CN104138365B - A kind of telmisartan capsules agent and preparation method thereof - Google Patents
A kind of telmisartan capsules agent and preparation method thereof Download PDFInfo
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- CN104138365B CN104138365B CN201310562886.4A CN201310562886A CN104138365B CN 104138365 B CN104138365 B CN 104138365B CN 201310562886 A CN201310562886 A CN 201310562886A CN 104138365 B CN104138365 B CN 104138365B
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Abstract
The invention discloses a kind of telmisartan capsules agent and preparation method thereof, every 1000 described telmisartan capsules agent comprise following components: telmisartan 40g, lactose 210g, sodium hydroxide 3.2g, meglumine 6.0g, PVP K30 alcoholic solution 25ml。The telmisartan capsules agent of the present invention, with telmisartan for principal agent, select sodium hydroxide, meglumine, lactose PVP K30 alcoholic solution be adjuvant, drastically increase the dissolution rate of telmisartan, thus improve the bioavailability of capsule；There are good initial stability and long-time stability；Oral absorption is good, and hypertension has significant curative effect。
Description
Technical field
The invention belongs to pharmaceutical technology field, be specifically related to a kind of telmisartan capsules agent, the preparation method also relating to a kind of telmisartan capsules agent。
Background technology
In recent years, hypertension has become one of primary killers of harm human health, and the drug main for the treatment of hypertension to have thiazide diuretic, beta-Blocking agent, calcium antagonist, angiotensin-convertion enzyme inhibitor (ACEI), alpha-2-adrenoceptor blocker and Angiotensin Ⅱ receptor antagonist (ATlreceptorantagonist)。Wherein, angiotensin-convertion enzyme inhibitor (ACE inhibitor) and Angiotensin Ⅱ receptor antagonist (AT1 receptor antagonist) are most important two class antihypertensive drug。Telmisartan is one of up-to-date best medicine of sartans。
Telmisartan (telmisartan), also known as BIBR277, is by Germany Behringerl Ying Gehaimu (BoehringerIngelheim) exploitation, on November 10th, 1998, obtains the approval of FDA (Food and Drug Adminstration)。Telmisartan is a kind of angiotensin II receptor antagonist, optionally, it is difficult to the retardance AT of reverse1Receptor, and to other receptors, especially relate to the receptor of cardiovascular system without impact。With AT1The affinity of receptor is AT2More than 3000 times of receptor。It optionally blocks Angiotensin II and the AT in many tissues (such as vascular smooth muscle and adrenal gland)1Receptor combines, thus blocks vasoconstriction and the Aldosterone Secretion effect of Angiotensin II, but does not affect other receptor systems in Cardiovascular regulation。
But, telmisartan dosage form in the market mostly is tablet, the problem that existence and stability is not high, dissolution rate is low, bioavailability is not high, it is impossible to meet the requirement of people。
Summary of the invention
It is an object of the invention to provide a kind of telmisartan capsules agent, solve the problem that existing telmisartan dosage form stability is not high, dissolution rate is low, bioavailability is not high。
The preparation method that second purpose of the present invention is to provide a kind of telmisartan capsules agent。
In order to realize object above, the technical solution adopted in the present invention is: a kind of telmisartan capsules agent, and every 1000 described telmisartan capsules agent comprise following components: telmisartan 40g, lactose 210g, sodium hydroxide 3.2g, meglumine 6.0g, PVP K30 alcoholic solution 25ml。
In the alcoholic solution of described PVP K30, the mass concentration of PVP K30 is 5%。
Described capsule is hard capsule。The capsule shells of described capsule is pharmagel。
The preparation method of a kind of above-mentioned telmisartan capsules agent, comprises the following steps:
1) sodium hydroxide and meglumine ethanol water are dissolved, add telmisartan, mix and grind, obtaining mixture A；
2) in mixture A, add lactose, be dried after mixing, pulverize afterwards, cross screen cloth, obtain mixing fine powders；
3) alcoholic solution of PVP K30 is added step 2) soft material processed in gained mixing fine powders, mistake screen cloth wet granular；
4) after step 3) gained wet grain drying, screen cloth will be crossed and carry out granulate；
5) metering dress capsule, to obtain final product。
The mass concentration of ethanol water described in step 1) is 50%。
Step 2) described in dry temperature be 50～60 DEG C, drying time is 30～60min。
Step 2) described in screen cloth be 40 orders。
Screen cloth described in step 3) is 20 orders。
Screen cloth described in step 4) is 18 orders。
Temperature dry described in step 4) is 50～60 DEG C, and drying time is 2～3h。
In the telmisartan capsules agent of the present invention, the effect in prescription of each component is as follows:
