CN104546732A - Dexibuprofen sustained-release tablet and preparation process thereof - Google Patents
Dexibuprofen sustained-release tablet and preparation process thereof Download PDFInfo
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Abstract
The invention discloses a dexibuprofen sustained-release tablet and a preparation process thereof. According to the preparation process, colloidal silicon dioxide is used as an antiplastering aid, and dry granulation is carried out by using a high-speed rotary tablet press; the prepared dry granules are respectively mixed with auxiliaries in specific quick-release and sustained-release layers to press a dual-layer tablet which is the dexibuprofen sustained-release tablet. The preparation process can be used for effectively reducing the sticking phenomenon caused by temperature increase when tabletting is carried out for a long time, and has simple process and relatively high efficiency; and the prepared sustained-release tablet has high bioavailability and good stability.
Description
Technical field
The present invention relates to pharmaceutical technology sectors, particularly relate to a kind of Dex-ibuprofen sustained release tablets and preparation technology thereof.
Background technology
DL ibuprofen is made up of the (S)-ibuprofen of equivalent and left-handed ibuprofen, as antiinflammatory and existing 30 years of analgesic clinical practice, is considered to safest nonsteroidal antiinflammatory drug (NSAID), and is a kind of nonprescription drugs.But DL ibuprofen still has multiple side reactions such as comprising gastrointestinal toxicity, water-sodium retention, renal perfusion reduction and anaphylaxis, and incidence rate reaches 15% ~ 30%.For developing safer NSAID, two kinds of medicines are recommended: pure space corresponding body, the especially (S)-ibuprofen of Cyclooxygenase-2 Inhibitor and NSAID.1996, (S)-ibuprofen started to be widely used in treatment rheumatoid arthritis in Austria, and as a kind of new NSAID, because it is the corresponding body in pure space of ibuprofen, and people have a large amount of clinical experience to ibuprofen, are therefore accepted accreditation very soon.
The people such as Dionne once have rated the effect of non-peptide level in acute pain and blood plasma that (S)-ibuprofen causes oral surgery.Find in initial 60 minutes, the analgesic effect of 200mg and 400mg (S)-ibuprofen is obviously better than DL ibuprofen and the placebo of 400mg.The analgesic effect of the 2nd and the 3rd hour 400mg (S)-ibuprofen is still stronger.The time that in all patients blood plasma, non-peptide declines occurs conforming to analgesic effect.Compared with DL ibuprofen, give the (S)-ibuprofen of DL ibuprofen one half-value dose, just can obtain even better clinical efficacy identical with the former, analgesic effect, higher analgesia peak value, similar effect time limit and lower rate of side effects faster can be produced.Its mechanism of action is except the synthesis by suppression prostaglandin, and that can suppress pituitary adrenal axis causes pain activity simultaneously.
The new comprehensive analytical standard such as Rahlfs has re-started assessment to the research about (S)-ibuprofen curative effect.In 6 researchs for the treatment of rheumatoid arthritis, ankylosing spondylitis, coxitis, gonarthritis, lumbar vertebra syndrome, ankle joint distortion, result is similarly effective.In effectiveness study to 178 routine coxitis patients, improve find by evaluating WOMAC OA index, (S)-ibuprofen 400mg every day 3 times is equal with the curative effect of 3 times DL ibuprofen 800mg every day.(S)-ibuprofen has obvious dose-effect relationship, and has critical busy (P=0.055).
Long-term safety experiment show, the rate of side effects of (S)-ibuprofen is only 15.2%, wherein digestive tract reaction 11.7%, reaction of central nervous system 1.3%, dermoreaction 1.3%, other 0.9%, toleration is good.After open application, it is 2.3% ~ 2.7% that the investigation of larger samples amount then shows rate of side effects.It combines two high efficiency of chloric acid phenol and the safety of ibuprofen, using value is not less than the cox 2 inhibitor of a new generation.
But (S)-ibuprofen material density is little, poor fluidity, and fusing point is very low, only have 49 ~ 53 DEG C, be easy to thawing and cause sticking in tableting processes, common wet granulation technology can not effectively solve sticking problem.
