CN102198129A - Oral tablets containing candesartan cflexetil and hydrochlorothiazide - Google Patents
Oral tablets containing candesartan cflexetil and hydrochlorothiazide Download PDFInfo
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- CN102198129A CN102198129A CN2011100747872A CN201110074787A CN102198129A CN 102198129 A CN102198129 A CN 102198129A CN 2011100747872 A CN2011100747872 A CN 2011100747872A CN 201110074787 A CN201110074787 A CN 201110074787A CN 102198129 A CN102198129 A CN 102198129A
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- candesartan cilexetil
- hydrochlorothiazide
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Abstract
The invention discloses oral tablets containing candesartan cflexetil and hydrochlorothiazide, which consist of hydrochlorothiazide, candesartan cflexetil with a particle size D (V, 0.9) ranging from 20 to 100 mu m and medicinal auxiliary materials. The medicinal auxiliary materials comprise a stabilizer and other auxiliary materials such as one or more of a filler, a bonder and a disintegrating agent. The candesartan cflexetil and hydrochlorothiazide oral tablets provided by the invention are attractive and have high quality and high bioavailability. The invention also provides a preparation method of the oral tablets. The oral tablets are simple in process, low in cost and more suitable for commercial production.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of candesartan cilexetil/hydrochlorothiazide oral tablet.
Background technology
Candesartan Cilexetil is a kind of novel angiotensin ii receptor antagonist, has caused widely to pay close attention on resisting hypertension market.The effect of such drug selectivity ground blocking-up AngII in circulation and tissue, antihypertensive effect is remarkable, action time is permanent.Its compound structure and synthetic method are open in EP 0459136, and its structural formula is as follows:
Hydrochlorothiazide is a kind of oral, be applicable to light, moderate hypertension, especially be suitable for the thiazide diuretic of the treatment of old people's systolic hypertension and heart failure accompanied with hypertension, its chemical name is a 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1, the 1-dioxide has following structural formula:
Hydrochlorothiazide has demonstrated better synergistic therapeutic action in candesartan Cilexetil therapeutic alliance hypertension.
Candesartan Cilexetil in the tabletting process because the crystal formation disorder easily takes place in pressurized or friction, cause the decomposition of active substance under preparation, storing process and hot environment, cause the reduction of medicament contg and the rising of impurity content, it is stable to guarantee it therefore to be necessary to add when the preparation candesartan cilexetil suitable stabilizing agent.
Patent EP0546358 and EP1468683 disclose a kind of compositions that contains candesartan Cilexetil and low melting point oily matter.Described oily matter can be the fatty acid ester of hydrocarbon, higher fatty acids, higher alcohol, polyol, the polyol ethers of higher alcohol, the high polymer or the copolymer of ethylene oxide, and their fusing point is greatly between 20 ℃ to 90 ℃.The low melting point oily matter can melt because of intergranular friction high temperature in the tabletting process, the oily matter of fusing can alleviate between the Candesartan crystalline esters, and the friction between Candesartan crystalline esters and other materials, make the crystalline crystal form disorder of candesartan Cilexetil reduce to minimum, thereby improve the stability of product.The main deficiency that this technical scheme exists is: contain low-melting oily matter such as Polyethylene Glycol used as stabilizers owing to used in the prescription, in the tabletting process,, the heating of material pressurized produces the sticking phenomenon owing to easily making the Polyethylene Glycol fusing, unilateral quality problems such as defective easily take place, and when adding the low melting point oily matter when improving solid dosage forms stable, the disintegration of solid preparation will reduce, and the dissolution characteristic of Candesartan from solid preparation obviously reduces.
