CN102949358B - A kind of minodronic acid tablet and preparation method thereof - Google Patents
A kind of minodronic acid tablet and preparation method thereof Download PDFInfo
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- CN102949358B CN102949358B CN201110236639.6A CN201110236639A CN102949358B CN 102949358 B CN102949358 B CN 102949358B CN 201110236639 A CN201110236639 A CN 201110236639A CN 102949358 B CN102949358 B CN 102949358B
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- minodronic acid
- cyclodextrin
- hydroxypropylβ
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Abstract
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of minodronic acid tablet and preparation method thereof.Inventors performed a large amount of experiments, determine the ratio of adjuvant and hydroxypropylβ-cyclodextrin, prepare a kind of tablet containing minodronic acid and hydroxypropylβ-cyclodextrin.This tablet is made up of minodronic acid, hydroxypropylβ-cyclodextrin, filler, disintegrating agent, lubricant and other pharmaceutically acceptable adjuvants; In preparation process, hydroxypropylβ-cyclodextrin and minodronic acid join as an aqueous solution in the mixed powder of filler and disintegrating agent.Dissolution of Tablet prepared by the present invention significantly improves, and is conducive to the Fast Stripping of minodronic acid in GI fluids and absorption, and its preparation process is fairly simple, easy to operate, be applicable to industrialized great production.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of minodronic acid tablet and preparation method thereof.
Background technology
Osteoporosis is one group of osteopathia that many reasons causes, and the current whole world about has 200,000,000 people to suffer from osteoporosis, its sickness rate leapt to commonly encountered diseases, the 7th of frequently-occurring disease, China patient about has 90,000,000.
Minodronic acid is the nitrogenous fragrant heterocycle Diphosphonate of the third generation, by suppressing farnesyl pyrophosphate synthase activity in osteoclast, suppress the bone resorption of osteoclast, reduce bone conversion, play the osteoporotic effect of control, this product, by Japanese ONO Pharmaceutical Co., Ltd. and Japanese Astellas Pharmaceutical Co., Ltd joint development, obtains Japanese health ministry approval on January 21st, 2009 and goes on the market in Japan.
Minodronic acid is almost insoluble in water, hydrochloric acid solution and phosphate buffer salt (pH6.8), and therefore its In Vitro Dissolution of common process is comparatively difficult.
Patent W09400462A1 discloses the prescription of minodronic acid preparation, and this prescription adds lactose, corn starch, 10% hyprolose aqueous solution, magnesium stearate make tablet, but its In Vitro Dissolution effect is undesirable;
Patent CN102114025A discloses a kind of technology, by minodronic acid raw material micronization, to improve the dissolution of minodronic acid, but after raw material micronization, more easily assembles, adds the difficulty of mixing, easily cause content uneven;
Patent CN102078323A discloses a kind of technology, adds the additives such as sodium carbonate to improve drug dissolution in minodronic acid preparation, but sodium carbonate alkalescence is comparatively strong, has destruction, patient's poor compliance to gastric acid.
Summary of the invention
The object of the invention is to overcome prior art defect, improve the dissolution in vitro of minodronic acid, for this reason, present inventor has performed a large amount of experiments, determine the ratio of adjuvant and hydroxypropylβ-cyclodextrin, prepare a kind of tablet containing minodronic acid and hydroxypropylβ-cyclodextrin.
This tablet is made up of minodronic acid, hydroxypropylβ-cyclodextrin, filler, disintegrating agent, lubricant and other pharmaceutically acceptable adjuvants.
In preparation process of the present invention, the weight ratio of selection minodronic acid, hydroxypropylβ-cyclodextrin, filler, disintegrating agent, lubricant is:
The weight ratio of preferred minodronic acid, hydroxypropylβ-cyclodextrin, filler, disintegrating agent, lubricant is further:
The weight ratio of most preferred minodronic acid, hydroxypropylβ-cyclodextrin, filler, disintegrating agent, lubricant is:
Wherein, filler is one or more in lactose, microcrystalline Cellulose, mannitol, preferably mannitol; Disintegrating agent is one or more in carboxymethyl starch sodium, starch, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, preferably polyvinylpolypyrrolidone; Lubricant is one or more in magnesium stearate, silicon dioxide, Pulvis Talci.
In preparation process, hydroxypropylβ-cyclodextrin and minodronic acid join as an aqueous solution in the mixed powder of filler and disintegrating agent.
