CN104739773B - A kind of Dexibuprofen sustained-release pellet and preparation method thereof - Google Patents
A kind of Dexibuprofen sustained-release pellet and preparation method thereof Download PDFInfo
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- CN104739773B CN104739773B CN201310727476.0A CN201310727476A CN104739773B CN 104739773 B CN104739773 B CN 104739773B CN 201310727476 A CN201310727476 A CN 201310727476A CN 104739773 B CN104739773 B CN 104739773B
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Abstract
The invention discloses a kind of Dexibuprofen sustained-release pellets and preparation method thereof, belong to field of pharmaceutical preparations.Its composition of the Dexibuprofen sustained-release pellet includes: wherein (S)-ibuprofen 50-80%, and slow-release material 0-5%, adhesive 0-2.5%, filler 8.75-47.5%, disintegrating agent 1.25-6.25%, the percentage is on the basis of pellet gross weight.Dexibuprofen sustained-release pellet stability of the present invention is good, quality is stablized, equipment, simple process, and strong operability is suitble to industrialized production.In Vitro Dissolution has good release profiles experiments have shown that 1 hour cumulative release, 10~35%, 2 hours cumulative releases, 25~55%, 4 hours cumulative releases, 50~80%, 7 hours 75% or more cumulative releases.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of Dexibuprofen sustained-release pellet and preparation method thereof.
Background technique
Brufen is a kind of non-steroid anti-inflammatory drug, clinically for rheumatism atrophic arthritis and the length of osteoarthritis
Phase treatment, while being also used to treat fever, various moderate pains and inflammation, it is curative for effect.Brufen by equivalent dextrorotation cloth Lip river
Fragrant and left-handed brufen composition plays treatment studies have shown that (S)-ibuprofen enantiomer is active constituent in racemic ibuprofen
Effect, and left-handed brufen enantiomer is non-active ingredient, and is related to potential toxic effect.
The (S)-ibuprofen dosage form of domestic listing mainly has conventional tablet, capsule, suppository and oral administration mixed suspension etc. at present, by
In (S)-ibuprofen half-life short, frequent multiple dosing is needed, is made troubles to patient, developed Dexibuprofen sustained-release preparation, subtract
Few medicining times, reducing the fluctuation of blood concentration peak valley has far reaching significance.
(S)-ibuprofen fusing point is lower than raceme brufen (fusing point is 75 DEG C), is 49-53 DEG C, to its sustained-release preparation
It develops and industrialized production brings larger difficulty.Chinese patent CN102293759A discloses a kind of Dexibuprofen sustained-release
Tablet preparation and preparation method thereof, when sustained-release tablet mass production, easily lead to drug and melt and generate sticking phenomenon, lead to tablet surface
Spottiness, related substance increase, it is seen that tablet is not the ideal dosage form of Dexibuprofen sustained-release preparation；Chinese patent
CN101269041A discloses a kind of Dexibuprofen sustained-release dropping pill and preparation method thereof, in dripping pill preparation process, drug warp
High temperature melt easily leads to related substance and increases, and Chinese patent CN102228441A and CN102526000A individually disclose a kind of right side
The preparation method of ibuprofen slow-release pellet is revolved, wherein dissolving or being suspended in appropriate solvent for drug based on blank capsule core
In, medicine is carried to blank capsule core by hydrojet mode, the release of drug is all made of the control of coating membrane prosecutor formula, and preparation process is multiple
Miscellaneous, coating membrane Drug controlled release is by compared with multifactor impact (coating weight gain, clothing film integrality, pore-foaming agent dosage etc.), industrialization
It is easy to produce release difference between batch when production, even generates burst drug release phenomenon, brings larger difficulty to industrialized production.
Summary of the invention
It is an object of that present invention to provide a kind of Dexibuprofen sustained-release pellets.The sustained release pellet is compared with ordinary preparation, medicine
Slowly, medicining times are reduced for object release, and poisonous side effect of medicine reduces, and improves patient's compliance.
Inventor passes through selection supplementary product kind and its use according to characteristics such as the diffusions, dissolution and osmotic pressure of (S)-ibuprofen
Amount, and suitable preparation method control the rate of release of (S)-ibuprofen to design and improve.