In published patent, CN101588793 discloses and is first mixed with silicon dioxide by ibuprofen, mix with adjuvants such as silicified microcrystalline celluloses again, last again with fluidizer and mix lubricant tabletting, the method of this kind of simple mixing effectively can not solve the sticking problem in low melting point substance tableting processes, and medicament contg is also lower.CN101330904 describes the ibuprofen by colloidal silica solidification of molten; prepare the method for solid dispersion; this kind of method needs special melt granulation machine; reach good solidification effect, the consumption of colloidal silica is more, and is unfavorable for the stable of medicine in heating process; consider that ibuprofen is as active pharmaceutical ingredient; its fusing point is 75 ~ 78 DEG C, and the fusing point of (S)-ibuprofen is lower, at 49 ~ 53 DEG C.When actual production, tabletting exceedes a certain amount of inherently generation sticking phenomenon, and above-mentioned patent cannot thoroughly solve this phenomenon.Patent WO2009084041 describes a kind of wet granulation method of (S)-ibuprofen tablet, mention in this patent the mixture of the (S)-ibuprofen of different-grain diameter and colloidal silica and microcrystalline Cellulose carried out wet granulation and the formulation and technology of tablet.But lacking in anti-stick measure situation, sticking phenomenon during tabletting cannot improve equally.
Summary of the invention
For the defect that above-mentioned prior art exists, the object of the invention is to propose a kind of Dex-ibuprofen sustained release tablets and preparation technology thereof; Described preparation technology effectively can solve the sticking problem of (S)-ibuprofen crude drug in preparation process, and gained Dex-ibuprofen sustained release tablets bioavailability is high, good stability.
For reaching this object, the present invention by the following technical solutions:
First aspect, the invention provides a kind of dry granulation process of (S)-ibuprofen, comprising: (S)-ibuprofen, antiplastering aid and other pharmaceutically acceptable adjuvant mixing are sieved, utilize high speed rotary tablet press tabletting, sieve, must containing the granule of (S)-ibuprofen.
Preferably, described antiplastering aid is colloidal silica.Colloidal silica density is little, and specific surface area is very large, and less consumption just can wrap up principal agent, plays anti-stick effect.
Because colloidal silica density is very little, cause the density of pastille mixed material also smaller, the common dry granulating machine of this material cannot be granulated smoothly, because the density of material is little, mobility does not meet equipment requirements.For this defect, the present invention adopts high speed rotary tablet press to carry out tabletting, because high speed rotary tablet press raises powder device with pressure, supplies flow in punch die, thus (material density is little, after filling up punch die can to suppress thin slice fast, compressedly become thin slice, after sieving, just become medicine-containing particle); Further, high speed rotary tablet press compacting web speed is faster than common dry granulation motor speed, is more suitable for producing preparing medicine-containing particle.In this dry granulation process, colloidal silica parcel (S)-ibuprofen, to play anti-stick effect.
Preferably, other pharmaceutically acceptable adjuvant described is filler and/or disintegrating agent.
Further preferably, described filler is any one or a few in microcrystalline Cellulose, lactose, starch, calcium hydrogen phosphate and low-substituted hydroxypropyl cellulose.The filler good fluidities such as microcrystalline Cellulose, can increase mobility and the compressibility of material.
Further preferably, described disintegrating agent is cross-linking sodium carboxymethyl cellulose and/or carboxymethyl starch sodium.The disintegrating agents such as cross-linking sodium carboxymethyl cellulose can promote the disintegrate of medicine-containing particle, contribute to the stripping of medicine.
Preferably, described in sieve into cross 20 ~ 30 mesh sieves, be more preferably 26 mesh sieves.
Said mixture material mobility and anti-stickly to make good use of, when high speed rotary tablet press is suppressed thin slice, can not sticking.Thin slice hardness is little, is easy to sieve obtain the granule of high medicament contg.
In a specific embodiment, above-mentioned dry granulation process is: (S)-ibuprofen, colloidal silica and microcrystalline Cellulose, preferably microcrystalline cellulose 102 mixing are sieved, utilize high speed rotary tablet press tabletting, sieve, obtain the granule containing (S)-ibuprofen; Preferably, with parts by weight, described (S)-ibuprofen is 200 ~ 400 weight portions, preferably 240 ~ 360 weight portions, more preferably 300 weight portions, described colloidal silica is 30 ~ 60 weight portions, preferably 40 ~ 50 weight portions, more preferably 45 weight portions, and described microcrystalline Cellulose is 30 ~ 60 weight portions, preferably 40 ~ 50 weight portions, more preferably 45 weight portions.
Second aspect, a kind of (s)-ibuprofen granules, is characterized in that, is prepared and obtain by dry granulation process described in first aspect.
As preferably, in described (s)-ibuprofen granules, the weight percentage of (S)-ibuprofen is 75%-90%, is preferably 76.9%-87%.
The third aspect, the invention provides a kind of Dex-ibuprofen sustained release tablets, and this Dex-ibuprofen sustained release tablets comprises release layer and slow release layer; Described release layer comprises (s)-ibuprofen granules described in second aspect, filler, disintegrating agent, lubricant and antiplastering aid, and described slow release layer comprises (s)-ibuprofen granules described in second aspect, skeleton agent, filler, lubricant and antiplastering aid.