Concrete preparation method comprises the following steps:
(1) recipe quantity took filler, the disintegrating agent of 100 mesh sieves, and mix homogeneously is for subsequent use;
(2), in the water-soluble solution of recipe quantity hydroxypropylβ-cyclodextrin, add the minodronic acid of recipe quantity, be stirred to dissolve;
(3) (2) solution is all joined in (1), granulate, dry, add lubricant, tabletting, to obtain final product.
The present invention achieves good technique effect:
(1) a kind of minodronic acid tablet of the present invention, improves the water solublity of minodronic acid, is conducive to the Fast Stripping of minodronic acid in GI fluids.
(2) a kind of minodronic acid tablet of the present invention, fairly simple, easy to operate, the applicable industrialized great production of its preparation process.
Detailed description of the invention
Now further describe the present invention by following examples, embodiment only for the object of illustration, does not limit the scope of the invention, and the simultaneously apparent change made according to the present invention of those of ordinary skill in the art and modification are also contained within the scope of the invention.
Prepared by embodiment 1 minodronic acid tablet
1 minodronic acid tablet prescription
2 preparation technologies
(1) recipe quantity took mannitol, the polyvinylpolypyrrolidone of 100 mesh sieves, and mix homogeneously is for subsequent use;
(2), in the water-soluble solution of recipe quantity hydroxypropylβ-cyclodextrin, add the minodronic acid of recipe quantity, be stirred to dissolve;
(3) (2) solution is all joined in (1), granulate, dry, add magnesium stearate, tabletting, to obtain final product.
Prepared by embodiment 2 minodronic acid tablet
1 minodronic acid tablet prescription
2 preparation technologies
(1) recipe quantity took lactose, the starch of 100 mesh sieves, and mix homogeneously is for subsequent use;
(2) recipe quantity hydroxypropylβ-cyclodextrin is soluble in water, adds the minodronic acid of recipe quantity, is stirred to dissolve;
(3) (2) solution is all joined in (1), granulate, dry, add magnesium stearate, tabletting, to obtain final product.
Prepared by embodiment 3 minodronic acid tablet
1 minodronic acid tablet prescription
2 preparation technologies
(1) recipe quantity took microcrystalline Cellulose, the carboxymethyl starch sodium mix homogeneously of 100 mesh sieves, for subsequent use;
(2) recipe quantity hydroxypropylβ-cyclodextrin is soluble in water, adds the minodronic acid of recipe quantity, is stirred to dissolve;
(3) (2) solution is all joined in (1), granulate, dry, add Pulvis Talci, tabletting, to obtain final product.
Prepared by embodiment 4 minodronic acid tablet
1 minodronic acid tablet prescription
2 preparation technologies
(1) recipe quantity took mannitol, the polyvinylpolypyrrolidone of 100 mesh sieves, and mix homogeneously is for subsequent use;
(2) recipe quantity hydroxypropylβ-cyclodextrin is soluble in water, adds the minodronic acid of recipe quantity, is stirred to dissolve;
(3) (2) solution is all joined in (1), granulate, dry, add magnesium stearate, tabletting, to obtain final product.
Prepared by embodiment 5 minodronic acid tablet
1 minodronic acid tablet prescription
2 preparation technologies
(1) recipe quantity took lactose, the polyvinylpolypyrrolidone of 100 mesh sieves, and mix homogeneously is for subsequent use;
(2) recipe quantity hydroxypropylβ-cyclodextrin is soluble in water, adds the minodronic acid of recipe quantity, is stirred to dissolve;
(3) (2) solution is all joined in (1), granulate, dry, add magnesium stearate, tabletting, to obtain final product.
Prepared by embodiment 6 minodronic acid tablet
1 minodronic acid tablet prescription
2 preparation technologies
(1) recipe quantity took mannitol, the cross-linking sodium carboxymethyl cellulose mix homogeneously of 100 mesh sieves, for subsequent use;
(2) recipe quantity hydroxypropylβ-cyclodextrin is soluble in water, adds the minodronic acid of recipe quantity, is stirred to dissolve;
(3) (2) solution is all joined in (1), granulate, dry, add Pulvis Talci, tabletting, to obtain final product.
Prepared by embodiment 7 minodronic acid tablet
1 minodronic acid tablet prescription
2 preparation technologies
(1) recipe quantity took mannitol, the low-substituted hydroxypropyl cellulose mix homogeneously of 100 mesh sieves, for subsequent use;
(2) recipe quantity hydroxypropylβ-cyclodextrin is soluble in water, adds the minodronic acid of recipe quantity, is stirred to dissolve;
(3) (2) solution is all joined in (1), granulate, dry, add silicon dioxide, tabletting, to obtain final product.
