CN102526063A - Compound preparation containing losartan potassium and hydrochlorothiazide and preparation method for compound preparation - Google Patents
Compound preparation containing losartan potassium and hydrochlorothiazide and preparation method for compound preparation Download PDFInfo
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- CN102526063A CN102526063A CN2012100380463A CN201210038046A CN102526063A CN 102526063 A CN102526063 A CN 102526063A CN 2012100380463 A CN2012100380463 A CN 2012100380463A CN 201210038046 A CN201210038046 A CN 201210038046A CN 102526063 A CN102526063 A CN 102526063A
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- hydrochlorothiazide
- losartan potassium
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- potassium
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Abstract
The invention relates to a compound preparation containing losartan potassium and hydrochlorothiazide and a preparation method for the compound preparation. The compound preparation containing the losartan potassium and the hydrochlorothiazide comprises a tablet core and a film coating, wherein the tablet core comprises active pharmaceutical ingredients of the losartan potassium and the hydrochlorothiazide, and minor pharmaceutical ingredients such as microcrystalline cellulose, lactose, low substituted hydroxyprepyl cellulose and magnesium stearate. The prepared compound preparation has high dissolubility, is simple in preparation process and can be easily produced in large scale; and moreover, the degradation speed and degree of the hydrochlorothiazide can be remarkably lowered, and impurities 4-amino-6-chloro-1,3-benzenedisulfonamide (DSA) and chlorothiazide can be prevented from increasing.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of compound preparation of forming by Losartan Potassium and hydrochlorothiazide and preparation method thereof.
Background technology
Hypertension is one of modal cardiovascular disease in the world, often causes the complication of internal organs such as the heart, brain, kidney, and human beings'health in serious harm.Show that according to the China's Statistical data it is about 25% that China's hypertension prevalence rose in per 10 years, present national patient's estimated number surpasses 100,000,000.China has become one of the most serious country of hypertension harm in the world.
The main pathogenesis of hypertension is that a variety of causes causes sympathoadrenal ability system and renin angiotensin aldosterone system hyperfunctioning, causes strong contraction of small artery and water-sodium retention in the body, thereby causes the generation of hypertension.Hypertension belongs to the general chronic disease, and long-time hypertension can undermine main target organs such as heart and brain kidney, even causes hypertension complication, and controlling hypertensive main means is excess moistures in diastole whole body small artery and the eliminating body.
The hypertension philtrum has quite a few patient singly not reach the effect of blood pressure lowering with a kind of depressor, need just can make blood pressure normal with two or more depressor.So, several kinds of antihypertensive drugs treatments of normal clinically Combined application, the synergism of medicine can improve curative effect; Several drugs plays a role jointly, can reduce the single dose of each medicine, reduces by every kind of side effects of pharmaceutical drugs; Make blood pressure drops steady, improve compliance of patients, improve the toleration of medicine.The most frequently used uniting is that diuretic share with other depressor, and diuretic both can strengthen multiple depressor curative effect, can alleviate the side effect that causes edema again.Losastan potassium/hydrochlorothiazide tablets agent of the present invention is exactly the composite antihypertensive preparation of being made up of Losartan Potassium and hydrochlorothiazide.
Losastan potassium/hydrochlorothiazide tablets is the compound preparation of first angiotensin-ii receptor (AT1) antagonist and diuretic.Be applicable to that drug combination treats hypertensive patient.Losartan Potassium chemistry 2-butyl by name-4-chloro-1-[[2 '-(1H-tetrazolium-5-yl) [1,1 ' xenyl]-the 4-yl] methyl]-1H-imidazoles-5-methanol monopotassium salt, be angiotensin-ii receptor (AT1 type) antagonist.Can block endogenous property and various pharmacological actions that ectogenic Angiotensin II produced (comprise and impel vasoconstriction; Effects such as aldosterone release); Optionally act on the AT1 receptor; Do not influence the function of ion channel important in other hormone receptors or the cardiovascular, the angiotensin converting enzyme (kininase II) of the Kallidin I that yet do not suppress to degrade does not influence the metabolic process of Angiotensin II and Kallidin I.Hydrochlorothiazide, the another name Hydrochlorothiazide, hydrochlorothiazide, chemistry 6-chloro-3 by name, 4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1, the 1-dioxide is middle effect diuretic.This type of mechanism of drug action mainly suppresses distal tubule leading portion and proximal tubule (acting on lighter) the heavily absorption of sodium chloride is produced diuresis, in addition, also has the effect of blood pressure lowering.
