CN103877581B - A kind of acetic acid Bazedoxifene slow releasing preparation of excellent performance - Google Patents
A kind of acetic acid Bazedoxifene slow releasing preparation of excellent performance Download PDFInfo
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- CN103877581B CN103877581B CN201410109188.3A CN201410109188A CN103877581B CN 103877581 B CN103877581 B CN 103877581B CN 201410109188 A CN201410109188 A CN 201410109188A CN 103877581 B CN103877581 B CN 103877581B
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- UCJGJABZCDBEDK-UHFFFAOYSA-N Cc1c(-c(cc2)ccc2O)[n](Cc(cc2)ccc2OCCN2CCCCCC2)c(cc2)c1cc2O Chemical compound Cc1c(-c(cc2)ccc2O)[n](Cc(cc2)ccc2OCCN2CCCCCC2)c(cc2)c1cc2O UCJGJABZCDBEDK-UHFFFAOYSA-N 0.000 description 1
Abstract
Present invention is disclosed a kind of acetic acid Bazedoxifene preparation and preparation technology thereof of excellent performance, said preparation is sustained-release dropping pill, this sustained-release dropping pill comprises the acetic acid Bazedoxifene that percentage by weight is 1-25%, percentage by weight is the hydrophobicity Basic compose of 40-70%, and percentage by weight is respectively the hydrophilic matrix of 5-40%, above-mentioned percentage by weight is based on whole drop pill gross weight.This sustained-release dropping pill has better chemical stability, physical stability (low crystal formation conversion ratio), in vivo release behavior (higher bioavailability and steadily lasting blood drug level).
Description
[technical field]
The present invention relates to a kind of particularly stable Bazedoxifene preparation of excellent performance.More particularly, the present invention relates to a kind of particularly stable acetic acid Bazedoxifene slow releasing preparation and preparation technology thereof of excellent performance.
[technical background]
Bazedoxifene (bazedoxifene) SERM Bazedoxifene of new generation, contestable suppresses the combination of 1,713 one estradiol and estrogen receptor ERoc and ER13, estrogen agonist activity is had to skeleton, the bone density of vertebra and hip can be improved, therefore significantly can reduce the vertebral fracture risk of osteoporosis menopausal women.Its principal indications is sclerotin after prevention and therapy menopause.
The chemical name of acetic acid Bazedoxifene is (1-[4-(2-azacyclo--1-in heptan base-ethyoxyl)-benzyl]-2-(4-hydroxy-pheny)-3-Methyl-1H-indole-5-ol acetic acid), has chemical constitution as follows:
In US2005/0227965, disclose the polymorphic A of acetic acid Bazedoxifene, and in US2005/0250762, disclose the polymorph b of acetic acid Bazedoxifene.In aqueous and organic solvent system, crystal form A is higher than the dissolubility of crystal form B.Particularly advantageous in this preparation at the dissolubility of concern particular composition or administration.Such as, higher dissolubility can affect bioavailability, and bioavailability then affects bio-absorbable and the distribution of medicine, and can be conducive to preparation in a liquid carrier.But crystal form A is the polymorphic of dynamically (or metastable state), and the crystal form B polymorphic that to be thermodynamics more stable.Crystal form A can be transformed into crystal form B at leisure in preparation preparation and storage.The crystalline polymorphs phenomenon of this medicine affects pharmacological characteristics in convenience, stability, dissolubility, storage stability, preparation convenience and body prepared by this medicine usually.
Bazedoxifene grinds by Hui Shi is former, after transfer Pfizer, gone on the market in Italy and Spain April 27 in 2009 by the approval of European Bureau of Drugs Supervision, commodity are called Conbriza, and in July, 2010 goes on the market in Japan, and commodity are called Viviant.Listing dosage form is conventional formulation, and blood drug level has certain undulatory property, will produce certain clinical adverse, therefore, be conducive to controlling the blood drug level of medicine if be made into slow releasing preparation, make its long lasting and stable effective, reach efficient and long-acting object simultaneously, and can compliance be improved.There is no the development report of its slow releasing preparation at present.
