CN104721147A - Azilsartan solid dispersion as well as preparation method and medicament composition thereof - Google Patents
Azilsartan solid dispersion as well as preparation method and medicament composition thereof Download PDFInfo
- Publication number
- CN104721147A CN104721147A CN201510158869.3A CN201510158869A CN104721147A CN 104721147 A CN104721147 A CN 104721147A CN 201510158869 A CN201510158869 A CN 201510158869A CN 104721147 A CN104721147 A CN 104721147A
- Authority
- CN
- China
- Prior art keywords
- azilsartan
- solid dispersion
- preparation
- raw material
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to an azilsartan solid dispersion as well as a preparation method and a medicament composition thereof. The preparation method of the azilsartan solid dispersion comprises the following steps: adding water into an azilsartan raw material and a surfactant, and grinding to obtain a suspension; and drying the suspension, and then crushing to obtain the azilsartan solid dispersion. The preparation method can increase the permeability and dissolution property of the azilsartan raw material to ensure that the solubility and dissolution rate of the azilsartan raw material are obviously increased, thereby improving the bioavailability of the azilsartan raw material; and moreover, the water replaces an organic solvent to ensure that the safety of the preparation process and the product is high. The solid dispersion obtained by the preparation method provided by the invention is high in solubility, and the medicament composition containing the solid dispersion is high in dissolution rate and good in stability.
Description
Technical field
The present invention relates to a kind of preparation containing insoluble drug and preparation method thereof, pharmaceutical composition, particularly a kind of azilsartan solid dispersion and preparation method thereof, pharmaceutical composition.
Background technology
Azilsartan (English name Azilsartan), chemical name: 2-ethyoxyl-1-[[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazoles-3-base) biphenyl-4-base] methyl]-1H-benzimidazole-7-carboxylic acid, molecular formula is C
25h
20n
4o
5, molecular weight: 456.45, this product is white or off-white color crystalline powder, odorless.Be soluble in N,N-dimethylacetamide, be slightly soluble in methanol, be insoluble in ethanol (99.5%), water-soluble hardly.The Angiotensin Ⅱ receptor antagonist medicine Azilsartan (Azilsartan, specification 20mg, 40mg) of the treatment vascular hypertension researched and developed by Japanese Wu Tian company, in January, 2012 gets permission listing, for hypertensive treatment in Japan.
Azilsartan is a kind of angiotensin Π receptor antagonist pharmaceuticals of the treatment vascular hypertension be in research and development, Angiotensin II Shou Shrink blood vessel function is blocked by the combination of selective exclusion Angiotensin II and vascular smooth muscle ATI receptor, being used for treating vascular hypertension, is also angiotensin ii receptor antagonist (the husky smooth class) medicine being uniquely in late-stage clinical at present.Azilsartan is as dual-use function ARBs of new generation, and not only 1 receptor (AT1 receptor) of antagonizing angiotensin II, also can reduce the risk of cardiovascular disease and diabetes by number of mechanisms.Clinical trial proves, this product have curative effect better, adverse reaction rate is lower, the good feature of compliance.
Azilsartan is almost insoluble in water, be slightly soluble in methanol, when it is made as medicinal preparation for oral administration, only has and could absorb well in gastrointestinal when Azilsartan can be dissolved in fast and efficiently or be scattered in water, otherwise, very large obstacle is had for its absorption and biological utilisation.Therefore, under the prerequisite of compound pharmacological properties not changing it, the water solublity and the dissolution that improve it are vital.
Solid dispersion refers to a kind of disperse system existed in solid form being highly dispersed in by medicine and being formed in solid carrier, at solid dispersion Chinese medicine with existence such as molecularity, colloidal state, inferior stable state, crystallite state and amorphous states.
In prior art Azilsartan preparation preparation method in still there is the defects such as complicated process of preparation, formulation dissolution is low, dissolution is low, bioavailability is low, further research and development solve the problem is very necessary.
Summary of the invention
In order to overcome defect of the prior art, the preparation method that the invention provides a kind of azilsartan solid dispersion and the azilsartan solid dispersion using the method to prepare, additionally provide pharmaceutical composition containing this azilsartan solid dispersion and preparation method thereof.The preparation method step of azilsartan solid dispersion is simple, by being prepared as the mode of solid dispersion to water-insoluble Azilsartan raw material moistened surface and modification, increase infiltration and the solubility property of Azilsartan raw material, its dissolubility and dissolution rate are increased significantly, thus improves its bioavailability; And make the safety of preparation process and product high with water to replace organic solvent.The preparation method of the pharmaceutical composition containing azilsartan solid dispersion has above-mentioned advantage equally.High according to the solid dispersion dissolubility that above-mentioned preparation method obtains, the pharmaceutical composition dissolution rate containing this solid dispersion is fast, good stability.
