CN108578404B - Medicinal composition containing irbesartan and amlodipine and preparation method thereof - Google Patents
Medicinal composition containing irbesartan and amlodipine and preparation method thereof Download PDFInfo
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Abstract
A medicinal composition containing irbesartan and amlodipine is composed of amlodipine or a medicinal salt thereof, irbesartan and a medicinal excipient, and is a tablet prepared by one-step mixing, granulating and drying. The technical problem to be solved by the invention is to provide a stable pharmaceutical composition containing irbesartan and amlodipine, wherein the irbesartan and amlodipine are prepared by one-step mixing, granulating and drying processes through a fluidized bed process.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a medicinal composition containing irbesartan and amlodipine and a preparation method thereof.
Background
Hypertension is one of the most common cardiovascular diseases and is also an important risk factor for the occurrence of other cerebrovascular events. At present, most single-drug therapies are not high in standard-reaching proportion and poor in curative effect. Therefore, for the middle-sized and severe patients who cannot satisfactorily control blood pressure by a single antihypertensive drug therapy or have high blood pressure, two or more antihypertensive drugs should be used in combination.
Irbesartan is an angiotensin II receptor subtype AT1 receptor antagonist. It competitively antagonizes the endogenous pressor substance angiotensin ii at the receptor level to exhibit a hypotensive effect. Since 1990, it has developed into a drug for the treatment of hypertension.
Amlodipine or salts thereof, such as amlodipine besylate, are dihydropyridine calcium channel blockers which selectively inhibit calcium ions from entering the vascular smooth machine and myocardium across the membrane, thereby reducing peripheral vascular resistance and blood pressure.
The combined use of an angiotensin II receptor antagonist and a calcium channel blocker is a combination recommended by various guidelines for the treatment of hypertension. The combination of the long-acting irbesartan and the long-acting amlodipine can improve the antihypertensive effect and the medication compliance.
Irbesartan is practically insoluble in water, irbesartan has a parabolic pH solubility profile in pH buffered saline solutions, a minimum solubility between pH2.0 and 6.0, and a maximum solubility in 0.1N hydrochloric acid solutions and pH7.5 phosphate buffer solutions. Irbesartan has relatively low bulk density and tap density, and also has strong adhesion, and is easy to generate electrostatic agglomeration. These properties of irbesartan make it difficult to prepare effective doses of the drug into small tablets having uniform weight, hardness and other desirable tablet properties. The extremely low water solubility of irbesartan also makes it challenging to prepare small tablets, since only limited excipients can be added to facilitate its wetting, disintegration and eventual fast release.
The second active ingredient, amlodipine besylate, has relatively low bulk and tap densities and exhibits poor flowability. The relatively small composition of the second active ingredient amlodipine besylate in the composition, based on total weight, can further lead to problems such as tableting or uniformity of dosage units.
WO2006/059217 discloses that amlodipine is highly hygroscopic, leading to decomposition in a hot and humid environment, one of the main pathways of decomposition being via catalytic oxidation, a process which is pH dependent. One of the major decomposition products known in the art is 2- [ (2-aminoethoxy) methyl ] -4- (2-chlorophenyl) -6-methylpyridine-3, 5-dicarboxylic acid-3-ethyl-5-methyl ester and is known as impurity D.
Japanese patent JP2011207873A discloses a pharmaceutical composition containing irbesartan and amlodipine or a salt thereof. Obtained by the following method: the traditional wet granulation process is adopted, firstly irbesartan and part of medicinal excipients are separately subjected to wet granulation and dried, and then the granulated irbesartan and amlodipine are blended to prepare tablets.
CN 106176745a of cenofilrene discloses a tablet containing irbesartan and amlodipine, which is obtained by: firstly, irbesartan and amlodipine besylate are respectively prepared into physically separated particles with medicinal excipients, and then the two particles are blended to prepare tablets.
As can be seen, there is currently no fixed dose stable pharmaceutical composition comprising irbesartan and amlodipine that is mixed, granulated, dried and prepared into tablets in one step. The traditional step granulation process is relatively complex, and has the characteristics of low efficiency and low yield.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a stable pharmaceutical composition containing irbesartan and amlodipine, wherein the irbesartan and amlodipine are prepared by one-step mixing, granulating and drying processes through a fluidized bed process.
