CN105250233B - (S)-ibuprofen enteric-coated sustained-release tablet and preparation method thereof - Google Patents
(S)-ibuprofen enteric-coated sustained-release tablet and preparation method thereof Download PDFInfo
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Abstract
Include the label with slow release effect and package label coating the present invention relates to a kind of (S)-ibuprofen enteric-coated sustained-release tablet；The label includes 70~90 parts of (S)-ibuprofens, 10~30 parts of sustained-release matrix agent, 0~10 part of filler, 0.2~1.5 part of lubricant and 0.2~1.5 portion of glidant；Wherein a effective amount of active constituent (S)-ibuprofen accounts for 70% or more of label weight.Prescription of the present invention is excellent, and reliable preparation process is easy to industrialized production；The experiment of gained enteric-coated sustained-release tablet In Vitro Dissolution shows：2 hours releases of gastric juice are less than 10%, meet the requirements；It is 50~80%, 8 hours Accumulation dissolutions up to 80% or more that 2 hours releases of intestinal juice, which are 25~55%, 4 hours Accumulation dissolutions, has good slow release effect.Present invention enteral slow release effect with insoluble in stomach, had both prevented the irritation to stomach, while extending the release time of drug in vivo, and had been conducive to absorption of human body, persistent.
Description
Technical field
The invention belongs to medicine preparation fields, and in particular to a kind of (S)-ibuprofen enteric-coated sustained-release tablet and preparation method thereof.
Background technology
Active constituent：(S)-ibuprofen
Chemical name：（2S）- 2- [4- (2- methyl-propyls) phenyl] propionic acid
English name：Dexibuprofen
English language Chemical title：S(+)-2(4-isobutylphenyl)propionic acid
Molecular formula：C13H18O2
Molecular weight：206.28
Structural formula：
Brufen as the non-steroidal anti-inflammatory drugs clinically used for many years, filled by safety and validity
The confirmation divided generates antipyretic, analgesia and anti-inflammatory effect by inhibiting prostaglandin synthesis, is mainly used for rheumatism and rheumatoid
Arthritis, it can also be used to which general antipyretic-antalgic is the first ladder drug of pain ladder medication.
(S)-ibuprofen is the S isomers of brufen, compared with brufen, is taken thirdly two dosage divided can obtain
Identical curative effect is obtained, and less side effects, in terms of efficacy and saferry advantageously；Clinically it is mainly used at present（1）It is slow
Solve the various chornic arthritis such as rheumatoid arthritis, osteoarthritis, spinal arthropathy, urarthritis, rheumatic arthritis
Acute attack stage or duration painful swelling of joints symptom, no etiological treatment and control the course of disease effect；（2）It treats non-arthrosis
Various soft tissue rheumatic pains, such as shoulder pain, key vaginitis, bursal synovitis, myalgia and movement after injury pain；（3）It is acute
Light, moderate pain such as；After operation, after wound, after old damage, primary dysmenorrhea, toothache, headache etc.；（4）To adult and children
Fever have refrigeration function.
The dosage form of (S)-ibuprofen domestic listing at present has conventional tablet, capsule and suspension oral preparation and rectum bolt
Agent etc., the daily multiple dosing of common oral preparation, patient adaptability is poor, and blood concentration is unstable, peak valley phenomenon occurs, high
The dense paddy summit of medicine generates corresponding toxic side effect；Suppositories for rectal is inconvenient to use, is chiefly used in pediatric patient.
There is the sustained release preparation research report of (S)-ibuprofen in the country at present, does not go public.Chinese patent CN102160855B
Dex-ibuprofen sustained release tablets and preparation method are all referred to CN102293759A, CN102160855B sustained release tablets are prepared using by speed
Release part and slow-released part and magnesium stearate composition；CN102293759A preparation processes all refer to the direct mixed pressuring plate technique of powder
Preparation method, it is clear that due to (S)-ibuprofen poor fluidity, the direct mixed pressuring plate technique of powder is not suitable for industrialized production.
Auxiliary material amount is big used in prescription proportioning involved by above-mentioned two patent, and active constituent (S)-ibuprofen weight shared by tablet is matched
Relatively low, piece is great, is not easy to swallow；And equal not acid resistance.
Although (S)-ibuprofen safety is higher, as nonsteroidal anti-inflammatory drug, the irritation of stomach is not sneezed at.
Being all the aspirin, naproxen and Diclofenac etc. of nonsteroidal anti-inflammatory drug has enteric coated preparations, in order to avoid pair
The irritation of stomach.
