CN102028670A - Composite capsule containing telmisartan and calcium ion channel antagonist - Google Patents
Composite capsule containing telmisartan and calcium ion channel antagonist Download PDFInfo
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- CN102028670A CN102028670A CN 201010279697 CN201010279697A CN102028670A CN 102028670 A CN102028670 A CN 102028670A CN 201010279697 CN201010279697 CN 201010279697 CN 201010279697 A CN201010279697 A CN 201010279697A CN 102028670 A CN102028670 A CN 102028670A
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- capsule agent
- compound capsule
- telmisartan
- micropill
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Abstract
The invention discloses a composite capsule containing telmisartan and a calcium ion channel antagonist, which is prepared by filling the first part containing the telmisartan and the second part containing the calcium ion channel antagonist into the same hollow capsule, wherein the physical isolation is formed between the two parts through filming. Therefore, the composite capsule has the purposes of preparing the calcium ion channel antagonist with the appropriate size containing the telmisartan and the calcium ion channel antagonist and simplifying the preparation process thereof. The composite capsule has the advantages of appropriate size and is convenient in administration, and the preparation method is suitable for automatic capsule fillers after the appropriate improvement.
Description
Technical field
The present invention is a kind of compound capsule agent, is filled in the same Capsules by the second portion of first that contains telmisartan and calcium ions channel antagonist and forms, and forms physical isolation by the bag film-coat between two parts.
Background technology
Disclosed among telmisartan such as the EP-A-502314, be a kind of angiotensin receptor inhibitor, be used for treating light, moderate hypertension clinically.Its chemical name is 4 '-[4-methyl-6-(1-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-2-propyl group-1H-benzimidazole-1-ylmethyl] xenyl-2-carboxylic acid, have following structural formula:
Telmisartan is a kind of white or off-white color crystalline powder, does not almost allow in water, and its alkali metal salt is easily molten in water and alcohol.When useful in preparing drug formulations, add with free form, contain at least a alkaline reagent in the adjuvant.Because the tetrazole ring that does not have other sartans all to contain in its molecular structure does not need to use in preparation process to cost an arm and a leg, and the azide of severe toxicity, so production cost is lower than other sartans.The effective dose of blood pressure lowering is moderate, and this dosage also has hypoglycemic effect simultaneously, long half time, and the persistent period of blood pressure lowering paddy peak ratio and effect shows the most outstanding in existing such medicine.So be that cost performance is the highest in such medicine.
Calcium-ion channel antagonists among the present invention is selected from amlodipine and Levamlodipine, amlodipine at first is disclosed among the EP-A-89167, belong to the dihydropyridine calcium ion channel antagonist, its chemistry 3-ethyl 5-methyl-2-(2-ammonia ethoxymethyl) by name-4-(2-chlorphenyl)-1,4-dihydro-6-methyl-3, the 5-pyridine dicarboxylate has following structural formula:
Amlodipine pharmaceutically uses with the form of benzene sulfonate and maleate.
Modern medicine thinks that the blood pressure lowering drug combination should be based on calcium-ion channel antagonists (CCB), and unites use with angiotensin receptor inhibitor (ARB), is present optimal combined treatment.Both share and can work in coordination with blood pressure lowering, have good glycolipid metabolism influence, and inhibition of cell proliferation can reverse organ injury, organs such as the protection heart, kidney.
CN200510052246.4 discloses a kind of composite antihypertensive preparation and application thereof that contains telmisartan and calcium ion antagonist.But composite antihypertensive preparation how to realize containing telmisartan and calcium ion antagonist is not described in its description, and in fact, telmisartan and calcium ion antagonist are made compound preparation, directly mix the back and adopt conventional formulation method can not obtain stay-in-grade product.And use being reported in of telmisartan and calcium ion antagonist in a lot of documents before report to be arranged all about uniting, this double-layer tablet was gone on the market by drugs approved by FDA in 2009.
CN200580033928.9 discloses a kind of double-layer tablet that contains telmisartan and amlodipine, wherein describe the method that preparation contains the double-layer tablet of telmisartan and amlodipine in detail, in this patent, think that by two kinds of components of physical isolation be necessary, because after both directly mix, can cause the stability of amlodipine to reduce.And think that these two kinds of components are prepared into the compound capsule agent to be difficult to realize.
Summary of the invention
Prepare a kind of compound capsule agent that contains telmisartan and amlodipine, size to fit is convenient to take, and its preparation method is applicable to by the automatic capsule filling machine after the suitable improvement.
