CN103462920A - Oral cyclo-oxygenase-2 inhibitor Celecoxib composition - Google Patents
Oral cyclo-oxygenase-2 inhibitor Celecoxib composition Download PDFInfo
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- CN103462920A CN103462920A CN2012101837315A CN201210183731A CN103462920A CN 103462920 A CN103462920 A CN 103462920A CN 2012101837315 A CN2012101837315 A CN 2012101837315A CN 201210183731 A CN201210183731 A CN 201210183731A CN 103462920 A CN103462920 A CN 103462920A
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Abstract
The invention relates to a cyclo-oxygenase-2 inhibitor Celecoxib composition consisting of a quick-release part and a sustained-release part. The quick-release part comprises a medicine, a quick release material, a binder and a lubricant with effect of suppression of crystal; and the sustained-release part comprises the medicine, a slow-release material with effect of suppression of crystal, an adhesive and a lubricant. The preparation prepared by the invention has characteristics of simple preparation process, low energy consumption, fast onset, long maintenance time of blood drug concentration and stable concentration.
Description
One, technical field
The present invention relates to the composition and method of making the same of cyclooxygenase-2 inhibitor celecoxib.
Two, background technology
Cyclooxygenase-2 inhibitor celecoxib Celecoxib, chemical name 4-[5-(4-aminomethyl phenyl)-3-(trifluoromethyl) 1H-pyrazol-1-yl] benzsulfamide is selectivity ring-type oxygenase-2 (COX-2) inhibitor.Inflammatory stimulus can induce COX-2 to generate, thereby causes the synthetic of inflammatory prostaglandins and build up, especially
pGE2, cause inflammation, edema and pain.Celecoxib can stop the generation of inflammatory prostaglandins by suppressing COX-2, reach antiinflammatory, analgesia and antipyretic effect.This class medicine is in the lenitive while, the serious gastrointestinal side effect that can avoid NSAID (non-steroidal anti-inflammatory drug) in the past to bring.Since cox 2 inhibitor application, the patient that the gastrointestinal side effect caused because of arthritis treatment is in hospital obviously reduces.Be mainly used in clinically treating acute stage or chronic phase osteoarthritis and symptom and the Signs of rheumatoid arthritis.
Celecoxib has the physical property of low solubility, caking property, low bulk density and low compressibility, causes in preparation body that its general preparation method makes degree of absorbing very low.When tabletting, thereby easily form viscosity minute hand shape crystallization crystalline state, melt in bulk simultaneously.When mixing with unclassified stores, because its easy crystallization forms bulky grain, with other separating substances, to cause mixing homogeneity poor.
Celecoxib preparation difficulty, degree of absorbing hang down main low relevant with easy crystallization with its dissolubility, therefore will reach celecoxib therapeutic effect preferably, and first-selection will solve dissolubility and a crystallinity difficult problem.Have in recent years by preparation binary release composition, prepare dense granule, add crystallizing inhibitor, prepare the several different methods such as self-emulsifying drug and reach and improve the effect that dissolubility suppresses crystallization, but method therefor complicated process of preparation, energy consumption are large at present.
Three, summary of the invention
The objective of the invention is: for existing methodical defect, provide a kind of preparation method of celecoxib oral formulations of applicable suitability for industrialized production.
Celecoxib oral formulations of the present invention is divided into two parts, and immediate release section discharges rapidly in vivo, and the short time reaches effective pain relieving concentration in vivo, pain relieving rapidly; Slow-released part slowly discharges, and can maintain blood drug level steady, reaches long-acting antiphlogistic effects.
Technical scheme of the present invention is as follows:
A kind of celecoxib compositions, it is comprised of immediate release section and slow-released part, immediate release section by medicine, rapid release material, excipient, there is the lubricant that presses down brilliant effect and form, slow-released part by medicine, there is the slow-release material, excipient, the lubricant that press down brilliant effect and form.Two parts respectively contain the cyclooxygenase-2 inhibitor of 50-150mg, and immediate release section and slow-released part mass ratio are 1 to compare 1-3.