Dexibuprofen sustained-release preparation of the present invention is enteric-coated sustained-release tablet, which not only has stomach juice-resistant effect, and has
The effect of standby slow release in the intestine.Therefore irritation of the (S)-ibuprofen to stomach can be not only prevented, and there is slow release effect,
Lasting medicine；Sheet body light and small is easy to swallow.Said preparation has obviously not compared with the various preparations of the (S)-ibuprofen reported at present
Same and intrinsic advantage, technology require higher；Product clinical safety is more preferable, and patient adaptability is strong.(S)-ibuprofen intestines of the present invention
The preparation method of molten sustained release tablets is pelletizing press sheet technique, is easy to industrialized production, high with (S)-ibuprofen weight proportion in time slice,
More than 70%, greatly reduce supplementary product consumption, reduces piece weight, accomplish the perfect adaptation of active constituent (S)-ibuprofen and auxiliary material.
Invention content
For existing (S)-ibuprofen preparation and related report, the purpose of the present invention is to provide a kind of (S)-ibuprofen intestines
Molten sustained release tablets and preparation method thereof, obtained (S)-ibuprofen enteric-coated sustained-release tablet not only reduce the administration number of times of (S)-ibuprofen,
Reduce the toxic side effect caused by paddy peak is excessively high after (S)-ibuprofen ordinary preparation is taken；(S)-ibuprofen can be prevented to stomach simultaneously
Irritation.
A kind of (S)-ibuprofen enteric-coated sustained-release tablet of the present invention includes the packet of label and package label with slow release effect
Clothing；The label with slow release effect is filled out including 70~90 parts of (S)-ibuprofens, 10~30 parts of sustained-release matrix agent, 0~10 part
Fill agent, 0.2~1.5 part of lubricant and 0.2~1.5 portion of glidant；Wherein a effective amount of active constituent (S)-ibuprofen accounts for label
70% or more of weight, preferably 75%~85%.
The package label includes spacer layer coating and enteric coating；Spacer layer coating amount is the 0~5 of label weight
wt %；Enteric coating amount is 1~10wt% of label weight.
The one kind of the skeleton agent in hydroxypropyl methyl cellulose, Hydroxypropylcelliloxe, ethyl cellulose
Or two kinds of mixtures；The preferred hydroxypropyl methyl cellulose of skeleton agent.
Parts by weight of the preferred hydroxypropyl methyl cellulose in being sustained label are 10~20 parts.
Preferred hydroxypropyl methyl cellulose skeleton agent is hydroxypropyl methylcellulose K100LV and HPMC K4M mixes
Object；Wherein hydroxypropyl methylcellulose K100LV is 5~10 parts by weight, and hydroxypropyl methylcellulose K4 is 8~15 parts by weight.
The filler selects one or both of lactose, calcium monohydrogen phosphate, microcrystalline cellulose etc. mixture, preferably newborn
Sugar.
The one kind or two kinds of the lubricant in magnesium stearate, stearic acid, preferably magnesium stearate；Glidant is selected from
Superfine silica gel powder, talcum powder and in one or two or more kinds, preferred superfine silica gel powder.
Coating material：
The main material of enteric coating is using one of enteric acrylic resin or cellulose acetate-phthalate.It is preferred that
Enteric crylic acid resin material.Enteric coating gain in weight is the 1%~10% of label, preferably 6%~8%.
The enteric acrylic resin is methacrylic acid-ethyl acrylate copolymer.
Hydroxypropyl methyl fiber is used in the main material of one layer of spacer layer coating of enteric coated preceding packet, spacer layer coating
One of element, Hydroxypropylcelliloxe.It is preferred that hydroxypropyl methyl cellulose.Spacer layer coating gain in weight is no more than plate core weight
The 5% of amount.
The present invention provides the preparation methods one of the (S)-ibuprofen enteric slow release tablet preparation, include the following steps：
（1）(S)-ibuprofen, sustained-release matrix agent and filler are uniformly mixed to obtain mixed material, with the second of 75~95wt%
Softwood is made in said mixture by alcoholic solution, pelletize 18~30 mesh wet granular, at a temperature of being placed in not higher than 55 DEG C in equipment
It is dry, within drying time 5h, obtain the dry particl of 18~30 mesh；
（2）Dry particl is uniformly mixed with lubricant and glidant, tabletting obtains Dex-ibuprofen sustained release tablets core；
（3）Dex-ibuprofen sustained release tablets label is placed in coating pan, is coated using enteric material coating solution, makes piece
Weightening 1~10%, obtains (S)-ibuprofen enteric-coated sustained-release tablet.
The present invention also provides the preparation methods two of the (S)-ibuprofen enteric slow release tablet preparation, include the following steps：
（1）(S)-ibuprofen, sustained-release matrix agent and filler are uniformly mixed to obtain mixture, it is right using dry granulating machine
Said mixture is pelletized, and after crossing 18~30 mesh screens, obtains dry particl；
（2）Dry particl is uniformly mixed with lubricant and glidant, tabletting obtains Dex-ibuprofen sustained release tablets core；
（3）Dex-ibuprofen sustained release tablets core is placed in coating pan, is coated using enteric material coating solution, makes label
Weightening 1~10%, obtains (S)-ibuprofen enteric-coated sustained-release tablet.
