CN101045040A - Wrapped tablets dichlororeytadin and its preparing method - Google Patents
Wrapped tablets dichlororeytadin and its preparing method Download PDFInfo
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- CN101045040A CN101045040A CNA2007100741704A CN200710074170A CN101045040A CN 101045040 A CN101045040 A CN 101045040A CN A2007100741704 A CNA2007100741704 A CN A2007100741704A CN 200710074170 A CN200710074170 A CN 200710074170A CN 101045040 A CN101045040 A CN 101045040A
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Abstract
A coated Desloratadine tablet features that it contains beta-cyclodextrin and leucine for preventing its degradation in oxygen and moisture, resulting in high stability. Its preparing process is also disclosed.
Description
Technical field
The present invention relates to a kind of composition and method of making the same of medicine, especially Desloratadine tablet and preparation method thereof.
Background technology
Desloratadine is the long-acting tricyclic antidepressants antihistaminic of non-sedating.U.S. Pat 4659716 is described in detail Desloratadine first.Desloratadine can be by optionally blocking peripheral H1-receptor, suppress the release that various anaphylaxis cause scorching chemical mediator, as: suppress mastocyte and basophilic leukocyte and discharge histamine, prostaglandin, interleukin etc., alleviate allergic rhinitis or the urticarial related symptoms of chronic idiopathic.
Desloratadine is the active metabolite of loratadine, for white or off-white color solid, is slightly soluble in water, is soluble in ethanol and propylene glycol.Its structure is as follows:
Disclose the preparation method of some Desloratadines among the patent WO02/42290, and disclose the compositions that contains this medicine and lactose.Commercially available Desloratadine tablet Clarinex
TMPharmaceutic adjuvant comprise calcium phosphate, microcrystalline Cellulose, corn starch, Pulvis Talci, palm wax, white beeswax, its coating material is: monohydroxy lactose, hydroxypropyl cellulose, titanium dioxide and polyethylene glycol.
Desloratadine is a secondary-amine compound, to acid and glucide sensitivity, the Maillard reaction very easily takes place and produce N-formyl Desloratadine, moreover, the primary amine of Desloratadine is to oxygen sensitive, oxidation by air easily, impurity such as dechlorination Desloratadine and dehydrogenation Desloratadine are given birth in degraded, and it is brown to cause the preparation color burn to become.Desloratadine is disclosed among patent US6100274 and the US2002/0123504 in the presence of conventional filler lactose, unstable in conventional storage condition, the Maillard reaction can take place with lactose in Desloratadine, thereby degraded produces N-formyl Desloratadine.
Disclose the instable method of multiple solution Desloratadine preparation in the U.S. Pat 2002/123504, having comprised: 1) used anhydrous Desloratadine raw material; 2) particle diameter of increase Desloratadine; 3) Desloratadine of employing no hygroscopicity; 4) use the protectiveness adjuvant to the Desloratadine powder coating; 5) avoid using adjuvants such as acidic excipient and lactose.
Disclose in the U.S. Pat 6100274 in the Desloratadine prescription and added alkaline calcium salt, sodium salt and aluminum salt, avoided using lactose and stearic acid to control the method for Desloratadine degraded simultaneously.The stabilization formulations of the Desloratadine that contains antioxidant, alkaline metal salt (as sodium salt, calcium salt and aluminum salt), alkaline organic matter and other pharmaceutical acceptable carriers is disclosed among the patent WO2005/065047, by the degraded in conjunction with the reduction Desloratadine of antioxidant and alkaline matter.Also disclose among the patent CN03129937 and used inorganic sulfur or this class antioxidant of organic sulfur to solve the problem that Desloratadine is easy to oxidation.In actual production process, though the use of alkali metal salt can reduce the influence of acidic excipient to Desloratadine stability, improve the content of the single maximum contaminant of Desloratadine easily, still can not well solve the unstability of Desloratadine preparation.
