hours 10～25%, and 4 hours 20～45%, 8 hours 40～70%, 12 hours 60～90%, 24 hours＞85%.
Preferably, described flurbiprofen slow releasing capsule adopts extrudes the spheronization preparation, comprises the steps:
(1) contain the preparation of pill core: with flurbiprofen and excipient mix homogeneously, mixing purified water (or ethanol) solution that adds solubilizing agent and binding agent is processed soft material, and employing is extruded spheronization and processed 20～40 purposes and contain pill core, drying.
(2) bag slow release layer: will contain pill core and place fluid bed, bag sustained release coating liquid makes slow-release micro-pill.
(3) ripening: slow-release micro-pill was placed 35 ℃～55 ℃ baking oven matured 8～24 hours.
(4) process capsule: the slow-release micro-pill after the ripening is filled in the Capsules.
Device parameter in the coating process, intake 20～30HZ, EAT are 35～55 ℃, and temperature of charge is 25～45 ℃, and atomizing pressure is 1.0bar, and hydrojet speed is 2～4g/min.
Thermostatic drying chamber is adopted in ripening, and temperature is controlled at 30 ℃～50 ℃, and the curing time is 8～24 hours.
The flurbiprofen slow releasing capsule that the present invention makes is made up of 1,100 uniform slow-release micro-pill of particle diameter; Error or the defective of indivedual micropills in preparation is unlikely drug release behavior to total formulation and produces and have a strong impact on; Therefore more safer than slow releasing tablet, littler to the gastrointestinal zest, blood drug level is more steady; Bioavailability is higher, and taking 1 time in one day can lasting release in 24 hours.
Method for preparing employing of the present invention is extruded round as a ball method preparation and is contained pill core, and particle diameter is 20～40 orders, adopts fluid bed bag sustained-release coating layer, and technology is simple, is easy to industrialized great production.
Description of drawings
Fig. 1～Fig. 3: the flurbiprofen slow releasing capsule that makes for the embodiment of the invention one～embodiment three releasing curve diagram of 2,4,8,12,24 hours in external multiple release medium.
The specific embodiment
In order to make those skilled in the art understand technical scheme of the present invention better, the present invention is done further detailed description below in conjunction with specific embodiment.
Embodiment one:
1, contain the preparation of pill core:
Preparation technology: with the method mix homogeneously that flurbiprofen and microcrystalline Cellulose adopt equivalent to increase progressively, sodium lauryl sulphate is added to that dissolving is mixed with the sodium lauryl sulphate alcoholic solution in 35% alcoholic solution, and above-mentioned mixed powder is processed soft material; Round as a ball machine-processed micropill is extruded in employing; The sieve plate particle diameter is 0.8mm, and 60 ℃ of oven dryings sieve; Choose 20～40 orders and contain pill core, carry out coating.
2, bag slow release layer:
The Sulisi of recipe quantity is joined in the purified water, it is fully disperseed, stir 45min, will contain pill core and place fluid bed, adjust each technological parameter, guarantee fluidized state, coating increases weight to 12%.
The technological parameter of fluid bed: intake: 20～30HZ, EAT: 45～55 ℃, temperature of charge: 40～45 ℃, atomizing pressure: 1.0bar, hydrojet speed: 2～4g/min.
3, ripening: 50 ℃ of baking oven matured 12 hours.
4, make capsule: capsule is filled, and promptly gets.
To make sample; Adopt pH1.2 hydrochloric acid solution, pH4.5 phosphate buffer, pH6.8 phosphate buffer, pH7.2 phosphate buffer and water as release medium respectively; With changeing the basket method, with 100 rev/mins, respectively sampling in 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours; Measure trap, calculating cumulative release degree with the UV method in the 246nm wavelength.The result is following:
Embodiment two:
1, contain the preparation of pill core:
Preparation technology: with the method mix homogeneously that flurbiprofen and lactose, microcrystalline Cellulose adopt equivalent to increase progressively, tween is added in 35% alcoholic solution, and above-mentioned mixed powder is processed soft material; Round as a ball machine-processed micropill is extruded in employing; The sieve plate particle diameter is 0.8mm, and 60 ℃ of oven dryings sieve; Choose 20～40 orders and contain pill core, carry out coating.