In order to solve the technical problems, the invention provides a medicinal composition containing irbesartan and amlodipine, which consists of amlodipine or a medicinal salt thereof, irbesartan and a medicinal excipient and is a tablet prepared by one-step mixing, granulation and drying.
Further, the tablets are film coated.
Further, the medicinal excipient comprises any one or a mixture of more of a filling agent, a binding agent, a disintegrating agent, a glidant and a lubricant; the amlodipine besylate is amlodipine.
Further, the weight of the irbesartan accounts for 40-60% of the total weight of the pharmaceutical composition; the weight of the amlodipine besylate accounts for 2-8% of the total weight of the medicinal composition.
Furthermore, the adhesive is polyvinyl alcohol, and the flow aid is micropowder silica gel.
Further, the irbesartan accounts for 75-150 mg of the total weight of the tablet; the composition amount of the amlodipine besylate is 2.5 mg-12.5 mg.
Further, the amount of irbesartan out of the total weight of the tablet is 100 mg; the content of amlodipine besylate (calculated as amlodipine) is 5mg or 10 mg.
The pharmaceutical compositions of the present invention contain one or more of the following components in the indicated ratio ranges (wt%); irbesartan, 40.0-60.0%, most preferably 50.0%, amlodipine besylate, 2.0-8.0%, most preferably 3.5-6.9%, microcrystalline cellulose as filler, 10.0-20.0%, most preferably 13.6-18.2%, mannitol as filler, 16.0-22.0%, most preferably 16.6-20.9%, polyvinyl alcohol as binder, 1.0-3.0%, most preferably 2.0%, glidant, 1.0-4.0%, most preferably 3.0%, disintegrant, 3.0-5.0%, most preferably 4.0%, lubricant, 0.5-2.0%, most preferably 1.5%. The amount of each ingredient (active ingredient and pharmaceutically acceptable excipients) in the pharmaceutical composition of the present invention can be varied specifically within the above ranges.
By adopting the medicinal composition containing irbesartan and amlodipine, irbesartan and amlodipine besylate are active ingredients of the composition, and the content uniformity (A +2.2S) of each active ingredient is less than 10; and each active ingredient is not degraded during the manufacturing process, and such pharmaceutical compositions show controlled impurity levels of each active ingredient in accelerated test studies and in the final packaged product; and each active ingredient is dissolved out rapidly.
The invention also provides another technical scheme, and the preparation method of the medicinal composition containing irbesartan and amlodipine comprises the operation steps of taking materials for standby, mixing, granulating and drying;
(1) the material taking standby step is as follows: sieving irbesartan and glidant micropowder silica gel to obtain a blend of irbesartan and glidant; sieving amlodipine or medicinal salt thereof and filler microcrystalline cellulose to obtain amlodipine and microcrystalline fiber blend; sieving mannitol as filler, disintegrating agent and lubricant respectively;
(2) the mixing and granulating steps are as follows: putting the irbesartan and flow aid blend, the amlodipine and microcrystalline fiber blend, mannitol and half of disintegrant into a fluidized bed mixing granulator, mixing, spraying an adhesive, and granulating by using a fluidized bed to obtain dry granules A, wherein the moisture in the dry granules A is controlled to be less than or equal to 2%;
(3) sieving and granulating the dry granules A to obtain dry granules B;
(4) adding the other half amount of disintegrant sieved in the step (1) into the dry granules B, mixing for 15min, adding the lubricant sieved in the step (1), and mixing for 10min to obtain dry granules C;
(5) and (4) tabletting the dry granules C obtained in the step (4) to obtain the tablet core.
Further, the air inlet temperature of the mixing granulator in the mixing granulation step is set to be 55-60 ℃, and the air volume is 50m3H, the air outlet temperature is 45-50 ℃, and the mixing time is 10 min; the spraying of the adhesive is 30.0r/min, and the spray gun atomization pressure of the fluidized bed is 0.2 Mpa.
Further, the step (5) is followed by a step (6) of coating the tablet cores.
To those skilled in the art, since amlodipine is highly hygroscopic and causes decomposition in a humid and hot environment, one of the main decomposition products known in the art is 2- [ (2-aminoethoxy) methyl ] -4- (2-chlorophenyl) -6-methylpyridine-3, 5-dicarboxylic acid-3-ethyl-5-methyl ester and is called impurity D, and therefore, in order to avoid such a situation, it is common to granulate irbesartan and amlodipine separately and then mix them together to avoid the formation of impurity D from amlodipine, which affects the quality of the medicine. The inventor just overcomes the technical defect, researches the preparation of the two by one-step mixing granulation at high temperature, and finds that the composition has close relation with the formula composition of the composition, the temperature during preparation and the moisture of final granules, and the composition components, the proportion and the parameter control during preparation are the core technical points for realizing the technical problem of the invention.