Specifically, celecoxib compositions of the present invention, in an embodiment of the present invention, by every 1000 slices/quality: the immediate release section Chinese medicine is the 50-100 gram, the rapid release material is the 30-50 gram, excipient is the 22-108 gram, having the lubricant that presses down brilliant effect is the 30-90 gram, slow-released part Chinese medicine 50-150 gram, and having the slow-release material that presses down brilliant effect is the 50-90 gram, excipient is the 45-147 gram, and in slow release layer, lubricant is the 3-4 gram.
Above-mentioned rapid release material is polyvinylpolypyrrolidone or cross-linking sodium carboxymethyl cellulose.
Above-mentioned excipient is microcrystalline Cellulose-lactose.
It is above-mentioned that to have the lubricant that presses down brilliant effect be glyceryl monostearate C40 or micropowder silica gel.
It is above-mentioned that to have the slow-release material that presses down brilliant effect be hydroxypropyl emthylcellulose.
Above-mentioned lubricant is one or more the mixture in magnesium stearate, Pulvis Talci.
Celecoxib compositions of the present invention can adopt the dry powder direct tabletting method for making.
A kind of method for making of celecoxib quick-release and slow-release tablet of the present invention, it comprises the steps:
Step 1. pre-treatment
Celecoxib is beaten to powder with having the mix lubricant that presses down brilliant effect, must mix powder 1.,
The preparation of the mixed powder of step 2.:
1. release layer batching: get mixed powder 1., rapid release material, excipient mixed 60 mesh sieves by the equivalent incremental method, mixes, and must mix powder 2.,
2. slow release layer batching: get celecoxib, slow-release material, excipient and mixed 60 mesh sieves by the equivalent incremental method, mix, add lubricant, mix, must mix powder 3.,
Step 3. tabletting
Get mixed powder 2. with mixed powder 3., after weighing respectively, release layer and slow release layer powder are placed in respectively to two hoppers of bi-layer tablet press, on bi-layer tablet press, compacting in flakes.
It is encapsulated that celecoxib compositions of the present invention can adopt dry granulation to divide.
A kind of method for making of celecoxib quick-release and slow-release capsule of the present invention, it comprises the steps:
Step 1. pre-treatment
Celecoxib is beaten to powder with having the mix lubricant that presses down brilliant effect, must mix powder 1.,
The preparation of the mixed powder of step 2.:
1. immediate release section batching: get mixed powder 1., rapid release material, excipient mixed 60 mesh sieves by the equivalent incremental method, mixes, and must mix powder 2.,
2. slow-released part batching: get celecoxib, slow-release material, excipient and mixed 60 mesh sieves by the equivalent incremental method, mix, must mix powder 3.,
Step 3. is granulated
2. and 3. get respectively mixed powder, dry granulation;
Step 4. is encapsulated
After the granule granulate, weigh respectively, add lubricant to mix, incapsulate the filler charge door, encapsulated.
Innovation of the present invention and benefit are:
1, the method for blood drug level in the preparation performance of the cyclooxygenase-2 inhibitor that improves low solubility and body has: preparation binary release composition, prepare dense granule, reduce tendency for drug crystallization, form the self emulsifying system.The preparation process of these methods is more complicated, and the present invention has adopted direct powder compression and dry granulation to divide encapsulated preparation method, and preparation technology is simple, and less energy consumption is beneficial to large production;
2, cyclooxygenase-2 inhibitor low solubility, caking property, low bulk density, lazy flow low compressibility, easily the crystallization vitreous clinker, to mix homogeneity poor, the basic method that usually improves the preparation performance is to add crystallizing inhibitor, improve dissolubility and mobility.Existing crystallizing inhibitor is selected from the cellulose substances such as polyvinylpyrrolidone, hydroxypropyl emthylcellulose, cross-linking sodium carboxymethyl cellulose usually, these materials usually play binding agent in preparation, although the effect that has crystallizing inhibitor concurrently can suppress the crystallization of cyclooxygenase-2 inhibitor, improve and can press row, inhibition crystallization to improve the mixing homogeneity, but but can not solve with this type of material the problem that improves dissolubility, mobility and bulk density, must prepare technical ability in conjunction with other.And the present invention has selected and has had lubricant glyceryl monostearate C40 and/or the micropowder silica gel that presses down brilliant effect, solved simultaneously low solubility, caking property, low bulk density, lazy flow low compressibility, easily the crystallization vitreous clinker, mix the poor problem of homogeneity.
