CN103405782A - Inclusion compound containing celecoxib and preparation method thereof - Google Patents
Inclusion compound containing celecoxib and preparation method thereof Download PDFInfo
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- CN103405782A CN103405782A CN2013103823167A CN201310382316A CN103405782A CN 103405782 A CN103405782 A CN 103405782A CN 2013103823167 A CN2013103823167 A CN 2013103823167A CN 201310382316 A CN201310382316 A CN 201310382316A CN 103405782 A CN103405782 A CN 103405782A
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- celecoxib
- clathrate
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- cyclodextrin
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Abstract
The invention relates to an inclusion compound containing celecoxib and a preparation method thereof. The inclusion compound containing celecoxib comprises celecoxib and an inclusion material, wherein the inclusion material is preferable one or two of beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin; the weight ratio of the inclusion material to the celecoxib is (0.5-10):1. The preparation method comprises the following steps: respectively dissolving the inclusion material and the celecoxib in water and an organic solvent; slowly dropwise adding the saturated aqueous solution of the inclusion material into the organic solution containing the celecoxib; continuously stirring to form a white suspension; preparing the inclusion compound containing the celecoxib by adopting a vacuum drying or freeze-drying mode. The inclusion compound can be crushed to be prepared into various solid preparations. According to the inclusion compound containing celecoxib, the problem of extremely poor dissolubility of celecoxib in water can be solved, a high-bioavailability solid preparation with stable property can be prepared by adopting a simple and practical process, and the problem that a celecoxib raw material medicine is difficult to crush can be solved.
Description
Technical field
The present invention relates to a kind of celecoxib clathrate, the method for the described clathrate of preparation and the solid preparation that comprises described clathrate.
Background technology
Celecoxib is former times cloth non-steroid antiphlogistic, it is the compound of new generation with unique effect mechanism, be that specificity suppresses Cycloxygenase-2, be mainly used in clinically the treatment of osteoarthritis, rheumatoid arthritis and the auxiliary treatment of familial adenomatous polyposis, this kind was got permission to go on the market in the U.S. in 1998.In JIUYUE, 2000, the celecoxib import packing of State Food and Drug Administration approval pfizer inc at Discussion on Chinese Listed.So far, celecoxib has been got permission the list marketing in tens countries (area).
Celecoxib is that white is to the off-white color crystalline powder, at methanol, ethanol, easily molten in acetone and dimethyl sulfoxine, almost insoluble in water, so oral absorption is poor, in order to improve its bioavailability, the patent No. is that 99802185.7 patent literature celecoxib granule D90 is less than 200um, be preferable over D90 and be less than 100um, more preferably in D90, be less than 45um, most preferably in D90, be less than 25um and make according to a conventional method preparation, just can reach the purpose of effective bioavailability, it is low that but the celecoxib raw material has a bulk density, the raw material pulverizing process in bulk that easily bonds, therefore micronization is more difficult, repeated multiple times comminution by gas stream just can reach D90 and be less than 35um, so industrialization comparision of production difficulty, the present invention considers to adopt a kind of inclusion technique to increase the dissolubility of celecoxib for this reason, thereby improve the purpose of various preparation bioavailability, can also solve simultaneously celecoxib and easily adsorb the difficult problem of pulverizing.
Summary of the invention
When our company copies research to this kind, be surprised to find that a kind of celecoxib clathrate and preparation method thereof, after the clathrate that uses the method to prepare is made corresponding preparation, can improve significantly dissolution and bioavailability, and preparation nature is stable, easy and simple to handle, favorable reproducibility, the simultaneously preparation of clathrate is simple, easy operating, control also.Be exactly to adopt a small amount of dissolution with solvents enclose material and celecoxib particularly, then mix and blend is made white suspension mutually, adopt drying under reduced pressure or cryodesiccated mode to obtain solid dispersion.
The present invention is to provide a kind of celecoxib clathrate, wherein said clathrate contains celecoxib and enclose material, and described enclose material is selected from cyclodextrin or cyclodextrin derivative, preferably one or both in beta-schardinger dextrin-, HP-β-CD.
Celecoxib clathrate of the present invention, wherein the weight ratio of required enclose material and celecoxib is 0.5-10: 1; Be preferably 1-6: 1,3-6 more preferably: 1.
Celecoxib clathrate of the present invention, in each specific embodiment, the celecoxib clathrate all is comprised of celecoxib and enclose material, and described enclose material is preferably one or both in beta-schardinger dextrin-, HP-β-CD.
