CN101849902B - Preparation method of solid pharmaceutical composition containing desloratadine - Google Patents
Preparation method of solid pharmaceutical composition containing desloratadine Download PDFInfo
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- CN101849902B CN101849902B CN2010101992472A CN201010199247A CN101849902B CN 101849902 B CN101849902 B CN 101849902B CN 2010101992472 A CN2010101992472 A CN 2010101992472A CN 201010199247 A CN201010199247 A CN 201010199247A CN 101849902 B CN101849902 B CN 101849902B
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Abstract
The invention relates to a method for stably preparing a solid drug combination containing desloratadine. The solid drug combination includes the active ingredient desloratadine and basic salt drug use auxiliary material, wherein the grain size of the desloratadine d(0.9) is 100-400mum, preferably 250-350mum, and the basic salt drug use auxiliary material is selected from one or more of anhydrous calcium hydrogen phosphate, dicalcium phosphate dehydrate, calcium sulfate, and calcium carbonate and accounts for 30%-60% of the total weight of the preparation.
Description
Technical field
The present invention relates to a kind of method for preparing of solid composite medicament, concrete relate to a kind of method for preparing that contains the solid composite medicament of Desloratadine.
Background technology
Desloratadine is the long-acting tricyclic antidepressants antihistaminic of non-sedating property, is used for allergic rhinitis, the urticarial treatment of chronic idiopathic.
Its chemistry is by name: 8-chloro-6,11-dihydro-11 (4-piperidylidene)-5H-benzo-[5,6] heptane [1,2-b] pyridine.
English by name: Desloratadine.
Skeleton symbol:
US 4659716 has carried out detailed description to Desloratadine first: it is the active metabolite of loratadine; Can be through optionally blocking peripheral H1-receptor; Suppress the release that various anaphylaxis cause scorching chemical mediator, discharge histamine, prostaglandin, interleukin etc. as suppressing mastocyte and basophilic leukocyte.
US 5595997 proposes; Desloratadine both can provide effectively, the antihistamine of no sedation treatment, also can avoid many often with common hydryllin and the relevant common serious side effects of other non-sedative antihistamine agent (especially for example loratadine, teldane and A Simi) administration.Importantly, the specific activity loratadine of known Desloratadine in tumor enhancement low 5 to 7 times, and the effectiveness of Desloratadine on histamine receptor is at least than high about 20 times of loratadine.
CN 1552324A discloses the antioxidant that in formulation products, adds 0.001%-2%, makes the stable method of Desloratadine sheet.Obviously, the pharmaceutic adjuvant antioxidant of extra increase can make drug prescription become more complicated, and will be quite difficult with the antioxidant mix homogeneously in formulation products that is low to moderate 0.001%, and this has increased the pharmaceutical industries production cost greatly.And uneven mixing will inevitably cause product stability there are differences; For example because the antioxidant mixing is inhomogeneous, some tablet contains more antioxidant, can keep stable in a long time; And other tablets lack the antioxidant of capacity, can not guarantee the stability of product.
WO 2007/096733 adopts cyclodextrin and the bonded method of Desloratadine, and the preparation clathrate improves the stability of product.And in embodiment, all used Butylated hydroxyanisole as antioxidant, and concrete is dissolved into Butylated hydroxyanisole in the mixed solvent of isopropyl alcohol or isopropanol, and the reuse adjuvant absorbs and is dry to guarantee the uniformity of antioxidant.This has increased the complexity of preparation prescription technology, and the use of isopropyl alcohol simultaneously also is unfavorable for protecting environment and reduces production costs.
It is unstable in acidic excipient that US 6100274 discloses Desloratadine, and main consequence is that color change and impurity raise, and its main degradation products is a N-formyl Desloratadine.This patent discloses the pharmaceutical composition that contains basic salt; Improved the stability of Desloratadine formulation products to a certain extent; But its disclosed embodiment shows; Its formulation products is at 40 ℃, and storage is after 6 months under the condition of 75% relative humidity, and the amount of impurity N-formyl Desloratadine increases to 0.8% (bottled) and 1.2% (aluminium-plastic bubble plate packing).The daily dose of Desloratadine is 5mg, evaluates the center guideline according to national drug, and its impurity Quality Control limit is 0.5%, and obviously, the disclosed scheme of patent is not enough to guarantee the stability of product.And the disclosed method for preparing of this patent, need heating starch/water dispersion liquid to 95 ℃ with the preparation starch slurry as binding agent, this method process is loaded down with trivial details, and energy consumption is bigger, is now replaced by other technology gradually.
