CN103720696A - Preparation process for improving bioavailability of valsartan and hydrochlorothiazid capsules - Google Patents
Preparation process for improving bioavailability of valsartan and hydrochlorothiazid capsules Download PDFInfo
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- CN103720696A CN103720696A CN201310738223.3A CN201310738223A CN103720696A CN 103720696 A CN103720696 A CN 103720696A CN 201310738223 A CN201310738223 A CN 201310738223A CN 103720696 A CN103720696 A CN 103720696A
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Abstract
The invention belongs to the technical field of medicine preparation, and particularly relates to a preparation process for improving bioavailability of valsartan and hydrochlorothiazid capsules. The process provided by the invention comprises the following specific steps: 1) processing valsartan and hydrochlorothiazid by means of micronization, sieving a filler, a disintegrating agent, an adhesive and a solubilizer with a 80-mesh sieve, and sieving a lubricating agent with a 40-mesh sieve for later use; 2) weighing a prescribed dose of the valsartan, the hydrochlorothiazid, the filler, the disintegrating agent, the adhesive and the solubilizer, and uniformly mixing in a high-speed mixing granulator; 3) granulating the uniformly-mixed powder by using a dry type granulator, adding a prescribed dose of the lubricating agent for strengthening granules and then uniformly mixing the lubricating agent with the powder; 4) filling capsules. Compared with the prior art, the preparation process for improving the bioavailability of valsartan and hydrochlorothiazid capsules can improve the dissolution rate and increase the solubility by processing the raw materials by means of micronization, adding special auxiliary materials and adopting dry granulation, thus the bioavailability of the valsartan and hydrochlorothiazid capsules is improved.
Description
Technical field
The invention belongs to medical preparing technical field, specifically, relate to a kind of preparation technology who improves valsartan and Hydrochlorothiade capsule bioavailability.
Background technology
According to ESH/ESC, about hypertension guideline of prevention and treatment, uncomplicated patients with hypertension target blood pressure need be controlled at <140/90mmHg; Complication with diabetes, nephropathy or other high risk factors (as cerebrovascular accident or myocardial infarction) patient's target blood pressure need be controlled at <130/80mmHg.In order to reach above-mentioned therapeutic goal value, current most of hypertension guideline of prevention and treatment all advises combining two kinds of dissimilar depressor of use in initial therapy.Yet many studies show that under two depressor combined treatments, only has 1/3 patients with hypertension can reach target.
Valsartan/hydrochlorothiazide Compound preparation is a kind of safety of extensive use clinically and orally active antihypertensive drug.Valsartan carrys out the activity of inhibition angiotensin II (A II) by antagonizing vessel Angiotensin Ⅱ receptor type I (AT1) specifically, thereby makes blood pressure drops.Hydrochlorothiazide is a kind of thiazide diuretic, and it,, by affecting renal tubules to electrolytical heavy absorption, directly increases the secretion of sodium ion and chloride ion, and urine amount is increased, and blood volume reduces.Meanwhile, hydrochlorothiazide, by its diuresis, reduces plasma volume, indirectly makes plasma renin activity increase, and Aldosterone Secretion increases, and urine potassium is discharged and increased, and blood potassium is reduced.In addition, the effect of feritin-aldosterone system is mediated by angiotensin, and therefore, hydrochlorothiazide share angiotensin receptor antagonist valsartan, can strengthen drug effect and reverse the mistake potassium effect due to hydrochlorothiazide.Valsartan and Hydrochlorothiade sheet is researched and developed by Novartis Co.,Ltd the earliest and is gone on the market in Germany.