A preparation method for azilsartan solid dispersion, comprises the following steps: be that the Azilsartan raw material of 100:5-500 and surface modifier add water and be ground to Azilsartan particle diameter D by mass ratio
90be not more than 80 μm, obtain suspension, then by suspension crushed after being dried, obtain azilsartan solid dispersion; Wherein: the mass ratio of described Azilsartan raw material and described water is 1:10-1000; Described surface modifier is selected from one or more in water-soluble polymer, water-soluble saccharides, surfactant; Described water-soluble polymer is selected from one or more in polyvinylpyrrolidone, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, polyvinyl alcohol; Described water-soluble saccharides is selected from one or more in lactose, sucrose, mannitol, sorbitol, xylitol; Described surfactant is selected from one or more in polyoxyethylene sorbitan monoleate, castor oil hydrogenated (such as CremophorRH 40, Cremophor RH60), Pluronic F68 (such as poloxamer188, poloxamer 118), sodium lauryl sulphate, lecithin, sucrose fatty acid ester.
A preparation method for azilsartan solid dispersion, wherein said Azilsartan raw material and surface modifier add water and are ground to Azilsartan particle diameter D
90it is 30 μm ~ 80 μm.
A preparation method for azilsartan solid dispersion, the mass ratio of wherein said Azilsartan raw material and described water is 1:20-50.
A preparation method for azilsartan solid dispersion, the mass ratio of wherein said Azilsartan raw material and surface modifier is 100:30-250.
A preparation method for azilsartan solid dispersion, wherein said surface modifier is one or more in hydroxypropyl emthylcellulose, polyoxyethylene sorbitan monoleate, sucrose fatty acid ester.
A preparation method for azilsartan solid dispersion, the surface modifier wherein needed for every 100 parts of described Azilsartan raw materials is made up of one or more surface modifiers being selected from lower group: 5-35 part hydroxypropyl emthylcellulose; 10-100 part polyoxyethylene sorbitan monoleate; 10-100 part sucrose fatty acid ester.
A kind of preparation method of azilsartan solid dispersion, surface modifier wherein needed for every 100 parts of described Azilsartan raw materials is surface modifier compositions 1 or surface modifier compositions 2, described surface modifier compositions 1 is made up of 20-35 part hydroxypropyl emthylcellulose and 10-20 part polyoxyethylene sorbitan monoleate, and described surface modifier compositions 2 is made up of 20-35 part hydroxypropyl emthylcellulose and 10-20 part sucrose fatty acid ester.
A preparation method for azilsartan solid dispersion, the mode of wherein said grinding is basket polishing.
A preparation method for azilsartan solid dispersion, the seasoning of any routine that wherein said drying can use field of pharmacology known is carried out, as fluid bed drying, spraying dry.
Present invention also offers the azilsartan solid dispersion obtained according to above-mentioned preparation method.
Invention further provides the pharmaceutical composition comprising described azilsartan solid dispersion and materia medica acceptable carrier.Pharmaceutical composition of the present invention can be semi-finished product containing azilsartan solid dispersion and pharmaceutic adjuvant composition or preparation.
Invention further provides the preparation method of described pharmaceutical composition.
A preparation method for troche medical composition, described method comprises the step mixture of described azilsartan solid dispersion and materia medica acceptable carrier being pressed into tablet.
A preparation method for capsule medicine compositions, described method comprises the mixture of described azilsartan solid dispersion and materia medica acceptable carrier is packed into stomach dissolution type Capsules, makes the step of capsule.
Compared with prior art, the present invention has following beneficial effect:
1. the preparation method of azilsartan solid dispersion of the present invention has following beneficial effect:
(1) step is simple, utilize hydrophilic and the permeability of water-soluble polymer, water-soluble saccharides and surfactant, it is fully ground with Azilsartan raw material under the condition added water, thus by carrying out moistened surface and modification to water-insoluble Azilsartan raw material and being prepared as the mode of solid dispersion, increase infiltration and the solubility property of Azilsartan raw material, its dissolubility and dissolution rate are obviously increased, thus improves its bioavailability;
(2) adopt water compositing dispersion medium, can avoid, by the potential Safety production questions with an organic solvent caused, also can avoiding the problem of residual solvent;
(3) preferred basket polishing utilizes aqueous solution to grind, and basket grinding has circulating cooling system, and process of lapping, without high temperataure phenomena, effectively avoids electrostatic to produce the gathering caused simultaneously; And comminution by gas stream micronization process, the instantaneous high-temperature of generation, also creates electrostatic, causes powder body to be assembled.Use solid dispersion good stability prepared by basket polishing, and jet mill or Universalpulverizer, easily produce the high temperature of moment at crushing process, Azilsartan is oxidable generation catabolite at high temperature, uses comminution by gas stream to make the impurity of Azilsartan newly increase 2.