Prepared by comparative example 1 minodronic acid tablet
1 minodronic acid tablet prescription
2 preparation technologies
(1) recipe quantity took mannitol, polyvinylpolypyrrolidone, hydroxypropylβ-cyclodextrin, the minodronic acid mix homogeneously of 100 mesh sieves, for subsequent use;
(2) add suitable quantity of water in (1), granulate, dry, add magnesium stearate, tabletting, to obtain final product.
Prepared by comparative example 2 minodronic acid tablet
1 minodronic acid tablet prescription
2 preparation technologies
(1) recipe quantity took mannitol, the polyvinylpolypyrrolidone mix homogeneously of 100 mesh sieves, for subsequent use;
(2) recipe quantity hydroxypropylβ-cyclodextrin is soluble in water, adds the minodronic acid of recipe quantity, is stirred to dissolve;
(3) (2) solution is all joined in (1), granulate, dry, add magnesium stearate, tabletting, to obtain final product.
Verify the stripping situation of other prescriptions.
Prepared by comparative example 3 minodronic acid tablet
1 minodronic acid tablet prescription
2 preparation technologies
(1) recipe quantity took the microcrystalline Cellulose of 100 mesh sieves, pregelatinized Starch, calcium carbonate, low-substituted hydroxypropyl cellulose mix homogeneously, for subsequent use;
(2) recipe quantity hydroxypropylβ-cyclodextrin is soluble in water, adds the minodronic acid of recipe quantity, is stirred to dissolve;
(3) (2) solution is all joined in (1), granulate, dry, add magnesium stearate, tabletting, to obtain final product.
Prepared by comparative example 4 minodronic acid tablet
1 minodronic acid tablet prescription
2 preparation technologies
1) preparation of supplementary material and process, pulverized 100 mesh sieves by minodronic acid, and it is for subsequent use that 100 mesh sieves crossed respectively by other adjuvants;
2) weigh and mix, taking above-mentioned supplementary material respectively, by above-mentioned supplementary material mix homogeneously according to recipe quantity through double calculating inventory of checking;
3) granulate, soft material water soft material processed, granulates with 30 order nylon screens, and obtained granule should lack fine powder, neatly without rectangular;
4) drying, granulate, total mixed, intermediate inspection, tabletting, coating and get final product.
Checking embodiment
Dissolution: get this product, according to dissolution method (Chinese Pharmacopoeia version in 2010 two annex XC second methods), with water 900ml for dissolution medium, rotating speed is 50 turns per minute, operate in accordance with the law, when 45min, get solution appropriate, filter, get subsequent filtrate, according to the chromatographic condition under assay item, precision measures subsequent filtrate 50 μ l injection liquid chromatography, record chromatogram; Another precision takes minodronic acid reference substance and is about 10mg, put in 100ml measuring bottle, add 0.1mol/L sodium hydroxide solution 5ml within ultrasonic 5 minutes, make minodronic acid dissolve after, be diluted with water to scale, shake up, precision measures 1ml and is placed in 100ml measuring bottle, be diluted with water to scale, shake up, product solution, is measured in the same method in contrast; By external standard method with the stripping quantity of minodronic acid in the every sheet of calculated by peak area, limit is 75% of labelled amount, should conform with the regulations.
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler, with 0.075% TBAH solution of 10mM tetrasodium pyrophosphate (phosphoric acid regulates pH7.0)-acetonitrile (95: 5) for mobile phase, determined wavelength is 218nm, and theoretical cam curve calculates should be not less than 3000 by minodronic acid peak.
Embodiment dissolution determination the results are shown in Table 1.
Table 1 embodiment dissolution determination result
Note: when disintegrate refers to detect dissolution, the disintegrate situation of slice, thin piece.
As seen from Table 1, embodiment 1-7 disintegrate is rapid, disintegrate in 5 minutes, and stripping in 10 minutes is complete; Comparative example 1, although disintegrate is rapid, due to technological reason, result of extraction is poor; Comparative example 2, although hydroxypropylβ-cyclodextrin consumption is large, because disintegrate dosage is few, cause slice, thin piece disintegrate slow, cause dissolution poor; Comparative example 3 adopts in the prescription of prior art and adds cyclodextrin, and result of extraction is undesirable; Documents 4 adopts prescription and the technique of prior art, and result of extraction is starkly lower than the present invention.As can be seen here, the present invention achieves unforeseeable technique effect in dissolution.