Specifically, the present invention provides a kind of Dexibuprofen sustained-release pellet, the pellet by following mass percent it is each at
It is grouped as: the (S)-ibuprofen of 50-80%, the slow-release material of 0-5%, the adhesive of 0-2.5%, the filler of 8.75-47.5%,
The disintegrating agent of 1.25-6.25%；Preferably (S)-ibuprofen is 60-70%, and slow-release material 1.5-3%, adhesive 1-2% are filled out
Filling agent is 17-32%, disintegrating agent 1.5-5.5%；
Wherein, the slow-release material is selected from stearic acid, glycerin monostearate, acrylic resin, ethyl cellulose, hydroxypropyl
The mixture of one or more of ylmethyl cellulose；Preferably stearic acid.
Adhesive is selected from the mixing of one or more of povidone, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose
Object.
Filler is selected from the mixture of one or more of microcrystalline cellulose, starch, sucrose, lactose, polyethylene glycol；Its
In preferably microcrystalline cellulose, sucrose or both mixture.
Disintegrating agent is selected from cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, interlinkage carboxylic first
The mixture of one or more of base sodium cellulosate.
It is demonstrated experimentally that the proportion of the selection of auxiliary material, auxiliary material and drug, can all influence release and the pharmaceutical preparation of drug
The stability in long-term storage.The technical scheme is that having filtered out above-mentioned auxiliary material kind on the basis of undergoing a large number of experiments
Class and its dosage meet the slow-release function of (S)-ibuprofen, while can guarantee the steady in a long-term of Dexibuprofen sustained-release pellet
Property compared with traditional sustained release preparation prescription, of the invention one is unique in that the selection of disintegrating agent type and dosage, hair
Bright people has found in the course of the research: can improve the drug release later period by preferred suitable disintegrating agent type and dosage and release the drug
Slow disadvantage can guarantee that drug is discharged by scheduled rate of releasing drug and guarantees that final drug release is complete in conjunction with suitable slow-release material
Entirely.
Traditional pellet molding is mainly realized by the selection preferable auxiliary material of balling-up, and drug content of the present invention is higher,
The dosage of auxiliary material is less, and (S)-ibuprofen pelletization itself is poor, so pellet molding is Dexibuprofen sustained-release pellet system
One of standby difficult point, the present invention increase main cohesive force by the suitable adhesive of dextrorotation, pellet are promoted to form.
It is another object of the present invention to provide the preparation method of above-mentioned Dexibuprofen sustained-release pellet, the preparation methods
Include the following steps:
1) (S)-ibuprofen, slow-release material, adhesive, filler, disintegrating agent are uniformly mixed, softwood is made, then will
Wet granular is made in softwood；
2) step 1 gained wet granular is round as a ball in rolling circle equipment, obtain (S)-ibuprofen pellet；
3) gained (S)-ibuprofen pellet in step 2 is dry in 50 DEG C or less, then sieve takes partial size small less than 14 purposes
Ball is to get finished product Dexibuprofen sustained-release pellet.
Wherein, wet granular preparation method is preferably but not limited to sieving granulation or stirring granulation in step 1)；Further preferably
For sieving granulation, cross 30-60 mesh, further preferably 30-40 mesh；
Rolling circle equipment described in step 2 can for centrifugal granulating spheronizator, coating pan is round as a ball and high-speed stirred shearing equipment,
Preferably centrifugal granulating spheronizator.
The dry drying temperature of (S)-ibuprofen pellet is preferably 25-40 DEG C in step 3).It is preferred that piller partial size is 14-40
Mesh.
The preparation of wet granular described in step 1 belong in the industry known to preparation method, can by high-shearing granulation, waved
Sieve granulation, fluidized-bed spray granulation are completed.It is described that pellet is prepared using wet granular spheronization compared with extrusion-spheronization pelletizing technique
Material be can avoid through squeezing the generation for generating high temperature and main ingredient being made to melt phenomenon.Wet granular spheronization is used for low melting point substance pellet
Preparation be one of another innovative point of the invention.