3, usually medicine and mix lubricant can be played and improve drug flow, effect anti-stick, attractive in appearance, but cyclooxygenase-2 inhibitor with have the lubricant that presses down brilliant effect conventional mixes for its press down brilliant, improve and mix homogeneity, improve and can press capable effect also bad, the present invention by cyclooxygenase-2 inhibitor with there is the lubricant that presses down brilliant effect and carry out pre-treatment, mix and beat powder, again with other material mix preparations, can effectively improve that cyclooxygenase-2 inhibitor dissolubility, resistance to bond, agglomeration resistance are capable, mobility, compressibility, mixing homogeneity.
4, the blood drug level-time graph that will take after slow-releasing tablets of oral medicine of the present invention and commercially available Celecoxib formulation products compares (see photo), can find out oral drugs of the present invention rapid-action, the blood drug level retention time long, concentration is more steady.
Four, accompanying drawing explanation
Compare Fig. 1, oral Celecoxib quick-release and slow-release sheet of the present invention and commercially available prod: the blood drug level-time plot after taking;
Compare Fig. 2, oral Celecoxib quick-release and slow-release capsule of the present invention and commercially available prod: the blood drug level-time plot after taking;
Five, the specific embodiment
The preparation method (dry powder vertical compression) of embodiment 1. celecoxib quick-release and slow-release sheets
At first, the 100g celecoxib is mixed with the 70g micropowder silica gel and beat powder, then mixed 60 mesh sieves with 40g cross-linking sodium carboxymethyl cellulose, 108g microcrystalline Cellulose-lactose by the equivalent incremental method, mix, obtain the mixed powder of rapid release; Separately get 100g celecoxib, 80g hydroxypropyl emthylcellulose, 98g microcrystalline Cellulose-lactose, 4g magnesium stearate and mixed 60 mesh sieves by the equivalent incremental method, mix, obtain the mixed powder of slow release; The mixed powder of rapid release and slow release are mixed to two hoppers that powder is placed in respectively bi-layer tablet press, be pressed into 1000 on bi-layer tablet press.Every containing the 200mg celecoxib.
The preparation method (dry powder vertical compression) of embodiment 2. celecoxib quick-release and slow-release sheets
At first, the 100g celecoxib is mixed with 90g glyceryl monostearate C40 and beat powder, then mixed 60 mesh sieves with 50g polyvinylpolypyrrolidone, 102g microcrystalline Cellulose-lactose by the equivalent incremental method, mix, obtain the mixed powder of rapid release; Separately get 100g celecoxib, 60g hydroxypropyl emthylcellulose, 94g microcrystalline Cellulose-lactose, 4g Pulvis Talci and mixed 60 mesh sieves by the equivalent incremental method, mix, obtain the mixed powder of slow release; The mixed powder of rapid release and slow release are mixed to two hoppers that powder is placed in respectively bi-layer tablet press, be pressed into 1000 on bi-layer tablet press.Every containing the 200mg celecoxib.
The preparation method (dry powder vertical compression) of embodiment 3. celecoxib quick-release and slow-release sheets
At first, the 50g celecoxib is mixed with 60g glyceryl monostearate C40 and beat powder, then mixed 60 mesh sieves with 30g polyvinylpolypyrrolidone, 70g microcrystalline Cellulose-lactose by the equivalent incremental method, mix, obtain the mixed powder of rapid release; Separately get 150g celecoxib, 90g hydroxypropyl emthylcellulose, 147g microcrystalline Cellulose-lactose, 1.5g Pulvis Talci, 1.5g magnesium stearate and mixed 60 mesh sieves by the equivalent incremental method, mix, obtain the mixed powder of slow release; The mixed powder of rapid release and slow release are mixed to two hoppers that powder is placed in respectively bi-layer tablet press, be pressed into 1000 on bi-layer tablet press.Every containing the 200mg celecoxib.