2, bag slow release layer:
With the Pulvis Talci of recipe quantity, join and stir 45min in the purified water, add the strange NE30D aqueous dispersion of You Te it is fully disperseed, continue to stir 45min, subsequent use.To contain pill core and place fluid bed, and regulate each technological parameter, and guarantee fluidized state, coating increases weight to 4%.
The technological parameter of fluid bed: intake: 20～30HZ, EAT: 35～45 ℃, temperature of charge: 30～35 ℃, atomizing pressure: 1.0bar, hydrojet speed: 2～4g/min.
3, ripening: 40 ℃ of baking oven matured 24 hours.
4, make capsule: capsule is filled, and promptly gets.
To make sample; Adopt pH1.2 hydrochloric acid solution, pH4.5 phosphate buffer, pH6.8 phosphate buffer, pH7.2 phosphate buffer and water as release medium respectively; With changeing the basket method, with 100 rev/mins, respectively sampling in 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours; Measure trap, calculating cumulative release degree with the UV method in the 246nm wavelength.The result is following:
Embodiment three:
1, contain the preparation of pill core:
Preparation technology: with the method mix homogeneously that flurbiprofen and microcrystalline Cellulose, mannitol adopt equivalent to increase progressively, PVP-K30 and tween are added in 35% alcoholic solution, and above-mentioned mixed powder is processed soft material; Round as a ball machine-processed micropill is extruded in employing; The sieve plate particle diameter is 0.8mm, and 60 ℃ of oven dryings sieve; Choose 20～40 orders and contain pill core, carry out coating.
2, bag slow release layer:
The Pulvis Talci of recipe quantity joined stir 45min in the purified water, add triethyl citrate, the strange RS30D of You Te and RL30D aqueous dispersion it is fully disperseed, continue to stir 45min, subsequent use.To contain pill core and place fluid bed, and regulate each technological parameter, and guarantee fluidized state, coating increases weight to 8%.
The technological parameter of fluid bed: intake: 20～30HZ, EAT: 35～45 ℃, temperature of charge: 30～35 ℃, atomizing pressure: 1.0bar, hydrojet speed: 2～4g/min.
3, ripening: 40 ℃ of baking oven matured 24 hours.
4, make capsule: capsule is filled, and promptly gets.
To make sample; Adopt pH1.2 hydrochloric acid solution, pH4.5 phosphate buffer, pH6.8 phosphate buffer, pH7.2 phosphate buffer and water as release medium respectively; With changeing the basket method, with 100 rev/mins, respectively sampling in 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours; Measure trap, calculating cumulative release degree with the UV method in the 246nm wavelength.The result is following:
Compliance test result
External release test:
Get slow releasing capsule that embodiment one, two, three makes as sample; Pressing the UV method detects; Adopt pH1.2 hydrochloric acid solution, pH4.5 phosphate buffer, pH6.8 phosphate buffer, pH7.2 phosphate buffer and water as release medium, carried out the release in vitro degree respectively at 2,4,8,12,24 hours and measure, detect among data and Fig. 1～Fig. 3 and can find out by the release degree; 3 lot sample article discharge in 24 hours evenly in multiple release medium; All meet one-level release dynamic process, be illustrated in the external slow release characteristic that has, the further research of release in the body.
More than the present invention has been carried out detailed introduction, use concrete example in the literary composition principle of the present invention and embodiment set forth, the explanation of above embodiment just is used for helping to understand method of the present invention and core concept thereof.Should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention, can also carry out some improvement and modification to the present invention, these improvement and modification also fall in the protection domain of claim of the present invention.