Preferably, the filler in described release layer and slow release layer is any one or a few in lactose, microcrystalline Cellulose, starch, calcium hydrogen phosphate and low-substituted hydroxypropyl cellulose.
Preferably, the disintegrating agent in described release layer is cross-linking sodium carboxymethyl cellulose and/or carboxymethyl starch sodium.
Preferably, the lubricant in described release layer and slow release layer is Pulvis Talci and/or magnesium stearate.
Preferably, the antiplastering aid in described release layer and slow release layer is colloidal silica.
Preferably, the skeleton agent in described slow release layer is hydrogel matrix agent, more preferably polyoxyethylene and/or hypromellose, and still more preferably, described hypromellose is HPMC K4M CR.
Preferably, according to the weight accounting for slow releasing tablet gross weight, described release layer comprises 120 ~ 160 weight portions, preferably 140 ~ 150 weight portions, (s)-ibuprofen granules described in the claim 4 or 5 of more preferably 143 weight portions, 80 ~ 120 weight portions, preferably 90 ~ 110 weight portions, more preferably the lactose of 100 weight portions, 60 ~ 100 weight portions, preferably 70 ~ 90 weight portions, more preferably the microcrystalline Cellulose of 80 weight portions, 8 ~ 12 weight portions, preferably 9 ~ 11 weight portions, more preferably the cross-linking sodium carboxymethyl cellulose of 10 weight portions, 3 ~ 4 weight portions, preferably 3 ~ 3.5 weight portions, more preferably the Pulvis Talci of 3.15 weight portions, 3 ~ 4 weight portions, preferably 3 ~ 3.5 weight portions, more preferably the magnesium stearate of 3.18 weight portions and 2 ~ 5 weight portions, preferably 3 ~ 4 weight portions, more preferably the colloidal silica of 3.7 weight portions.
Preferably, according to the weight accounting for slow releasing tablet gross weight, described slow release layer comprises 230 ~ 260 weight portions, preferably 240 ~ 250 weight portions, (s)-ibuprofen granules described in the claim 4 or 5 of more preferably 247 weight portions, 40 ~ 80 weight portions, preferably 50 ~ 70 weight portions, more preferably the polyoxyethylene of 60 weight portions, 40 ~ 70 weight portions, preferably 50 ~ 60 weight portions, more preferably the hypromellose of 55 weight portions, 25 ~ 45 weight portions, preferably 30 ~ 40 weight portions, more preferably the calcium hydrogen phosphate of 36.5 weight portions, 1 ~ 3 weight portion, preferably 1.5 ~ 2.5 weight portions, more preferably the low-substituted hydroxypropyl cellulose of 2 weight portions, 5 ~ 8 weight portions, preferably 6 ~ 7 weight portions, more preferably the colloidal silica of 6.75 weight portions, 5 ~ 8 weight portions, preferably 6 ~ 7 weight portions, more preferably the Pulvis Talci of 6.75 weight portions and 3.5 ~ 5 weight portions, preferably 4 ~ 4.5 weight portions, more preferably the magnesium stearate of 4.25 weight portions.
Fourth aspect, the invention provides the preparation technology of the Dex-ibuprofen sustained release tablets as described in the third aspect, and this preparation technology comprises the following steps:
(1) dry granulation process described in first aspect is adopted to prepare (s)-ibuprofen granules (i.e. (s)-ibuprofen granules described in second aspect);
(2) step (1) gained (s)-ibuprofen granules is mixed homogeneously with filler, disintegrating agent, lubricant and antiplastering aid, obtain release layer mixed material;
(3) step (1) gained (s)-ibuprofen granules is mixed homogeneously with skeleton agent, filler, lubricant and antiplastering aid, obtain slow release layer mixed material;
(4) step (2) gained release layer mixed material and step (3) gained slow release layer mixed material are suppressed double-layer tablet, obtain Dex-ibuprofen sustained release tablets.
In step (2), preferably, described filler is any one or a few in lactose, microcrystalline Cellulose, starch, calcium hydrogen phosphate and low-substituted hydroxypropyl cellulose;
Preferably, described disintegrating agent is cross-linking sodium carboxymethyl cellulose and/or carboxymethyl starch sodium;
Preferably, described lubricant is Pulvis Talci and/or magnesium stearate;
Preferably, described antiplastering aid is colloidal silica.
