CN101530415A - Pharmaceutical composition containing bisphosphates and preparation method thereof - Google Patents
Pharmaceutical composition containing bisphosphates and preparation method thereof Download PDFInfo
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- CN101530415A CN101530415A CN200810101632A CN200810101632A CN101530415A CN 101530415 A CN101530415 A CN 101530415A CN 200810101632 A CN200810101632 A CN 200810101632A CN 200810101632 A CN200810101632 A CN 200810101632A CN 101530415 A CN101530415 A CN 101530415A
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- pharmaceutical composition
- diphosphonate
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- metal ion
- salt
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Abstract
The invention discloses an oral pharmaceutical composition containing bisphosphates and a preparation method thereof, wherein the oral pharmaceutical composition comprises bisphosphates drugs, a metal-ion complexing agent and other pharmaceutically acceptable drug carriers. The composition has good stability and pharmacokinetics property and is applied to the treatment of bone diseases and certain metabolic calcium disorders.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition that contains diphosphonate and preparation method thereof, added the complexing of metal ion agent in this compositions, effectively avoided the sequestration of metal ion and diphosphate, strengthened the absorption of active constituents of medicine.Be used for the treatment of osteopathia and some disorder of calcium metabolism disease.
Background technology
Bisphosphonate compound contains (P-C-P) key in its molecular structure, the same with general phosphate compounds, with divalent metal ion such as calcium ion stronger affinity is arranged, and can combine with these metal ions, forms insoluble complex.Therefore, after bisphosphonate compound is taken, or under the situation of taking simultaneously with calcium preparation, will generate the complex of slightly solubility in the digestive tube, thereby the absorbability of bisphosphonate compound in digestive tube reduced greatly.
CN01812935 discloses a kind of pharmaceutical composition with diphosphate and amino alkyl methacrylate copolymer E and acidic materials, amino alkyl methacrylate copolymer E and diphosphate are united use, have improved medicine to the permeability of digestive tube mucosa and/or rete malpighii and have the oral absorption of improving medicine.WO9918972 discloses a kind of pharmaceutical composition that medium-chain glyceride promotes that diphosphate absorbs that adds.WO0061111 discloses a kind of absorption enhancer that adds sodium caprylate and sodium chloride as diphosphate.
Absorption enhancer be added in the absorption that has strengthened active constituents of medicine in a way, do not combine the problem that forms insoluble complex with calcium or other metal ion but solve bisphosphonate substances may.Therefore find a kind of method head it off to be necessary.
Common medicine preparation for oral use usually is to produce in equipment with metal surface and instrument, but the active substance that therefore very easily forms complex when processing diphosphonate contacts with composite.This situation especially severe when having used water or water-bearing media in the processing.
CN89106373 discloses a kind of preparation method of heterocyclic ring di-phosphonic acid derivatives, wherein adopt lactose and corn starch as filler, hyprolose is as binding agent, and carboxymethylcellulose calcium is as disintegrating agent, magnesium stearate adopts the method preparation of wet granule compression tablet as lubricant.CN03809840 relates to a kind of ibandronic acid preparation of high dose, and prescription adopts is common adjuvant such as lactose microcrystal, and technology be diphosphate to be mixed with a certain amount of adjuvant afterwards mix with the adjuvant of surplus behind the spray-drying process again, tabletting, and coating makes.CN99811229 discloses the pharmaceutical composition of adjuvant step pelletize tabletting in fluidised bed granulator of a kind of diphosphonate and no abrasive action.
Adopt wet granulation technology very big to the influence of diphosphonate; Adopt spray drying, coating and fluid bed one step pelletize reduction wet-granulation process Chinese medicine and Metal Contact to form the chance of complex, effectively avoided the content of the active constituents of medicine that causes because of pelletization to reduce, but technology is loaded down with trivial details, to the requirement height of production equipment.Therefore, seek the preparation technology of simple possible, it is extremely urgent to comply with need of industrial production.
Summary of the invention
The present invention is in order to address the above problem; find through long term test; use is united in complexing of metal ion agent and bisphosphonates material, adopt dry granulation simultaneously or directly adopt the mode of pressed powder to prepare, solved the problem that bisphosphonates material and metal form complex effectively.Simultaneously, this preparation technology is simple, is fit to suitability for industrialized production.