In addition, candesartan Cilexetil is embarrassed water-soluble medicine, and for improving the bioavailability of insoluble drug, way is to improve the dissolution characteristic of such medicine usually.Patent EP2058010 discloses a kind of solid composite medicament that contains candesartan Cilexetil, low melting point oily matter and low viscosity adhesive.This pharmaceutical composition uses oily matter to make stabilizing agent equally, and in order to reduce the effect that oily matter hinders candesartan Cilexetil stripping behavior, this scheme is by adding low viscous binding agent to improve the dissolution characteristic of medicine.Though the candesartan Cilexetil in the said composition has stripping behavior preferably, the use of low melting point oily matter is absolutely necessary, and has technologic problems such as sticking in process of production equally, is unfavorable for commercially producing
The conventional method that improves the insoluble drug dissolubility is to reduce the particle diameter of insoluble drug, as the disclosed Candesartan ester formulation of patent CN101132770, wherein the particulate effective average particle size particle size of candesartan Cilexetil is less than 2 μ m, owing to adopted the more candesartan Cilexetil of fine grain, said preparation and conventional Candesartan ester formulation relatively have stripping behavior faster.But the candesartan Cilexetil of fine grain is to be difficult to preparation, and routine obtains more that the method for fine grain medicine is that medicine is pulverized, the common D of candesartan Cilexetil particle diameter for preparing in disclosed synthesis technique
(V, 0.9)More than 20 μ m, for obtaining thinner candesartan Cilexetil raw material, candesartan Cilexetil can only be pulverized, the candesartan Cilexetil raw material also can be squeezed or rub in crushing process, the character of candesartan Cilexetil can not get guaranteeing that the oral administration solid tablet stability that uses the candesartan Cilexetil after pulverizing to prepare can decline to a great extent.
Hydrochlorothiazide is as insoluble drug in addition, has certain hydrophobicity, when it is united when making tablet with candesartan Cilexetil, because its hydrophobic interaction can further make the candesartan Cilexetil stripping slow down, this also is one of general slow partially reason of candesartan Cilexetil stripping in the candesartan Cilexetil hydrochlorothiazide tablet in the market.
Therefore at present still be necessary to provide a kind of new solution to overcome above shortcoming, make the candesartan Cilexetil Aquazide H unilateral attractive in appearance, up-to-standard, candesartan Cilexetil has good stable and stripping behavior, and there are not technological problemses such as sticking in process of production, help commercially producing.
Summary of the invention
The inventor discovers, when preparation candesartan Cilexetil Aquazide H, as control candesartan Cilexetil particle diameter D
(V, 0.9)In 20 μ m～100 mu m ranges, and when using glycerol to make stabilizing agent, resulting product has unilateral attractive in appearance, steady quality, candesartan Cilexetil has characteristics such as good stripping behavior.
Therefore the present invention at first provides a kind of candesartan Cilexetil hydrochlorothiazide tablet, contains:
Wherein, stabilizing agent is a glycerol, and the particle diameter D of used candesartan Cilexetil
(V, 0.9)Be 20 μ m～100 μ m.
Candesartan Cilexetil belongs to insoluble drug, for insoluble drug, for guaranteeing medicine stripping smoothly from tablet, usually can reduce the particle diameter of insoluble drug, improve the solubility property of medicine self, to reach the effect of medicine rapid stripping from tablet, yet discover candesartan Cilexetil is crushed to 20 μ m when following, can cause its stability significantly to reduce, though before its stripping behavior of tablet of using the candesartan Cilexetil after pulverizing to make is pulverized raising is arranged, but product stability but declines to a great extent, and mainly shows as tablet Candesartan ester content in storage process and reduces fast, the content of related substance rises rapidly.Prepared tablet does not belong to qualified fine tablet equally.
For guaranteeing the stability of candesartan Cilexetil in formulation products, prior art normally adopts the method that adds the sebaceous material used as stabilizers of low melting point, as add Polyethylene Glycol as stabilizing agent, but after adding low melting point grease-like material such as Polyethylene Glycol, the thawing of easily being heated such as Polyethylene Glycol can cause the generation of sticking problem, and then cause unilateral rough in the tabletting production process, influence product appearance, also be unfavorable for commercially producing simultaneously.
The inventor passes through repeatedly experimentation, finds to use the glycerol used as stabilizers to address the above problem, and the candesartan Cilexetil hydrochlorothiazide tablet that makes has profile attractive in appearance, stabilized quality and excellent drug stripping behavior.In one embodiment of the invention, use particle diameter D
(V, 0.9)Candesartan Cilexetil between 20～100 μ m as stabilizing agent, prepares candesartan Cilexetil hydrochlorothiazide tablet in conjunction with hydrochlorothiazide and other pharmaceutic adjuvants with glycerol, and product appearance is good, stable in properties, and stripping is complete rapidly.