Further preferably, according to the weight accounting for slow releasing tablet gross weight, step (2) gained release layer mixed material comprises 120 ~ 160 weight portions, preferably 140 ~ 150 weight portions, (s)-ibuprofen granules described in the claim 4 or 5 of more preferably 143 weight portions, 80 ~ 120 weight portions, preferably 90 ~ 110 weight portions, more preferably the lactose of 100 weight portions, 60 ~ 100 weight portions, preferably 70 ~ 90 weight portions, more preferably the microcrystalline Cellulose of 80 weight portions, 8 ~ 12 weight portions, preferably 9 ~ 11 weight portions, more preferably the cross-linking sodium carboxymethyl cellulose of 10 weight portions, 3 ~ 4 weight portions, preferably 3 ~ 3.5 weight portions, more preferably the Pulvis Talci of 3.15 weight portions, 3 ~ 4 weight portions, preferably 3 ~ 3.5 weight portions, more preferably the magnesium stearate of 3.18 weight portions and 2 ~ 5 weight portions, preferably 3 ~ 4 weight portions, more preferably the colloidal silica of 3.7 weight portions.
In step (3), preferably, described skeleton agent is hydrogel matrix agent, more preferably polyoxyethylene and/or hypromellose, and still more preferably, described hypromellose is HPMC K4M CR;
Preferably, described filler is any one or a few in lactose, microcrystalline Cellulose, starch, calcium hydrogen phosphate and low-substituted hydroxypropyl cellulose;
Preferably, described disintegrating agent is cross-linking sodium carboxymethyl cellulose and/or carboxymethyl starch sodium;
Preferably, described lubricant is Pulvis Talci and/or magnesium stearate;
Preferably, described antiplastering aid is colloidal silica.
Further preferably, according to the weight accounting for slow releasing tablet gross weight, step (3) gained slow release layer mixed material comprises 230 ~ 260 weight portions, preferably 240 ~ 250 weight portions, (s)-ibuprofen granules described in the claim 4 or 5 of more preferably 247 weight portions, 40 ~ 80 weight portions, preferably 50 ~ 70 weight portions, more preferably the polyoxyethylene of 60 weight portions, 40 ~ 70 weight portions, preferably 50 ~ 60 weight portions, more preferably the hypromellose of 55 weight portions, 25 ~ 45 weight portions, preferably 30 ~ 40 weight portions, more preferably the calcium hydrogen phosphate of 36.5 weight portions, 1 ~ 3 weight portion, preferably 1.5 ~ 2.5 weight portions, more preferably the low-substituted hydroxypropyl cellulose of 2 weight portions, 5 ~ 8 weight portions, preferably 6 ~ 7 weight portions, more preferably the colloidal silica of 6.75 weight portions, 5 ~ 8 weight portions, preferably 6 ~ 7 weight portions, more preferably the Pulvis Talci of 6.75 weight portions and 3.5 ~ 5 weight portions, preferably 4 ~ 4.5 weight portions, more preferably the magnesium stearate of 4.25 weight portions.
Beneficial effect of the present invention:
(1) the (S)-ibuprofen dry granulation process of first aspect present invention does not need screening, and in obtained granule, drug content is high, and granule yield is high, and speed is fast, priorly can effectively solve sticking phenomenon; Simplify technique, improve efficiency.
(2) (s)-ibuprofen granules of second aspect present invention, drug content is high, good fluidity, after mixing with other adjuvants, i.e. directly compressible, pelletization without solvent, so do not need drying.
(3) the Dex-ibuprofen sustained release tablets preparation technology of fourth aspect present invention, uses colloidal silica as antiplastering aid and uses high speed rotary tablet press dry granulation, effectively reducing long-time tabletting and cause temperature to raise the sticking phenomenon caused; Mixed with release layer, slow release layer adjuvant respectively by granule obtained by dry granulation, compacting double-layer tablet obtains Dex-ibuprofen sustained release tablets; Compared with the like product of S. Korea and the USA of Korea S of going on the market, Dex-ibuprofen sustained release tablets of the present invention has bioequivalence, but has better stability.
Accompanying drawing explanation
Fig. 1 is the (S)-ibuprofen dry granulation process flow chart of embodiment 1;
Fig. 2 is the stripping curve of the Dex-ibuprofen sustained release tablets of embodiment 2;
Fig. 3 is the pharmacokinetic curve of Dex-ibuprofen sustained release tablets of the present invention in beasle dog body.
Detailed description of the invention
Technical scheme of the present invention is further illustrated below by detailed description of the invention.
The dry granulation of embodiment 1 (S)-ibuprofen
(1) dry granulation prescription, in table 1.
Table 1, dry granulation prescription (mg/ sheet)
| Supplementary material | Prescription 1 | Prescription 2 |
| (S)-ibuprofen | 300(mean diameter 70 μm) | 300(mean diameter 30 μm) |
| Microcrystalline Cellulose 102 | 45 | 45 |
| Colloidal silica | 45 | 45 |
(2) preparation method
(S)-ibuprofen, microcrystalline Cellulose 102 and colloidal silica are mixed; cross 26 mesh sieves; after use high speed rotary tablet press (GZPK3045 type high speed rotary tablet press; 45 punchings; Shanghai Tianxiang Jian Tai pharmaceutical Co. Ltd) suppress thin slice, slice, thin piece is crossed oscillating granulator (26 eye mesh screen) and is obtained dry method granule.Fig. 1 is shown in technological process.