The preparation method of celecoxib clathrate of the present invention is simple, exactly celecoxib is dissolved in organic solvent, keeps certain temperature, slowly splash in the saturated aqueous solution that contains the enclose material, continuous stirring is made white suspension, after adopting drying under reduced pressure or lyophilization and get final product.
Organic solvent described in preparation method of the present invention is selected from one or more in methanol, ethanol, acetone, dichloromethane.
The further application in solid preparation of celecoxib clathrate of the present invention, is characterized in that applying celecoxib clathrate prepared by this kind method and be prepared into solid preparation, and described solid preparation is tablet, pill, granule or capsule etc.
The solid preparation preparation method of celecoxib clathrate of the present invention: the clathrate that first will prepare adds 100 mesh sieves and pulverizes, with the required diluent of solid preparation molding and disintegrating agent etc., mix homogeneously again, add the binding agent wet granulation, the particle drying of preparation sieves even with mix lubricant after granulate, is prepared into capsule, granule or tablet; Also the available packages compound adds the directly production technology of encapsulated or direct compression of suitable adjuvant; As required, also can be further by gained granule or plain coating tablets.
Form is described in further detail content of the present invention more by the following examples, but should not be interpreted as in the above-mentioned subject area of the present invention at this point and only limit to following examples.Do not breaking away under the above-mentioned technology prerequisite of the present invention, the corresponding replacement of making according to ordinary skill knowledge and customary means or the modification of change, include within the scope of the invention
.
Test 1: the preparation of celecoxib clathrate
Embodiment 1
Formula forms:
The celecoxib raw material is by our company's self-control, and authentication code is: the accurate word H20133228 of traditional Chinese medicines.
Preparation method: take the formula ratio celecoxib, adding appropriate ethanol dissolves it fully, keep certain temperature, be added dropwise to the saturated aqueous solution of the enclose carrier of formula ratio, continue to stir 1 hour stopped heating, continue again to be stirred to room temperature, obtain white suspended matter, filter final vacuum and be drying to obtain, also can be by the direct lyophilization of white suspended matter.
Embodiment 2
Formula forms:
Preparation method: take the formula ratio celecoxib, add appropriate ethanol it is dissolved fully, keep certain temperature, be added dropwise to the saturated aqueous solution of the enclose carrier of formula ratio, continue to stir 1 hour stopped heating, continue again to be stirred to room temperature, obtain white suspended matter, directly lyophilization and get final product.
Embodiment 3
Formula forms:
Preparation method: take the formula ratio celecoxib, add appropriate ethanol it is dissolved fully, keep certain temperature, be added dropwise to the saturated aqueous solution of the enclose carrier of formula ratio, continue to stir 1 hour stopped heating, continue again to be stirred to room temperature, obtain white suspended matter, filter final vacuum and be drying to obtain.
Embodiment 4
Formula forms:
Preparation method: take the formula ratio celecoxib, add appropriate ethanol it is dissolved fully, keep certain temperature, be added dropwise to the saturated aqueous solution of the enclose carrier of formula ratio, continue to stir 1 hour stopped heating, continue again to be stirred to room temperature, obtain white suspended matter, filter final vacuum and be drying to obtain.
Test 2: contain the preparation of the oral solid formulation of celecoxib clathrate
Embodiment 5: contain the preparation of celecoxib 200mg capsule
Prescription forms:
Preparation method: cross 100 mesh sieves after clathrate is pulverized, with lactose, 30 POVIDONE K 30 BP/USP
30And the cross-linking sodium carboxymethyl cellulose mix homogeneously, water is cooked the wetting agent wet granulation, after the wet grain drying granulate with encapsulated after magnesium stearate is mixed homogeneously and get final product.
Embodiment 6: contain the preparation of celecoxib 100mg capsule
Prescription forms:
Preparation method: cross 100 mesh sieves after clathrate is pulverized, with lactose, 30 POVIDONE K 30 BP/USP
30And the cross-linking sodium carboxymethyl cellulose mix homogeneously, water is cooked the wetting agent wet granulation, after the wet grain drying granulate with encapsulated after magnesium stearate is mixed homogeneously and get final product.
Embodiment 7: contain the preparation of celecoxib 100mg conventional tablet
Prescription forms:
Preparation method: after clathrate is pulverized, cross 100 mesh sieves, mix homogeneously with lactose, microcrystalline Cellulose and cross-linking sodium carboxymethyl cellulose, water is cooked the wetting agent wet granulation, after the wet grain drying granulate with tabletting after magnesium stearate is mixed homogeneously and get final product.