In CN200580033928.9, disclose and made preparation after telmisartan and amlodipine directly mix, can cause the amlodipine instability, so, in the technical program, also adopt physically-isolated method, this isolated material adopts the film coating of stomach dissolution type.
In CN200580033928.9, pointed out and to be filled in the capsule by two kinds of coated tablet that will contain single component, but the capsule of No. 0, needs or bigger model is unfavorable for taking.So the prior purpose of the present invention is that said composition is filled in the less Capsules that compares.
The alkaline reagent that CN200580033928.9 pointed out the coated granule, the micropill that contain amlodipine to be exposed to the telmisartan part is unstable down, the present invention also aims to address this problem, result's proof can address this problem after we adopt the film-coat physical isolation.
Disclosed double-layer tablet will realize aborning among the CN200580033928.9, and for general pharmaceutical factory, needing increases the equipment that plant area is used to place the compacting double-layer tablet, and common tablet machine can not be realized.And the objective of the invention is to utilize common automatic capsule filling machine to realize, and perhaps common automatic capsule filling machine is improved a little and can realize, do not need newly-increased plant area and acquire novel production equipment.
So the objective of the invention is: a kind of sizeable compound blood pressure reducing capsule that contains telmisartan and amlodipine of (1) preparation; (2) simplification contains the preparation technology of the compound preparation of telmisartan and amlodipine.
The Telmisartan formulations of having gone on the market at present has tablet and capsule, all needs telmisartan is made sodium salt at these products, uses a large amount of water soluble adjuvants, thereby causes the very easily moisture absorption of product, packaging material is required high.Technical scheme in EP1797872A1, can replace alkaline reagent by adding surfactant, can obtain the external stripping behavior preparation consistent with " Micardis ", so (1) of the compound preparation among the present invention part adopts the technical scheme of EP1797872A1, alkaline reagent only uses meglumine, preferred surfactants is a poloxamer 188, and filler is a microcrystalline Cellulose.Main material and amount ranges are as shown in table 1.
The component of table 1 the present invention (1) part
| The material title | Effect | Mass percent (%) |
| Telmisartan | Active component | 12.5～15.5 |
| Microcrystalline Cellulose | Water-insoluble diluent | 40～70 |
| Poloxamer 188 | Surfactant | 2.0～3.5 |
| Meglumine | Alkalescence substrate | 9～12 |
| 30 POVIDONE K 30 BP/USP-30 | Binding agent | 1.0～1.5 |
| Carboxymethyl starch sodium | Disintegrating agent | 7.5～10 |
| Sorbitol | Filler | 0～17 |
| Magnesium stearate | Lubricant | 0.5～1.0 |
The present invention (1) part can be made into granule or micropill, and preferred for preparation becomes granule, because the complicated process of preparation of micropill, yield are low, and length consuming time, apparatus expensive.
The active component of (2) part of the present invention is amlodipine or Levamlodipine, with reference to the description of " living and like in the Lip river ", and relative product patent, material and amount ranges that (2) part is main are as shown in table 2.
The component of table 2 the present invention (2) part
| The material title | Effect | Mass percent (%) |
| Amlodipine (or Levamlodipine) | Active component | 3～15 |
| Calcium phosphate dibasic anhydrous | Filler | 35～95 |
| Microcrystalline Cellulose | Filler | 0～60 |
| Carboxymethyl starch sodium | Disintegrating agent | 0～5 |
| 30 POVIDONE K 30 BP/USP-30 | Binding agent | 1～3 |
| Magnesium stearate | Lubricant | 0.5～1 |
(2) of the present invention part can be made into micropill, granule, small pieces, and needs the bag film-coat, the micropill made from be filled in the Capsules after the micropill that (1) part is made mixes, can realize the present invention, but the preparation technology of micropill complexity too; (2) granule made of part be filled in the Capsules after granule that (1) part is made mixes, also can realize the present invention, but granule coating technology that is that all right for domestic most pharmacy corporation is ripe; So preferably the coated pellets that (2) part is made is filled in earlier in the capsule, fill the granule that adding (1) part is made by secondary again.In this preferred version, use all be solid preparation technology and the equipment of using always, comprise that capsular secondary fills, common automatic capsule filling machine can be realized.
The specific embodiment
The present invention is further illustrated to enumerate the following examples.Should correct understanding be: these embodiment only are used to the present invention is described and provide, rather than limitation of the present invention, so on the basis of these embodiment, to simple modifications of the present invention, all belong to the scope of protection of present invention.
Embodiment 1 contains the particulate preparation of telmisartan
Required material and consumption are as shown in table 3.