(3) result
In above-mentioned compacting flaking process, there is no sticking phenomenon; In gained dry method granule, the weight percentage of (S)-ibuprofen is 76.9%.
The preparation of embodiment 2 Dex-ibuprofen sustained release tablets of the present invention and dissolved corrosion
With the dry method granule prepared by the prescription of two in embodiment 1, respectively by following prescription tabletting, investigated the dissolved corrosion of the Dex-ibuprofen sustained release tablets prepared by different-grain diameter raw material by dissolution test.
(1) Dex-ibuprofen sustained release tablets prescription, in table 2.
Table 2, Dex-ibuprofen sustained release tablets prescription (mg/ sheet)
(2) preparation method
Embodiment 1 gained dry method granule and other adjuvants are taken respectively, mix homogeneously by release layer prescription; Embodiment 1 gained dry method granule and other adjuvants are taken respectively again, mix homogeneously by slow release layer prescription; Suppress double-layer tablet (DPG-30 single punch tablet machine, Beijing Gylongli Sci.&Tech. Co., Ltd., manual tabletting) afterwards.
(3) dissolution test
Leaching condition:
PH6.8 phosphate buffer: 6.8g potassium dihydrogen phosphate and 0.9583g sodium hydroxide, be dissolved in water and be diluted to 1000ml, shaking up, to obtain final product;
Medium volume: 900ml;
Device: paddle method (Chinese Pharmacopoeia version in 2010 two annex X C second methods);
Rotating speed: 50 turns;
Medium temperature: 37 DEG C;
Sample time: 0.5,1,2,4,6,8,10,12,18,24hr.
Assay:
Measure according to high performance liquid chromatography (China's coastal port two annex V D).
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler; With acetonitrile-water (phosphoric acid regulates pH2.5) (60:40) for mobile phase; Determined wavelength is 220nm.Number of theoretical plate calculates should be not less than 2000 by (S)-ibuprofen peak.
Algoscopy gets this product, and 0.45um filter membrane filters, and precision measures subsequent filtrate 20 μ l, injection liquid chromatography, record chromatogram; Drying under reduced pressure in phosphorus pentoxide desiccator of separately learning from else's experience is appropriate to the (S)-ibuprofen reference substance of constant weight, accurately weighed, add 50% dissolve with methanol and dilute the solution made about containing 0.3mg (S)-ibuprofen in every 1ml, being measured in the same method, by external standard method with calculated by peak area, to obtain final product.
Result: the stripping curve of two kinds of Dex-ibuprofen sustained release tablets is shown in Fig. 2; As seen from Figure 2, stripping is slightly quicker for micro powder grade raw material (mean diameter 30 μm), but the dissolved corrosion of two prescriptions is similar.
The dissolved corrosion of embodiment 3 Dex-ibuprofen sustained release tablets of the present invention in different dissolution medium
By in embodiment 1 with the dry method granule prepared by prescription 2, batch preparation Dex-ibuprofen sustained release tablets of the present invention (hereinafter referred to as " self-control sample ") is amplified in workshop by sustained-release tablet recipe described in embodiment 2, with like product (the trade name Maxibupen ER of the S. Korea and the USA of Korea S of going on the market, specification 300mg, lot number 11003, manufacturer: Hanmi Pharm Ind. Co., Ltd of Korea S; Hereinafter referred to as " reference preparation ") in different dissolution medium, do stripping comparative study:
Dissolution medium:
1, pH1.0 hydrochloric acid solution: 9ml hydrochloric acid, is diluted with water to 1000ml, shakes up, and to obtain final product;
2, pH6.8 phosphate buffer: 6.8g potassium dihydrogen phosphate and 0.9583g sodium hydroxide, be dissolved in water and be diluted to 1000ml, shaking up, to obtain final product;
3, pH4.0 acetate buffer: 0.738g anhydrous sodium acetate, is dissolved in water and is diluted to 1000ml, regulates pH to 4.0 to shake up, to obtain final product with glacial acetic acid;
4, water.
Medium volume: 900ml.
Device: paddle method (Chinese Pharmacopoeia version in 2010 two annex X C second methods).
Rotating speed: 50 turns.
Medium temperature: 37 DEG C.
Sample time: 0.5,1,2,4,6,8,10,12,18,24hr.
Result of the test is in table 3.