The preparation method of the pharmaceutical composition 2, containing azilsartan solid dispersion has above-mentioned advantage equally.
3, the azilsartan solid dispersion that obtains of above-mentioned preparation method and Azilsartan raw material ratio comparatively, have desirable dissolubility; The tablet become by solid dispersion preparation or capsule, its dissolved corrosion and listing are former, and to grind medicine consistent.
Accompanying drawing explanation
Fig. 1 is Azilsartan sheet in embodiment 8, Azilsartan capsule and the former stripping curve figure grinding medicine that goes on the market;
Fig. 2 is Azilsartan sheet in embodiment 9, Azilsartan capsule and the former stripping curve figure grinding medicine that goes on the market;
Fig. 3 is Azilsartan sheet in embodiment 10, Azilsartan capsule and the former stripping curve figure grinding medicine that goes on the market;
Fig. 4 is Azilsartan sheet in embodiment 11, Azilsartan capsule and the former stripping curve figure grinding medicine that goes on the market;
Fig. 5 is Azilsartan sheet in embodiment 12, Azilsartan capsule and the former stripping curve figure grinding medicine that goes on the market;
Fig. 6 is Azilsartan sheet in embodiment 13, Azilsartan capsule and the former stripping curve figure grinding medicine that goes on the market;
Fig. 7 is Azilsartan capsule and the former stripping curve figure grinding medicine of listing in embodiment 14;
Fig. 8 is in comparative example, the high-efficient liquid phase chromatogram containing determination of related substances in the granule of azilsartan solid dispersion replacing lapping mode to obtain with the Azilsartan material powder of comminution by gas stream;
Fig. 9 is in embodiment 6, the high-efficient liquid phase chromatogram containing determination of related substances in the granule of azilsartan solid dispersion adopting basket polishing to obtain.
Detailed description of the invention
Below in conjunction with accompanying drawing, the specific embodiment of the present invention is described in detail, but is to be understood that protection scope of the present invention not by the restriction of detailed description of the invention.
D in the present invention
90adopt Europe Mec AS, model to be that the laser particle size analyzer of LS-C (I I I) measures by dry method.In the present invention, hydroxypropyl emthylcellulose can be any one in Dow Chemical model VL, V, E3LV, E5LV, E6LV, E50LV.In the present invention, sucrose fatty acid ester can be any sucrose fatty acid ester that HLB value (hydrophile-lipophile balance value) is 8-10, especially sucrose stearate, Surfhope SE Cosme C 1216, sucrose palmitate.
Embodiment 1-4 is the preparation of solid dispersion; Embodiment 5-7 is the preparation of granule containing solid dispersion or micropill; Embodiment 8-14 is the preparation of the pharmaceutical composition containing solid dispersion.
The preparation of embodiment 1 solid dispersion
Azilsartan raw material 100g
Hydroxypropyl emthylcellulose E3LV 20g
Polyoxyethylene sorbitan monoleate 15g
Preparation method: (1) takes the hydroxypropyl emthylcellulose E3LV of 20g, is dissolved in 1000ml purified water; Add 15g polyoxyethylene sorbitan monoleate again, stirring and dissolving; Add 100g Azilsartan raw material, it is 1 little of Azilsartan particle diameter D to be placed in basket-type grinder grinding
90be 80 μm, obtain uniform suspension; (2) inlet temperature setting 80 ~ 110 DEG C, dry by bed spray by gained suspension, then pulverized the azilsartan solid dispersion that 120 mesh sieves obtain surface modification.
The preparation of embodiment 2 solid dispersion
Azilsartan raw material 100g
HPMC E50 LV 20g
Sucrose stearate 10g
Preparation method: (1) takes the HPMC E50 LV of 20g, is dissolved in 2000ml purified water; Add the sucrose stearate that 10g, HLB are 8.0 again, stirring and dissolving; Add 100g Azilsartan raw material, it is 1 little of Azilsartan particle diameter D to be placed in basket-type grinder grinding
90be 80 μm, obtain uniform suspension; (2) inlet temperature setting 80 ~ 110 DEG C, dry by bed spray by gained suspension, then the azilsartan solid dispersion that 120 orders obtain surface modification was made in pulverizing.