The telmisartan capsules agent of the present invention, during telmisartan dissolving in alkali is sourer rapidly and completely, uses sodium hydroxide can increase it and dissolves；In order to keep the solubility property of principal agent and increase its stability, in prescription except adding sodium hydroxide, add appropriate conventional cosolvent meglumine, telmisartan dissolving in sodium hydroxide solution can be accelerated on the one hand, tablet is kept to be generally in alkaline environment on the other hand, thus eliminating the acid ingredient of the adjuvant impact on the sodium salt of telmisartan in prescription；Adopting lactose can more effectively absorb moisture as filler, drying course is simple, and in aqueous solution, dissolution rate is very fast。
The telmisartan capsules agent of the present invention, with telmisartan for principal agent, select sodium hydroxide, meglumine, lactose PVP K30 alcoholic solution be adjuvant, drastically increase the dissolution rate of telmisartan, thus improve the bioavailability of capsule；There are good initial stability and long-time stability；Oral absorption is good, and hypertension has significant curative effect。
The preparation method of the telmisartan capsules agent of the present invention, adopts wet granulation dress capsule and takes the granularity reducing telmisartan to increase its dissolution, the good fluidity of gained Capsule content；Technique is simple, easy to operate, can control the quality of capsule preferably, is suitable for large-scale industrial production。
Detailed description of the invention
Below in conjunction with detailed description of the invention, the present invention is further illustrated。
Embodiment 1
The telmisartan capsules agent of the present embodiment, every 1000 described telmisartan capsules agent comprise following components: telmisartan 40g, lactose 210g, sodium hydroxide 3.2g, meglumine 6.0g, PVP K30 alcoholic solution 25ml。
Described capsule is hard capsule。
The preparation method of the telmisartan capsules agent of the present embodiment, comprises the following steps:
1) sodium hydroxide of 3.2g and the meglumine of the 6.0g ethanol water that a small amount of mass concentration is 50% are dissolved, add telmisartan, mix and grind, obtaining mixture A；
2) in mixture A, add the lactose of 210g, carry out dry 60min under 50 DEG C of conditions after mixing, pulverize afterwards, cross 40 eye mesh screens, obtain mixing fine powders；
3) alcoholic solution of the PVP K30 that 25ml, mass concentration are 5% is added step 2) soft material processed in gained mixing fine powders, mistake 20 eye mesh screen wet granulars；
4) step 3) gained wet granular after dry 3h, is crossed 18 eye mesh screens and is carried out granulate under 50 DEG C of conditions；
5) measure content main in granule, calculate loading amount, fill capsule, pack after passed examination, obtain telmisartan capsules。
Embodiment 2
The telmisartan capsules agent of the present embodiment, every 1000 described telmisartan capsules agent comprise following components: telmisartan 40g, lactose 210g, sodium hydroxide 3.2g, meglumine 6.0g, PVP K30 alcoholic solution 25ml。
Described capsule is hard capsule。
The preparation method of the telmisartan capsules agent of the present embodiment, comprises the following steps:
1) sodium hydroxide of 3.2g and the meglumine of the 6.0g ethanol water that a small amount of mass concentration is 50% are dissolved, add telmisartan, mix and grind, obtaining mixture A；
2) in mixture A, add the lactose of 210g, carry out dry 30min under 60 DEG C of conditions after mixing, pulverize afterwards, cross 40 eye mesh screens, obtain mixing fine powders；
3) alcoholic solution of the PVP K30 that 25ml, mass concentration are 5% is added step 2) soft material processed in gained mixing fine powders, mistake 20 eye mesh screen wet granulars；
4) step 3) gained wet granular after dry 2h, is crossed 18 eye mesh screens and is carried out granulate under 60 DEG C of conditions；
5) measure content main in granule, calculate loading amount, fill capsule, pack after passed examination, obtain telmisartan capsules。
Embodiment 3
The telmisartan capsules agent of the present embodiment, every 1000 described telmisartan capsules agent comprise following components: telmisartan 40g, lactose 210g, sodium hydroxide 3.2g, meglumine 6.0g, PVP K30 alcoholic solution 25ml。
Described capsule is hard capsule。
The preparation method of the telmisartan capsules agent of the present embodiment, comprises the following steps:
1) sodium hydroxide of 3.2g and the meglumine of the 6.0g ethanol water that a small amount of mass concentration is 50% are dissolved, add telmisartan, mix and grind, obtaining mixture A；
2) in mixture A, add the lactose of 210g, carry out dry 45min under 55 DEG C of conditions after mixing, pulverize afterwards, cross 40 eye mesh screens, obtain mixing fine powders；