Table 3, Dex-ibuprofen sustained release tablets of the present invention compare with the dissolved corrosion of reference preparation in four kinds of media
Table 3 result shows, and self-control sample is similar with the stripping of reference preparation in four kinds of dissolution mediums.
Influence factor's test of embodiment 4 Dex-ibuprofen sustained release tablets of the present invention
The similar sample (i.e. reference preparation, with embodiment 3) of Dex-ibuprofen sustained release tablets of the present invention (namely making sample by oneself, with embodiment 3) and S. Korea and the USA of Korea S of having gone on the market is carried out influence factor's test as shown in table 4.
Influence factor's test of table 4, Dex-ibuprofen sustained release tablets of the present invention
Table 4 result shows, and the stability of the similar sample of S. Korea and the USA of Korea S that Dex-ibuprofen sustained release tablets of the present invention has gone on the market more is better; Comparatively speaking, the impact of illumination on sample is larger.
The pharmacokinetic trial of embodiment 5 Dex-ibuprofen sustained release tablets of the present invention and evaluation of bioequivalence
Subjects: Dex-ibuprofen sustained release tablets of the present invention (self-control sample, with embodiment 3) and the similar sample of S. Korea and the USA of Korea S gone on the market (reference preparation, with embodiment 3).
(1) pharmacokinetic trial
Experimental animal: beasle dog (Beagle);
Grouping: 2 groups, often organizes 5 Canis familiaris L.s;
EXPERIMENTAL DESIGN: binary cycle intersects at random;
Dosing interval: 7 days;
Get the blood time: 0.25,0.5,1,1.5,2,3,4,6,8,11,24,34,48hr.
Blood concentration-time curve as shown in Figure 3; As seen from Figure 3, the pharmacokinetic curve of Dex-ibuprofen sustained release tablets of the present invention is similar with the similar sample of S. Korea and the USA of Korea S of going on the market.
(2) relative bioavailability and evaluation of bioequivalence
With the similar sample of S. Korea and the USA of Korea S gone on the market for reference preparation, ask the relative bioavailability calculating Dex-ibuprofen sustained release tablets of the present invention, and evaluate its bioequivalence.With AUC (0 ~ 48hr) for parameter carries out evaluation of bioequivalence and relative bioavailability analysis.Three factors (namely between dosage, during week and between individuality) variance analysis and Doubled haploid population result as shown in table 5, (1-2a) % confidence interval is as shown in table 6.
Table 5, three-factor analysis of variance and Doubled haploid population
| Source of variation | Degree of freedom | SS | MS | F value | P value |
| Total error | 19 | 0.7767 | |||
| Between dosage | 1 | 0.0064 | 0.0064 | 0.1613 | 0.6985 |
| During week | 1 | 0.0035 | 0.0035 | 0.0877 | 0.7746 |
| Between individuality | 9 | 0.4493 | 0.0499 | 1.2577 | 0.3785 |
| Error | 8 | 0.3175 | 0.0397 |
Doubled haploid population and 90% credibility interval
| S | Downside T value | High side T value | T(1-0.05,ν) | 90%CL-L | 90%CL-U |
| 0.1992 | 2.10 | 2.91 | 1.86 | 83.15 | 116.34 |
Table 6, (1-2a) % confidence interval
| (1-2a)%L | (1-2a)%U |
| 5.60 | 5.71 |
Result: with the similar sample of S. Korea and the USA of Korea S gone on the market for reference preparation, the relative bioavailability of Dex-ibuprofen sustained release tablets of the present invention (self-control sample) is 99.74%; Dex-ibuprofen sustained release tablets of the present invention and reference preparation have bioequivalence (low, high side T value is more than or equal to T value simultaneously).
Applicant states, the present invention illustrates the present invention by above-described embodiment, but the present invention is not limited to above-mentioned, does not namely mean that the present invention must rely on above-mentioned could enforcement.Person of ordinary skill in the field should understand, any improvement in the present invention, to equivalence replacement and the interpolation of auxiliary element, the concrete way choice etc. of raw material selected by the present invention, all drops within protection scope of the present invention and open scope.
Claims (10)
1. a dry granulation process for (S)-ibuprofen, is characterized in that, comprising: (S)-ibuprofen, antiplastering aid and other pharmaceutically acceptable adjuvant mixing are sieved, utilize high speed rotary tablet press tabletting, sieve, must containing the granule of (S)-ibuprofen.
2. dry granulation process according to claim 1, is characterized in that, described antiplastering aid is colloidal silica;
Preferably, other pharmaceutically acceptable adjuvant described is filler and/or disintegrating agent;
Further preferably, described filler is any one or a few in microcrystalline Cellulose, lactose, starch, calcium hydrogen phosphate and low-substituted hydroxypropyl cellulose;
Further preferably, described disintegrating agent is cross-linking sodium carboxymethyl cellulose and/or carboxymethyl starch sodium;
Preferably, described in sieve into cross 20 ~ 30 mesh sieves, be more preferably 26 mesh sieves.