The preparation of embodiment 3 solid dispersion
Preparation method: (1) takes the HPMC E50 LV of 30g, is dissolved in 4000ml purified water; Add sucrose stearate and 200g lactose that 20g, HLB are 8.0 again, stirring and dissolving; Add 100g Azilsartan raw material, it is 2 little of Azilsartan particle diameter D to be placed in basket-type grinder grinding
90be 50 μm, obtain uniform suspension.(2) inlet temperature setting 80 ~ 110 DEG C, dry by bed spray by gained suspension, then pulverized the azilsartan solid dispersion that 120 orders obtain surface modification.
The preparation of embodiment 4 solid dispersion
Preparation method: (1) takes the HPMC E5 LV of 35g, is dissolved in 5000ml purified water; Add 15g polyoxyethylene sorbitan monoleate and 200g mannitol again, stirring and dissolving; Add 100g Azilsartan raw material, it is 3 little of Azilsartan particle diameter D to be placed in basket-type grinder grinding
90be 50 μm, obtain uniform suspension; (2) inlet temperature setting 80 ~ 110 DEG C, dry by bed spray by gained suspension, then the azilsartan solid dispersion that 120 orders obtain surface modification was made in pulverizing.
The preparation of the granule of embodiment 5 containing solid dispersion
Preparation method: (1) takes the hydroxypropyl emthylcellulose E6LV of 20g, is dissolved in 2000ml purified water; Add 10g polyoxyethylene sorbitan monoleate again, stirring and dissolving; Add 100g Azilsartan raw material, it is 3 little of Azilsartan particle diameter D to be placed in basket-type grinder grinding
90be 30 μm, obtain uniform suspension.(2) take hydroxypropyl cellulose and the 400g mannitol of 75g respectively, mixing, makes uniform mixed-powder, is placed in fluid unit.(3) inlet temperature setting 80 ~ 110 DEG C, gained suspension bed spray is also dry on mixed-powder, the granule of the obtained azilsartan solid dispersion containing surface modification.
The preparation of the granule of embodiment 6 containing solid dispersion
Preparation method: (1) takes the hydroxypropyl emthylcellulose E3LV of 20g, is dissolved in 2000ml purified water; Add the sucrose palmitate that 15g, HLB are 10.0 again, stirring and dissolving; Add 100g Azilsartan raw material, it is 3 little of Azilsartan particle diameter D to be placed in basket-type grinder grinding
90be 35 μm, obtain uniform suspension.(2) take polyvinylpolypyrrolidone and the 450g lactose of 22g respectively, mixing, makes uniform mixed-powder, is placed in fluid unit.(3) inlet temperature setting 80 ~ 110 DEG C, gained suspension bed spray is also dry on mixed-powder, the granule of the obtained azilsartan solid dispersion containing surface modification.
The preparation of the micropill of embodiment 7 containing solid dispersion
Preparation method: (1) takes the hydroxypropyl emthylcellulose E3LV of 20g, is dissolved in 2000ml purified water; Add the sucrose palmitate that 15g, HLB are 9.0 again, stirring and dissolving; Add 100g Azilsartan raw material, it is 1.5 little of Azilsartan particle diameter D to be placed in basket-type grinder grinding
90be 70 μm, obtain uniform suspension.(2) take the sucrose ball core of 865g in addition, be placed in fluid unit, inlet temperature setting 50 ~ 70 DEG C, gained suspension bed spray is added medicine to also dry on sucrose ball core, the micropill of the obtained azilsartan solid dispersion containing surface modification.
The preparation of embodiment 8 tablet or capsule
Preparation method: (1) takes the azilsartan solid dispersion that 100g embodiment 1 obtains, and add 70g microcrystalline Cellulose, 300g lactose, 25g hydroxypropyl cellulose, 2.5g silicon dioxide and 2.5g magnesium stearate, mix homogeneously obtains mixed-powder.(2) by mixed-powder tabletted be heavily the tablet of 130mg, also can be filled in stomach dissolution type Capsules and make capsule, content is 130mg.
The preparation of embodiment 9 tablet or capsule
Preparation method: (1) takes the azilsartan solid dispersion that 100g embodiment 2 obtains, and add 130g microcrystalline Cellulose, 250g lactose, 10g polyvinylpolypyrrolidone, 5g silicon dioxide and 5g polyethylene glycol 6000, mix homogeneously obtains mixed-powder.(2) by the tablet of heavy for mixed-powder tabletted 130mg, also can be filled in stomach dissolution type Capsules and make capsule, content 130mg.
The preparation of embodiment 10 tablet or capsule
Preparation method: (1) takes the azilsartan solid dispersion that 200g embodiment 3 obtains, and add 142g microcrystalline Cellulose, 50g hydroxypropyl cellulose, 4g silicon dioxide and 4g magnesium stearate, mix homogeneously obtains mixed-powder.(2) by the tablet of heavy for mixed-powder tabletted 140mg, also can be filled in stomach dissolution type Capsules and make capsule, content 140mg.