Gained (S)-ibuprofen enteric-coated sustained-release tablet 2 hours releases in the acid medium of pH1.0 or so are less than 2%, then at
pH6.8（Or pH7.2）In medium, accumulation 1h releases are more than 10%, and accumulation 2h releases are more than 25%, and accumulation 3h releases are more than
35%, accumulation 4h releases are more than 50%, and accumulation 6h releases are more than 65%, and accumulation 8h releases are more than 80%.
To sum up, according to the present invention the (S)-ibuprofen enteric-coated sustained-release tablet obtained by provided prescription and preparation method in hydrochloric acid in gastric juice
It hardly discharges, reaches enteral just meeting slow release, and gradually discharge active component.To reach：First, almost preventing dextrorotation
Brufen to the irritation of stomach, two be to ensure that (S)-ibuprofen in vivo slow-absorbing and play dauer effect.
Elegant formulations are that active constituent reaches perfect adaptation with auxiliary material by suitable preparation process, are convenient for Clinical practice, make
Patient is benefited.Active constituent (S)-ibuprofen is not only irritant to stomach after having certain irritation, ordinary preparation to take in stomach,
And causing side effect because of the dense peaks Gao Gu of medicine, patient adaptability is poor.The present invention is by preparing (S)-ibuprofen enteric-coated sustained-release tablet Du
Its exhausted irritation to stomach；Drug reduces the excessively high caused toxic side effect in the dense paddy peak of medicine by enteron aisle slow-absorbing；In addition, because subtracting
The adaptability taken number less and increase patient medication has apparent compared with the dosage form that current (S)-ibuprofen is had been reported that
Difference and intrinsic advantage, technology require higher；Product clinical safety is more preferable, and patient adaptability is strong..
Drug has extremely strong particularity：Dosage form of the same race, its prescription of the drug of different cultivars and preparation method are different,
There is no general prescription and preparation method, enteric-coated sustained-release tablet successfully develops kind not both at home and abroad as a kind of newtype drug dosage form
It is more.The (S)-ibuprofen enteric-coated sustained-release tablet of the present invention fully combines the property and auxiliary material characteristic of active constituent (S)-ibuprofen, living
Property ingredient (S)-ibuprofen weight ratio shared by label be up to 70% or more, under the premise of keeping active constituent effective dosage,
Label not only has excellent slow release effect, but also accomplishes sheet body light and small, is easy to swallow；Label and casing（Or add barrier gown）It is perfect
In conjunction with, it is ensured that in selection casing（Or add barrier gown）Enteric-coated sustained-release tablet in weightening range hardly discharges in hydrochloric acid in gastric juice, and
Enteral has slow release effect, has the function that lasting medicine, has itself good characteristic.
Description of the drawings
Fig. 1 is (S)-ibuprofen enteric-coated sustained-release tablet release curve prepared by the embodiment of the present invention 2；
Fig. 2 is (S)-ibuprofen enteric-coated sustained-release tablet release curve prepared by the embodiment of the present invention 3；
Fig. 3 is (S)-ibuprofen enteric-coated sustained-release tablet release curve prepared by the embodiment of the present invention 4；
Fig. 4 is (S)-ibuprofen enteric-coated sustained-release tablet release curve prepared by the embodiment of the present invention 5.
Specific implementation mode：
As a kind of specific preferred embodiment of the present invention, the Dex-ibuprofen sustained release tablets each group is grouped as specifically
For：
It is sustained label parts by weight：
70-90 parts of (S)-ibuprofen
10~20 parts of skeleton agent
0~10 part of filler
0.2~1.5 part of lubricant
0.2~1.5 part of glidant
Coating material：
Separation layer clothing, the amount of spacer layer coating are the 0~5% of label weight；
Enteric coating, the amount of enteric coating are the 6%~8% of label weight.
Preparation method is preferably wet granule compression tablet preparation process
1, wet granulation technology step：
（1）(S)-ibuprofen is crossed at least 80 mesh sieve and then and hypromellose（K4M）And hypromellose
（K100LV）And the lactose that may be used is sufficiently mixed uniformly；
（2）Above-mentioned material is prepared into softwood with suitable 75%~95% ethanol solution, pelletize 18~30 mesh wet granular；
（3）At a temperature of wet granular is placed in not higher than 55 DEG C, forced air drying is taken out in 3~5h, measures moisture, particle water
Divide and be kept for no more 3%, whole grain obtains 18~30 dry particl；
（4）The stearic acid and differential silica gel that 80 mesh sieve was added to dry particl, was uniformly mixed；
（5）Tabletting obtains Dex-ibuprofen sustained release tablets core.