According to above analysis, still be necessary to study a kind of easier and effective production technology at present, to improve the stability of Desloratadine formulation products, simplify technology simultaneously, reduce production costs.
Summary of the invention
Therefore, the invention provides a kind of method for preparing that contains the solid composite medicament of active component Desloratadine and alkaline salt pharmaceutic adjuvant.It is simple that this method has technical process, is fit to suitability for industrialized production, better according to the Desloratadine tablet stability that this method makes.
The inventor finds to use the Desloratadine of greater particle size can make the dissolution rate of product too slow under study for action, can not guarantee its bioavailability and clinical efficacy; And the product that the Desloratadine that uses superfine particle diameter prepares impurity growth in stability experiment is very fast, is difficult to guarantee the stability of product, and this possibly be that the less raw material ratio surface area of granularity is bigger, more easily with airborne water, due to oxygen reacts.
Therefore, according to the present invention, the particle diameter d (0.9) of Desloratadine is between 100-400 μ m.
According to the present invention, preferred, the particle diameter d (0.9) of Desloratadine is between 150-400 μ m.
According to the present invention, preferred, the particle diameter d (0.9) of Desloratadine is between 250-350 μ m.
Wherein particle diameter is all represented with particle volume diameter, can adopt laser particle degree appearance to measure.
The inventor also finds to use the alkaline salt pharmaceutic adjuvant can improve the stability of product to a certain extent.The particle diameter d (0.9) that particularly works as the control Desloratadine uses when being equivalent to the alkaline salt pharmaceutic adjuvant of tablet total weight amount 30%-60% between 100-400 μ m simultaneously, can well improve the stability of product.
So according to the present invention, described alkaline salt pharmaceutic adjuvant can be selected from one or more in calcium phosphate dibasic anhydrous, dicalcium phosphate dehydrate, calcium sulfate, the calcium carbonate.
According to the present invention, preferred, described alkaline salt pharmaceutic adjuvant can be selected from one or more in calcium phosphate dibasic anhydrous, the dicalcium phosphate dehydrate.
According to the present invention, preferred, described alkaline salt pharmaceutic adjuvant is selected from dicalcium phosphate dehydrate.
According to the present invention, preferred, the consumption of described alkaline salt pharmaceutic adjuvant is the 30%-50% that is equivalent to the tablet total weight amount.
According to the present invention, preferred, the consumption of described alkaline salt pharmaceutic adjuvant is the 35%-45% that is equivalent to the tablet total weight amount.
According to Desloratadine sheet of the present invention, can also include fluidizer, lubricant, and acceptable auxiliary on other pharmaceuticss.
According to the present invention, fluidizer can be selected from Pulvis Talci, silicon dioxide, colloidal silica, and the ratio of fluidizer is 0-5%, is preferably 0.5%-3%.
According to according to the present invention, lubricant can be selected from magnesium stearate, sodium stearyl fumarate, and the ratio of lubricant is 0-2%, is preferably 0.5%-1%.
According to the present invention, acceptable auxiliary can be selected from microcrystalline Cellulose, optimize microcrystalline Cellulose, corn starch, pregelatinized Starch on other pharmaceuticss.Obvious, more novel composite auxiliary material such as starch microcrystalline Cellulose complex also are applicable to the present invention.These adjuvants are mainly used in gains in weight, and to obtain the tablet of suitable dimension, makes things convenient for the patient to take.
According to Desloratadine sheet of the present invention, can also further be prepared into coated tablet.
According to the present invention; Can use Opadry
coating powder to carry out coating; Coating weightening finish is 1%～6%, preferably 2%～4%.
The polymorphism of medicine is very general, and crystal formation is different, they
PhysicsAspect differences such as character such as density, fusing point, hardness, outward appearance, dissolubility and dissolution rate all have significance.Under uniform temperature and pressure, having only a kind of in the polymorphic is stable type, and chemical stability is best.Therefore different crystal forms can influence the stability of product and influence the clinical efficacy and the safety of medicine to a certain extent.