According to the present invention, the particle diameter D of the candesartan Cilexetil of use
(V, 0.9)Between 20～100 μ m, the candesartan Cilexetil of this particle size range can obtain by common crystallization processes, and need not to carry out extra pulverizing, has avoided the stability decreases problem of candesartan Cilexetil through causing after pulverizing; Glycerol as stabilizing agent has good water-solubility in addition, and glycerol mixes contact with candesartan Cilexetil in process of production, has increased the hydrophilic of candesartan Cilexetil, has promoted the dissolving of candesartan Cilexetil, guarantees that candesartan Cilexetil has good stripping behavior; There is not the phenomenon of being heated in the tabletting process and melting in glycerol simultaneously, and the sticking problem that has produced when also having avoided tabletting has guaranteed unilateral attractive in appearance.
Candesartan Cilexetil that can the selective freezing form according to the present invention, or the candesartan Cilexetil of noncrystalline form are preferably the C crystal formation.
According to candesartan Cilexetil hydrochlorothiazide tablet of the present invention, filler, binding agent, disintegrating agent, selection of lubricants are conventional, those skilled in the art can select in the conventional scope of application of adjuvant, and for example: filler is selected from one or more in mannitol, lactose, microcrystalline Cellulose, xylitol, sorbitol, galactitol, erythritol, lactose, maltose alcohol or the 1,2,3,4,5-pentanepentol; Binding agent is selected from one or more in polyvidone, copolyvidone or the hydroxypropyl cellulose; Disintegrating agent is selected from one or more in polyvinylpolypyrrolidone, cross-linked carboxymethyl cellulose calcium, corn starch or the cross-linking sodium carboxymethyl cellulose; Lubricant is selected from magnesium stearate or sodium stearyl fumarate.
Further, according to candesartan Cilexetil hydrochlorothiazide tablet of the present invention, filler is selected from mannitol; Binding agent is selected from copolyvidone; Disintegrating agent is selected from corn starch; Lubricant is selected from magnesium stearate.
According to candesartan Cilexetil hydrochlorothiazide tablet of the present invention, further, can also contain color lake (as red ferric oxide, yellow ferric oxide etc.), sweeting agent (steviosin, saccharin sodium, aspartame etc.), aromatic (fragrant citrus essence, strawberry essence etc.) etc., to regulate color, mouthfeel and the abnormal smells from the patient of tablet.Perhaps use conventional water solublity coating.
According to a preferred embodiment of the invention, described candesartan Cilexetil hydrochlorothiazide tablet contains:
And the particle diameter D of candesartan Cilexetil wherein
(V, 0.9)Be 20 μ m～100 μ m.
The present invention also provides the preparation method of aforementioned candesartan Cilexetil hydrochlorothiazide tablet:
A. it is standby as wetting agent that glycerol is dissolved in dehydrated alcohol;
B. candesartan Cilexetil, hydrochlorothiazide and granulation are mixed in the high shear wet mixing pelletizer with adjuvant;
The ethanol solution that c. will contain glycerol slowly adds in the granulation pot among the step b granulates, and obtains wet granular;
D. wet granular is transferred to that drying obtains dried granule in the fluid bed;
E. dried granule mixing adds material and obtains mixing granule;
F. mix granule and use the rotary tablet machine compacting in flakes; Selectable
G. the plain sheet to gained carries out coating, makes coated tablet.
According to the present invention, it is faster to access the candesartan Cilexetil stripping, and stripping is tablet more completely, and solid dosage forms disintegrate reduction and the sticking phenomenon that can avoid low melting point grease-like material to occur.The present invention adopts conventional wet granulation technology to prepare candesartan cilexetil, and technology is simple, and cost savings are more suitable for commercially producing.
The specific embodiment
In order to more fully understand the present invention, the spy provides following specific embodiment, but the present invention is not limited to following examples.
Embodiment 1:
4 prescriptions use different-grain diameters candesartan Cilexetil, wherein: the candesartan Cilexetil particle diameter D that prescription 1 uses
(V, 0.9)=10 μ m are by particle diameter D
(V, 0.9)The candesartan Cilexetil of=23 μ m obtains through pulverizing; The candesartan Cilexetil particle diameter D that prescription 2 uses
(V, 0.9)=23 μ m; The prescription 3 candesartan Cilexetil particle diameters that use are D
(V, 0.9)=96 μ m, the prescription 4 candesartan Cilexetil particle diameters that use are D
(V, 0.9)Be 150 μ m.
Dehydrated alcohol is removed in process of production.