Embodiment 8: contain the preparation of celecoxib 50mg conventional tablet
Prescription forms:
Preparation method: after clathrate is pulverized, cross 100 mesh sieves, mix homogeneously with lactose, microcrystalline Cellulose and cross-linking sodium carboxymethyl cellulose, water is cooked the wetting agent wet granulation, after the wet grain drying granulate with tabletting after magnesium stearate is mixed homogeneously and get final product.
Embodiment 9: contain the preparation of celecoxib 200mg granule
Prescription forms:
Preparation method: after clathrate is pulverized, cross 100 mesh sieves, mix homogeneously with lactose, microcrystalline Cellulose and cross-linking sodium carboxymethyl cellulose, water is cooked the wetting agent wet granulation, after the wet grain drying granulate with packing after magnesium stearate is mixed homogeneously and get final product.
Embodiment 10: contain the preparation of celecoxib 100mg granule
Prescription forms:
Preparation method: after clathrate is pulverized, cross 100 mesh sieves, mix homogeneously with lactose, microcrystalline Cellulose and cross-linking sodium carboxymethyl cellulose, water is cooked the wetting agent wet granulation, after the wet grain drying granulate with packing after magnesium stearate is mixed homogeneously and get final product.
Embodiment 11: contain the preparation of celecoxib 50mg granule
Prescription forms
Preparation method: after clathrate is pulverized, cross 100 mesh sieves, mix homogeneously with lactose, microcrystalline Cellulose and cross-linking sodium carboxymethyl cellulose, water is cooked the wetting agent wet granulation, after the wet grain drying granulate with packing after magnesium stearate is mixed homogeneously and get final product.
Test 3: comparative example's preparation
The comparative example: with the homemade raw material of our company, directly prepare the celecoxib capsule without pulverization process, specification is 200mg.
Prescription forms:
The celecoxib crude drug is mixed homogeneously with lactose, cross-linking sodium carboxymethyl cellulose, sodium lauryl sulphate, use 30 POVIDONE K 30 BP/USP
30Aqueous solution carry out wet granulation, after the wet grain drying granulate with encapsulated after magnesium stearate is mixed homogeneously and get final product.
Test 4: the test of celecoxib clathrate dissolubility in water of different enclose ratios:
The celecoxib clathrate that takes a certain amount of celecoxib crude drug and prepare by above-mentioned each formula adds respectively the 100ml purified water in conical flask, jolting was dissolved 30 minutes under the condition of 25 ± 2 ℃ of room temperature, the saturated solution of gained after filtering, pipette a certain amount of dilution standardize solution to volumetric flask, with HPLC, measure its concentration, obtain dissolubility.
Dissolubility without enclose celecoxib raw material is: 0.885 μ g/ml, and the dissolving testing result of other enclose sample is in Table 1:
Table 1: dissolubility testing result
As can be seen from Table 1, its dissolubility of clathrate that adopts beta-schardinger dextrin-and HP-β-CD and celecoxib to prepare obviously is greater than the enclose carrier that adopts other, pass through in addition the celecoxib clathrate dissolubility of preparation of inclusion complex far away higher than the celecoxib raw material without enclose, reached the goal of the invention that improves its dissolubility by preparation of inclusion complex.
Test 5: the In Vitro Dissolution Experimental Comparison of different embodiment:
To contain the capsule formula 18 to 22 of celecoxib clathrate and comparative example's formula sample (formula 34) and the listing product (celecoxib of Pfizer Inc., the capsule that contains celecoxib 200mg, lot number BK11CCEE120) carry out the In Vitro Dissolution test.
Test method: above-mentioned sample is respectively according to dissolution method (two appendix X C the second methods of Chinese Pharmacopoeia version in 2010), with the 0.04M trisodium phosphate solution (regulating PH12.0 ± 0.1 with phosphoric acid or sodium hydroxide test solution) that contains 1% lauryl sulphate acid, 1000ml is dissolution medium, rotating speed is per minute 50 to turn, operation in accordance with the law, respectively with 5, 15, 30, 45, in the time of 60 minutes, get solution 8ml(and supplement simultaneously the equivalent dissolution medium), filter, it is appropriate that precision measures subsequent filtrate respectively, with the mobile phase dissolved dilution, become the solution that approximately contains 0.1mg in every 1ml, as need testing solution, according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2010), place measures respectively its peak area at the 256nm wavelength.Separately get the celecoxib reference substance appropriate, add the appropriate dissolved dilution of mobile phase and make the solution that every 1ml contains 0.1mg, solution, be measured in the same method in contrast, calculates every stripping quantity at different time.