The preparation method (dry granulation) of embodiment 4. celecoxib quick-release and slow-release capsules
At first, the 50g celecoxib is mixed with 40g glyceryl monostearate C40 and beat powder, then mixed 60 mesh sieves with 30g polyvinylpolypyrrolidone, 98g microcrystalline Cellulose-lactose by the equivalent incremental method, mix, obtain the mixed powder of rapid release, dry granulation; Separately get 50g celecoxib, 60g hydroxypropyl emthylcellulose, 68g microcrystalline Cellulose-lactose and mixed 60 mesh sieves by the equivalent incremental method, mix, obtain the mixed powder of slow release, dry granulation; After the granule granulate, add 2g Pulvis Talci, 2g magnesium stearate to mix, incapsulate the filler charge door, fill 1000 capsules.Every capsules is containing the 100mg celecoxib.
The preparation method (dry granulation) of embodiment 5. celecoxib quick-release and slow-release capsules
At first, the 80g celecoxib is mixed with 20g glyceryl monostearate C40,10g micropowder silica gel and beat powder, then mixed 60 mesh sieves with 35g cross-linking sodium carboxymethyl cellulose, 22g microcrystalline Cellulose-lactose by the equivalent incremental method, mix, obtain the mixed powder of rapid release, dry granulation; Separately get 120g celecoxib, 55g hydroxypropyl emthylcellulose, 55g microcrystalline Cellulose-lactose and mixed 60 mesh sieves by the equivalent incremental method, mix, obtain the mixed powder of slow release, dry granulation; After the granule granulate, add the 3g magnesium stearate to mix, incapsulate the filler charge door, fill 1000 capsules.Every capsules is containing the 200mg celecoxib.
The preparation method (dry granulation) of embodiment 6. celecoxib quick-release and slow-release capsules
At first, the 100g celecoxib is mixed with 15g glyceryl monostearate C40,15g micropowder silica gel and beat powder, then mixed 60 mesh sieves with 36g polyvinylpolypyrrolidone, 35g microcrystalline Cellulose-lactose by the equivalent incremental method, mix, obtain the mixed powder of rapid release, dry granulation; Separately get 100g celecoxib, 50g hydroxypropyl emthylcellulose, 45g microcrystalline Cellulose-lactose and mixed 60 mesh sieves by the equivalent incremental method, mix, obtain the mixed powder of slow release, dry granulation; After the granule granulate, add 2g magnesium stearate, 2g Pulvis Talci to mix, incapsulate the filler charge door, fill 1000 capsules.Every capsules is containing the 200mg celecoxib.
Claims (6)
1. the compositions of an oral cyclooxygenase-2 inhibitor celecoxib, it is characterized in that: it is comprised of immediate release section and slow-released part, wherein, immediate release section by medicine, rapid release material, excipient, there is the lubricant that presses down brilliant effect and form, slow-released part by medicine, there is the slow-release material, excipient, the lubricant that press down brilliant effect and form.Two parts respectively contain the cyclooxygenase-2 inhibitor of 50-150mg, and immediate release section and slow-released part mass ratio are 1 to compare 1-3; Described rapid release material is polyvinylpolypyrrolidone or cross-linking sodium carboxymethyl cellulose; Described excipient is microcrystalline Cellulose-lactose; It is described that to have the lubricant that presses down brilliant effect be glyceryl monostearate C40 or micropowder silica gel; It is described that to have the slow-release material that presses down brilliant effect be hydroxypropyl emthylcellulose; Described lubricant is one or more the mixture in magnesium stearate, Pulvis Talci.
2. the compositions of claim 1, wherein said compositions is the form of tablet or capsule.
3. the compositions of claim 2, immediate release section:
The content of described medicine is that 8.33wt% is to 25wt%
The content of described rapid release material is that 5wt% is to 9wt%
The content of described excipient is that 5.5wt% is to 24.5wt%
It is described that to have the lubricant content that presses down brilliant effect be that 7.5wt% is to 15wt%.