Table 3
| Telmisartan | ?40mg |
| Microcrystalline Cellulose | ?150mg |
| Poloxamer 188 | ?6mg |
| Meglumine | 40mg |
| 30 POVIDONE K 30 BP/USP-30 | 5mg |
| Carboxymethyl starch sodium | 15mg |
| Magnesium stearate | 1.5mg |
Get poloxamer 188,30 POVIDONE K 30 BP/USP-30 be dissolved in the adequate amount of ethanol standby, behind telmisartan, microcrystalline Cellulose, meglumine, carboxymethyl starch sodium mix homogeneously, add above-mentioned alcoholic solution system mix homogeneously after, granulate, 60 ℃ of dryings are behind the granulate, add magnesium stearate, mix homogeneously promptly.
Embodiment 2 contains the preparation of the small pieces of Amlodipine Besylate Tablet
Required material and consumption are as shown in table 4.
Table 4
| Amlodipine Besylate Tablet | 6.7mg |
| Calcium phosphate dibasic anhydrous | 60mg |
| Microcrystalline Cellulose | 13mg |
| 30 POVIDONE K 30 BP/USP-30 | 2mg |
| Carboxymethyl starch sodium | 5mg |
| Magnesium stearate | 0.5mg |
Get Amlodipine Besylate Tablet, calcium phosphate dibasic anhydrous, microcrystalline Cellulose, carboxymethyl starch sodium mix homogeneously, granulate as binding agent, 60 ℃ of dryings with the alcoholic solution of 30 POVIDONE K 30 BP/USP-30, behind the granulate, add magnesium stearate, behind the mix homogeneously, be pressed into the disk of diameter 4.5mm, the bag film-coat and.
Embodiment 3 contains the preparation of the small pieces of Levamlodipine besylate
Required material and consumption are as shown in table 5.
Table 5
| Levamlodipine besylate | 6.7mg |
| Calcium phosphate dibasic anhydrous | 60mg |
| Microcrystalline Cellulose | 13mg |
| 30 POVIDONE K 30 BP/USP-30 | 2mg |
| Carboxymethyl starch sodium | 5mg |
| Magnesium stearate | 0.5mg |
Get Levamlodipine besylate, calcium phosphate dibasic anhydrous, microcrystalline Cellulose, carboxymethyl starch sodium mix homogeneously, alcoholic solution with 30 POVIDONE K 30 BP/USP-30 is granulated as binding agent, 60 ℃ of dryings, behind the granulate, add magnesium stearate, behind the mix homogeneously, be pressed into the disk of diameter 4.5mm, the bag film-coat and.
The capsular preparation of embodiment 4 compound recipe telmisartan Amlodipine Besylate Tablets
Earlier the small pieces of embodiment 2 gained are filled in No. 1 Capsules, in again the granule of embodiment 1 gained being incapsulated, promptly.Dress as execute 1 of the small pieces of example 2 gained, the granule 257mg of embodiment 1 gained in every capsules.
The capsular preparation of the embodiment 5 left-handed Flordipines of compound recipe telmisartan benzenesulfonic acid ammonia
Earlier the small pieces of embodiment 3 gained are filled with No. 1 Capsules in, in again the granule of embodiment 1 gained being incapsulated, promptly.Dress as execute 1 of the small pieces of example 3 gained, the granule 257mg of embodiment 1 gained in every capsules.
Claims (16)
1. compound capsule agent that comprises telmisartan and calcium-ion channel antagonists is characterized in that it comprises:
(1) granule of forming by telmisartan and pharmaceutical carrier, micropill or small pieces part;
(2) granule of forming by calcium-ion channel antagonists and pharmaceutical carrier, micropill or small pieces part.
2. compound capsule agent according to claim 1, it is characterized in that between two ingredient, need to pass through to wherein part or all wraps film-coat arbitrarily, preferred two parts wrap film-coat respectively, more preferably a part bag film-coat to the calcium ions channel antagonist.
3. compound capsule agent according to claim 1, wherein calcium-ion channel antagonists of (2) part is selected from Amlodipine Besylate Tablet, amlodipine maleate, and Levamlodipine besylate, maleic acid levo amido chloro diping.
4. compound capsule agent according to claim 1, wherein (1) part is fit to make coating or the not micropill and the granule of coating.
5. compound capsule agent according to claim 1, wherein (2) part is fit to make coated granules, micropill, small pieces.
6. compound capsule agent according to claim 1 is made with being filled in the Capsules after the micropill that partly makes (2) mixes by the micropill made of (1) part.
7. compound capsule agent according to claim 1, the coated pellets of being made by the granule made of (1) part and (2) part is filled in the Capsules to be formed.