Compared with the prior art, the invention has the following advantages: the fluidized bed one-step granulation process is adopted, three processes of mixing, granulating and drying two active ingredients are completed in one device at one time, the process is simple, the production efficiency is high, and the method is suitable for industrial large-scale production.
The preparation method comprises the steps of fluidized bed one-step mixing, granulating and drying, the obtained granules are uniform in granularity and good in flowability, and the fixed-dose medicinal composition containing irbesartan and amlodipine, which is prepared according to the formula and the preparation process, has good dissolution rate and content uniformity and active ingredients are not degraded.
Detailed Description
The present invention is illustrated below by specific examples, but the present invention is not limited to only the following examples.
The medicinal composition containing irbesartan and amlodipine, which is suitable for the invention, consists of amlodipine besylate, irbesartan and medicinal excipients, wherein the medicinal excipients are selected from binders such as polyvinyl alcohol, glidants such as micropowder silica gel, fillers such as microcrystalline cellulose and (or) mannitol, disintegrants such as croscarmellose sodium and lubricants such as magnesium stearate.
The pharmaceutical composition is in the form of a tablet, and is coated with a film-coated tablet.
The percentage contents of the active ingredients and the pharmaceutical excipients in the pharmaceutical composition containing irbesartan and amlodipine are shown in table 1: in the table, "100 mg, 5mg specification" means that the content of the active ingredient in the composition is 100mg, 5mg specification, and means that the composition contains 100mg of irbesartan, which is an active ingredient, and 5mg of amlodipine, which is an active ingredient. The specification of 100mg and 10mg indicates that the composition contains 100mg of irbesartan serving as an active ingredient and 10mg of amlodipine serving as an active ingredient.
TABLE 1
Example 1
Preparation of pharmaceutical composition T of the invention1、T2Wherein irbesartan and amlodipine are mixed in one step by a fluidized bedGranulating and drying. The raw material components and the proportion are shown in table 2:
TABLE 2
According to the formula T1And T2A process for preparing a fixed dose pharmaceutical composition containing irbesartan and amlodipine besylate in the form of a tablet.
Step 1: dissolving polyvinyl alcohol in purified water to obtain polyvinyl alcohol aqueous solution as adhesive; sieving irbesartan and silica gel micropowder, sieving amlodipine besylate and microcrystalline cellulose, and sieving mannitol, croscarmellose sodium and magnesium stearate respectively for later use;
step 2: placing the sieved irbesartan and micropowder silica gel blend, amlodipine besylate and microcrystalline fiber blend, mannitol and half of croscarmellose sodium into a fluidized bed mixing granulator, setting the air inlet temperature to be 55-60 ℃ and the air volume to be 50m3H, mixing for 10min at the air outlet temperature of 45-50 ℃, spraying the adhesive in the step (1), granulating by using a fluidized bed to obtain dry particles A, and controlling the water content in the dry particles A to be not more than 2%; the spraying of the adhesive is 30.0r/min, and the atomization pressure of a spray gun is 0.2 Mpa;
and step 3: sieving the dry particles A with a 24-mesh stainless steel sieve for finishing particles to obtain dry particles B;
and 4, step 4: adding the other half amount of the croscarmellose sodium sieved in the step (1) into the dry granules B, mixing for 15min, adding the magnesium stearate sieved in the step (1), and mixing for 10min to obtain dry granules C;
and 5: tabletting the dry granules C obtained in the step (4);
step 6: and (3) dissolving the coating material with the prescription amount in a proper amount of purified water, and coating the tablet core obtained in the step (5) in a high-efficiency coating machine.
Example 2
Preparation of pharmaceutical composition T of the invention3、T4Wherein irbesartan and amlodipine are mixed in one step by a fluidized bedGranulating and drying. The raw material components and proportions thereof are shown in table 3:
TABLE 3
According to the formula T3And T4Formulations were prepared as in example 1.