Preparation method is: recipe quantity glycerol is dissolved in an amount of dehydrated alcohol, and it is standby to make binding agent; Candesartan Cilexetil, hydrochlorothiazide and other pelletize adjuvants are mixed in the pot of granulating, get mixture A; Granulate with mixture A in the alcoholic solution binding agent adding granulation pot with glycerol, get wet granular, wet grain drying must be done granule; Dried granule mixing adds material, must mix granule; Mix granule and use rotary tablet machine to carry out tabletting, the heavy 130mg of sheet makes 3000.
According to dissolution determination method (2010 editions appendix XC second methods of Chinese Pharmacopoeia), the pH6.5 phosphate buffer that uses the 900ml be added with 0.35% polysorbas20 is as dissolution medium, and rotating speed is 75rpm, and above 4 prescriptions are carried out dissolution test.Gained the results are shown in Table 1.
Table 1:
Wherein HCTZ represents hydrochlorothiazide, and CAND represents candesartan Cilexetil.
The stripping result shows, as candesartan Cilexetil particle diameter D
(V, 0.9)When being 150 μ m, the dissolution rate of candesartan Cilexetil significantly slow down and the candesartan Cilexetil stripping incomplete; And candesartan Cilexetil particle diameter D
(V, 0.9)Be that 10 μ m are quicker slightly than the stripping of particle diameter 23 μ m and 96 μ m, but do not have notable difference.Therefore candesartan Cilexetil is to be directly related with the particle diameter of candesartan Cilexetil in the stripping behavior of candesartan cilexetil/hydrochlorothiazide sheet, speed along with reducing of candesartan Cilexetil particle diameter, but after the candesartan Cilexetil particle diameter was less than 100 μ m, the particle diameter of crude drug did not make significant difference to the stripping behavior.
To write out a prescription 1, prescription 2, prescription 3, prescription 4 slice, thin pieces be placed on 60 ℃ simultaneously and preserved 10 days down, adopts high-efficient liquid phase technique to detect candesartan Cilexetil impurity situation of change, and total impurities situation of change relatively.Gained the results are shown in Table 2.
Table 2:
| Time | Prescription 1 | Prescription 2 | Prescription 3 | Prescription 4 |
| 0 day | 1.02 | 0.45 | 0.50 | 0.41 |
| 10 days | 3.63 | 0.90 | 0.88 | 0.89 |
Stability result shows: no matter be 0 day or 10 days, the candesartan Cilexetil after the pulverizing is particle diameter D
(V, 0.9)The prepared slice, thin piece related substance of candesartan Cilexetil that is 10 μ m is obviously pulverized preceding high; And it is lower and increases slowly by the slice, thin piece related substance that makes without the candesartan Cilexetil of pulverizing.
Embodiment 2
Prescription 5 is that preparation according to the present invention is stabilizing agent with glycerol, and prescription 6 is to use polyethylene glycol 6000 to be stabilizing agent according to EP2058010.Dehydrated alcohol is removed in process of production.
Preparation method is:
1) prescription 5: recipe quantity glycerol is dissolved in an amount of dehydrated alcohol, and it is standby to make binding agent; Candesartan Cilexetil, hydrochlorothiazide and other pelletize adjuvants are mixed in the pot of granulating, get mixture A; Granulate with mixture A in the alcoholic solution binding agent adding granulation pot with glycerol, get wet granular, wet grain drying must be done granule; Dried granule mixing adds material, must mix granule; Mix granule and use rotary tablet machine to carry out tabletting, the heavy 130mg of sheet makes 5000.
2) prescription 6: be dissolved in an amount of dehydrated alcohol hydroxypropyl cellulose and polyethylene glycol 6000 standby jointly; Mix candesartan Cilexetil, hydrochlorothiazide and interior granulation adjuvant; Spraying contains the ethanol solution of hydroxypropyl cellulose and polyethylene glycol 6000, granulates, and mixing adds material and obtains mixing granule behind the wet grain drying, and dark granule uses rotary tablet machine to carry out tabletting, and the heavy 130mg of sheet makes 5000.
Investigating prescription 5 and the tabletting situation of prescription 6 under different humitures, phenomenon is described and is seen Table 3:
Table 3:
The humiture of clean room requires to be 18～26 ℃ of temperature, humidity 40-60% under the conventional GPM condition.
The tabletting phenomenon shows: with the polyethylene glycol 6000 is stabilizing agent, is prone to the sticking phenomenon, for fear of sticking, and need be to the strict control of production environment humiture; And when being stabilizing agent with glycerol, under conventional working condition, can produce, be more suitable for industrialized great production.