The In Vitro Dissolution result of the test is in Table 2:
Table 2: In Vitro Dissolution result of the test
In analysis, the dissolution test result of table 2 is visible, the stripping of the solid preparation of the medicinal inclusion compound of the formula 18 to 22 of the embodiment of the present invention 5,6 obviously is better than the dissolution of the pharmaceutical composition that comparative example's crude drug do not pulverize, and is better than simultaneously the sample formulation of going on the market.
By research of the present invention, realized increasing the dissolubility of medicine, improve the In Vitro Dissolution of its solid preparation, thereby improve the purpose of various solid preparation bioavailability.
Claims (8)
1. clathrate that contains celecoxib, wherein said clathrate contains celecoxib and enclose material, and described enclose material is selected from cyclodextrin or cyclodextrin derivative, preferably
β-Cyclodextrin, hydroxypropyl
-β-One or both in cyclodextrin.
2. celecoxib clathrate according to claim 1, the weight ratio of wherein said enclose material and celecoxib is 0.5-10: 1.
3. celecoxib clathrate according to claim 1 and 2, wherein the weight ratio of enclose material and celecoxib is preferably 1-6: 1.
4. according to the described celecoxib clathrate of claims 1 to 3, the weight ratio of enclose material and celecoxib 3-6 more preferably wherein: 1.
5. according to the described celecoxib clathrate of claim 1 to 4 any one, wherein the celecoxib clathrate is comprised of celecoxib and carrier material.
6. the preparation method of the described celecoxib clathrate of claim 1 to 5 any one, comprising celecoxib is dissolved in organic solvent, keep certain temperature, slowly splash into the saturated aqueous solution of enclose material, continuous stirring is made white suspension, adopts drying under reduced pressure or cryodesiccated mode to obtain containing the clathrate of celecoxib.
7. preparation method according to claim 6, wherein said organic solvent is selected from one or more in methanol, ethanol, acetone, dichloromethane.
8. according to the application of the described celecoxib clathrate of claim 1 to 5 any one in solid preparation, it is characterized in that applying celecoxib clathrate prepared by this kind method and be prepared into solid preparation, described solid preparation is tablet, pill, granule or capsule.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2013103823167A CN103405782A (en) | 2013-08-29 | 2013-08-29 | Inclusion compound containing celecoxib and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2013103823167A CN103405782A (en) | 2013-08-29 | 2013-08-29 | Inclusion compound containing celecoxib and preparation method thereof |
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| CN103405782A true CN103405782A (en) | 2013-11-27 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113521308A (en) * | 2021-09-16 | 2021-10-22 | 奥信阳光(北京)药业科技有限公司 | Inclusion compound of celecoxib and gallic acid modified sulfobutyl betacyclodextrin sodium and preparation method thereof |
| CN114191440A (en) * | 2021-12-30 | 2022-03-18 | 江苏同禾药业有限公司 | Celecoxib composition and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101410012A (en) * | 2006-03-28 | 2009-04-15 | 杰佛林制药公司 | Formulations of low dose non-steroidal anti-inflammatory drugs and beta-cyclodextrin |
-
2013
- 2013-08-29 CN CN2013103823167A patent/CN103405782A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101410012A (en) * | 2006-03-28 | 2009-04-15 | 杰佛林制药公司 | Formulations of low dose non-steroidal anti-inflammatory drugs and beta-cyclodextrin |
Non-Patent Citations (1)
| Title |
|---|
| 梅兴国: "《药物新剂型与制剂新技术》", 31 January 2007 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113521308A (en) * | 2021-09-16 | 2021-10-22 | 奥信阳光(北京)药业科技有限公司 | Inclusion compound of celecoxib and gallic acid modified sulfobutyl betacyclodextrin sodium and preparation method thereof |
| CN113521308B (en) * | 2021-09-16 | 2021-12-07 | 奥信阳光(北京)药业科技有限公司 | Inclusion compound of celecoxib and gallic acid modified sulfobutyl betacyclodextrin sodium and preparation method thereof |
| CN114191440A (en) * | 2021-12-30 | 2022-03-18 | 江苏同禾药业有限公司 | Celecoxib composition and preparation method thereof |
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Application publication date: 20131127 |