Example 3
Preparation of pharmaceutical composition T of the invention5、T6Wherein irbesartan and amlodipine are mixed, granulated and dried in one step by a fluidized bed. The raw material components and proportions thereof are shown in table 4:
TABLE 4
According to the formula T5And T6Formulations were prepared as in example 1.
Comparative example 1 preparation of pharmaceutical composition R1、R2Wherein irbesartan is separately granulated and dried by adopting a traditional wet granulation process, and then is mixed with amlodipine to prepare a comparative preparation. The raw material components and proportions thereof are shown in table 5:
TABLE 5
The preparation method comprises the following steps:
step 1: dissolving polyvinyl alcohol in purified water to obtain polyvinyl alcohol aqueous solution as adhesive; respectively sieving irbesartan, amlodipine besylate, microcrystalline cellulose, mannitol, croscarmellose sodium, aerosil and magnesium stearate for later use;
step 2: placing the screened irbesartan, microcrystalline fibers, mannitol, a half amount of croscarmellose sodium and aerosil into a wet granulator, setting the rotation number of a stirring paddle to be 300r/min and the rotation number of a cutter to be 1500r/min, performing wet granulation by using a polyvinyl alcohol aqueous solution, drying wet granules to obtain dry granules A, and controlling the moisture in the dry granules A to be not more than 2%;
and step 3: sieving the dry particles A with a 24-mesh stainless steel sieve for finishing particles to obtain dry particles B;
and 4, step 4: adding the amlodipine besylate sieved in the step (1) and the other half amount of croscarmellose sodium into the dry granules B, mixing for 15min, adding the magnesium stearate sieved in the step (1), and mixing for 10min to obtain dry granules C; (ii) a
And 5: tabletting the dry granules C obtained in the step (4);
step 6: and (3) dissolving the coating material with the prescription amount in a proper amount of purified water, and coating the tablet core obtained in the step (5) in a high-efficiency coating machine.
Comparative example 2 preparation of pharmaceutical composition R3、R4Wherein irbesartan and amlodipine besylate are simultaneously granulated by adopting a traditional wet granulation process to prepare a comparative preparation. The raw material components and proportions thereof are shown in table 6:
TABLE 6
The preparation method comprises the following steps:
step 1: dissolving polyvinyl alcohol in purified water to obtain polyvinyl alcohol aqueous solution as adhesive; sieving irbesartan and silica gel micropowder, sieving amlodipine besylate and microcrystalline cellulose, and sieving mannitol, croscarmellose sodium and magnesium stearate respectively for later use;
step 2: placing the sieved irbesartan and aerosil blend, amlodipine besylate and microcrystalline fiber blend, mannitol and half of croscarmellose sodium into a wet granulator, uniformly mixing, setting the rotation number of a stirring paddle to be 300r/min and the rotation number of a cutter to be 1500r/min, performing wet granulation by using a polyvinyl alcohol aqueous solution, drying wet granules to obtain dry granules A, and controlling the moisture in the dry granules A to be not more than 2%;
and step 3: sieving the dry particles A with a 24-mesh stainless steel sieve for finishing particles to obtain dry particles B;
and 4, step 4: adding the other half amount of croscarmellose sodium sieved in the step (1) into the dry granules B, mixing for 15min, adding the magnesium stearate sieved in the step (1), and mixing for 10min to obtain dry granules C; (ii) a
And 5: tabletting the dry granules C obtained in the step (4);
step 6: and (3) dissolving the coating material with the prescription amount in a proper amount of purified water, and coating the tablet core obtained in the step (5) in a high-efficiency coating machine.
Experiment one: content uniformity determination test
Content uniformity of the irbesartan amlodipine tablets prepared in examples 1 to 3 of the present invention and comparative examples 1 to 2 was measured according to the chinese pharmacopoeia tablet content uniformity assay method, and the results are shown in table 7.
TABLE 7 content uniformity results
| Product(s) | Irbesartan content uniformity (A +2.2S) | Content uniformity of amlodipine besylate (A +2.2S) |
| T1 | 3.5 | 5.8 |
| T2 | 3.2 | 5.0 |
| T3 | 3.6 | 5.6 |
| T4 | 3.5 | 5.8 |
| T5 | 3.1 | 4.5 |
| T6 | 3.9 | 4.7 |
| R1 | 7.2 | 16.3 |
| R2 | 6.8 | 15.7 |
| R3 | 5.6 | 10.6 |
| R4 | 6.3 | 10.8 |
The test results in the table show that the irbesartan amlodipine tablet has good content uniformity and is superior to a comparative preparation.