The pharmaceutical composition of the diphosphonate among the present invention contains diphosphonate and other pharmaceutically acceptable carrier.
Diphosphonate described in the present invention comprises YM 529, alendronate, neridronic acid salt, olpadronate, Pamidronate, Risedronate, Tiludronate, the sharp phosphonate of assistant, they are the form of the form, particularly sodium salt of free acid, drug compatibility salt or hydrate.
Contain one or more complexing of metal ion agent in the pharmaceutically acceptable carrier of the present invention.This complexing of metal ion agent is selected from one or more the mixture in the materials such as b diammonium disodium edta, diethyl triamine five acetic acid, dimercaptopropanol, BAL.
Pharmaceutically acceptable carrier of the present invention also comprises filler, disintegrating agent, binding agent and lubricant.But this filler does not comprise calcium salt and phosphate, as calcium sulfate, calcium phosphate, calcium hydrogen phosphate, calcium carbonate, calcium lactate etc.
Pharmaceutical composition of the present invention adopts the mode of dry granulation tabletting to prepare.
Pharmaceutical composition of the present invention adopts the method preparation of direct powder compression.
The present invention further describes with reference to the following example, but does not limit the present invention.
Specific embodiment
Embodiment 1
Prescription is formed
Title percentage composition (%)
Minodronic acid 1.00
EDTA-2Na 1.00
Lactose 61.0
Microcrystalline Cellulose 30.0
Low-substituted hydroxypropyl cellulose 5.00
Micropowder silica gel 1.00
Magnesium stearate 1.00
Technology:
After supplementary material sieved, mix homogeneously was directly put the tablet machine tabletting.
The content that detects active component in the finished product is 99.96%.
Embodiment 2
Prescription is formed
Title percentage composition (%)
Alendronate 10.0
EDTA-2Na 1.00
Lactose 52.0
Microcrystalline Cellulose 30.0
Low-substituted hydroxypropyl cellulose 5.00
Micropowder silica gel 1.00
Magnesium stearate 1.00
Technology:
After supplementary material sieved, mix homogeneously was directly put the tablet machine tabletting.
Embodiment 3
Prescription is formed
Title percentage composition (%)
She the class sodium phosphate 20.0
Three second pentaacetic acids 1.00
Lactose 42.0
Microcrystalline Cellulose 30.0
Low-substituted hydroxypropyl cellulose 5.00
Micropowder silica gel 1.00
Magnesium stearate 1.00
Technology:
After supplementary material sieved, mix homogeneously was directly put the tablet machine tabletting.
Embodiment 4 (comparative example 1)
Prescription is formed
Title percentage composition (%)
Minodronic acid 1.00
EDTA-2Na 1.00
Lactose 62.0
Microcrystalline Cellulose 30.0
Low-substituted hydroxypropyl cellulose 5.00
Magnesium stearate 1.00
Technology:
After supplementary material sieved, mix homogeneously was granulated with aqueous solution, and dry back adds the magnesium stearate tabletting.
The content that detects active component in the finished product is 97.55%.
The content of the sample of direct compression prepared is than the finished product content height of wet granulation technology preparation.Direct compression technology is little to the influence of bisphosphonate substances may, has avoided the interference of the metal ion that brings in the wet granulation technology.
Embodiment 4 (comparative example 2)
Prescription is formed
Title percentage composition (%)
Minodronic acid 1.00
Lactose 63.0
Microcrystalline Cellulose 30.0
Low-substituted hydroxypropyl cellulose 5.00
Magnesium stearate 1.00
Technology:
After supplementary material sieved, mix homogeneously was granulated with aqueous solution, and dry back adds the magnesium stearate tabletting.Embodiment 5 pharmacokineticss are measured
Divide two groups at random to 8 human volunteers, first group of 4 volunteer takes the tablet that contains the complexing of metal ion agent of embodiment 2 preparations, and second group of 4 volunteer takes the tablet of embodiment 4 (comparative example 2) preparation.
Everyone was carried out minodronic acid in 0,1,2,3,4,5,6,7,10,12,14,16 and 24 hour and detect taking the back, write down the maximum plasma concentration (Cmax of this active component, ng/ml), and blood drug level to the area under curve of time (AUC, ng.h/ml).