The bibliographical information Desloratadine has multiple crystal formation at present, comprises crystalline form I and crystal form II, and its characteristic is following:
The Desloratadine crystalline form I, its X ray diffracting characteristic peak roughly is expressed as:
Table 1
D spacing (± 0.04) RI
9.04 a little less than
6.42 a little less than
5.67 a little less than
5.02 a little less than
3.58 a little less than
Characteristic peak is 3303,1290,803 and 780cm in its IR spectrum
-1
The Desloratadine crystal form II, its X ray diffracting characteristic peak roughly is expressed as:
Table 2
D spacing (± 0.04) RI
8.34 a little less than
6.87 it is medium
6.20 it is medium
4.90 it is medium
Characteristic peak is 3326,1153,1133,795,771 and 655cm in its IR spectrum
-1
According to the present invention, preferably loratadine is a crystalline form I.
The present invention adopts the one-step palletizing process advantage to be: mixing in the production technology, granulation, dry run are accomplished at an equipment, simplify production technology, save time, and labor intensity is low.The granule that makes is the soft granule of porous, and density is little, and intensity is little, and particulate even particle size distribution, and is mobile, compression forming property is good.Simultaneously, the method that the present invention adopted has compared with prior art been avoided reducing the material loss when shifting like material transfer step repeatedly in the technologies such as wet granulation, dry granulation, direct compression; Improve product yield, save time, improved production efficiency; Reduce production costs; Be fit to suitability for industrialized production, can also prevent dust from flying, important function has been played in healthy and environmental conservation to operator.
The inventor finds that marumerization can obviously improve product stability than additive method when research Desloratadine piece preparation method in addition.The particle diameter d (0.9) that particularly works as the control Desloratadine is between 100-400 μ m; When application is equivalent to the alkaline salt pharmaceutic adjuvant of tablet total weight amount 30%-60%; Adopt the one-step palletizing method again, can greatly improve the stability of product, the formulation products that makes commercially available back is at 40 ℃; Quicken after 6 months under the 75% relative humidity condition, product still conforms to quality requirements.
Therefore, the invention provides the preparation technology of said Desloratadine sheet, its concrete production process comprises following steps:
A, Desloratadine is distributed in the purified water, fully stirs to form dispersion liquid;
B, acceptable auxiliary on alkaline salt pharmaceutic adjuvant and other pharmaceuticss is placed fluid bed; And under the heating fluidized, spray Desloratadine aqueous dispersions with steps A;
C, the material in the fluid bed is carried out drying, make dried dry materials weightlessness less than 3.0%;
D, with the processing of sieving of dried material, and the adding fluidizer and the mix lubricant that need;
E, the material that adopts suitable tabletting punch holder " step D " to obtain are suppressed in flakes;
F, tablet is carried out film coating.
Have according to the Desloratadine sheet of the inventive method gained that stripping is no less than 85% dissolution characteristic in the hydrochloric acid solution of 30 minutes inherent pH1.0.
Dissolution test is to carry out according to the oar method mode of Chinese Pharmacopoeia.The temperature of dissolve medium is 37 ± 0.5 ℃, paddle rotating speed 50rpm.The volume of employed dissolve medium is 500 milliliters.Measure the stripping percentage ratio of Desloratadine through ultraviolet spectrophotometry.
The specific embodiment
Below in conjunction with embodiment the present invention is done further description, but the present invention does not receive the restriction of embodiment.
Embodiment 1-3:
Prescription is seen table 3:
Table 3
Wherein, the Desloratadine granularity d (0.9) of embodiment 1 use is 150 μ m; The Desloratadine granularity d (0.9) that embodiment 2 uses is 330 μ m; The Desloratadine granularity d (0.9) that embodiment 3 uses is 350 μ m.
Preparation technology:
1, is distributed to the 5g Desloratadine in the 100g water, forms dispersion liquid;
2, be poured into dicalcium phosphate dihydrate, microcrystalline Cellulose, corn starch in the fluid bed, spray is with the Desloratadine aqueous dispersions under the heating fluidized;
3, material in the fluid bed is carried out heat drying, the loss on drying that makes material is less than 3.0%;
4,, and add Pulvis Talci and mix the formation mixture with magnesium stearate the processing of sieving of dried material;
5, with the 7mm round punch in flakes, obtain the tablet that sheet heavily is about 100mg with the mixture compacting.