Use oarse-grained Desloratadine to avoid the reaction of Desloratadine and lactose among the patent CN1246794, still, influence the dissolution of medicine, and then influence the decline of bioavailability owing to particulate increase.
Use inertia or inactive coating material method among the patent CN1246794, avoid contacting of Desloratadine and lactose, reduce its degraded the Desloratadine granule coating.Also adopt anhydrous condition of storage, be suitable for the specific inhibition material that compositions is exposed under the moisture that prevents it is packed.But these special packaging material have increased the medicine production cost greatly.
Disclose among the patent CN02128998 and become the method for complex salt to improve its stability with mineral acid or organic acid reaction loratadine, CN02144874 then discloses Desloratadine and the salifiable method of fumaric acid has been solved its stable problem; Though these two kinds of methods do not limit the use of lactose or acidic excipient, need by decolouring, concentrate, process such as crystallize, increased the synthesis technique of crude drug, improved production cost.
It is that adjuvant can reduce Desloratadine and the lactose reaction is degraded into N-formyl Desloratadine that patent CA02547274 discloses selection aminoacid, and used aminoacid comprises arginine, lysine, cysteine, histidine and tyrosine.But this patent is not reported the influence of aminoacid to acidic excipient, does not report whether aminoacid has the effect that prevents Desloratadine generation oxidative degradation yet.
It is the Desloratadine tablet of adjuvant with ion exchange resin that patent WO2006/020534 discloses a kind of, has well solved the unstability of Desloratadine to acidic excipient and lactose, and Desloratadine can be made up with multiple adjuvant.But the adjuvant price height that this method is used has increased production cost.
Find that in practice in the Desloratadine tablet, Desloratadine is oxidation and degrading easily not only, deliquescence very easily also causes that related substance increases sharply in the Desloratadine tablet, influences the outward appearance and the quality of medicine.The content of the related substance of Desloratadine sheet has become an important parameter of quality of production control, and up to the present, the stable control problem of Desloratadine does not obtain fine solution always.
Summary of the invention
The coated tablet that the purpose of this invention is to provide a kind of Desloratadine has solved Desloratadine and has met the problem that oxygen is met damp problem of unstable and met the oxygen degraded, improves the safety and the stability of Desloratadine tablet, makes its more effective performance therapeutical effect.Moreover, also avoided use high price adjuvant, reduced handling procedure, reduced production cost crude drug.
Adopt following technical scheme among the present invention: a) as principal agent, be equipped with beta cyclodextrin, mannitol, low-substituted hydroxypropyl cellulose, calcium sulfate dihydrate, PEG and leucine is adjuvant to label with Desloratadine; And b) the coating adjuvant is hydroxyethyl-cellulose, stearic acid and PEG6000.
Among the present invention, use beta cyclodextrin as the raw material coating agent, can both avoid Desloratadine to be subject to the problem of oxygen degraded effectively the good embedding of Desloratadine, play parcel Desloratadine dampproof effect again, improved Desloratadine stability.And experiment finds that beta cyclodextrin can promote the stripping of medicine, helps the intravital absorption of Desloratadine
Among the present invention, use leucine, find that leucine can replace alkali metal or alkali salt series lubricant agent, have the effect that prevents the Desloratadine oxidation, solved the rising of the related substance that alkali metal or alkali salt cause effectively as lubricant.
The present invention is surprised to find that also beta cyclodextrin and leucic use can also reduce the influence of acidic excipient for Desloratadine, reduces Desloratadine because of the degraded that acidic excipient produces, and has further improved the stability of Desloratadine.
The content of above-mentioned Desloratadine be total sheet heavy 2.3～5.0%.
In the adjuvant of above-mentioned label, the content of beta cyclodextrin be total sheet heavy 4.2～9.2%, the content of mannitol be total sheet heavy 19.3～24.5%, the content of low-substituted hydroxypropyl cellulose be total sheet heavy 5.5～10.6%, the content of calcium sulfate dihydrate be total sheet heavy 2.7～7.0%, the content of PEG be total sheet heavy 4.6～9.8%, leucic content be total sheet heavy 0.5～3%.