Embodiment 3
| Name of material | Ratio % |
| Candesartan Cilexetil | 12.3 |
| Hydrochlorothiazide | 9.6 |
| Corn starch | 15 |
| Mannitol | 48.4 |
| Yellow ferric oxide | 0.10 |
| Red ferric oxide | 0.05 |
| Copolyvidone | 9.0 |
| Glycerol | 5.0 |
| Dehydrated alcohol | In right amount |
| Magnesium stearate | 0.5 |
| Add up to | 100.0 |
The candesartan Cilexetil particle diameter is D
(V, 0.9)=40 μ m.Dehydrated alcohol is removed in process of production.
Preparation method: candesartan Cilexetil, hydrochlorothiazide, corn starch, mannitol, yellow ferric oxide, red ferric oxide, the copolyvidone that takes by weighing recipe quantity places the pot of granulating to mix, the alcoholic solution of glycerol adding is granulated, dryly must do granule, dried granule is with adding the material mixing, adopt the rotary tablet machine tabletting, the heavy 130mg of sheet makes 5000.
According to dissolution determination method (2010 editions appendix XC second methods of Chinese Pharmacopoeia), use is added with the pH6.5 phosphate buffer of 900ml of 0.35% polysorbas20 as dissolution medium, rotating speed is 75rpm, to carrying out dissolution test with embodiment 3 and commercial goods Atacand HCT.Gained the results are shown in Table 4, and data show can be made the product of the quick stripping of candesartan Cilexetil according to the present invention.
Table 4:
Embodiment 4
| Name of material | Ratio % |
| Candesartan Cilexetil | 12.30 |
| Hydrochlorothiazide | 4.81 |
| Corn starch | 15.0 |
| Mannitol | 53.24 |
| Yellow ferric oxide | 0.15 |
| Copolyvidone | 9.0 |
| Glycerol | 5.0 |
| * dehydrated alcohol | In right amount |
| Magnesium stearate | 0.5 |
| Add up to | 100.0 |
The candesartan Cilexetil particle diameter is D
(V, 0.9)=40 μ m.Dehydrated alcohol is removed in process of production.
Preparation method: candesartan Cilexetil, hydrochlorothiazide, corn starch, mannitol, yellow ferric oxide, red ferric oxide, the copolyvidone that takes by weighing recipe quantity places the pot of granulating to mix, the alcoholic solution of glycerol adding is granulated, dryly must do granule, dried granule is with adding the material mixing, adopt the rotary tablet machine tabletting, the heavy 260mg of sheet makes 5000.
According to dissolution determination method (2010 editions appendix XC second methods of Chinese Pharmacopoeia), use is added with the pH6.5 phosphate buffer of 900ml of 0.35% polysorbas20 as dissolution medium, rotating speed is 75rpm, to carrying out dissolution test with embodiment 4 and commercial goods Atacand HCT.Gained the results are shown in Table 5, and data show can be made the product of the quick stripping of candesartan Cilexetil according to the present invention.
Table 5:
Embodiment 5
| Name of material | Ratio % |
| Candesartan Cilexetil | 6.15 |
| Hydrochlorothiazide | 9.62 |
| Corn starch | 15.0 |
| Mannitol | 54.73 |
| Copolyvidone | 9.0 |
| Glycerol | 5.0 |
| Dehydrated alcohol | In right amount |
| Magnesium stearate | 0.5 |
| Add up to | 100.0 |
The candesartan Cilexetil particle diameter is D
(V, 0.9)=40 μ m.Dehydrated alcohol is removed in process of production.
Preparation method: candesartan Cilexetil, hydrochlorothiazide, corn starch, mannitol, yellow ferric oxide, red ferric oxide, the copolyvidone that takes by weighing recipe quantity places the pot of granulating to mix, the alcoholic solution of glycerol adding is granulated, dryly must do granule, dried granule is with adding the material mixing, adopt the rotary tablet machine tabletting, the heavy 130mg of sheet makes 5000.
According to dissolution determination method (2010 editions appendix XC second methods of Chinese Pharmacopoeia), use is added with the pH6.5 phosphate buffer of 900ml of 0.35% polysorbas20 as dissolution medium, rotating speed is 75rpm, to carrying out dissolution test with embodiment 4 and commercial goods Atacand HCT.Gained the results are shown in Table 6, and data show can be made the product of the quick stripping of candesartan Cilexetil according to the present invention.