[goal of the invention]
Goal of the invention is just to provide a kind of slow releasing preparation of particularly stable Bazedoxifene of excellent performance.Particularly, the object of this invention is to provide a kind of particularly stable acetic acid Bazedoxifene sustained-release dropping pill and preparation technology thereof of excellent performance.
[summary of the invention]
The present invention relates to a kind of acetic acid Bazedoxifene sustained-release dropping pill of excellent performance, it is 1-25% (preferred 2-20% that this sustained-release dropping pill comprises percentage by weight, more preferably 2-15%, most preferably 2-10%) active component acetic acid Bazedoxifene, percentage by weight is 40-70% (preferred 45-70%, more preferably 50-70%, most preferably 60-70%) hydrophobicity Basic compose, and percentage by weight is respectively 5-40% (preferred 10-40%, more preferably 15-35%, most preferably 20-30%) hydrophilic matrix, above-mentioned percentage by weight is based on whole drop pill gross weight.
The hydrophobicity Basic compose that the present invention relates to is selected from but is not limited to stearic acid, octadecanol, glycerol monostearate acid, fat insect wax etc.; The hydrophilic matrix that the present invention relates to is selected from VE TPGS.
VE TPGS except making hydrophilic matrix in the present invention, regulates outside the drug release rate of sustained-release dropping pill, also has following prior effect:
1), acetic acid Bazedoxifene (having phenolic hydroxyl group) is oxidizable, and VE TPGS makes antioxidant, can improve the chemical stability of acetic acid Bazedoxifene sustained-release dropping pill in the processes such as preparation, storage;
2), VE TPGS is the water soluble surfactant active of low melting point, acetic acid Bazedoxifene can be made to be easy to dispersion at hydrophobicity Basic compose, and it can be made to be easy to stripping at aqueous medium, thus improves bioavailability in the preparation convenience of its preparation and body;
3), VE TPGS is as surfactant, good affinity is had with acetic acid Bazedoxifene and hydrophobicity Basic compose, VE TPGS and the coupling of hydrophobicity Basic compose are conducive to slowing down acetic acid Bazedoxifene crystal form A and prepare at preparation and change to crystal form B in storage, improve the physical stability of acetic acid Bazedoxifene preparation, thus bioavailability in its body can be improved.
The acetic acid Bazedoxifene sustained-release dropping pill that the present invention relates to can also comprise lipophile antioxidant, such as, at least one in vitamin E, Propylgallate and BHA/BHT etc., the percentage by weight of above-mentioned lipophile antioxidant in drop pill, 0.1-15% (preferred 0.5-10%, more preferably 1-8%, most preferably 1-5%), above-mentioned percentage by weight is based on whole drop pill gross weight.
The acetic acid Bazedoxifene sustained-release dropping pill that the present invention relates to can also comprise other hydrophilic Basic composes, such as Polyethylene Glycol, polyethylene glycol-propylene glycol copolymers, polyoxyethylene groups (40) stearate, the percentage by weight of above-mentioned hydrophilic Basic compose in drop pill is 1-40% (preferred 5-30%, more preferably 10-25%, most preferably 10-20%), above-mentioned percentage by weight is based on whole drop pill gross weight.
The sustained-release dropping pill that the present invention relates to can also comprise other wetting agents, such as sucrose palmitate, metal alkyl sulfate, sodium lauryl sulfate, polyoxyethylene sorbitan carboxylic ester, polyoxyethylene alkyl ether, castor oil derivatives, many storehouse acid sodium, quaternary ammonium compound, the sugar ester of fatty acid, Polyethoxylated fatty acids ester, at least one in the glyceride of fatty acid and polyglycolyzed glyceride, the percentage by weight of above-mentioned wetting agent in drop pill, 0.1-15% (preferred 0.5-10%, more preferably 1-8%, most preferably 1-5%), above-mentioned percentage by weight is based on whole drop pill gross weight.