4. the compositions of claim 2, slow-released part
The content of described medicine is that 16.66wt% is to 30wt%
The described content with the slow-release material that presses down brilliant effect is that 10wt% is to 15wt%
The content of described excipient is that 11.25wt% is to 24.5wt%
Described lubricant content is that 0.5wt% is to 1wt%.
5. the production technology of a celecoxib compositions claimed in claim 2 is characterized in that it comprises following steps:
(1) pre-treatment
Celecoxib is beaten to powder with having the mix lubricant that presses down brilliant effect, must mix powder 1.,
(2) preparation of mixed powder:
Release layer batching: get mixed powder 1., rapid release material, excipient mixed 60 mesh sieves by the equivalent incremental method, mixes, and must mix powder 2.,
Slow release layer batching: get celecoxib, slow-release material, excipient and mixed 60 mesh sieves by the equivalent incremental method, mix, add lubricant, mix, must mix powder 3.,
(3) tabletting
Get mixed powder 2. with mixed powder 3., after weighing respectively, release layer and slow release layer powder are placed in respectively to two hoppers of bi-layer tablet press, on bi-layer tablet press, compacting in flakes.
6. the production technology of a celecoxib compositions claimed in claim 2 is characterized in that it comprises following steps:
(1) pre-treatment
Celecoxib is beaten to powder with having the mix lubricant that presses down brilliant effect, must mix powder 1.,
(2) preparation of mixed powder:
Immediate release section batching: get mixed powder 1., rapid release material, excipient mixed 60 mesh sieves by the equivalent incremental method, mixes, and must mix powder 2.,
Slow-released part batching: get celecoxib, slow-release material, excipient and mixed 60 mesh sieves by the equivalent incremental method, mix, must mix powder 3.,
(3) granulate
2. and 3. get respectively mixed powder, dry granulation;
(4) encapsulated
After the granule granulate, weigh respectively, add lubricant to mix, incapsulate the filler charge door, encapsulated.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012101837315A CN103462920A (en) | 2012-06-06 | 2012-06-06 | Oral cyclo-oxygenase-2 inhibitor Celecoxib composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012101837315A CN103462920A (en) | 2012-06-06 | 2012-06-06 | Oral cyclo-oxygenase-2 inhibitor Celecoxib composition |
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| CN103462920A true CN103462920A (en) | 2013-12-25 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2012101837315A Pending CN103462920A (en) | 2012-06-06 | 2012-06-06 | Oral cyclo-oxygenase-2 inhibitor Celecoxib composition |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108524527A (en) * | 2017-03-02 | 2018-09-14 | 北京德立福瑞医药科技有限公司 | Celecoxib pharmaceutical composition and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001045706A1 (en) * | 1999-12-22 | 2001-06-28 | Pharmacia Corporation | Dual-release compositions of a cyclooxygenase-2- inhibitor |
| CN1411447A (en) * | 1999-12-08 | 2003-04-16 | 药品公司 | Polymorphic crystalline forms of celecoxib |
| CN1434713A (en) * | 1999-12-22 | 2003-08-06 | 法马西亚公司 | Sustained-release formulation of a cyclooxygenase-2 inhibitor |
-
2012
- 2012-06-06 CN CN2012101837315A patent/CN103462920A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1411447A (en) * | 1999-12-08 | 2003-04-16 | 药品公司 | Polymorphic crystalline forms of celecoxib |
| WO2001045706A1 (en) * | 1999-12-22 | 2001-06-28 | Pharmacia Corporation | Dual-release compositions of a cyclooxygenase-2- inhibitor |
| CN1434713A (en) * | 1999-12-22 | 2003-08-06 | 法马西亚公司 | Sustained-release formulation of a cyclooxygenase-2 inhibitor |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108524527A (en) * | 2017-03-02 | 2018-09-14 | 北京德立福瑞医药科技有限公司 | Celecoxib pharmaceutical composition and preparation method thereof |
| CN108524527B (en) * | 2017-03-02 | 2020-08-04 | 北京德立福瑞医药科技有限公司 | Celecoxib pharmaceutical composition and preparation method thereof |
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Application publication date: 20131225 |