The preparation of embodiment 11 tablet or capsule
Preparation method: (1) takes the azilsartan solid dispersion that 200g embodiment 4 obtains, and add 80g microcrystalline Cellulose, 100g lactose, 12g polyvinylpolypyrrolidone, 4g silicon dioxide and 4g sodium stearyl fumarate, mix homogeneously obtains mixed-powder.(2) by the tablet of heavy for mixed-powder tabletted 140mg, also can be filled in stomach dissolution type Capsules and make capsule, content 140mg.
The preparation of embodiment 12 tablet or capsule
Preparation method: (1) takes the granule containing azilsartan solid dispersion that 500g embodiment 5 obtains, and add 35g microcrystalline Cellulose, 35g lactose, 3g silicon dioxide and 4g magnesium stearate, mix homogeneously obtains mixed-powder.(2) by the tablet of heavy for mixed-powder tabletted 140mg, also can be filled in stomach dissolution type Capsules and make capsule, content 140mg.
The preparation of embodiment 13 tablet or capsule
Preparation method: (1) takes the granule containing azilsartan solid dispersion that 500g embodiment 6 obtains, and add 67g microcrystalline Cellulose, 6g silicon dioxide and 4g magnesium stearate, mix homogeneously obtains mixed-powder.(2) by the tablet of heavy for mixed-powder tabletted 140mg, also can be filled in stomach dissolution type Capsules and make capsule, content 140mg.
The preparation of embodiment 14 capsule
Preparation method: take the micropill containing azilsartan solid dispersion that 500g embodiment 7 obtains, micropill is filled in stomach dissolution type Capsules and makes capsule, according to the drug content of micropill, content is 200mg.
Comparative example
The preparation of the granule containing azilsartan solid dispersion
Preparation method: (1) takes the hydroxypropyl emthylcellulose of 20g, is dissolved in 2000ml purified water; Add 15g sucrose fatty acid ester again, stirring and dissolving; Under stirring, add 100g Azilsartan raw material (this raw material particle size D adopting comminution by gas stream to obtain
90be 35 μm), stir and make uniform suspension.(2) take polyvinylpolypyrrolidone and the 450g lactose of 22g respectively, mixing, makes uniform mixed-powder, is placed in fluid unit.(3) inlet temperature setting 80 ~ 110 DEG C, gained suspension bed spray is also dry on mixed-powder, the comparative particle of the obtained azilsartan solid dispersion containing surface modification.
The preparation of capsule
Preparation method: (1) takes the comparative particle that above-mentioned 500g contains azilsartan solid dispersion, add 67g microcrystalline Cellulose, 6g silicon dioxide and 4g magnesium stearate, mix homogeneously obtains mixed-powder.(2) mixed-powder is filled in stomach dissolution type Capsules and makes capsule, content 140mg.
Embodiment 15 solubility test
The azilsartan solid dispersion of mistake 80 mesh sieve got the Azilsartan raw material of 100 mesh sieves, obtaining according to the method for embodiment 1 ~ 7, the powder crossing the solid dispersion particles of 80 mesh sieves and medicine-feeding micropill; measure its dissolubility respectively; the results are shown in following table 1, result shows azilsartan solid dispersion and the granule containing this solid dispersion or micropill can significantly improve dissolubility.
Table 1
The detection of the dissolution of embodiment 16 Azilsartan sheet, Azilsartan capsule
The Azilsartan sheet obtained by preparation method in embodiment 8 ~ 14 or Azilsartan capsule, detect its dissolution, evaluate its dissolved corrosion.Testing result is in table 2 and table 3, and stripping curve figure is shown in Fig. 1 to Fig. 7.
Leaching condition is as follows:
Dissolving-out method: get Azilsartan sheet or Azilsartan capsule, according to dissolution method (Chinese Pharmacopoeia version in 2010 two annex Ⅹ C second methods), with 0.1mol/L hydrochloric acid solution 900ml for dissolution medium, rotating speed is 50 turns per minute, operates in accordance with the law, respectively at 10,15,20,30,45 minutes, in time, samples, filter, get subsequent filtrate 5ml, be diluted to 10ml.According to ultraviolet visible spectrophotometry (Chinese Pharmacopoeia version in 2010 two annex IV A), measure trap at 240nm wavelength place; It is appropriate that another precision takes Azilsartan reference substance, adds after methanol makes dissolving in right amount, adds 0.1mol/L hydrochloric acid solution and dilute and make the solution that every 1ml contains Azilsartan 8 μ g, be measured in the same method, calculate the accumulative dissolution of every sheet (grain).