According to the dissolution test method of tablets in Chinese pharmacopoeia, the dissolution rate of the irbesartan amlodipine tablets prepared in examples 1-3 and comparative examples 1-2 of the invention is tested, the dissolution medium is 900mL of phosphate buffer solution with pH6.8, the sampling is carried out for 30min at 50rpm by a paddle method, and the test results are shown in Table 8.
Table 8 dissolution results
| Product(s) | Irbesartan dissolution% (30min) | Dissolution of amlodipine besylate (30min) |
| T1 | 98.5％ | 99.3％ |
| T1 | 98.2％ | 99.5％ |
| T2 | 98.9％ | 98.9％ |
| T3 | 99.2％ | 99.0％ |
| T4 | 98.7％ | 98.7％ |
| T5 | 99.3％ | 99.3％ |
| T6 | 98.5％ | 98.6％ |
| R1 | 87.7％ | 95.8％ |
| R2 | 89.2％ | 92.3％ |
| R3 | 86.7％ | 95.1％ |
| R4 | 88.9％ | 94.7％ |
As can be seen from the test results in Table 8, the pharmaceutical composition of the present invention comprising irbesartan and amlodipine has the advantage of rapid dissolution of the two active ingredients over the comparative formulation.
Example 5
Stability study
Accelerated stability studies were conducted on oral pharmaceutical compositions of the present invention at 40 ℃/75% relative humidity.
The test was carried out under the following conditions.
The tablet is packaged in aluminum bag, and tested according to Chinese pharmacopoeia stability test guidance principle
The stability test results are shown in table 9.
TABLE 9
From the results in the table, it can be seen that the level of amlodipine impurity D and amlodipine total impurity in the tablet stability test result of synchronous granulation of irbesartan and amlodipine by adopting the traditional wet granulation process is higher, while the stability test result of the product prepared by one-step mixing, granulating and drying of irbesartan and amlodipine by adopting the fluidized bed is good, and is equivalent to the product prepared by respectively granulating and then mixing irbesartan and amlodipine, but the product prepared by respectively granulating and then mixing irbesartan and amlodipine is easy to cause the risk of product content uniformity.
The above-mentioned embodiments only express several embodiments of the present invention, and the description is specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (8)
1. A medicinal composition containing irbesartan and amlodipine is composed of amlodipine besylate, irbesartan and medicinal excipients, and is characterized in that: it is a tablet prepared by one-step mixing, granulating and drying; the medicinal excipient comprises a filler, a binder, a disintegrant, a glidant and a lubricant; the adhesive is polyvinyl alcohol, and the flow aid is micropowder silica gel;
the pharmaceutical composition is prepared by the following method:
the operation steps comprise taking materials for standby, mixing, granulating and drying;
(1) the material taking standby step is as follows: taking irbesartan and glidant micropowder silica gel and sieving to obtain a blend of irbesartan and glidant; taking amlodipine besylate and microcrystalline cellulose as a filler, and sieving to obtain an amlodipine besylate and microcrystalline cellulose blend; sieving mannitol as filler, disintegrating agent and lubricant respectively;
(2) the mixing and granulating steps are as follows: putting the irbesartan and flow aid blend, the amlodipine besylate and microcrystalline cellulose blend, mannitol and half of disintegrant into a fluidized bed mixing granulator, mixing, spraying an adhesive, and granulating by using a fluidized bed to obtain dry granules A, wherein the water content in the dry granules A is controlled to be less than or equal to 2%;
(3) sieving and granulating the dry granules A to obtain dry granules B;
(4) adding the other half amount of disintegrant sieved in the step (1) into the dry granules B, mixing for 15min, adding the lubricant sieved in the step (1), and mixing for 10min to obtain dry granules C;
(5) and (4) tabletting the dry granules C obtained in the step (4) to obtain the tablet core.
2. The pharmaceutical composition comprising irbesartan and amlodipine according to claim 1, wherein: the tablets are film coated.
3. The pharmaceutical composition comprising irbesartan and amlodipine according to claim 1 or 2, wherein: the weight of the irbesartan accounts for 40-60% of the total weight of the medicinal composition; the weight of the amlodipine besylate accounts for 2-8% of the total weight of the medicinal composition.