The preparation technology of the sustained-release dropping pill that the present invention relates to comprises after hydrophilic matrix heat fused, suspension is become after adding the mixing of hydrophobicity Basic compose after adding the mixing of acetic acid Bazedoxifene again, suspension is inserted in a tank of the band water dropper of insulation, in instillation condensed fluid, be condensed into spherical, after blotting, obtain finished product.Heat fused temperature is 80-i00 DEG C; Temperature in suspension insulation instillation condensed fluid controls at 80-110 DEG C.The preparation technology of the sustained-release dropping pill that the present invention relates to is simple, with low cost.
For achieving the above object, the preferred following technical scheme of the present invention: the acetic acid Bazedoxifene fine powder of 2-20% percentage by weight is added in the substrate of the melting of 80-98% percentage by weight, fully mixes, dropping preparation method is condensed into ball in coolant, except coolant, dry, to obtain final product.
Coolant in the present invention includes but not limited to dimethicone, liquid paraffin, plant wet goods, best with dimethicone.
The external diameter of above-mentioned sustained-release dropping pill is preferably 0.5-5mm, is more preferably 1-4mm.
Above-mentioned sustained-release dropping pill is filled in capsule makes capsule.
Acetic acid Bazedoxifene is made sustained-release dropping pill, is conducive to the long lasting and stable of blood drug level, avoid or reduce the generation of side effect, improve compliance.
Accompanying drawing explanation
The release test result of active component in Fig. 1: embodiment 1-4 sample
Fig. 2: experimental example 3 and reference examples 1 blood drug level test result
[embodiment]
Embodiment 1
Prescription: every 1000 consumptions:
Acetic acid Bazedoxifene 2.26g
VE TPGS 5.0g
Stearic acid 42.74g
Specification: drug content 2.26mg/ grain, the heavy 50mg/ grain of ball.
Technique: acetic acid Bazedoxifene raw material pulverizing, porphyrize are reached more than 150 orders; VE TPGS, stearic acid is taken by prescription; After hydrophilic matrix heat fused, after adding the mixing of hydrophobicity Basic compose after adding the mixing of acetic acid Bazedoxifene again, become suspension; By above-mentioned eutectic liquids 80-85 DEG C of insulation; Above-mentioned solution is transferred to dripping in dripping device, and solution temperature controls at 80-85 DEG C, in the dimethicone of instillation room temperature, pulls drop silicone oil to the greatest extent out, with absorbent gauze, the silicone oil of drop pill surface attachment is cleaned.
Embodiment 2
Prescription: every 1000 consumptions:
Acetic acid Bazedoxifene 4.52g
VE TPGS 10.0g
Glycerol monostearate acid 35.48g
Specification: drug content 4.52mg/ grain, the heavy 50mg/ grain of ball.
Technique: acetic acid Bazedoxifene raw material pulverizing, porphyrize are reached more than 150 orders; VE TPGS, glycerol monostearate acid is taken by prescription; After hydrophilic matrix heat fused, after adding the mixing of hydrophobicity Basic compose after adding the mixing of acetic acid Bazedoxifene again, become suspension; By above-mentioned eutectic liquids 80-90 DEG C of insulation; Above-mentioned solution is transferred to dripping in dripping device, and solution temperature controls at 80-90 DEG C, in the dimethicone of instillation room temperature, pulls drop silicone oil to the greatest extent out, with absorbent gauze, the silicone oil of drop pill surface attachment is cleaned.
Embodiment 3
Prescription: every 1000 consumptions:
Acetic acid Bazedoxifene 2.26g
VE TPGS 15.0g
Octadecanol 32.74g
Specification: drug content 2.26mg/ grain, the heavy 50mg/ grain of ball.
Technique: acetic acid Bazedoxifene raw material pulverizing, porphyrize are reached more than 150 orders; VE TPGS, octadecanol is taken by prescription; After hydrophilic matrix heat fused, after adding the mixing of hydrophobicity Basic compose after adding the mixing of acetic acid Bazedoxifene again, become suspension; By above-mentioned eutectic liquids 80-90 DEG C of insulation; Above-mentioned solution is transferred to dripping in dripping device, and solution temperature controls at 80-90 DEG C, in the dimethicone of instillation room temperature, pulls drop silicone oil to the greatest extent out, with absorbent gauze, the silicone oil of drop pill surface attachment is cleaned.