In the above-mentioned coating adjuvant, hydroxyethyl-cellulose content be total sheet heavy 18.0～23.0%, stearic content be total sheet heavy 1.0%～3.0%, the content of PEG6000 be total sheet heavy 13.0～18.4%.
Label adjuvant PEG of the present invention can be that fusing points such as PEG600, PEG1000, PEG1500, PEG1540, PEG2000, PEG3000, PEG4000, PEG6000, PEG8000, PEG20000 are 4～70 ℃ Polyethylene Glycol.Preferred PEG4000 or PEG6000.
The invention provides the preparation method that a kind of Desloratadine coated tablet reaches, this method may further comprise the steps:
1) below 20 ℃, with Desloratadine and beta cyclodextrin, PEG ground and mixed, the granulation of sieving;
2) will operate 1) in behind gained granule and mannitol, low-substituted hydroxypropyl cellulose, calcium sulfate dihydrate and the leucine mix homogeneously tabletting get label;
3), get coating material with hydroxyethyl-cellulose, stearic acid and PEG6000 mix homogeneously;
4) will operate 3) coating material that obtains is filled on the tablet machine punch die, adds operation 2 then) label that obtains, and then in label upper strata padding 3) coating material that obtains, tabletting gets the Desloratadine coated tablet.
Aforesaid operations 1) in, Desloratadine and beta cyclodextrin and PEG are by the ball mill grinding mix homogeneously, and temperature can avoid Desloratadine rotten under high-temperature condition below 20 ℃.The described granulation of sieving is to pulverize by Fast granulate machine 1.0mm screen cloth granulate to make granule.
Aforesaid operations 1) in, described PEG is meant that fusing points such as PEG600, PEG1000, PEG1500, PEG1540, PEG2000, PEG3000, PEG4000, PEG6000, PEG8000, PEG20000 are 4～70 ℃ Polyethylene Glycol.Preferred PEG4000 or PEG6000.
Aforesaid operations 2) in, the label hardness that makes is 3.2kg/cm
2To 4.5kg/cm
2
Aforesaid operations 3) in, adopts the room temperature dry powder blend, avoided contacting of coating adjuvant and water.
Aforesaid operations 4) in, earlier the weight of the coating adjuvant of filling be total sheet heavy 3%, the adjuvant weight of putting into the coating material of inserting again behind the label be total sheet heavy 3%.Different with common packaging technique, what coating process of the present invention adopted is compacting formula art for coating solvent-free and heating.
The preparation method of tablet of the present invention is not used solvent and heating, has reduced heating and moist influence to Desloratadine, has reduced the handling procedure to raw material, has well solved in the tablet rise problem faster of related substance.
The present invention has solved the influence of adjuvant to Desloratadine effectively, reduced that Desloratadine is met oxygen and to the acidic excipient problem of unstable, compared with prior art, also solve the problem that Desloratadine makes moist and degrades, further improved the stability of medicine.Moreover, Desloratadine coated tablet of the present invention does not need to adopt expensive packaging material and adjuvant, has also reduced the production cost of medicine when improving drug quality.