Gained Dexibuprofen sustained-release pellet of the invention can encapsulated preparation Dexibuprofen slow-release capsule, can also lead to
The mode for crossing compaction of pellet prepares Dex-ibuprofen sustained release tablets agent.
Compared with prior art, technical solution of the present invention has the following beneficial effects:
1) Dexibuprofen sustained-release pellet of technical solution of the present invention realizes drug and obtains slow release, patient's medicining times
It reduces, improves patient's compliance.
2) sustained release preparation technique of the present invention, which avoids in medicine production process, melts, and ensure that drug quality.
3) technical solution of the present invention simple process is easily-controllable, low in cost, technique favorable reproducibility, is suitble to technology mass production.
4) there are also an excellent characteristics for technical solution of the present invention, that is, Dexibuprofen sustained-release pellet provided by the invention
Long-time stability are good, and total related content of material is low, and laevoisomer is not detected.
Specific embodiment
The present invention will be further described in detail below with reference to the embodiments, but the scope of the present invention is non-is only limitted to these realities
The range of example is applied, undeclared place is the prior art.
The release research method of Dexibuprofen sustained-release pellet obtained by technical solution of the present invention is as follows:
This product is taken, according to dissolution method (two the first methods of annex XC of Chinese Pharmacopoeia version in 2010), with phosphate-buffered
Liquid [ takes potassium dihydrogen phosphate 68.05g, adding sodium hydroxide liquid (1mol/L) 56ml to be diluted with water to 1000ml, shake up, surveys pH value and answer
It is 6.0 ± 0.05 ] 900ml is solvent, revolving speed is 30 turns per minute, it operates according to methods, through 1,2,4 and 7 hour, respectively takes solution 5ml,
And the phosphate buffer of mutually synthermal same volume is supplemented simultaneously, it filters, precision measures 20 μ l of subsequent filtrate, injects liquid chromatogram
Instrument records chromatogram；Another precision weighs (S)-ibuprofen reference substance 15mg, sets in 50ml measuring bottle, methanol 2ml is added to make to dissolve, with releasing
Medium is put to scale, shakes up and is measured in the same method.Dexibuprofen sustained-release pellet is calculated separately out in the amount of dissolution of different time.
This product every 1,2,4 with 7 hours when the amount of dissolution mutually should be 10~35%, 25~55%, the 50~80% of labelled amount respectively
With 75% or more, regulation should all be met.
Liquid phase chromatogram condition used in above-mentioned detection are as follows:
Using octadecylsilane chemically bonded silica as filler, with acetonitrile -0.02mol/L potassium dihydrogen phosphate (pH3.0,
It 47:53) is mobile phase；Detection wavelength 264nm；Column temperature: 25 DEG C；Flow velocity: 1.0ml/min.
Assay: chromatographic condition is using octadecylsilane chemically bonded silica as filler；Mobile phase is acetonitrile -0.02mol/
L potassium dihydrogen phosphate (pH3.0,47:53)；Detection wavelength 264nm；Column temperature is 25 DEG C；Flow velocity 1.0ml/min；Sample volume:
20ul is measured according to high performance liquid chromatography (two annex VD of Chinese Pharmacopoeia version in 2010), and this product should be mark containing (S)-ibuprofen
The 90~110% of the amount of showing.
Related substance-measuring: by chromatographic condition under content determination item, according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010
Two annex VD) it measures, this product impurity is not greater than 1.0%
Laevoisomer: chromatographic condition chiral chromatographic column (CHIRALCEL OD-H, 250mm × 4.6mm, 5um), with just oneself
Alkane-ethyl alcohol-trifluoroacetic acid (39:1:0.1) is mobile phase, Detection wavelength 264nm, flow velocity 0.8ml/min.According to high performance liquid chromatography
Method (two annex VD of Chinese Pharmacopoeia version in 2010) measurement, this product laevoisomer are not greater than 0.5%
Embodiment 1
By following proportion, Dexibuprofen sustained-release pellet is prepared:
(S)-ibuprofen and auxiliary materials and mixing are weighed by recipe quantity, adds 10% ethanol water 80ml softwood, softwood sieving system
Wet granular, wet granular is round as a ball in centrifugal granulating spheronizator to obtain (S)-ibuprofen pellet, and (S)-ibuprofen pellet is in 40 DEG C of conditions
Under be drying to obtain Dexibuprofen sustained-release pellet.