（6）With enteric-coating material crylic acid resin（Such as Eudragit L 30D-55）Prepare enteric coating solution packet
Casing（Or adds and use low-viscosity hydroxypropylmethylc,llulose configuration isolation layer solution packet barrier gown）, obtain (S)-ibuprofen enteric slow release
Piece.
In above-mentioned preparation method, skeleton agent is preferably hypromellose, wherein hypromellose model K4M
And K100LV；Enteric-coating material preferred acrylic resins class；The preferred low-viscosity hydroxypropylmethylc,llulose of separation layer clothing material；
The preferred lactose of additive；Preferably 45 ± 5 DEG C of drying temperature；Particle mesh number preferably 24 mesh.
Suitable piece weight can be made in the (S)-ibuprofen enteric-coated sustained-release tablet of the present invention as needed, and preferably piece weight is every
0.35~0.55g.Every (S)-ibuprofen containing active constituent is 0.30g.
2, dry granulation
（1）(S)-ibuprofen is crossed at least 80 mesh sieve and then and hypromellose（K4M）And hypromellose
（K100LV）, be sufficiently mixed uniformly；
（2）Above-mentioned material is placed in dry granulating machine, the particle of 18~30 mesh is made；
（3）The stearic acid and differential silica gel that 80 mesh sieve was added to above-mentioned particle, was uniformly mixed；
（4）Tabletting obtains Dex-ibuprofen sustained release tablets core.
（5）With enteric-coating material crylic acid resin（Such as Eudragit L 30D-55）Coating（Or adds and use low viscosity
Hydroxypropyl methyl cellulose configuration isolation layer solution packet barrier gown）, obtain (S)-ibuprofen enteric-coated sustained-release tablet.
In the preparation method of above-mentioned pelletizing press sheet preparation process, skeleton agent is preferably hypromellose, wherein hydroxypropyl
There are two types of models for methylcellulose, are respectively K4M and K100LV；Enteric-coating material preferred acrylic resins class；Additive
It is preferred that lactose.
Suitable piece weight can be made in the (S)-ibuprofen enteric-coated sustained-release tablet of the present invention as needed, and preferably piece weight is every
0.35~0.55g.Every (S)-ibuprofen containing active constituent is 0.30g.
The present invention fully combines the property and auxiliary material characteristic of active constituent (S)-ibuprofen, passes through preferred suitable skeleton
Agent and coating material appropriate, being prepared using pelletizing press sheet technique has slow release effect label, then wraps and meet the intestines that weightening requires
Clothing layer（It is not excluded for one layer of separation layer of packet）, obtain (S)-ibuprofen enteric-coated sustained-release tablet.Enteric slow release tablet recipe is excellent, preparation process
Reliably, it is easy to industrialized production.
(S)-ibuprofen is made enteric-coated sustained-release tablet by the present invention has preferable formulation properties：In gastric juice medium（pH1.0）In
Hardly discharge；In pH6.8 intestinal juice media（Or pH7.2）In release have good elution profiles；Activity after coated
The stability of ingredient (S)-ibuprofen is more preferable.(S)-ibuprofen enteric-coated sustained-release tablet almost prevents active constituent and discharges and draw in stomach
The stomach irritation risen；Excellent slow release effect effectively reduces administration number of times, can keep drug effect concentration for a long time, reach
Long-acting purpose；Toxic side effect of the ordinary preparation caused by paddy peak height acute drug is decreased simultaneously, on Clinical practice
With obviously preferred.
Experimental technique scheme：
Sustained release preparation can make drug slow release according to certain rules, and the long period keeps effective blood medicine to active constituent in vivo
Concentration reduces drug number to reach, reduces because excessively high blood concentration, that is, Gu Fenger causes the purpose of adverse reaction；It carries simultaneously
High patient compliance and reduction administration cost.Common enteric coated preparations have the effect of that stomach is insoluble and enteral dissolves rapidly, reduce medicine
Irritation of the object to stomach.Non-steroidal anti-inflammatory drugs all has different degrees of stomach irritation, the dextrorotation cloth as non-steroidal anti-inflammatory drugs
Ibuprofen, although safely and effectively, but still there is larger stomach internal stimulus.The (S)-ibuprofen enteric-coated sustained-release tablet of the present invention has anti-
Only drug to the irritation of the stomach and in the intestine effect of slow release.