Embodiment
Embodiment 1
The coated tablet prescription and the preparation method of Desloratadine content 2.3%
| Form | Content (g) | |
| Label | Desloratadine | 5 |
| Beta cyclodextrin | 20 | |
| Mannitol | 53 | |
| Low-substituted hydroxypropyl cellulose | 23 | |
| Calcium sulfate dihydrate | 10.2 | |
| PEG4000 | 15.6 | |
| Leucine | 4.56 | |
| Coating | Hydroxyethyl-cellulose | 49.9 |
| Stearic acid | 6.51 | |
| PEG6000 | 29.3 | |
1) below 20 ℃, with 5g Desloratadine and 20g beta cyclodextrin and 15.6gPEG4000 by behind the ball mill grinding mix homogeneously, with the mixture of gained with the granulation of Fast granulate machine 1.0mm screen cloth pulverize granule;
2) will operate 1) in suppress behind gained granule and 53g mannitol, 23g low-substituted hydroxypropyl cellulose, 10.2g calcium sulfate dihydrate and the 4.56g leucine mix homogeneously label, the hardness of control strip is at 3.2kg/cm2 to 4.5kg/cm2;
3), get coating material with 49.9g hydroxyethyl-cellulose, 6.51g stearic acid and 29.3gPEG6000 mix homogeneously;
4) get coating material (account for total sheet heavy 3%) and be filled on the tablet machine punch die, add label then, and then fill coating material on the label upper strata (account for total sheet heavy 3%), tabletting gets the Desloratadine coated tablet.
Embodiment 2
The coated tablet prescription and the preparation method of Desloratadine content 5.0%
| Form | Content (g) | |
| Label | Desloratadine | 5 |
| Beta cyclodextrin | 7.3 | |
| Mannitol | 21.8 | |
| Low-substituted hydroxypropyl cellulose | 10.6 | |
| Calcium sulfate dihydrate | 5.4 | |
| PEG4000 | 7 | |
| Leucine | 3 | |
| Coating | Hydroxyethyl-cellulose | 20 |
| Stearic acid | 2 | |
| PEG6000 | 17.9 | |
1) below 20 ℃, with 5g Desloratadine and 7.3g beta cyclodextrin and 7gPEG4000 by behind the ball mill grinding mix homogeneously, with the mixture of gained with the granulation of Fast granulate machine 1.0mm screen cloth pulverize granule;
2) will operate 1) in suppress behind gained granule and 21.8g mannitol, 10.6g low-substituted hydroxypropyl cellulose, 5.4g calcium sulfate dihydrate and the 3g leucine mix homogeneously label, the hardness of control strip is at 3.2kg/cm2 to 4.5kg/cm2;
3), get coating material with 20g hydroxyethyl-cellulose, 2g stearic acid and 17.9gPEG6000 mix homogeneously;
4) get coating material (account for total sheet heavy 3%) and be filled on the tablet machine punch die, add label then, and then fill coating material on the label upper strata (account for total sheet heavy 3%), tabletting gets the Desloratadine coated tablet.
Embodiment 3
The coated tablet prescription and the preparation method of Desloratadine content 3.0%
| Form | Content (g) | |
| Label | Desloratadine | 5 |
| Beta cyclodextrin | 15.36 | |
| Mannitol | 35.24 | |
| Low-substituted hydroxypropyl cellulose | 13.19 | |
| Calcium sulfate dihydrate | 10.81 | |
| PEG6000 | 16.36 | |
| Leucine | 4.18 | |
| Coating | Hydroxyethyl-cellulose | 37.66 |
| Stearic acid | 1.67 | |
| PEG6000 | 29.23 | |
1) below 20 ℃, with 5g Desloratadine and 15.36g beta cyclodextrin and 16.36gPEG6000 by behind the ball mill grinding mix homogeneously, with the mixture of gained with the granulation of Fast granulate machine 1.0mm screen cloth pulverize granule;
2) will operate 1) in suppress behind gained granule and 35.24g mannitol, 13.19g low-substituted hydroxypropyl cellulose, 10.81g calcium sulfate dihydrate and the 4.18g leucine mix homogeneously label, the hardness of control strip is at 3.2kg/cm2 to 4.5kg/cm2;
3), get coating material with 37.66g hydroxyethyl-cellulose, 1.67g stearic acid and 29.23gPEG6000 mix homogeneously;
4) get coating material (account for total sheet heavy 3%) and be filled on the tablet machine punch die, add label then, and then fill coating material on the label upper strata (account for total sheet heavy 3%), tabletting gets the Desloratadine coated tablet.