3) alcoholic solution of the PVP K30 that 25ml, mass concentration are 5% is added step 2) soft material processed in gained mixing fine powders, mistake 20 eye mesh screen wet granulars；
4) step 3) gained wet granular after dry 2.5h, is crossed 18 eye mesh screens and is carried out granulate under 55 DEG C of conditions；
5) measure content main in granule, calculate loading amount, fill capsule, pack after passed examination, obtain telmisartan capsules。
Experimental example 1
The stability of embodiment 1～3 gained telmisartan capsules is detected by this experimental example。
1.1 influence factor's tests
1.1.1 hot test (60 DEG C): Example 1～3 gained telmisartan capsules, it is placed in the container of cleaning, it is opened in the calorstat of 60 DEG C and places 10 days, sampled respectively at the 0th, 5,10 days, detect by stability high spot reviews project, detection data compare with 0 day data, and result is in Table 1。
60 DEG C of result of the tests of table 1 high temperature
1.1.2 high wet test (RH92.5%): Example 1～3 gained telmisartan capsules, it is placed in the container of cleaning, opening is placed in constant humidity (relative humidity 92.5%) hermetic container, place 10 days in 25 DEG C, sampled respectively at 0,5,10 days, detecting by stability high spot reviews project, detection data compare with 0 day data, and result is in Table 2。
Table 2 high humility (25 DEG C, RH92.5%) result of the test
1.1.3 exposure experiments to light (4500Lx): Example 1～3 gained telmisartan capsules, it is placed in the container of cleaning, opening is placed in lighting box (illumination 4500Lx), place 10 days, in the 0th, 5,10 days separately sampled, detecting by stability high spot reviews project, detection data compare with 0 day data, and result is in Table 3。
Table 3 exposure experiments to light (4500LX) result
1.2 accelerated tests
Example 1～3 gained telmisartan capsules, is placed in temperature 40 ± 2 DEG C, when relative humidity is the constant temperature and humidity of 75 ± 5%, places 6 months, detects each relevant item in 0 and the 1st, 2,3,6 sampling at the end of month, and result is in Table 4。
Table 4 accelerated test result
From table 4, it can be seen that detect projects data after the accelerated test of embodiment 1～3 gained telmisartan capsules, the data with zero month compare, and significant change does not all occur, and illustrate that the telmisartan capsules of the application has good stability when accelerated test。
1.3 long term tests
Example 1～3 gained telmisartan capsules, is placed in temperature 25 ± 2 DEG C, places when relative humidity is 60 ± 10%, respectively at the 3rd, 6,9,12,18,24,36 sampling detection at the end of month relevant item, and the results contrast with zero month, result is in Table 5。
Table 5 stability long-term test results
As can be seen from Table 5, embodiment 1～3 gained telmisartan capsules is through long term test, 3rd, 6,9., 12,18,24 and detection in 36 months be respectively arranged with pass project result and compared with 0 month, projects have no significant change, illustrate that the telmisartan capsules of the present invention has good long-time stability at ambient temperature, can steady in a long-term preserve。
Experimental example 2
The dissolution of embodiment 1～3 gained telmisartan capsules is detected by this experimental example。
Dissolution determination method: Example 1～3 gained telmisartan capsules, according to dissolution method (Chinese Pharmacopoeia two annex XC the first methods of version in 2010), with water 800ml for solvent, rotating speed is 100 turns per minute, operate in accordance with the law, after 30 minutes, take solution appropriate, filter, take subsequent filtrate 2ml in putting in 10ml measuring bottle, it is diluted with water to scale, shake up, according to spectrophotography (Chinese Pharmacopoeia two annex IV A of version in 2010), trap is measured at 295nm wavelength place, the telmisartan reference substance being dried to constant weight of separately learning from else's experience 105 DEG C is appropriate, dissolve with 0.1mol/L caustic lye of soda and dilute makes every 1ml solution containing 10 μ g, operate with method, calculate the stripping quantity of every capsules。Measurement result is in Table 5。
Table 5 dissolution determination result (30min)
| Subjects | Experimental example 1 | Experimental example 2 | Experimental example 3 |
| Dissolution, % | 99.77 | 99.89 | 99.69 |
Experimental example 3
The pharmacokinetics of embodiment 1～3 gained telmisartan capsules is tested by this experimental example。
Embodiment 1～3 gained telmisartan capsules, oral easily absorption, Tmax average out to 1h, the Cmax of single dose 40mg are 44.7 μ g/L, and about 7d can reach steady plasma-drug concentration, its absolute bioavailability is 43%, protein binding rate > 99%, is mainly distributed on liver, is secondly blood, adrenal cortex and heart, few in brain。This product t1/2About 24h。84% with original shape, is metabolite excretion from feces and urine on a small quantity, and the former accounts for > 98%, all excretes after about 5d。