6, adopt the high-efficiency coating pot that tablet is carried out coating.
With embodiment 1,2, the sample of 3 preparations is with aluminium-plastic bubble plate packing, and carry out accelerated test (temperature: 40 ℃, relative humidity: 75%) investigate, measure related substance, the result sees table 4:
Table 4
And prior art is seen among the embodiment 10 of patent US6100274, wherein explain sample after the blister package under acceleration environment (temperature: 40 ℃, relative humidity: 75%) place June after, N-formylDCL impurity rises to 1.2%.The relative prior art of the present invention is described, the impurity of the more effective inhibition product of ability raises, and can better guarantee product stability.
Embodiment 4-6:
Prescription is seen table 5:
Table 5
Preparation technology:
1, is distributed to the 5g Desloratadine in the 100g water, forms dispersion liquid;
2, be poured into dicalcium phosphate dihydrate, optimization microcrystalline Cellulose, corn starch in the fluid bed, spray is with the Desloratadine aqueous dispersions under the heating fluidized;
3, material in the fluid bed is carried out heat drying, the loss on drying that makes material is less than 3.0%;
4,, and add Pulvis Talci and mix the formation mixture with magnesium stearate the processing of sieving of dried material;
5, with the 7mm round punch in flakes, obtain the tablet that sheet heavily is about 100mg with the mixture compacting.
6, adopt the high-efficiency coating pot that tablet is carried out coating.
Claims (8)
1. method for preparing that contains the solid composite medicament of active component Desloratadine and alkaline salt pharmaceutic adjuvant is characterized in that:
(1) the particle diameter d (0.9) of active component Desloratadine is 100-400 μ m;
(2) the alkaline salt pharmaceutic adjuvant is selected from one or more of calcium phosphate dibasic anhydrous, dicalcium phosphate dehydrate, calcium sulfate, calcium carbonate, accounts for the 30%-60% of total formulation weight amount;
(3) method for preparing comprises following steps:
A, Desloratadine is distributed in the purified water, fully stirs to form dispersion liquid;
B, acceptable auxiliary on alkaline salt pharmaceutic adjuvant and other pharmaceuticss is placed fluid bed, and under the heating fluidized spray with the Desloratadine aqueous dispersions of steps A;
C, the material in the fluid bed is carried out drying, make dried dry materials weightlessness less than 3.0%;
D, with the processing of sieving of dried material, and the adding fluidizer and the mix lubricant that need;
E, the suitable tabletting drift of employing are suppressed " step D " resulting material in flakes;
F, optionally tablet is carried out film coating.
2. the method for preparing of a solid composite medicament as claimed in claim 1 is characterized in that the particle diameter d (0.9) of active component Desloratadine is preferably 150-400 μ m.
3. the method for preparing of a solid composite medicament as claimed in claim 2 is characterized in that the particle diameter d (0.9) of active component Desloratadine further is preferably 250-350 μ m.
4. the method for preparing of a solid composite medicament as claimed in claim 1 is characterized in that the active component Desloratadine is crystal formation I.
5. the method for preparing of a solid composite medicament as claimed in claim 1 is characterized in that the alkaline salt pharmaceutic adjuvant is preferably from calcium phosphate dibasic anhydrous, dicalcium phosphate dehydrate.
6. the method for preparing of a solid composite medicament as claimed in claim 5 is characterized in that the alkaline salt pharmaceutic adjuvant is a dicalcium phosphate dehydrate.
7. the method for preparing of a solid composite medicament as claimed in claim 1 is characterized in that the alkaline salt pharmaceutic adjuvant accounts for the 30%-50% of total formulation weight amount.
8. the method for preparing of a solid composite medicament as claimed in claim 7 is characterized in that the alkaline salt pharmaceutic adjuvant accounts for the 35%-45% of total formulation weight amount.
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| CN104224733B (en) * | 2014-09-30 | 2016-08-17 | 蔡伦 | A kind of loratadine granule and preparation method thereof |
| CN108498481B (en) * | 2018-06-20 | 2020-09-25 | 国药集团致君（深圳）制药有限公司 | Cefixime composition and preparation method thereof |
| CN110403910A (en) * | 2019-09-02 | 2019-11-05 | 广东九明制药有限公司 | Desloratadine piece and preparation method thereof |
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| 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 |
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