The dissolved corrosion (n=6) of table 2 different time Azilsartan sheet
| Test sample | 10min(％) | 15min(％) | 20min(％) | 30min(％) | 45min(％) |
| The Azilsartan sheet that embodiment 8 is obtained | 46.8 | 75.8 | 84.4 | 94.7 | 101.5 |
| The Azilsartan sheet that embodiment 9 is obtained | 50.6 | 78.6 | 93.4 | 99.1 | 98.8 |
| The Azilsartan sheet that embodiment 10 is obtained | 45.7 | 73.1 | 89.5 | 96.6 | 97.9 |
| The Azilsartan sheet that embodiment 11 is obtained | 48.7 | 76.5 | 82.4 | 93.4 | 99.1 |
| The Azilsartan sheet that embodiment 12 is obtained | 43.9 | 72.7 | 85.9 | 95.6 | 98.4 |
| The Azilsartan sheet that embodiment 13 is obtained | 44.4 | 70.4 | 87.6 | 92.4 | 98.7 |
| Go on the market and formerly grind medicine Azilsartan sheet | 55.9 | 79.7 | 91.7 | 93.8 | 101.9 |
The dissolved corrosion (n=6) of table 3 different time Azilsartan capsule
| Test sample | 10min(％) | 15min(％) | 20min(％) | 30min(％) | 45min(％) |
| The Azilsartan capsule that embodiment 8 is obtained | 41.6 | 81.6 | 93.3 | 98.2 | 98.3 |
| The Azilsartan capsule that embodiment 9 is obtained | 43.7 | 84.7 | 94.1 | 102.3 | 102.1 |
| The Azilsartan capsule that embodiment 10 is obtained | 41.1 | 83.5 | 92.7 | 101.7 | 101.8 |
| The Azilsartan capsule that embodiment 11 is obtained | 44.5 | 82.0 | 90.6 | 100.2 | 99.7 |
| The Azilsartan capsule that embodiment 12 is obtained | 42.7 | 83.2 | 91.8 | 98.6 | 99.1 |
| The Azilsartan capsule that embodiment 13 is obtained | 40.9 | 82.1 | 94.6 | 100.8 | 99.9 |
| The Azilsartan capsule that embodiment 14 is obtained | 39.8 | 77.7 | 90.1 | 97.6 | 100.7 |
| Go on the market and formerly grind medicine Azilsartan sheet | 55.9 | 79.7 | 91.7 | 93.8 | 101.9 |
Testing result shows, and Azilsartan raw material surface modification is become solid dispersion, the tablet made or capsule, its dissolution rate obviously increases, dissolved corrosion with go on the market that former to grind medicine consistent.
Embodiment 17 accelerated stability test
We are by representative embodiment 8, embodiment 10, embodiment 13, and the sample aluminium-plastic bubble plate packing that comparative example obtains, outsourcing aluminium plastic bag, put into climatic chamber (constant temperature 40 DEG C ± 1 DEG C.Constant humidity RH75% ± 2.5%), place 6 months continuously, sampled Observe and measure 1,2,3,6 month the end of month respectively.
Each measurement result display, the preparation of the solid dispersion adopting basket polishing to prepare composition, every inspection target does not become substantially, drug regimen material stable in properties.Azilsartan solid dispersion preparation technology and pharmaceutical composition stable preparation process thereof are described, the quality controllable of product can be ensured; And adopt the capsule replacing basket grinding preparation in comparative example with comminution by gas stream, multiple impurity within 0 month, is namely had to produce, visible comminution by gas stream micronization process, the instantaneous high-temperature produced, Azilsartan oxidative degradation is made to increase by 2 new impurity, see Fig. 8 and Fig. 9, in Fig. 8, two materials of 25min and 30min are the new impurity (wherein in Fig. 8 and Fig. 9, the material of 20min is Azilsartan, and the material of 10min is intrinsic contaminant in raw material) of 2 of adopting comminution by gas stream micronized mode to increase.The results are shown in Table four.
Table 4 Azilsartan sheet, Azilsartan capsule accelerated stability test result
Embodiment 18
Formula in embodiment 1-4 is replaced as arbitrarily one of following formula, after said method measures to specifications, all dissolubility of not appreciable impact product, dissolution and stability.
(1) 100g Azilsartan, 35g HPMC E5 LV, 10g polyoxyethylene sorbitan monoleate;
(2) 100g Azilsartan, 35g HPMC E50 LV, 20g polyoxyethylene sorbitan monoleate;
(3) 100g Azilsartan, 30g HPMC E5 LV, 20g, HLB are the sucrose palmitate of 9.0.
Be only specific embodiments of the invention above, but the present invention is not limited thereto, the changes that any person skilled in the art can think of all should fall into protection scope of the present invention.