Valsartan and hydrochlorothiazide are all insoluble in water, make after tablet, and its dissolution is generally on the low side, and along with the prolongation of standing time occurs that dissolution significantly declines.In order to address these problems, people start research center of gravity to turn to capsule.Chinese patent (CN201310136853.3) provide a kind of valsartan and Hydrochlorothiade capsule and preparation method thereof, this invention is attached to poly(ethylene oxide) surface by valsartan and hydrochlorothiazide and forms, because valsartan and hydrochlorothiazide are attached to the top layer of poly(ethylene oxide), drug particle size is little, run into after dissolution medium, poly(ethylene oxide) water suction rapid expanding, fine medicine is distributed to rapidly in dissolution medium, and dissolution rate significantly improves.But, due to valsartan and hydrochlorothiazide particle diameter larger, the dissolubility in water is poor, the absorbability of poly(ethylene oxide) is stronger in addition, the loss of valsartan and hydrochlorothiazide is more, bioavailability is lower, can affect the performance of drug effect.
Summary of the invention
In order to solve the problems of the technologies described above, to the invention provides that a kind of rate of dissolution is fast, dissolution is high and then can improve the valsartan and Hydrochlorothiade capsules preparation technique of bioavailability.
The preparation technology of raising valsartan and Hydrochlorothiade capsule bioavailability of the present invention, described technique concrete steps are: 1) by valsartan, hydrochlorothiazide micronization processes, 80 mesh sieves are crossed in filler, disintegrating agent, binding agent, solubilizing agent, and lubricant is crossed 40 mesh sieves, standby; 2) valsartan, hydrochlorothiazide, filler, disintegrating agent, binding agent, the solubilizing agent that take recipe quantity are placed in high-speed mixing granulating machine mix homogeneously; 3) powder mixing is granulated with dry granulating machine, mix after adding the lubricant granulate of recipe quantity; 4) filling capsule.
The preparation technology of raising valsartan and Hydrochlorothiade capsule bioavailability of the present invention, by mass parts, calculate, described valsartan accounts for 30-50 part, described hydrochlorothiazide accounts for 5-10 part, described filler accounts for 40-80 part, and described disintegrating agent accounts for 5-50 part, and described binding agent accounts for 0.1-5 part, described solubilizing agent accounts for 0.1-5 part, and described lubricant agent accounts for 0.1-5 part.
In above-mentioned preparation technology, described valsartan, hydrochlorothiazide all pass through pulverization process, can pass through 120 mesh sieves, and particle mean size is between 5 μ m-20 μ m.
In above-mentioned preparation technology, one or more in starch, microcrystalline Cellulose, pregelatinized Starch, mannitol, lactose, Icing Sugar, calcium hydrogen phosphate, Icing Sugar, dextrin of described filler form.
In above-mentioned preparation technology, one or more in sodium carboxymethyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone of described disintegrating agent form.
In above-mentioned preparation technology, described binding agent by hypromellose or/and hyprolose form.
In above-mentioned preparation technology, one or more in magnesium stearate, stearic acid, Pulvis Talci, micropowder silica gel of described lubricant form.
In above-mentioned preparation technology, described solubilizing agent by sodium lauryl sulphate or/and tween 80 form.
In above-mentioned preparation technology, described disintegrating agent is Auricularia polycose MHA.
Compared with prior art, in the valsartan and Hydrochlorothiade capsules preparation technique that can improve bioavailability of the present invention, its raw material is through micronization processes, add special adjuvant, and adopted dry granulation, can improve its dissolution rate, increase dissolubility, and then improve its bioavailability.
The specific embodiment
Below in conjunction with specific embodiment, preparation method of the present invention is described further, but protection scope of the present invention is not limited to this.
Embodiment 1: valsartan and Hydrochlorothiade capsule
Method for making:
1) by valsartan and hydrochlorothiazide micronization processes, make its particle mean size at 15 μ m, pregelatinized Starch, carboxymethyl starch sodium, dextrin, hypromellose, sodium lauryl sulphate are crossed 80 mesh sieves, and magnesium stearate is crossed 40 mesh sieves, standby;
2) take valsartan, hydrochlorothiazide, pregelatinized Starch, dextrin, carboxymethyl starch sodium, the lauryl sulphate acid of recipe quantity, set high mix homogeneously in fast granulator;
3) powder mixing is granulated with dry granulating machine, mix after adding the magnesium stearate granulate of recipe quantity.
4) filling capsule.