Claims (4)
1. the slow releasing capsule of a flurbiprofen; It is characterized in that; Form by slow-release micro-pill and Capsules two parts; Count by weight percentage, said slow-release micro-pill by 75～97% contain pill core, 3～25% sustained release coating layer is formed, wherein; Contain pill core and comprise flurbiprofen 40～65%, excipient 22～56.5%, binding agent 3～8% and solubilizing agent 0.5～5%, the sustained release coating layer comprises slow-release material 3～25%, antiplastering aid 15～80%, plasticizer 10～30% and porogen 3～30%.
More than in each component, the percentage by weight of excipient, binding agent, solubilizing agent and slow-release material to be containing the total weight of pill core, the percentage by weight of antiplastering aid, plasticizer and porogen is all with the total weight of slow-release material.
2. flurbiprofen slow releasing capsule according to claim 1 is characterized in that,
Said excipient is one or more the mixture in lactose, microcrystalline Cellulose, mannitol, starch, dextrin, the sucrose.
Said binding agent is one or more the mixture in polyvinylpyrrolidone, hydroxypropyl emthylcellulose, the carboxymethyl cellulose.
Said solubilizing agent is one or more the mixture in sodium lauryl sulphate, tween, the Polyethylene Glycol.
Said slow-release material is one or more a mixture of methacrylic resin polymer or ethyl cellulose.
Said antiplastering aid is one or more the mixture in Pulvis Talci, magnesium stearate, silicon dioxide, the titanium dioxide.
Said plasticizer is one or more the mixture in diethyl phthalate, dibutyl phthalate, triethyl citrate, ATBC, dibutyl sebacate, the glycerol.
Said porogen is one or more the mixture in lactose, polyvinylpyrrolidone, polyethylene glycols, the hydroxypropyl emthylcellulose.
3. flurbiprofen slow releasing capsule according to claim 1 is characterized in that, the release in vitro degree is: 2 hours 10～25%, and 4 hours 20～45%, 8 hours 40～70%, 12 hours 60～90%, 24 hours＞85%.
4. the method for preparing of flurbiprofen slow releasing capsule according to claim 1 comprises the steps:
(1) contain the preparation of pill core: with flurbiprofen and excipient mix homogeneously, mixing purified water (or ethanol) solution that adds solubilizing agent and binding agent is processed soft material, and employing is extruded spheronization and processed 20～40 purposes and contain pill core, drying.
(2) bag slow release layer: will contain pill core and place fluid bed, bag sustained release coating liquid makes slow-release micro-pill.
(3) ripening: slow-release micro-pill was placed 35 ℃～55 ℃ baking oven matured 8～24 hours.
(4) process capsule: the slow-release micro-pill after the ripening is filled in the Capsules.
Device parameter in the coating process, intake 20～30HZ, EAT are 35～55 ℃, and temperature of charge is 25～45 ℃, and atomizing pressure is 1.0bar, and hydrojet speed is 2～4g/min.
Thermostatic drying chamber is adopted in ripening, and temperature is controlled at 30 ℃～50 ℃, and the curing time is 8～24 hours.
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| CN2012100209893A CN102600108A (en) | 2012-01-17 | 2012-01-17 | Flurbiprofen sustained release capsules and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113350304A (en) * | 2021-07-15 | 2021-09-07 | 上海博悦生物科技有限公司 | Non-steroidal anti-inflammatory sustained release preparation and preparation method thereof |
| CN114432257A (en) * | 2022-01-24 | 2022-05-06 | 南京一诺医药科技有限公司 | Difluofen sustained-release tablet and preparation method thereof |
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Patent Citations (4)
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| CN1628648A (en) * | 2004-08-26 | 2005-06-22 | 复旦大学 | Loxoprofen sodium sustained release preparation |
| CN101453993A (en) * | 2006-04-03 | 2009-06-10 | 伊萨·奥迪迪 | Controlled release delivery device comprising an organosol coat |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113350304A (en) * | 2021-07-15 | 2021-09-07 | 上海博悦生物科技有限公司 | Non-steroidal anti-inflammatory sustained release preparation and preparation method thereof |
| CN114432257A (en) * | 2022-01-24 | 2022-05-06 | 南京一诺医药科技有限公司 | Difluofen sustained-release tablet and preparation method thereof |
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