First group of 4 volunteer takes the tablet that contains the complexing of metal ion agent of embodiment 2 preparations, and second group of 4 volunteer takes the Cmax of tablet and relatively the seeing the following form of AUC value of embodiment 4 (comparative example 2) preparation.
| The ratio of Cmax | The ratio of AUC | |
| Take embodiment 4 (comparative example 2) | 1 | 1 |
| Take embodiment 2 | 2.42 | 2.17 |
These results show that adding the complexing of metal ion agent can solve the bisphosphonates material effectively in the intravital absorption problem of people.
Claims (8)
1. a pharmaceutical composition that contains diphosphonate is characterized in that containing diphosphonate and other pharmaceutically acceptable carrier.
2. pharmaceutical composition as claimed in claim 1, it is characterized in that described diphosphonate comprises YM 529, alendronate, neridronic acid salt, olpadronate, Pamidronate, Risedronate, Tiludronate, the sharp phosphonate of assistant, they are the form of the form, particularly sodium salt of free acid, drug compatibility salt or hydrate.
3. pharmaceutical composition as claimed in claim 1 is characterized in that containing one or more complexing of metal ion agent.
4. pharmaceutical composition as claimed in claim 3, it is characterized in that described complexing of metal ion agent can be selected from one or more the mixture in b diammonium edta, b diammonium disodium edta, 1,2-1,2-diaminocyclohexane tetraacetic acid, three second pentaacetic acids, 2-trisodium hydroxyethylene diamine triacetate, diethyl triamine five acetic acid.
5. pharmaceutical composition as claimed in claim 1 is characterized in that described pharmaceutically acceptable carrier also comprises filler, disintegrating agent, binding agent and lubricant.
6. pharmaceutical composition as claimed in claim 5 is characterized in that described filler does not comprise calcium salt and phosphate.
7. pharmaceutical composition as claimed in claim 1 is characterized in that adopting the mode of dry granulation tabletting to prepare.
8. pharmaceutical composition as claimed in claim 1 is characterized in that adopting the method preparation of direct powder compression.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810101632A CN101530415A (en) | 2008-03-10 | 2008-03-10 | Pharmaceutical composition containing bisphosphates and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810101632A CN101530415A (en) | 2008-03-10 | 2008-03-10 | Pharmaceutical composition containing bisphosphates and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101530415A true CN101530415A (en) | 2009-09-16 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200810101632A Pending CN101530415A (en) | 2008-03-10 | 2008-03-10 | Pharmaceutical composition containing bisphosphates and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112972400A (en) * | 2021-03-09 | 2021-06-18 | 华侨大学 | Rapidly disintegrable minodronic acid granules and preparation method thereof |
| CN114028411A (en) * | 2021-11-18 | 2022-02-11 | 中国医学科学院基础医学研究所 | Use of nitrogen-containing bisphosphonates for preventing or treating viral pneumonia |
| WO2022142539A1 (en) * | 2020-12-30 | 2022-07-07 | 华南理工大学 | Minodronate calcium complex and preparation method therefor |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1396830A (en) * | 2000-01-20 | 2003-02-12 | 弗·哈夫曼-拉罗切有限公司 | Pharmaceutical parenteral composition containing biphosphonate |
| CN1956706A (en) * | 2004-05-24 | 2007-05-02 | 宝洁公司 | Enteric solid oral dosage form of bisphosphonate containing a chelating agent |
-
2008
- 2008-03-10 CN CN200810101632A patent/CN101530415A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1396830A (en) * | 2000-01-20 | 2003-02-12 | 弗·哈夫曼-拉罗切有限公司 | Pharmaceutical parenteral composition containing biphosphonate |
| CN1956706A (en) * | 2004-05-24 | 2007-05-02 | 宝洁公司 | Enteric solid oral dosage form of bisphosphonate containing a chelating agent |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022142539A1 (en) * | 2020-12-30 | 2022-07-07 | 华南理工大学 | Minodronate calcium complex and preparation method therefor |
| CN112972400A (en) * | 2021-03-09 | 2021-06-18 | 华侨大学 | Rapidly disintegrable minodronic acid granules and preparation method thereof |
| CN114028411A (en) * | 2021-11-18 | 2022-02-11 | 中国医学科学院基础医学研究所 | Use of nitrogen-containing bisphosphonates for preventing or treating viral pneumonia |
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Application publication date: 20090916 |