Embodiment 2
By following proportion, Dexibuprofen sustained-release pellet is prepared:
(S)-ibuprofen and auxiliary materials and mixing are weighed by recipe quantity, adds purified water 100ml softwood, softwood sieving makes wet
Grain, wet granular are round as a ball that (S)-ibuprofen pellet, (S)-ibuprofen pellet are drying to obtain the right side under the conditions of 35 DEG C in coating pan
Revolve ibuprofen slow-release pellet.
Embodiment 3
By following proportion, Dexibuprofen sustained-release pellet is prepared:
(S)-ibuprofen and auxiliary materials and mixing are weighed by recipe quantity, adds purified water 110ml softwood, softwood sieving makes wet
Grain, wet granular are round as a ball that (S)-ibuprofen pellet, (S)-ibuprofen pellet are done under the conditions of 30 DEG C in centrifugal granulating spheronizator
Dry Dexibuprofen sustained-release pellet to obtain the final product.
Embodiment 4
By following proportion, Dexibuprofen sustained-release pellet is prepared:
(S)-ibuprofen and auxiliary materials and mixing are weighed by recipe quantity, adds purified water 80ml softwood, softwood is sieved wet granular processed,
Wet granular is round as a ball that (S)-ibuprofen pellet, the drying under the conditions of 40 DEG C of (S)-ibuprofen pellet are in centrifugal granulating spheronizator
Obtain Dexibuprofen sustained-release pellet.
Embodiment 5
By following proportion, Dexibuprofen sustained-release pellet is prepared:
(S)-ibuprofen and auxiliary materials and mixing are weighed by recipe quantity, adds purified water 65ml softwood, softwood is sieved wet granular processed,
Wet granular stirs round as a ball that (S)-ibuprofen pellet, (S)-ibuprofen pellet are done under the conditions of 40 DEG C in high shear homomixer
Dry Dexibuprofen sustained-release pellet to obtain the final product.
Verify embodiment
Quality testing is carried out to Dexibuprofen sustained-release pellet obtained by Examples 1 to 5, while carrying out 25 DEG C of temperature, relatively
60% ± 10% long term test of humidity and 40 DEG C of temperature, the accelerated test of relative humidity 75% ± 5% each 6 months, detect each quality
The variation of index, according to Dexibuprofen sustained-release dropping pill obtained by first group of experiment in specific embodiment in CN101269041A
For control group.The data obtained is as follows:
1.0 days sample detection results of table
By " 0 day sample detection result " it is found that the related substance of Dexibuprofen sustained-release pellet of the invention is lower, release
Steadily.
2.25 DEG C of table, 60% ± 10% long term test of relative humidity, 6 months sample detection results
3.40 DEG C of table, 75% ± 5% accelerated test of relative humidity, 6 months sample detection results
There is each embodiment sample quality research result as it can be seen that each index meets regulation, through long-term and accelerated test 6
Month, the related substance of sample, content, laevoisomer and release variation are unobvious, illustrate that sample quality is stable, reliable.
Claims (8)
1. a kind of Dexibuprofen sustained-release pellet, it is characterised in that: the pellet is by each at being grouped as of following mass percent:
The (S)-ibuprofen of 50-80%, the slow-release material of 0-5%, the adhesive of 0-2.5%, the filler of 8.75-47.5%, 1.25-
6.25% disintegrating agent；
Wherein, the slow-release material is selected from stearic acid；
Adhesive is selected from the mixture of one or more of povidone, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose；
Filler is selected from microcrystalline cellulose and sucrose；
Disintegrating agent is selected from crosslinked polyvinylpyrrolidone.
2. a kind of Dexibuprofen sustained-release pellet as described in claim 1, it is characterised in that: the pellet is by following quality percentage
Ratio it is each at being grouped as: (S)-ibuprofen 60-70%, slow-release material 1.5-3%, adhesive 1-2%, filler 17-
32%, disintegrating agent 1.5-5.5%.