4. The pharmaceutical composition containing irbesartan and amlodipine according to claim 3, wherein: the irbesartan accounts for 75-150 mg of the total weight of the tablet; the composition amount of the amlodipine besylate is 2.5 mg-12.5 mg.
5. The pharmaceutical composition containing irbesartan and amlodipine according to claim 4, wherein: the amount of irbesartan out of the total weight of the tablet is 100 mg; the constituent amount of amlodipine besylate is 5mg or 10 mg.
6. The method for preparing the pharmaceutical composition containing irbesartan and amlodipine according to claim 4 or 5, wherein: the operation steps comprise taking materials for standby, mixing, granulating and drying;
(1) the material taking standby step is as follows: taking irbesartan and glidant micropowder silica gel and sieving to obtain a blend of irbesartan and glidant; taking amlodipine besylate and microcrystalline cellulose as a filler, and sieving to obtain an amlodipine besylate and microcrystalline cellulose blend; sieving mannitol as filler, disintegrating agent and lubricant respectively;
(2) the mixing and granulating steps are as follows: putting the irbesartan and flow aid blend, the amlodipine besylate and microcrystalline cellulose blend, mannitol and half of disintegrant into a fluidized bed mixing granulator, mixing, spraying an adhesive, and granulating by using a fluidized bed to obtain dry granules A, wherein the water content in the dry granules A is controlled to be less than or equal to 2%;
(3) sieving and granulating the dry granules A to obtain dry granules B;
(4) adding the other half amount of disintegrant sieved in the step (1) into the dry granules B, mixing for 15min, adding the lubricant sieved in the step (1), and mixing for 10min to obtain dry granules C;
(5) and (4) tabletting the dry granules C obtained in the step (4) to obtain the tablet core.
7. The method for preparing a pharmaceutical composition comprising irbesartan and amlodipine according to claim 6, wherein: in the mixing and granulating step, the set air inlet temperature of the mixing and granulating machine is 55-60 ℃, and the air volume is 50m3H, the air outlet temperature is 45-50 ℃, and the mixing time is 10 min; the spraying of the adhesive is 30.0r/min, and the spray gun atomization pressure of the fluidized bed is 0.2 Mpa.
8. The preparation method of the pharmaceutical composition containing irbesartan and amlodipine according to claim 7, wherein: and (5) coating the tablet core in step (6).
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| CN108578404B true CN108578404B (en) | 2020-04-28 |
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|---|---|---|---|
| CN201810405199.4A Active CN108578404B (en) | 2018-04-28 | 2018-04-28 | Medicinal composition containing irbesartan and amlodipine and preparation method thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1596896A (en) * | 2003-09-19 | 2005-03-23 | 上海家化医药科技有限公司 | Aminochlorodipin, irbesartan compound preparation |
| JP2011207873A (en) * | 2010-03-10 | 2011-10-20 | Dainippon Sumitomo Pharma Co Ltd | Pharmaceutical composition containing irbesartan and amlodipine or salt of the same |
| CN103860511A (en) * | 2012-12-09 | 2014-06-18 | 海南中济医药科技有限公司 | Pharmaceutical composition containing irbesartan and amlodipine benzenesulfonate and preparation method thereof |
| CN106176745A (en) * | 2009-06-30 | 2016-12-07 | 赛诺菲 | Comprise the solid pharmaceutical composition of the fixed dosage of irbesartan and amlodipine, their preparation and their treatment use |
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2018
- 2018-04-28 CN CN201810405199.4A patent/CN108578404B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1596896A (en) * | 2003-09-19 | 2005-03-23 | 上海家化医药科技有限公司 | Aminochlorodipin, irbesartan compound preparation |
| CN106176745A (en) * | 2009-06-30 | 2016-12-07 | 赛诺菲 | Comprise the solid pharmaceutical composition of the fixed dosage of irbesartan and amlodipine, their preparation and their treatment use |
| JP2011207873A (en) * | 2010-03-10 | 2011-10-20 | Dainippon Sumitomo Pharma Co Ltd | Pharmaceutical composition containing irbesartan and amlodipine or salt of the same |
| CN103860511A (en) * | 2012-12-09 | 2014-06-18 | 海南中济医药科技有限公司 | Pharmaceutical composition containing irbesartan and amlodipine benzenesulfonate and preparation method thereof |
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| CN108578404A (en) | 2018-09-28 |
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