8. compound capsule agent according to claim 1, the small pieces of being made by the micropill made of (1) part and (2) part are filled in the Capsules to be formed.
9. compound capsule agent according to claim 1 behind the granule mix homogeneously of being made by the granule made of (1) part and (2) part, is filled in the Capsules and makes.
10. compound capsule agent according to claim 1, wherein (1) part contains telmisartan 20～80mg.
11. compound capsule agent according to claim 1, wherein (2) part contains amlodipine or Levamlodipine 2.5～10mg.
12. compound capsule agent according to claim 1, wherein (1) part comprises a kind of alkaline reagent at least, is selected from NaOH, KOH, Na
2CO
3, K
2CO
3, NaHCO
3, KHCO
3, NH
3, and the aminoacid and the meglumine of alkalescence.
13. compound capsule agent according to claim 1, wherein the carrier of (1) part comprises a kind of surfactant at least, be selected from poloxamer, Polyethylene Glycol, polyethyleneglycol monostearate, Polysorbate, sodium lauryl sulfate, poly-ethoxyquin and castor oil hydrogenated, preferred poloxamer 182LF, poloxamer 331 and poloxamer 188.
14. compound capsule agent according to claim 1, wherein the pharmaceutical carrier of (1) part comprises a kind of water miscible pharmaceutic adjuvant at least as diluent, preferred mannitol.
15. compound capsule agent according to claim 1, wherein the pharmaceutical carrier of (1) part comprises a kind of disintegrating agent at least, preferred carboxymethyl starch sodium.
16. compound capsule agent according to claim 1, wherein the pharmaceutical carrier of (2) part contains calcium phosphate dibasic anhydrous and other pharmaceutic adjuvants.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010279697 CN102028670A (en) | 2010-09-06 | 2010-09-06 | Composite capsule containing telmisartan and calcium ion channel antagonist |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010279697 CN102028670A (en) | 2010-09-06 | 2010-09-06 | Composite capsule containing telmisartan and calcium ion channel antagonist |
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| Publication Number | Publication Date |
|---|---|
| CN102028670A true CN102028670A (en) | 2011-04-27 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201010279697 Pending CN102028670A (en) | 2010-09-06 | 2010-09-06 | Composite capsule containing telmisartan and calcium ion channel antagonist |
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| Country | Link |
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| CN (1) | CN102028670A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102247367A (en) * | 2011-05-24 | 2011-11-23 | 苏州东瑞制药有限公司 | Pharmaceutical composition containing telmisartan and amlodipine and preparation method thereof |
| CN103127108A (en) * | 2012-03-12 | 2013-06-05 | 成都自豪药业有限公司 | Telmisartan amlodipine tablet, and preparation method and use thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101564536A (en) * | 2008-04-21 | 2009-10-28 | 鲁南制药集团股份有限公司 | Sustained and controlled release preparation for pharmaceutical composition for curing hypertension |
| CN101674811A (en) * | 2007-02-09 | 2010-03-17 | 阿尔法制药有限公司 | A dosage form containing two or more active pharmaceutical ingredients in different physical forms |
| CN101797250A (en) * | 2010-04-22 | 2010-08-11 | 重庆市力扬医药开发有限公司 | Stable compound preparation |
-
2010
- 2010-09-06 CN CN 201010279697 patent/CN102028670A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101674811A (en) * | 2007-02-09 | 2010-03-17 | 阿尔法制药有限公司 | A dosage form containing two or more active pharmaceutical ingredients in different physical forms |
| CN101564536A (en) * | 2008-04-21 | 2009-10-28 | 鲁南制药集团股份有限公司 | Sustained and controlled release preparation for pharmaceutical composition for curing hypertension |
| CN101797250A (en) * | 2010-04-22 | 2010-08-11 | 重庆市力扬医药开发有限公司 | Stable compound preparation |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102247367A (en) * | 2011-05-24 | 2011-11-23 | 苏州东瑞制药有限公司 | Pharmaceutical composition containing telmisartan and amlodipine and preparation method thereof |
| CN102247367B (en) * | 2011-05-24 | 2014-05-21 | 苏州东瑞制药有限公司 | Pharmaceutical composition containing telmisartan and amlodipine and preparation method thereof |
| CN103127108A (en) * | 2012-03-12 | 2013-06-05 | 成都自豪药业有限公司 | Telmisartan amlodipine tablet, and preparation method and use thereof |
| CN103127108B (en) * | 2012-03-12 | 2015-01-21 | 成都自豪药业有限公司 | Telmisartan amlodipine tablet, and preparation method and use thereof |
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Application publication date: 20110427 |