After oral, 0.5～1h reaches peak serum concentration。After single oral dose 20,40,80 and 120mg, its peak concentration respectively 17,100,870 and 1442ng ml-1。Oral 40 and 80mg after drug-time curve under area (AUC) be 811 and 2735ngh ml-1。The bioavailability of this product is affected little by food。
This product is combined into inactive glucuronide mainly through liver, and cytochrome P 450 enzymes is not engaged in the metabolism of this product。In Nonlinear elimination in 20～160mg dosage range, terminal elimination half-life is about 24h。Acting duration is 24h at least。Daily blood plasma cumulative index once is 1.5～2.0。Blood plasma overall elimination factor > 800ml min-1；This product and albumin and α1Acid Glycoprotein binding, protein binding rate is more than 99.5%。Distribution volume is about 500L, and prompting has substantial amounts of tissue to combine。
The removing of this product enters feces mainly through bile, minimum by renal function。
Claims (9)
1. a telmisartan capsules agent, it is characterised in that: every 1000 described telmisartan capsules agent are made up of following raw material: telmisartan 40g, lactose 210g, sodium hydroxide 3.2g, meglumine 6.0g, the alcoholic solution 25ml of PVP K30, ethanol water；
In the alcoholic solution of described PVP K30, the mass concentration of PVP K30 is 5%；
The preparation method of described telmisartan capsules agent, comprises the following steps:
1) sodium hydroxide and meglumine ethanol water are dissolved, add telmisartan, mix and grind, obtaining mixture A；
2) in mixture A, add lactose, be dried after mixing, pulverize afterwards, cross screen cloth, obtain mixing fine powders；
3) alcoholic solution of PVP K30 is added step 2) soft material processed in gained mixing fine powders, mistake screen cloth wet granular；
4) by step 3) after gained wet grain drying, cross screen cloth and carry out granulate；
5) metering dress capsule, to obtain final product。
2. telmisartan capsules agent according to claim 1, it is characterised in that: described capsule is hard capsule。
3. the preparation method of a telmisartan capsules agent as claimed in claim 1, it is characterised in that: comprise the following steps:
1) sodium hydroxide and meglumine ethanol water are dissolved, add telmisartan, mix and grind, obtaining mixture A；
2) in mixture A, add lactose, be dried after mixing, pulverize afterwards, cross screen cloth, obtain mixing fine powders；
3) alcoholic solution of PVP K30 is added step 2) soft material processed in gained mixing fine powders, mistake screen cloth wet granular；
4) by step 3) after gained wet grain drying, cross screen cloth and carry out granulate；
5) metering dress capsule, to obtain final product。
4. the preparation method of telmisartan capsules agent according to claim 3, it is characterised in that: step 1) described in the mass concentration of ethanol water be 50%。
5. the preparation method of telmisartan capsules agent according to claim 3, it is characterised in that: step 2) described in dry temperature be 50～60 DEG C, drying time is 30～60min。
6. the preparation method of telmisartan capsules agent according to claim 3, it is characterised in that: step 2) described in screen cloth be 40 orders。
7. the preparation method of telmisartan capsules agent according to claim 3, it is characterised in that: step 3) described in screen cloth be 20 orders。
8. the preparation method of telmisartan capsules agent according to claim 3, it is characterised in that: step 4) described in screen cloth be 18 orders。
9. the preparation method of telmisartan capsules agent according to claim 3, it is characterised in that: step 4) described in dry temperature be 50～60 DEG C, drying time is 2～3h。
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| CN111265488B (en) * | 2020-03-18 | 2021-11-12 | 重庆康刻尔制药股份有限公司 | Telmisartan tablets and preparation method thereof |
| CN115245497A (en) * | 2021-04-26 | 2022-10-28 | 武汉伯睿科医药科技有限公司 | Telmisartan capsule and preparation process thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101313905A (en) * | 2007-05-29 | 2008-12-03 | 上海信谊嘉华药业有限公司 | Composition containing telmisartan and preparing method thereof |
| CN101897676A (en) * | 2010-07-27 | 2010-12-01 | 北京京丰制药有限公司 | Telmisartan tablet composition |
| CN102266328A (en) * | 2011-06-01 | 2011-12-07 | 西安新通药物研究有限公司 | Preparation method of compound preparation of telmisartan and amlodipine and high stability preparation thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101313905A (en) * | 2007-05-29 | 2008-12-03 | 上海信谊嘉华药业有限公司 | Composition containing telmisartan and preparing method thereof |
| CN101897676A (en) * | 2010-07-27 | 2010-12-01 | 北京京丰制药有限公司 | Telmisartan tablet composition |
| CN102266328A (en) * | 2011-06-01 | 2011-12-07 | 西安新通药物研究有限公司 | Preparation method of compound preparation of telmisartan and amlodipine and high stability preparation thereof |
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