Embodiment 4
1, long-term stable experiment
Discover: the present invention can effectively control the single maximum contaminant content of tablet, and single maximum contaminant can not increase in storage period (in two years), and single maximum contaminant is between 0.08%-0.12%; Reference substance then increases obviously in storage period (in two years), and single maximum contaminant is between 0.4%-1.2%.
2, accelerated stability test
Accelerated test result shows: when 40 ℃ ± 2 ℃ relative humiditys 75% ± 5% quickened 6 months, the single maximum contaminant of reference substance reached 2.7%, and the single maximum contaminant of sample of the present invention is 0.24%.
The present invention relates to a kind of Wrapped tablets dichlororeytadin with and preparation method thereof.Added beta cyclodextrin and leucine in the label of this tablet, by beta cyclodextrin embedding and dry powder direct tabletting coating method, reduced the degraded of Desloratadine in oxygen and dampness effectively, the stability of tablet and safety have reduced production cost.
Claims (7)
1, a kind of coated tablet of Desloratadine is characterized in that: a) as principal agent, be equipped with beta cyclodextrin, mannitol, low-substituted hydroxypropyl cellulose, calcium sulfate dihydrate, PEG and leucine is adjuvant to label with Desloratadine; And b) the coating adjuvant is hydroxyethyl-cellulose, stearic acid and PEG6000.
2, tablet as claimed in claim 1, the content that it is characterized in that Desloratadine in the described label be total sheet heavy 2.3～5.0%, the content of beta cyclodextrin be total sheet heavy 4.2～9.2%, the content of mannitol be total sheet heavy 19.3～24.5%, the content of low-substituted hydroxypropyl cellulose be total sheet heavy 5.5～10.6%, the content of calcium sulfate dihydrate be total sheet heavy 2.7～7.0%, the content of PEG be total sheet heavy 4.6～9.8%, leucic content be total sheet heavy 0.5～3%; In the described coating hydroxyethyl-cellulose content be total sheet heavy 1 8.0～23.0%, stearic content be total sheet heavy 1.0%～3.0%, the content of PEG6000 be total sheet heavy 13.0～18.4%.
3, tablet as claimed in claim 1 or 2 is characterized in that described label PEG is that fusing point is 4～70 ℃ a Polyethylene Glycol.
4, tablet as claimed in claim 3 is characterized in that described label PEG is PEG4000 or PEG6000.
5, a kind of preparation method of coated tablet of Desloratadine is characterized in that may further comprise the steps:
1) below 20 ℃, with Desloratadine and beta cyclodextrin, PEG ground and mixed, the granulation of sieving;
2) will operate 1) in behind gained granule and mannitol, low-substituted hydroxypropyl cellulose, calcium sulfate dihydrate and the leucine mix homogeneously tabletting get label;
3), get coating material with hydroxyethyl-cellulose, stearic acid and PEG6000 mix homogeneously;
4) will operate 3) coating material that obtains is filled on the tablet machine punch die, adds operation 2 then) label that obtains, and then in label upper strata padding 3) coating material that obtains, tabletting gets the Desloratadine coated tablet.
6, the preparation method of coated tablet as claimed in claim 5 is characterized in that, the described PEG of step 1) is that fusing point is 4～70 ℃ a Polyethylene Glycol.