Claims (10)
1. a preparation method for azilsartan solid dispersion, is characterized in that, comprises the following steps: be that the Azilsartan raw material of 100:5-500 and surface modifier add water and be ground to Azilsartan particle diameter D by mass ratio
90be not more than 80 μm, obtain suspension, then by suspension crushed after being dried, obtain azilsartan solid dispersion; Wherein: the mass ratio of described Azilsartan and described water is 1:10-1000; Described surface modifier is selected from one or more in water-soluble polymer, water-soluble saccharides, surfactant; Described water-soluble polymer is selected from one or more in polyvinylpyrrolidone, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, polyvinyl alcohol; Described water-soluble saccharides is selected from one or more in lactose, sucrose, mannitol, sorbitol, xylitol; Described surfactant is selected from one or more in polyoxyethylene sorbitan monoleate, castor oil hydrogenated, Pluronic F68, sodium lauryl sulphate, lecithin, sucrose fatty acid ester.
2. the preparation method of azilsartan solid dispersion according to claim 1, is characterized in that, described Azilsartan raw material and surface modifier add water and be ground to Azilsartan particle diameter D
90it is 30 μm ~ 80 μm.
3. the preparation method of azilsartan solid dispersion according to claim 1, is characterized in that, the mass ratio of described Azilsartan raw material and described water is 1:20-50.
4. the preparation method of azilsartan solid dispersion according to claim 1, is characterized in that, the mass ratio of described Azilsartan raw material and surface modifier is 100:30-250.
5. the preparation method of azilsartan solid dispersion according to claim 4, is characterized in that, described surface modifier is one or more in hydroxypropyl emthylcellulose, polyoxyethylene sorbitan monoleate, sucrose fatty acid ester.
6. the preparation method of azilsartan solid dispersion according to claim 1, is characterized in that, the mode of described grinding is basket polishing.
7. use the azilsartan solid dispersion that the described preparation method of one of claim 1-6 obtains.
8. a pharmaceutical composition, is characterized in that, comprises azilsartan solid dispersion described in claim 7 and materia medica acceptable carrier.
9. a preparation method for troche medical composition, is characterized in that, comprises the step mixture of azilsartan solid dispersion described in claim 7 and materia medica acceptable carrier being pressed into tablet.
10. a preparation method for capsule medicine compositions, is characterized in that, comprises and the mixture of azilsartan solid dispersion described in claim 7 and materia medica acceptable carrier is packed into stomach dissolution type Capsules, make the step of capsule.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510158869.3A CN104721147A (en) | 2015-04-03 | 2015-04-03 | Azilsartan solid dispersion as well as preparation method and medicament composition thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510158869.3A CN104721147A (en) | 2015-04-03 | 2015-04-03 | Azilsartan solid dispersion as well as preparation method and medicament composition thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104721147A true CN104721147A (en) | 2015-06-24 |
Family
ID=53445949
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510158869.3A Pending CN104721147A (en) | 2015-04-03 | 2015-04-03 | Azilsartan solid dispersion as well as preparation method and medicament composition thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104721147A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106214649A (en) * | 2016-08-30 | 2016-12-14 | 佛山市弘泰药物研发有限公司 | A kind of Azilsartan potassium salt solid dispersion preparation and preparation method thereof |
| CN106821995A (en) * | 2017-02-22 | 2017-06-13 | 佛山市南海东方澳龙制药有限公司 | Triclabendazole preparation and its preparation method and application |
| CN108904459A (en) * | 2018-09-11 | 2018-11-30 | 南京瑞捷医药科技有限公司 | A kind of preparation method of tacrolimus solid dispersion tablet |
| CN111405893A (en) * | 2017-11-30 | 2020-07-10 | 保宁制药株式会社 | Pharmaceutical composition containing fimasartan |
| CN111643461A (en) * | 2019-03-04 | 2020-09-11 | 鲁南制药集团股份有限公司 | Tablet for treating hypertension and preparation method thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101066264A (en) * | 2007-06-12 | 2007-11-07 | 杨喜鸿 | Solid olmesartan medoxmil dispersion and its prepn and medicinal application |
| CN102406604A (en) * | 2011-12-05 | 2012-04-11 | 沈阳药科大学 | Fenofibrate ground suspension, as well as preparation method and application thereof |