【Acid resistance measures】This product is taken, according to dissolution rate and release inspection technique, using the device of the first method, with hydrochloric acid solution
（pH1.0）900ml is solvent, and rotating speed is 100 turns per minute, operates in accordance with the law, solution 10ml is taken in 2h, through 0.45 μm of membrane filtration,
Subsequent filtrate is taken, according to visible determined by ultraviolet spectrophotometry, trap is measured respectively at the wavelength of 263nm；Another precision weighs the right side
It is appropriate to revolve brufen reference substance, dissolves in addition stating solvent and is quantitatively diluted to the solution in every 1ml containing about 0.25mg, be measured in the same method
Trap.Calculate separately out the every burst size in the 2h times.
【Standard requirement】The every burst size in 2h should be no more than the 10% of labelled amount, meet States Pharmacopoeia specifications.
【Drug release determination】This product is taken, according to dissolution rate and release inspection technique, using the device of the first method, first through hydrochloric acid
Solution medium enters back into phosphate-buffered liquid medium, and rotating speed is 100 turns per minute, is operated in accordance with the law, in 2h in hydrochloric acid solution
After sample, in 1h, 2h, 4h in phosphate-buffered liquid medium, 6h, 8h sampling take medium solution 10ml to filter respectively, and in time
Above-mentioned medium solution 10ml is supplemented in process container；Take subsequent filtrate as test sample.It is surveyed according to visible ultraviolet spectrophotometry
It is fixed, trap is measured respectively at the wavelength of 263nm；It is appropriate that another precision weighs (S)-ibuprofen reference substance, in addition it is molten to state solvent
It solves and is quantitatively diluted to the solution in every 1ml containing about 0.25mg, be measured in the same method trap.Every is calculated separately out in different Jie
Matter, the cumulative release amount of different time.
【Standard requirement】The every cumulative release amount in 2h, 4h, 8h should mutually should be 25%~55%, the 50% of labelled amount respectively
~80%, 80% or more, regulation should all be met.
【Assay】Chromatographic condition is filler with octadecylsilane chemically bonded silica, with -0.02 mol of acetonitrile
L-1Potassium dihydrogen phosphate pH 3.50（63∶37）For mobile phase, Detection wavelength 263nm, according to high effective liquid chromatography for measuring, sheet
Product should be the 90.0%~110% of labelled amount containing (S)-ibuprofen.
【Related substance-measuring】By the chromatographic condition under this product Related substances separation item, according to high effective liquid chromatography for measuring,
The single impurity of this product is not greater than 1.0%；Total groceries are not greater than 2.0%.
The sample prepared to the embodiment of the present invention according to above-mentioned detection method is detected, and to stability test sample into
Row is investigated, and the quality of the pharmaceutical preparations reliability and stability of the present invention are embodied with data.
The preparation of 1 (S)-ibuprofen enteric-coated sustained-release tablet of embodiment：
Core formulation forms（G/1000 pieces：
(S)-ibuprofen 300
Hydroxypropyl methyl cellulose（HPMC）-K4M 40
Hydroxypropyl methyl cellulose（HPMC）-K100LV 20
Lactose 30
75% ethanol solution Q.S
Superfine silica gel powder 3
Magnesium stearate 2
Enteric coating formula：
Acrylic resin（Eudragit® L30D-55） 160g
Triethyl citrate 4.8g
Mono stearate glyceryl ester 2.4g
Tween-80 1.0g
Water 160g
【Preparation process describes】
（1）The (S)-ibuprofen of recipe quantity is crossed into 80 mesh sieve, with hypromellose（K4M）, hypromellose
（K100LV）And lactose is sufficiently mixed uniformly；
（2）Appropriate 75% ethyl alcohol is added and prepares softwood, crosses 24 mesh sieve and wet granular is made；
（3）After wet granular sets 45 DEG C of air dry oven drying 4h, crosses 24 mesh sieve and dry particl is made；
（4）The superfine silica gel powder and magnesium stearate of 80 mesh sieve were added into dry particl, was uniformly mixed；
（5）Trimmer weight and pressure, tabletting obtain Dex-ibuprofen sustained release tablets core；
（6）Coating solution is configured, by coating recipe quantity, configures coating solution；
（7）With configuration coating solution, label is coated in high-efficiency coating machine, coating tablet weightening 2%~8%；
（8）Detection, obtains (S)-ibuprofen enteric-coated sustained-release tablet.
Acid resistance release test is carried out to (S)-ibuprofen enteric-coated sustained-release tablet prepared by embodiment 1, it is as a result as follows.