3. dry granulation process according to claim 1 and 2, it is characterized in that, (S)-ibuprofen, colloidal silica and microcrystalline Cellulose, preferably microcrystalline cellulose 102 mixing are sieved, utilizes high speed rotary tablet press tabletting, sieve, obtain the granule containing (S)-ibuprofen;
Preferably, with parts by weight, described (S)-ibuprofen is 200 ~ 400 weight portions, preferably 240 ~ 360 weight portions, more preferably 300 weight portions, described colloidal silica is 30 ~ 60 weight portions, preferably 40 ~ 50 weight portions, more preferably 45 weight portions, and described microcrystalline Cellulose is 30 ~ 60 weight portions, preferably 40 ~ 50 weight portions, more preferably 45 weight portions.
4. a (s)-ibuprofen granules, is characterized in that, is prepared and obtain by dry granulation process described in any one of claim 1-3.
5. (s)-ibuprofen granules as claimed in claim 4, it is characterized in that, in described granule, the weight percentage of (S)-ibuprofen is 75%-90%, is preferably 76.9%-87%.
6. a Dex-ibuprofen sustained release tablets, is characterized in that, comprises release layer and slow release layer; Described release layer comprises (s)-ibuprofen granules described in claim 4 or 5, filler, disintegrating agent, lubricant and antiplastering aid, and described slow release layer comprises (s)-ibuprofen granules described in claim 4 or 5, skeleton agent, filler, lubricant and antiplastering aid;
Preferably, the filler in described release layer and slow release layer is any one or a few in lactose, microcrystalline Cellulose, starch, calcium hydrogen phosphate and low-substituted hydroxypropyl cellulose;
Preferably, the disintegrating agent in described release layer is cross-linking sodium carboxymethyl cellulose and/or carboxymethyl starch sodium;
Preferably, the lubricant in described release layer and slow release layer is Pulvis Talci and/or magnesium stearate;
Preferably, the antiplastering aid in described release layer and slow release layer is colloidal silica;
Preferably, the skeleton agent in described slow release layer is hydrogel matrix agent, more preferably polyoxyethylene and/or hypromellose, and more preferably, described hypromellose is HPMC K4M CR.
7. Dex-ibuprofen sustained release tablets according to claim 6, it is characterized in that, according to the weight accounting for slow releasing tablet gross weight, described release layer comprises 120 ~ 160 weight portions, preferably 140 ~ 150 weight portions, (s)-ibuprofen granules described in the claim 4 or 5 of more preferably 143 weight portions, 80 ~ 120 weight portions, preferably 90 ~ 110 weight portions, more preferably the lactose of 100 weight portions, 60 ~ 100 weight portions, preferably 70 ~ 90 weight portions, more preferably the microcrystalline Cellulose of 80 weight portions, 8 ~ 12 weight portions, preferably 9 ~ 11 weight portions, more preferably the cross-linking sodium carboxymethyl cellulose of 10 weight portions, 3 ~ 4 weight portions, preferably 3 ~ 3.5 weight portions, more preferably the Pulvis Talci of 3.15 weight portions, 3 ~ 4 weight portions, preferably 3 ~ 3.5 weight portions, more preferably the magnesium stearate of 3.18 weight portions and 2 ~ 5 weight portions, preferably 3 ~ 4 weight portions, more preferably the colloidal silica of 3.7 weight portions,
Preferably, according to the weight accounting for slow releasing tablet gross weight, described slow release layer comprises 230 ~ 260 weight portions, preferably 240 ~ 250 weight portions, (s)-ibuprofen granules described in the claim 4 or 5 of more preferably 247 weight portions, 40 ~ 80 weight portions, preferably 50 ~ 70 weight portions, more preferably the polyoxyethylene of 60 weight portions, 40 ~ 70 weight portions, preferably 50 ~ 60 weight portions, more preferably the hypromellose of 55 weight portions, 25 ~ 45 weight portions, preferably 30 ~ 40 weight portions, more preferably the calcium hydrogen phosphate of 36.5 weight portions, 1 ~ 3 weight portion, preferably 1.5 ~ 2.5 weight portions, more preferably the low-substituted hydroxypropyl cellulose of 2 weight portions, 5 ~ 8 weight portions, preferably 6 ~ 7 weight portions, more preferably the colloidal silica of 6.75 weight portions, 5 ~ 8 weight portions, preferably 6 ~ 7 weight portions, more preferably the Pulvis Talci of 6.75 weight portions and 3.5 ~ 5 weight portions, preferably 4 ~ 4.5 weight portions, more preferably the magnesium stearate of 4.25 weight portions.