Embodiment 2: valsartan and Hydrochlorothiade capsule
Method for making:
1), by valsartan and hydrochlorothiazide micronization processes, make its particle mean size at 10 μ m, microcrystalline Cellulose, Auricularia polycose MHA(molecular weight 3 * 10
4-4 * 10
4), hypromellose, sodium lauryl sulphate cross 80 mesh sieves, Pulvis Talci is crossed 40 mesh sieves, standby;
2) take valsartan, hydrochlorothiazide, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, hypromellose, the sodium lauryl sulphate of recipe quantity, set high mix homogeneously in fast granulator;
3) powder mixing is granulated with dry granulating machine, mix after adding the Pulvis Talci granulate of recipe quantity.
4) filling capsule.
Embodiment 3: valsartan and Hydrochlorothiade capsule
Method for making:
1) by valsartan and hydrochlorothiazide micronization processes, make its particle mean size at 5 μ m, microcrystalline Cellulose, dextrin, cross-linking sodium carboxymethyl cellulose, hyprolose, sodium lauryl sulphate are crossed 80 mesh sieves, and Pulvis Talci is crossed 40 mesh sieves, standby;
2) take valsartan, hydrochlorothiazide, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, dextrin, the sodium lauryl sulphate of recipe quantity, set high mix homogeneously in fast granulator;
3) powder mixing is granulated with dry granulating machine, mix after adding the Pulvis Talci granulate of recipe quantity.
4) filling capsule.
Embodiment 4: valsartan and Hydrochlorothiade capsule
Method for making:
1) by valsartan and hydrochlorothiazide micronization processes, make its particle mean size at 20 μ m, and cross 120 mesh sieves, hypromellose, lactose, cross-linking sodium carboxymethyl cellulose, poloxamer are crossed 80 mesh sieves, and Pulvis Talci is crossed 40 mesh sieves, standby;
2) take valsartan, hydrochlorothiazide, hypromellose, lactose, cross-linking sodium carboxymethyl cellulose, the poloxamer of recipe quantity, set high mix homogeneously in fast granulator;
3) powder mixing is granulated with dry granulating machine, mix after adding the Pulvis Talci granulate of recipe quantity.
4) filling capsule.
Prior art:
Method for making:
1) poly(ethylene oxide) is crossed 100 mesh sieves, joins in fluid bed, sprays into the acetone soln of hydrochlorothiazide, makes hydrochlorothiazide be attached to poly(ethylene oxide) surface, dry;
2) will containing the alcoholic solution of valsartan, spray in the granule that step (1) obtains, obtain the granule that contains valsartan and hydrochlorothiazide, dry;
3) medicine-containing particle obtaining is mixed homogeneously with Pulvis Talci, incapsulate shell.
Embodiment testing result
Dissolution to embodiment 1-4 product is measured, 5,10,15,20,30min samples respectively, detects its dissolution.Result is as following table 1.
Table 1: the stripping result of embodiment 1-4.
By above data, can be found out, compared with prior art, the valsartan and Hydrochlorothiade capsule that technique of the present invention prepares is because raw material has adopted micronization processes and dry granulation, accelerated the dissolution rate of medicine, improve its dissolution velocity, thereby improved the bioavailability of whole effective ingredient.In embodiment 2, adopted Auricularia polycose MHA as adjuvant, valsartan in capsule and hydrochlorothiazide are more discharged in this time period of 5-15min in collective, be more conducive to targeting and absorb.
Claims (9)
1. a preparation technology who improves valsartan and Hydrochlorothiade capsule bioavailability, it is characterized in that, described technique concrete steps are: 1), by valsartan, hydrochlorothiazide micronization processes, 80 mesh sieves are crossed in filler, disintegrating agent, binding agent, solubilizing agent, lubricant is crossed 40 mesh sieves, standby; 2) valsartan, hydrochlorothiazide, filler, disintegrating agent, binding agent, the solubilizing agent that take recipe quantity are placed in high-speed mixing granulating machine mix homogeneously; 3) powder mixing is granulated with dry granulating machine, mix after adding the lubricant granulate of recipe quantity; 4) filling capsule.