1 (S)-ibuprofen enteric-coated sustained-release tablet acid resisting test result of table
The preparation of 2 Dex-ibuprofen sustained release tablets of embodiment
Core formulation forms（G/1000 pieces：
(S)-ibuprofen 300
Hydroxypropyl methyl cellulose（HPMC）-K4M 40
Hydroxypropyl methyl cellulose（HPMC）-K100LV 20
Lactose 30
75% ethanol solution Q.S
Superfine silica gel powder 3
Magnesium stearate 2
Enteric coating formula：
Acrylic resin（Eudragit® L30D-55） 160g
Triethyl citrate 4.8g
Mono stearate glyceryl ester 2.4g
Tween-80 1.0g
Water 160g
【Preparation process describes】
（1）The (S)-ibuprofen of recipe quantity is crossed into 80 mesh sieve, with hypromellose（K4M）, hypromellose
（K100LV）And lactose is sufficiently mixed uniformly；
（2）Appropriate 75% ethyl alcohol is added and prepares softwood, crosses 24 mesh sieve and wet granular is made；
（3）After wet granular sets 45 DEG C of air dry oven drying 4h, crosses 24 mesh sieve and dry particl is made；
（4）The superfine silica gel powder and magnesium stearate of 80 mesh sieve were added into dry particl, was uniformly mixed；
（5）Trimmer weight and pressure, tabletting obtain Dex-ibuprofen sustained release tablets core；
（6）Coating solution is configured, by coating recipe quantity, configures coating solution；
（7）With configuration coating solution, label is coated in high-efficiency coating machine, coating tablet weightening about 7%；
（8）Detection, obtains (S)-ibuprofen enteric-coated sustained-release tablet.
The preparation of 3 Dex-ibuprofen sustained release tablets of embodiment
Core formulation forms（G/1000 pieces）：
(S)-ibuprofen 300
Hydroxypropyl methyl cellulose（HPMC）-K4M 45
Hydroxypropyl methyl cellulose（HPMC）-K100LV 15
85% ethanol solution Q.S
Superfine silica gel powder 3
Magnesium stearate 2
Coated formula：
Acrylic resin（Eudragit® L30D-55） 160g
Triethyl citrate 4.8g
Mono stearate glyceryl ester 2.4g
Tween-80 1.0g
Water 160g
【Preparation process describes】
（1）The (S)-ibuprofen of recipe quantity is crossed into 80 mesh sieve, with hypromellose（K4M）, hypromellose
（K100LV）It is sufficiently mixed uniformly；
（2）Appropriate 85% ethyl alcohol is added and prepares softwood, crosses 24 mesh sieve and wet granular is made；
（3）After wet granular sets 45 DEG C of air dry oven drying 4h, crosses 24 mesh sieve and dry particl is made；
（4）The superfine silica gel powder and magnesium stearate of 80 mesh sieve were added into dry particl, was uniformly mixed；
（5）Trimmer weight and pressure, tabletting obtain Dex-ibuprofen sustained release tablets core；
（6）Coating solution is configured, by coating recipe quantity, configures coating solution；
（7）With configuration coating solution, label is coated in high-efficiency coating machine, coating tablet weightening about 7%；
（8）Detection, obtains (S)-ibuprofen enteric-coated sustained-release tablet.
The preparation of 4 Dex-ibuprofen sustained release tablets of embodiment
Core formulation forms（G/1000 pieces）：
(S)-ibuprofen 300
Hydroxypropyl methyl cellulose（HPMC）-K4M 40
Hydroxypropyl methyl cellulose（HPMC）-K100LV 20
Lactose 30
75% ethanol solution Q.S
Superfine silica gel powder 3
Magnesium stearate 2
Coated formula：
Spacer layer coating formula：
Hydroxypropyl methyl cellulose（5E） 60g
Talcum powder 20g
Water 520g
Enteric coating formula：
Acrylic resin（Eudragit® L30D-55） 160g
Triethyl citrate 4.8g
Mono stearate glyceryl ester 2.4g
Tween-80 1.0g
Water 160g
【Preparation process describes】
（1）The (S)-ibuprofen of recipe quantity is crossed into 80 mesh sieve, with hypromellose（K4M）, hypromellose
（K100LV）And lactose, it is sufficiently mixed uniformly；
（2）Appropriate 75% ethyl alcohol is added and prepares softwood, crosses 24 mesh sieve and wet granular is made；
（3）After wet granular sets 45 DEG C of air dry oven drying 4h, crosses 24 mesh sieve and dry particl is made；
（4）The superfine silica gel powder and magnesium stearate of 80 mesh sieve were added into dry particl, was uniformly mixed；
（5）Trimmer weight and pressure, tabletting obtain Dex-ibuprofen sustained release tablets core；
（6）Configuration isolation layer coating solution, by spacer layer coating recipe quantity, configuration isolation layer coating solution；
（7）Enteric coating liquid is configured, by enteric coating recipe quantity, configures enteric coating liquid；
（8）With configuration coating solution, label is coated in high-efficiency coating machine, first packet separation layer clothing, coating weight gain 5%,
Enteric layers, casing coating weight gain about 7% are reported again；
（9）Detection, obtains (S)-ibuprofen enteric-coated sustained-release tablet.