8. the preparation technology of Dex-ibuprofen sustained release tablets as claimed in claims 6 or 7, is characterized in that, comprise the following steps:
(1) dry granulation process described in any one of claim 1-3 is adopted to prepare (s)-ibuprofen granules;
(2) step (1) gained (s)-ibuprofen granules is mixed homogeneously with filler, disintegrating agent, lubricant and antiplastering aid, obtain release layer mixed material;
(3) step (1) gained (s)-ibuprofen granules is mixed homogeneously with skeleton agent, filler, lubricant and antiplastering aid, obtain slow release layer mixed material;
(4) step (2) gained release layer mixed material and step (3) gained slow release layer mixed material are suppressed double-layer tablet, obtain Dex-ibuprofen sustained release tablets.
9. preparation technology according to claim 8, is characterized in that, in step (2), described filler is any one or a few in lactose, microcrystalline Cellulose, starch, calcium hydrogen phosphate and low-substituted hydroxypropyl cellulose;
Preferably, described disintegrating agent is cross-linking sodium carboxymethyl cellulose and/or carboxymethyl starch sodium;
Preferably, described lubricant is Pulvis Talci and/or magnesium stearate;
Preferably, described antiplastering aid is colloidal silica;
Further preferably, according to the weight accounting for slow releasing tablet gross weight, step (2) gained release layer mixed material comprises 120 ~ 160 weight portions, preferably 140 ~ 150 weight portions, (s)-ibuprofen granules described in the claim 4 or 5 of more preferably 143 weight portions, 80 ~ 120 weight portions, preferably 90 ~ 110 weight portions, more preferably the lactose of 100 weight portions, 60 ~ 100 weight portions, preferably 70 ~ 90 weight portions, more preferably the microcrystalline Cellulose of 80 weight portions, 8 ~ 12 weight portions, preferably 9 ~ 11 weight portions, more preferably the cross-linking sodium carboxymethyl cellulose of 10 weight portions, 3 ~ 4 weight portions, preferably 3 ~ 3.5 weight portions, more preferably the Pulvis Talci of 3.15 weight portions, 3 ~ 4 weight portions, preferably 3 ~ 3.5 weight portions, more preferably the magnesium stearate of 3.18 weight portions and 2 ~ 5 weight portions, preferably 3 ~ 4 weight portions, more preferably the colloidal silica of 3.7 weight portions.
10. preparation technology according to claim 8 or claim 9, is characterized in that, in step (3), described skeleton agent is hydrogel matrix agent, be preferably polyoxyethylene and/or hypromellose, more preferably, described hypromellose is HPMC K4M CR;
Preferably, described filler is any one or a few in lactose, microcrystalline Cellulose, starch, calcium hydrogen phosphate and low-substituted hydroxypropyl cellulose;
Preferably, described disintegrating agent is cross-linking sodium carboxymethyl cellulose and/or carboxymethyl starch sodium;
Preferably, described lubricant is Pulvis Talci and/or magnesium stearate;
Preferably, described antiplastering aid is colloidal silica;
Further preferably, according to the weight accounting for slow releasing tablet gross weight, step (3) gained slow release layer mixed material comprises 230 ~ 260 weight portions, preferably 240 ~ 250 weight portions, (s)-ibuprofen granules described in the claim 4 or 5 of more preferably 247 weight portions, 40 ~ 80 weight portions, preferably 50 ~ 70 weight portions, more preferably the polyoxyethylene of 60 weight portions, 40 ~ 70 weight portions, preferably 50 ~ 60 weight portions, more preferably the hypromellose of 55 weight portions, 25 ~ 45 weight portions, preferably 30 ~ 40 weight portions, more preferably the calcium hydrogen phosphate of 36.5 weight portions, 1 ~ 3 weight portion, preferably 1.5 ~ 2.5 weight portions, more preferably the low-substituted hydroxypropyl cellulose of 2 weight portions, 5 ~ 8 weight portions, preferably 6 ~ 7 weight portions, more preferably the colloidal silica of 6.75 weight portions, 5 ~ 8 weight portions, preferably 6 ~ 7 weight portions, more preferably the Pulvis Talci of 6.75 weight portions and 3.5 ~ 5 weight portions, preferably 4 ~ 4.5 weight portions, more preferably the magnesium stearate of 4.25 weight portions.
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| CN201310507816.9A CN104546732A (en) | 2013-10-24 | 2013-10-24 | Dexibuprofen sustained-release tablet and preparation process thereof |
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| CN201310507816.9A CN104546732A (en) | 2013-10-24 | 2013-10-24 | Dexibuprofen sustained-release tablet and preparation process thereof |
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