Embodiment 4
Prescription: every 1000 consumptions:
Acetic acid Bazedoxifene 4.52g
VE TPGS 20.0g
Fat insect wax 25.48g
Specification: drug content 4.52mg/ grain, the heavy 50mg/ grain of ball.
Technique: acetic acid Bazedoxifene raw material pulverizing, porphyrize are reached more than 150 orders; VE TPGS, fat insect wax is taken by prescription; After hydrophilic matrix heat fused, after adding the mixing of hydrophobicity Basic compose after adding the mixing of acetic acid Bazedoxifene again, become suspension; By above-mentioned eutectic liquids 80-85 DEG C of insulation; Above-mentioned solution is transferred to dripping in dripping device, and solution temperature controls at 80-85 DEG C, in the dimethicone of instillation room temperature, pulls drop silicone oil to the greatest extent out, with absorbent gauze, the silicone oil of drop pill surface attachment is cleaned.
Test example 1 is prepared and principal agent stability test in storage
Experimental example sample: the sample (altogether containing bazedoxifene acetate (BZA) 22.6mg in sample, closing Bazedoxifene 20mg) prepared in embodiment 1-4
Reference examples sample 1: bazedoxifene acetate (BZA) sheet 1 (specification: every sheet, containing bazedoxifene acetate (BZA) 22.6mg, closes Bazedoxifene 20mg) that commodity are called Viviant (comprises BZA crystal form A, lactose monohydrate, ascorbic acid, microcrystalline Cellulose, pregelatinized Starch, sodium starch glycollate, colloidal silica, magnesium stearate and sodium lauryl sulphate.This tablet comprises and contains
white and
the coatings of Clear.)
Reference substance 2: bazedoxifene acetate (BZA) sheet 2 (wherein ascorbic acid is substituted by VE TPGS, and other are all constant) prepared by the bazedoxifene acetate sheet that reference commodity are called Viviant.
Illustrate: the active component in above-mentioned homemade experimental example 1-4 and reference examples sample 2 all derives from same batch sample, and the bazedoxifene acetate Form B ratio accounted in total bazedoxifene acetate is 0.56%.
Above-mentioned experimental example and reference examples sample are inserted lower 30 days of the environment of temperature 40 DEG C and relative humidity 90% and within 60 days, are detected the content (relative labelled amount) of bazedoxifene acetate afterwards and bazedoxifene acetate Form B accounts for ratio (assay method is see CN101657421A) in total bazedoxifene acetate.The results are shown in Table 1:
The content (relative labelled amount) of table 1 bazedoxifene acetate and bazedoxifene acetate Form B account for the measurement result of ratio in total bazedoxifene acetate
Result shows, and embodiment sample has higher chemical stability and physical stability (lower crystal formation conversion ratio) compared with reference examples sample activity composition.Result also shows simultaneously, and in embodiment Sample Preparation Procedure, active component crystal formation conversion ratio is starkly lower than reference examples 2.
The release of active component and blood drug level test in test example 2 embodiment sample
Experimental example sample: the sample (altogether containing bazedoxifene acetate (BZA) 22.6mg in sample, closing Bazedoxifene 20mg) prepared in embodiment 1-4
Reference examples sample 1: commodity are called bazedoxifene acetate (BZA) sheet 1 (specification: every sheet, containing bazedoxifene acetate (BZA) 22.6mg, closes Bazedoxifene 20mg) of Viviant
Measure the release of active component in (using HPLC method) embodiment 1-4 sample, the results are shown in accompanying drawing 1.
With BEAGLE dog for subjects, single dose intersection oral administration: once take 10, the sample of preparation in embodiment 3 respectively (altogether containing bazedoxifene acetate (BZA) 22.6mg in sample, close Bazedoxifene 20mg) and 1 one, reference examples sample (altogether containing bazedoxifene acetate (BZA) 22.6mg in sample, close Bazedoxifene 20mg), within one day, be administered once, measure blood drug level, the results are shown in Figure 2.