The preparation of 5 Dex-ibuprofen sustained release tablets of embodiment
Core formulation forms（G/1000 pieces）：
(S)-ibuprofen 300
Hydroxypropyl methyl cellulose（HPMC）-K4M 45
Hydroxypropyl methyl cellulose（HPMC）-K100LV 15
85% ethanol solution Q.S
Superfine silica gel powder 3
Magnesium stearate 2
Coated formula：
Spacer layer coating formula：
Hydroxypropyl methyl cellulose（5E） 60g
Talcum powder 20g
Water 520g
Enteric coating formula：
Acrylic resin（Eudragit® L30D-55） 160g
Triethyl citrate 4.8g
Mono stearate glyceryl ester 2.4g
Tween-80 1.0g
Water 160g
【Preparation process describes】
（1）The (S)-ibuprofen of recipe quantity is crossed into 80 mesh sieve, with hypromellose（K4M）, hypromellose
（K100LV）It is sufficiently mixed uniformly；
（2）Appropriate 85% ethyl alcohol is added and prepares softwood, crosses 24 mesh sieve and wet granular is made；
（3）After wet granular sets 45 DEG C of air dry oven drying 4h, crosses 24 mesh sieve and dry particl is made；
（4）The superfine silica gel powder and magnesium stearate of 80 mesh sieve were added into dry particl, was uniformly mixed；
（5）Trimmer weight and pressure, tabletting obtain Dex-ibuprofen sustained release tablets core；
（6）Configuration isolation layer coating solution, by spacer layer coating recipe quantity, configuration isolation layer coating solution；
（7）Enteric coating liquid is configured, by enteric coating recipe quantity, configures enteric coating liquid；
（8）With configuration coating solution, label is coated in high-efficiency coating machine, first packet separation layer clothing, coating weight gain 5%,
Enteric layers, casing coating weight gain about 7% are reported again；
（9）Detection, obtains (S)-ibuprofen enteric-coated sustained-release tablet.
Release test is carried out to (S)-ibuprofen enteric-coated sustained-release tablet prepared by embodiment 2~5, the results are shown in Table 2~5 and figure
1~4.By the results show that (S)-ibuprofen enteric-coated sustained-release tablet prepared by the present invention have under good acid resistance and enteric medium delay
Release profiles are released, the requirement of clinical application is fully met.
2 embodiment 2 of table discharges degrees of data
3 embodiment 3 of table discharges degrees of data
4 embodiment 4 of table discharges degrees of data
5 embodiment 5 of table discharges degrees of data
Stability study
【Preparation process stability study】
This product preparation process can both select dry granulation tablet forming technique, can also select wet granule compression tablet technique；It is dry
Method granulation is not due to by making soft ability and drying process, related substance of the entire film-making process to active constituent (S)-ibuprofen
It has no significant effect, this is also the advantage place of dry granulation process, but the particle obtained by dry granulation is in uniformity and mobility
Particle obtained by upper too late wet granulation, that is, reflect the compressibility of the particle of the dry granulation in tableting processes not as good as wet granulation
The particle of gained.For this purpose, this product carries out special investigation to the stability of wet granulation technology.As a result it see the table below：
6 variation of the legal system grain technical process (S)-ibuprofen in relation to substance of table
Raw material standard requires left-handed brufen that must not cross 1.0%；Single impurity must not cross 0.3%；In addition to left-handed brufen, no
Obtained 0.7%.Testing result meets the requirements；
Preparation, which drafts the left-handed brufen of standard, must not cross 1.0%；Single impurity must not cross 0.5%；In addition to left-handed brufen, always
Impurity must not cross 1.0%.
It can be defined by upper table, wet granulation technology process has no significant effect the related substance of (S)-ibuprofen, this product
It can also select the preparation process of wet granule compression tablet.
【Sample stability is studied】
10,000 scale-ups are carried out to 2 prescription of embodiment, prepared (S)-ibuprofen enteric-coated sustained-release tablet carries out quality inspection
It surveys.It is carried out at the same time accelerated test（40℃、RH75%±5%）6 months and long term test（25℃、RH60%±10%）It examines within 6 months
It examines, detects the variation of every quality index, the data obtained is as shown in table 7~8：
Table 7 accelerated test, 6 months data
Table 8 long term test, 6 months data
Conclusion：The (S)-ibuprofen enteric slow release tablet quality that it can be seen from data above result prepared by the present invention meets
Standard requirement, and after accelerating experiment in 6 months and long-term 6 months, every quality index meets without significant change and drafts matter
Amount standard illustrates that the sample quality of the preparation of the present invention has good stability.