2. preparation technology as claimed in claim 1, it is characterized in that, by mass parts, calculate, described valsartan accounts for 30-50 part, and described hydrochlorothiazide accounts for 5-10 part, and described filler accounts for 40-80 part, described disintegrating agent accounts for 5-50 part, described binding agent accounts for 0.1-5 part, and described solubilizing agent accounts for 0.1-5 part, and described lubricant agent accounts for 0.1-5 part.
3. preparation technology as claimed in claim 1, is characterized in that, described valsartan, hydrochlorothiazide all pass through pulverization process, can pass through 120 mesh sieves, and particle mean size is between 5 μ m-20 μ m.
4. preparation technology as claimed in claim 1, is characterized in that, one or more in starch, microcrystalline Cellulose, pregelatinized Starch, mannitol, lactose, Icing Sugar, calcium hydrogen phosphate, Icing Sugar, dextrin of described filler form.
5. preparation technology as claimed in claim 1, is characterized in that, one or more in sodium carboxymethyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone of described disintegrating agent form.
6. preparation technology as claimed in claim 1, is characterized in that, described binding agent by hypromellose or/and hyprolose form.
7. preparation technology as claimed in claim 1, is characterized in that, one or more in magnesium stearate, stearic acid, Pulvis Talci, micropowder silica gel of described lubricant form.
8. preparation technology as claimed in claim 1, is characterized in that, described solubilizing agent by sodium lauryl sulphate or/and tween 80 form.
9. preparation technology as claimed in claim 1, is characterized in that, described disintegrating agent is Auricularia polycose MHA.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310738223.3A CN103720696B (en) | 2013-12-27 | 2013-12-27 | A kind of preparation technology improving valsartan and Hydrochlorothiade capsule bioavailability |
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| CN201310738223.3A CN103720696B (en) | 2013-12-27 | 2013-12-27 | A kind of preparation technology improving valsartan and Hydrochlorothiade capsule bioavailability |
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| CN103720696A true CN103720696A (en) | 2014-04-16 |
| CN103720696B CN103720696B (en) | 2016-03-30 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112999186A (en) * | 2021-03-04 | 2021-06-22 | 海南锦瑞制药有限公司 | Preparation method of valsartan capsule and valsartan capsule |
| CN113041250A (en) * | 2021-04-06 | 2021-06-29 | 上海耀大生物科技有限公司 | Valsartan and hydrochlorothiazide compound preparation and preparation process thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1732952A (en) * | 2005-09-02 | 2006-02-15 | 姚俊华 | Compound dispersible tablet for treating hypertension |
| CN1840197A (en) * | 2006-01-12 | 2006-10-04 | 武汉大学 | Application of pachyman as disintegrating agent in preparation of medicinal tablet |
| CN101829111A (en) * | 2010-05-23 | 2010-09-15 | 浙江华海药业股份有限公司 | Valsartan-containing solid preparation and preparation method thereof |
-
2013
- 2013-12-27 CN CN201310738223.3A patent/CN103720696B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1732952A (en) * | 2005-09-02 | 2006-02-15 | 姚俊华 | Compound dispersible tablet for treating hypertension |
| CN1840197A (en) * | 2006-01-12 | 2006-10-04 | 武汉大学 | Application of pachyman as disintegrating agent in preparation of medicinal tablet |
| CN101829111A (en) * | 2010-05-23 | 2010-09-15 | 浙江华海药业股份有限公司 | Valsartan-containing solid preparation and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 周建平等: "《药剂学》", 31 March 2007 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112999186A (en) * | 2021-03-04 | 2021-06-22 | 海南锦瑞制药有限公司 | Preparation method of valsartan capsule and valsartan capsule |
| CN113041250A (en) * | 2021-04-06 | 2021-06-29 | 上海耀大生物科技有限公司 | Valsartan and hydrochlorothiazide compound preparation and preparation process thereof |
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| Publication number | Publication date |
|---|---|
| CN103720696B (en) | 2016-03-30 |
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