| CN102429874A (en) * | 2011-12-06 | 2012-05-02 | 沈阳药科大学 | Nifedipine framework sustained-release pellets and preparation method and application thereof |
| CN102488673A (en) * | 2011-12-06 | 2012-06-13 | 沈阳药科大学 | Probucol nanometer dispersion and preparation method thereof |
| CN102793680A (en) * | 2011-05-23 | 2012-11-28 | 江苏恒瑞医药股份有限公司 | Azilsartan solid dispersion and preparation method and medicinal composition thereof |
-
2015
- 2015-04-03 CN CN201510158869.3A patent/CN104721147A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101066264A (en) * | 2007-06-12 | 2007-11-07 | 杨喜鸿 | Solid olmesartan medoxmil dispersion and its prepn and medicinal application |
| CN102793680A (en) * | 2011-05-23 | 2012-11-28 | 江苏恒瑞医药股份有限公司 | Azilsartan solid dispersion and preparation method and medicinal composition thereof |
| CN102406604A (en) * | 2011-12-05 | 2012-04-11 | 沈阳药科大学 | Fenofibrate ground suspension, as well as preparation method and application thereof |
| CN102429874A (en) * | 2011-12-06 | 2012-05-02 | 沈阳药科大学 | Nifedipine framework sustained-release pellets and preparation method and application thereof |
| CN102488673A (en) * | 2011-12-06 | 2012-06-13 | 沈阳药科大学 | Probucol nanometer dispersion and preparation method thereof |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106214649A (en) * | 2016-08-30 | 2016-12-14 | 佛山市弘泰药物研发有限公司 | A kind of Azilsartan potassium salt solid dispersion preparation and preparation method thereof |
| CN106821995A (en) * | 2017-02-22 | 2017-06-13 | 佛山市南海东方澳龙制药有限公司 | Triclabendazole preparation and its preparation method and application |
| CN106821995B (en) * | 2017-02-22 | 2020-08-21 | 佛山市南海东方澳龙制药有限公司 | Triclabendazole preparation and preparation method and application thereof |
| CN111405893A (en) * | 2017-11-30 | 2020-07-10 | 保宁制药株式会社 | Pharmaceutical composition containing fimasartan |
| CN108904459A (en) * | 2018-09-11 | 2018-11-30 | 南京瑞捷医药科技有限公司 | A kind of preparation method of tacrolimus solid dispersion tablet |
| CN111643461A (en) * | 2019-03-04 | 2020-09-11 | 鲁南制药集团股份有限公司 | Tablet for treating hypertension and preparation method thereof |
| CN111643461B (en) * | 2019-03-04 | 2022-09-13 | 鲁南制药集团股份有限公司 | Tablet for treating hypertension and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104721147A (en) | Azilsartan solid dispersion as well as preparation method and medicament composition thereof | |
| EP1634908A1 (en) | Cellulose powder | |
| CN102138903A (en) | Everolimus solid oral medicinal composition | |
| CN102232937A (en) | Nanometer preparation and preparation method thereof | |
| CN106687112A (en) | Abiraterone acetate formulation and methods of use | |
| US20150238616A1 (en) | Solid preparation comprising enteric solid dispersion | |
| Suo et al. | Lentinan as a natural stabilizer with bioactivities for preparation of drug–drug nanosuspensions | |
| CN103479643A (en) | Preparation method of compound preparation for treating high blood pressure | |
| CN102600132A (en) | Oral preparation containing amisulpride | |
| CN112353845B (en) | Hot-melt extrusion composition containing traditional Chinese medicine volatile oil, preparation method thereof and pharmaceutical preparation | |
| CN110638768B (en) | Preparation method of medicine for treating male erectile dysfunction | |
| AU2006257428B2 (en) | Oral solid pharmaceutical formulation of the tubulin inhibitor indibulin | |
| CN104940152A (en) | Pharmaceutical composition containing solifenacin succinate | |
| CN104415034B (en) | A kind of imidafenacin pharmaceutical composition and preparation method thereof | |
| CN104546667A (en) | Solid dispersion containing posaconazole and preparation method thereof | |
| CN106389428A (en) | Composition capable of improving Azilsartan bioavailability and stability and preparation method of composition | |
| CN106913538B (en) | Abiraterone acetate sublingual tablet and preparation method thereof | |
| CN101843596A (en) | Methadone hydrochloride dispersible tablet and preparation method thereof | |
| Solanki et al. | Formulation and Evaluation of CurcuminLiquisolid Tablets | |
| CN104721827A (en) | Insoluble antifungal medicament solid dispersion and preparation method thereof | |
| CN108125918A (en) | Everolimus pharmaceutical composition | |
| CN101385717B (en) | Solid dispersion containing sofalcone as active ingredient and preparation method thereof | |
| CN104415340A (en) | Solid drug preparation and preparing method thereof | |
| CN104248769B (en) | A kind of lurasidone medicine composition and preparation method thereof | |
| Mahammed et al. | Formulation and evaluation of clopidogrel bisulphate tablets by liquisolid compact technique |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20150624 |