As the preparation method of claim 5 or 6 described coated tablets, it is characterized in that 7, the described PEG of step 1) is PEG4000 or PEG6000.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100741704A CN100518722C (en) | 2007-04-30 | 2007-04-30 | Wrapped tablets dichlororeytadin and its preparing method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100741704A CN100518722C (en) | 2007-04-30 | 2007-04-30 | Wrapped tablets dichlororeytadin and its preparing method |
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| Publication Number | Publication Date |
|---|---|
| CN101045040A true CN101045040A (en) | 2007-10-03 |
| CN100518722C CN100518722C (en) | 2009-07-29 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2007100741704A Expired - Fee Related CN100518722C (en) | 2007-04-30 | 2007-04-30 | Wrapped tablets dichlororeytadin and its preparing method |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101849902A (en) * | 2010-06-03 | 2010-10-06 | 浙江华海药业股份有限公司 | Preparation method of solid pharmaceutical composition containing desloratadine |
| CN102697711A (en) * | 2012-05-24 | 2012-10-03 | 广州新济药业科技有限公司 | Desloratadine oral liquid preparation and preparation method thereof |
| CN101548959B (en) * | 2008-04-03 | 2012-11-21 | 万特制药(海南)有限公司 | Coated tablet containing desloratadine and preparation method thereof |
| CN102038645B (en) * | 2009-10-12 | 2013-11-27 | 杭州赛利药物研究所有限公司 | Desloratadine grain and preparation method thereof |
| CN103721267A (en) * | 2013-12-16 | 2014-04-16 | 扬子江药业集团广州海瑞药业有限公司 | Composition containing desloratadine citrate disodium |
| CN103877006A (en) * | 2012-12-20 | 2014-06-25 | 杭州赛利药物研究所有限公司 | Desloratadine gel and its preparation method |
| CN106957349A (en) * | 2017-04-26 | 2017-07-18 | 深圳市海滨制药有限公司 | A kind of Desloratadine impurity compound and its production and use |
| CN113893357A (en) * | 2021-11-29 | 2022-01-07 | 河南省儿童医院郑州儿童医院 | Desloratadine preparation and preparation method thereof |
-
2007
- 2007-04-30 CN CNB2007100741704A patent/CN100518722C/en not_active Expired - Fee Related
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101548959B (en) * | 2008-04-03 | 2012-11-21 | 万特制药(海南)有限公司 | Coated tablet containing desloratadine and preparation method thereof |
| CN102038645B (en) * | 2009-10-12 | 2013-11-27 | 杭州赛利药物研究所有限公司 | Desloratadine grain and preparation method thereof |
| CN101849902A (en) * | 2010-06-03 | 2010-10-06 | 浙江华海药业股份有限公司 | Preparation method of solid pharmaceutical composition containing desloratadine |
| CN102697711A (en) * | 2012-05-24 | 2012-10-03 | 广州新济药业科技有限公司 | Desloratadine oral liquid preparation and preparation method thereof |
| CN103877006A (en) * | 2012-12-20 | 2014-06-25 | 杭州赛利药物研究所有限公司 | Desloratadine gel and its preparation method |
| CN103721267A (en) * | 2013-12-16 | 2014-04-16 | 扬子江药业集团广州海瑞药业有限公司 | Composition containing desloratadine citrate disodium |
| CN106957349A (en) * | 2017-04-26 | 2017-07-18 | 深圳市海滨制药有限公司 | A kind of Desloratadine impurity compound and its production and use |
| CN113893357A (en) * | 2021-11-29 | 2022-01-07 | 河南省儿童医院郑州儿童医院 | Desloratadine preparation and preparation method thereof |
| CN113893357B (en) * | 2021-11-29 | 2024-04-12 | 河南省儿童医院郑州儿童医院 | Deslorata customization agent and preparation method thereof |
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|---|---|
| CN100518722C (en) | 2009-07-29 |
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Address after: Shenzhen City, Guangdong Province, 518040 Shennan Road No. 6009 Che Kung Temple Green Plaza building 37 layer Patentee after: Shenzhen Salubris Pharmaceuticals Co., Ltd. Address before: 518040, 1901, 1902, 1903, 1923, Shennan Exhibition Center, 6007 Shennan Road, Shenzhen, Guangdong, Futian District Patentee before: Shenzhen Salubris Pharmaceuticals Co., Ltd. |
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Granted publication date: 20090729 Termination date: 20200430 |