Claims (8)
1. a minodronic acid tablet, is characterized in that it is made up of minodronic acid, hydroxypropylβ-cyclodextrin, filler, disintegrating agent and lubricant; The weight ratio of minodronic acid, hydroxypropylβ-cyclodextrin, filler, disintegrating agent and lubricant is:
Minodronic acid 1 part
Hydroxypropylβ-cyclodextrin 1-20 part
Filler 30-400 part
Disintegrating agent 3-50 part
Lubricant 0.1-6 part;
Its preparation method comprises following steps:
(1) recipe quantity took filler, the disintegrating agent of 100 mesh sieves, and mix homogeneously is for subsequent use;
(2), in the water-soluble solution of recipe quantity hydroxypropylβ-cyclodextrin, add the minodronic acid of recipe quantity, be stirred to dissolve;
(3) (2) solution is all joined in (1), granulate, dry, add lubricant, tabletting, to obtain final product.
2. minodronic acid tablet as claimed in claim 1, is characterized in that the weight ratio of minodronic acid, hydroxypropylβ-cyclodextrin, filler, disintegrating agent and lubricant is:
Minodronic acid 1 part
Hydroxypropylβ-cyclodextrin 3-14 part
Filler 30-70 part
Disintegrating agent 9-20 part
Lubricant 0.1-1 part.
3. minodronic acid tablet as claimed in claim 2, is characterized in that the weight ratio of minodronic acid, hydroxypropylβ-cyclodextrin, filler, disintegrating agent and lubricant is:
Minodronic acid 1 part
Hydroxypropylβ-cyclodextrin 8 parts
Filler 50 parts
Disintegrating agent 10 parts
Lubricant 0.7 part.
4. the minodronic acid tablet as described in any one of claim 1-3, is characterized in that described filler is one or more in lactose, microcrystalline Cellulose, mannitol.
5. minodronic acid tablet as claimed in claim 4, is characterized in that described filler is mannitol.
6. the minodronic acid tablet as described in any one of claim 1-3, is characterized in that described disintegrating agent is one or more in carboxymethyl starch sodium, starch, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose.
7. minodronic acid tablet as claimed in claim 6, is characterized in that described disintegrating agent is polyvinylpolypyrrolidone.
8. the minodronic acid tablet as described in any one of claim 1-3, is characterized in that described lubricant is one or more in magnesium stearate, silicon dioxide, Pulvis Talci.
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| CN201110236639.6A CN102949358B (en) | 2011-08-17 | 2011-08-17 | A kind of minodronic acid tablet and preparation method thereof |
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| CN102949358B true CN102949358B (en) | 2015-10-21 |
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| CN106913540A (en) * | 2015-12-25 | 2017-07-04 | 山东新时代药业有限公司 | A kind of Minodronic acid tablets and preparation method thereof |
| CN106913546B (en) * | 2015-12-28 | 2021-06-22 | 山东新时代药业有限公司 | Fast-dissolving minodronic acid tablet and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1443065A (en) * | 2000-07-17 | 2003-09-17 | 山之内制药株式会社 | Pharmaceutical composition improved in peroral absorbability |
| US20060013893A1 (en) * | 2004-07-19 | 2006-01-19 | Stockel Richard F | Bisphosphonates inorganic carriers |
| CN102114025A (en) * | 2011-03-30 | 2011-07-06 | 北京美迪康信医药科技有限公司 | Pharmaceutical composition for treating osteoporosis |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1443065A (en) * | 2000-07-17 | 2003-09-17 | 山之内制药株式会社 | Pharmaceutical composition improved in peroral absorbability |
| US20060013893A1 (en) * | 2004-07-19 | 2006-01-19 | Stockel Richard F | Bisphosphonates inorganic carriers |
| CN102114025A (en) * | 2011-03-30 | 2011-07-06 | 北京美迪康信医药科技有限公司 | Pharmaceutical composition for treating osteoporosis |
Non-Patent Citations (1)
| Title |
|---|
| 谢伯泰等.羟丙基- β- 环糊精特性及其在医药领域中的应用与安全性.《国外医药--合成药、生化药、制剂分册》.2002,第23卷(第5期),第302-306页,第304-305页第5节第1段、第5.1节. * |
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