3. the preparation method of Dexibuprofen sustained-release pellet described in -2 any claims according to claim 1, which is characterized in that
It comprises the steps of:
1) (S)-ibuprofen, slow-release material, adhesive, filler, disintegrating agent are uniformly mixed, softwood is made, then by softwood
Wet granular is made；
2) wet granular obtained by step 1) is round as a ball in rolling circle equipment, obtain (S)-ibuprofen pellet；
3) gained (S)-ibuprofen pellet in step 2 is dry in 50 DEG C or less, then sieve takes partial size less than 14 mesh pillers, i.e.,
Obtain finished product Dexibuprofen sustained-release pellet.
4. the preparation method of Dexibuprofen sustained-release pellet according to claim 3, which is characterized in that softwood in step 1)
For sieving granulation or stirring granulation.
5. the preparation method of Dexibuprofen sustained-release pellet according to claim 4, which is characterized in that softwood in step 1)
For sieving granulation, 30-60 mesh is crossed.
6. the preparation method of Dexibuprofen sustained-release pellet according to claim 5, which is characterized in that softwood in step 1)
For sieving granulation, 30-40 mesh is crossed.
7. the preparation method of Dexibuprofen sustained-release pellet according to claim 3, which is characterized in that dextrorotation in step 3)
The dry drying temperature of brufen pellet is 25-40 DEG C.
8. the preparation method of Dexibuprofen sustained-release pellet according to claim 3, which is characterized in that piller in step 3)
Partial size be 14-30 mesh.
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| CN105935445B (en) * | 2016-03-28 | 2019-02-01 | 赤峰赛林泰药业有限公司 | Pharmaceutical composition and preparation method thereof containing 2- (- 4- isobutyl phenenyl) propionic acid dextrogyre |
| CN106511280B (en) * | 2016-12-20 | 2019-03-29 | 南京康川济医药科技有限公司 | A kind of ibuprofen slow-release dry suspensoid agent and preparation method thereof |
| CN106727393A (en) * | 2016-12-26 | 2017-05-31 | 浙江工业大学 | A kind of sustained release preparations of ibuprofen containing grid internal structure and preparation method thereof |
| CN111135146A (en) * | 2018-11-05 | 2020-05-12 | 珠海润都制药股份有限公司 | Ibuprofen sustained-release pellet and preparation method thereof |
| CN110123769B (en) * | 2019-05-24 | 2021-02-19 | 北京悦康科创医药科技股份有限公司 | Ibuprofen sustained-release pellet and preparation method thereof |
| CN110755396B (en) * | 2019-12-06 | 2022-04-08 | 北京悦康科创医药科技股份有限公司 | Ibuprofen sustained-release pellet and preparation method thereof |
| CN110859809A (en) * | 2019-12-17 | 2020-03-06 | 卓和药业集团有限公司 | Pharmaceutical composition and preparation method thereof |
| CN113546049B (en) * | 2021-04-30 | 2023-03-17 | 贵州汉方药业有限公司 | Flexible pill medicine adhesive and flexible pill prepared by using same |
| CN113181127A (en) * | 2021-05-07 | 2021-07-30 | 苏州康恒研新药物技术有限公司 | Preparation method of dapoxetine hydrochloride pellet tablets |
| CN115702883A (en) * | 2021-08-05 | 2023-02-17 | 上海博志研新药物技术有限公司 | Ibuprofen pharmaceutical composition, preparation method and application thereof |
| CN115120575B (en) * | 2022-07-01 | 2023-05-30 | 云鹏医药集团有限公司 | Preparation method of ibuprofen sustained-release capsule |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1330920A (en) * | 2000-06-28 | 2002-01-16 | 哈尔滨中药三厂 | Process for preparing granular ibuprofen |
| CN102961339A (en) * | 2012-12-11 | 2013-03-13 | 山西云鹏制药有限公司 | Preparation method of sustained release preparation containing ibuprofen mini-pills |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1330920A (en) * | 2000-06-28 | 2002-01-16 | 哈尔滨中药三厂 | Process for preparing granular ibuprofen |
| CN102961339A (en) * | 2012-12-11 | 2013-03-13 | 山西云鹏制药有限公司 | Preparation method of sustained release preparation containing ibuprofen mini-pills |
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