Claims (8)
1. a kind of (S)-ibuprofen enteric-coated sustained-release tablet, it is characterised in that：Include label and package label with slow release effect
Coating；The label with slow release effect include 70~90 parts of (S)-ibuprofens, 10~30 parts of sustained-release matrix agent, 0~10 part
Filler, 0.2~1.5 part of lubricant and 0.2~1.5 portion of glidant；Wherein a effective amount of active constituent (S)-ibuprofen accounts for piece
70% or more of core weight；The sustained-release matrix agent is the mixing of hypromellose K4M and hypromellose K100LV
Object；Wherein the amount ratio of hypromellose K4M and hypromellose K100LV are 40:20-45:15；The package
Label includes spacer layer coating and enteric coating；Spacer layer coating amount is 0~5 wt % of label weight；Enteric coating amount
For 1~10wt% of label weight.
2. (S)-ibuprofen enteric-coated sustained-release tablet according to claim 1, it is characterised in that：The filler selects lactose, phosphorus
One of sour hydrogen calcium, microcrystalline cellulose or two.
3. (S)-ibuprofen enteric-coated sustained-release tablet according to claim 1, it is characterised in that：Lubricant selects stearic acid, tristearin
One of sour magnesium or two；Glidant select superfine silica gel powder, one of talcum powder or two.
4. (S)-ibuprofen enteric-coated sustained-release tablet according to claim 1, it is characterised in that：The main material of enteric coating uses
One of enteric acrylic resin or cellulose acetate-phthalate.
5. (S)-ibuprofen enteric-coated sustained-release tablet according to claim 1, it is characterised in that：In enteric coated one layer of isolation of preceding packet
Layer coating, the main material of spacer layer coating is using one of hydroxypropyl methyl cellulose, Hydroxypropylcelliloxe.
6. (S)-ibuprofen enteric-coated sustained-release tablet according to claim 4, it is characterised in that：The enteric acrylic resin is first
Base acrylic acid-ethyl acrylate copolymer.
7. the preparation method of claims 1 or 2 or the 3 or 4 or 5 or 6 (S)-ibuprofen enteric slow release tablet preparations, including it is following
Step：
（1）(S)-ibuprofen, sustained-release matrix agent and filler are uniformly mixed to obtain mixed material, it is molten with the ethyl alcohol of 75~95wt%
Softwood is made in said mixture by liquid, pelletize 18~30 mesh wet granular, it is dry in equipment at a temperature of being placed in not higher than 55 DEG C,
Within drying time 5h, the dry particl of 18~30 mesh is obtained；
（2）Dry particl is uniformly mixed with lubricant and glidant, tabletting obtains Dex-ibuprofen sustained release tablets core；
（3）Dex-ibuprofen sustained release tablets label is placed in coating pan, is coated using enteric material coating solution, piece is made to increase weight
1~10%, obtain (S)-ibuprofen enteric-coated sustained-release tablet.
8. the preparation method of claims 1 or 2 or the 3 or 4 or 5 or 6 (S)-ibuprofen enteric slow release tablet preparations, including it is following
Step：
（1）(S)-ibuprofen, sustained-release matrix agent and filler are uniformly mixed to obtain mixture, using dry granulating machine, to above-mentioned
Granulating mixture obtains dry particl after crossing 18~30 mesh screens；
（2）Dry particl is uniformly mixed with lubricant and glidant, tabletting obtains Dex-ibuprofen sustained release tablets core；
（3）Dex-ibuprofen sustained release tablets core is placed in coating pan, is coated using enteric material coating solution, label is made to increase weight
1~10%, obtain (S)-ibuprofen enteric-coated sustained-release tablet.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102293759A (en) * | 2011-09-05 | 2011-12-28 | 南京海陵中药制药工艺技术研究有限公司 | Dextral ibuprofen sustained release tablet preparation and preparation method thereof |
| WO2013154512A1 (en) * | 2012-04-13 | 2013-10-17 | Mahmut Bilgic | Pharmaceutical formulations comprising dexibuprofen |
-
2015
- 2015-11-02 CN CN201510728542.5A patent/CN105250233B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102293759A (en) * | 2011-09-05 | 2011-12-28 | 南京海陵中药制药工艺技术研究有限公司 | Dextral ibuprofen sustained release tablet preparation and preparation method thereof |
| WO2013154512A1 (en) * | 2012-04-13 | 2013-10-17 | Mahmut Bilgic | Pharmaceutical formulations comprising dexibuprofen |
Non-Patent Citations (2)
| Title |
|---|
| Enteric coating of ibuprofen tablets (200 mg) using an aqueous dispersion system;Rabia Bushra et al;《Brazilian Journal of Pharmaceutical Sciences》;20101231;第46卷(第1期);第99-107页，第99页摘要，第102页左栏第1段 * |
| 布洛芬缓释片的研究;陈晓燕等;《中国现代应用药学杂志》;20010930;第18卷(第7期);第29-31页，第30页第2.4节 * |
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