Table 6:
Claims (6)
1. contain the oral tablet of candesartan Cilexetil and hydrochlorothiazide, comprise:
It is characterized in that described stabilizing agent is a glycerol, and the particle diameter D of candesartan Cilexetil wherein
(V, 0.9)Be 20 μ m～100 μ m.
2. oral tablet according to claim 1 is characterized in that the particle diameter D of candesartan Cilexetil
(V, 0.9)Be 40 μ m～80 μ m.
3. oral tablet according to claim 1 is characterized in that filler is selected from one or more in mannitol, lactose, microcrystalline Cellulose, xylitol, sorbitol, galactitol, erythritol, lactose, maltose alcohol or the 1,2,3,4,5-pentanepentol; Binding agent is selected from one or more in polyvidone, copolyvidone or the hydroxypropyl cellulose; Disintegrating agent is selected from one or more in polyvinylpolypyrrolidone, cross-linked carboxymethyl cellulose calcium, corn starch or the cross-linking sodium carboxymethyl cellulose; Lubricant is selected from magnesium stearate or sodium stearyl fumarate.
4. oral tablet according to claim 3 is characterized in that filler is selected from mannitol; Binding agent is selected from copolyvidone; Disintegrating agent is selected from corn starch; Lubricant is selected from magnesium stearate.
5. oral tablet according to claim 1 is characterized in that described oral tablet comprises:
And the particle diameter D of candesartan Cilexetil wherein
(V, 0.9)Be 20 μ m～100 μ m.
6. the preparation method of candesartan cilexetil/hydrochlorothiazide oral tablet according to claim 1 is characterized in that adopting wet granulation, specifically may further comprise the steps:
1) candesartan Cilexetil, hydrochlorothiazide and interior the granulation are placed high shear wet granulator mixing with adjuvant;
2) alcoholic solution of glycerol or alcohol-water solution are added to granulate in the pot of granulating obtain wet granular;
3) wet granular adopts fluid bed drying to obtain dried granule;
4) dried granule with compacting after adding the material mixing in flakes.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201110074787.2A CN102198129B (en) | 2011-03-22 | 2011-03-22 | Oral tablet containing candesartan Cilexetil and hydrochlorothiazide |
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|---|---|---|---|
| CN201110074787.2A CN102198129B (en) | 2011-03-22 | 2011-03-22 | Oral tablet containing candesartan Cilexetil and hydrochlorothiazide |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104758252A (en) * | 2014-01-03 | 2015-07-08 | 广东东阳光药业有限公司 | Candesartan cilexetil composition |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5196444A (en) * | 1990-04-27 | 1993-03-23 | Takeda Chemical Industries, Ltd. | 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate and compositions and methods of pharmaceutical use thereof |
| WO2005123720A1 (en) * | 2004-06-18 | 2005-12-29 | Ranbaxy Laboratories Limited | Fine particles of the angiotensin ii antagonist candesartan cilexetil and process for production thereof |
| CN101612151A (en) * | 2008-06-25 | 2009-12-30 | 浙江华海药业股份有限公司 | Contain solid orally ingestible of candesartan Cilexetil or candesartan cilexetil/hydrochlorothiazide and preparation method thereof |
-
2011
- 2011-03-22 CN CN201110074787.2A patent/CN102198129B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5196444A (en) * | 1990-04-27 | 1993-03-23 | Takeda Chemical Industries, Ltd. | 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate and compositions and methods of pharmaceutical use thereof |
| WO2005123720A1 (en) * | 2004-06-18 | 2005-12-29 | Ranbaxy Laboratories Limited | Fine particles of the angiotensin ii antagonist candesartan cilexetil and process for production thereof |
| CN101612151A (en) * | 2008-06-25 | 2009-12-30 | 浙江华海药业股份有限公司 | Contain solid orally ingestible of candesartan Cilexetil or candesartan cilexetil/hydrochlorothiazide and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104758252A (en) * | 2014-01-03 | 2015-07-08 | 广东东阳光药业有限公司 | Candesartan cilexetil composition |
| CN104758252B (en) * | 2014-01-03 | 2019-11-12 | 广东东阳光药业有限公司 | Candesartan cilexetil composition |
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| CN102198129B (en) | 2016-03-30 |
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