Result shows, and experimental example comparatively reference examples has blood drug level very stably.
Claims (8)
1. an acetic acid Bazedoxifene preparation, it is characterized in that said preparation is sustained-release dropping pill, this sustained-release dropping pill comprises the acetic acid Bazedoxifene that percentage by weight is 1-25%, percentage by weight is the hydrophobicity Basic compose of 40-70%, and percentage by weight is respectively the hydrophilic matrix of 5-40%, above-mentioned hydrophobicity Basic compose is selected from octadecanol, and above-mentioned hydrophilic matrix is selected from VE TPGS, above-mentioned percentage by weight is based on whole drop pill gross weight, and the prescription of said preparation is: every 1000 consumptions:
Acetic acid Bazedoxifene 2.26g
VE TPGS 15.0g
Octadecanol 32.74g
Specification: drug content 2.26mg/ grain, the heavy 50mg/ grain of ball.
2. a capsule, is characterized in that this capsule comprises according to the preparation in claim 1.
3. the preparation method of an acetic acid Bazedoxifene preparation as claimed in claim 1, comprise after described hydrophilic matrix heat fused, suspension is become after adding described hydrophobicity Basic compose mixing after adding the mixing of acetic acid Bazedoxifene again, again suspension is inserted in a tank of the band water dropper of insulation, in instillation condensed fluid, be condensed into spherical, after blotting, obtain drop pill finished product.
4. preparation method according to claim 3, is characterized in that described condensed fluid is selected from dimethicone, liquid paraffin or vegetable oil.
5. preparation method according to claim 3, is characterized in that described condensed fluid is selected from dimethicone.
6. preparation method according to claim 3, is characterized in that the temperature of described heat fused is 80-100 DEG C.
7. preparation method according to claim 3, is characterized in that comprising the temperature that described suspension instills in described condensed fluid and controls at 80-110 DEG C.
8. preparation method according to claim 3, is characterized in that described preparation is filled in capsule and makes capsule.
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| CN201410109188.3A CN103877581B (en) | 2014-03-24 | 2014-03-24 | A kind of acetic acid Bazedoxifene slow releasing preparation of excellent performance |
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| CN201410109188.3A CN103877581B (en) | 2014-03-24 | 2014-03-24 | A kind of acetic acid Bazedoxifene slow releasing preparation of excellent performance |
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| CN103877581B true CN103877581B (en) | 2016-03-02 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101304731B (en) * | 2005-08-24 | 2012-06-20 | 惠氏公司 | Bazedoxifene acetate formulations and preparation method |
| US8183367B2 (en) * | 2008-02-11 | 2012-05-22 | Wyeth Llc | Methods of preparing polymorphic form A of bazedoxifene acetate |
| CA2775599A1 (en) * | 2009-10-27 | 2011-05-12 | Wyeth Llc | Bazedoxifene formulations with antioxidants |
| CN103494787B (en) * | 2013-07-22 | 2014-10-29 | 南通广泰生化制品有限公司 | Tamoxifen citrate dropping pill |
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Address after: 214000, 35, Jing Xin Road, tin Beizhen Industrial Park, Xishan District, Jiangsu, Wuxi Applicant after: JIANGSU ZEYUN PHARMACEUTICAL CO., LTD. Address before: 214111 Jiangsu Province, Wuxi City District Town Square Xinming Road No. 29 Applicant before: Jiangsu Sempoll Pharmaceutical Co., Ltd. |
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Address after: No. 35, Jingxin Road, industrial park, Xibei Town, Xishan District, Wuxi City, Jiangsu Province, 214000 Patentee after: Jiangsu Zhiyuan Pharmaceutical Co.,Ltd. Address before: No. 35, Jingxin Road, industrial park, Xibei Town, Xishan District, Wuxi City, Jiangsu Province, 214000 Patentee before: JIANGSU ZHIYUAN PHARMACEUTICAL Co.,Ltd. |