There are some patents to disclose the formulation and technology of this compound preparation at present.
CN101797230A discloses a kind of Losartan Potassium and hydrochlorothiazide pharmaceutical composition lipidosome solid preparation and preparation method thereof; It is characterized in that earlier active component Losartan Potassium, hydrochlorothiazide and specific combined hydrogenated yolk lecithin, cholesterol, poloxamer 188 being prepared into liposome, be mixed and made into solid preparation with pharmaceutically useful other adjuvants again.
CN101327195A discloses a kind of losastan potassium/hydrochlorothiazide tablets and preparation method thereof; Described losastan potassium/hydrochlorothiazide tablets comprises label and film-coat layer, and wherein label is made up of Losartan Potassium, hydrochlorothiazide, microcrystalline Cellulose, pre-paying starch, lactose monohydrate, 30 POVIDONE K 30 BP/USP 30 and magnesium stearate.Its preparation method is earlier hydrochlorothiazide to be mixed the back with the Losartan Potassium, the lactose monohydrate that are prone to dissolve to granulate; In the Losartan Potassium that hydrochlorothiazide is dispersed in be prone to dissolve, the lactose monohydrate, mix with microcrystalline Cellulose, pre-paying starch, lactose monohydrate, magnesium stearate again, film-making.The tablet hydrochlorothiazide stripping that makes with method of the present invention is good, no hygroscopicity under super-humid conditions.
CN101461814A discloses a kind of pharmaceutical composition that contains Losartan Potassium and hydrochlorothiazide and preparation method thereof; Also contain adjuvant sodium alginate and lactose in this pharmaceutical composition; Add other suitable pharmaceutic adjuvants in this pharmaceutical composition, can be made into capsule, tablet, granule etc.
CN101632678A discloses a kind of losartan potassium hydrochlorothiazide composition and preparation method thereof.It is characterized in that; Said label is made up of with pharmaceutically acceptable auxiliaries respectively Losartan Potassium, hydrochlorothiazide, and used pharmaceutic adjuvant is microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch, lactose, polyvinylpyrrolidone, starch, magnesium stearate, Pulvis Talci.Adopt respectively tabletting behind the granulating process mix homogeneously, avoided adopting the Chinese medicine of once granulating to interact and cause lower dissolution.
The main purpose of above-mentioned patent all is the dissolutions that are used for improving hydrochlorothiazide, does not all mention the main degradation products of hydrochlorothiazide in all patents: 4-amino-6-chloro-1,3-benzene disulfonic acid amide (DSA) and chlorothiazide.Through a large amount of experimentatioies, we prove, adopt above-mentioned wet granulation method can not obtain gratifying stable hydrochlorothiazide, prevent the method that main degradation products raises.In carrying out influence factor's experiment and accelerated test process, related substance can constantly raise.Even two medicines are granulated respectively, related substance also can increase.
CN102058602A discloses a kind of stable oral solid formulation that contains Losartan Potassium and hydrochlorothiazide.In the solid preparation that contains Losartan Potassium and hydrochlorothiazide, add the acidic materials that a certain amount of pharmacology allows; The compositions of processing can significantly reduce the speed and the degree of hydrochlorothiazide degraded; Prevent impurity 4-amino-6-chloro-1, the rising of 3-benzene disulfonic acid amide (DSA).
The losastan potassium/hydrochlorothiazide tablets of the present invention's preparation adopts powder art direct compression prepared, even do not add the acidic materials that pharmacology allows in the prescription, in carrying out influence factor's experiment and accelerated test process, related substance can not raise yet.Therefore this preparation technology obviously overcome conventional wet granulate in related substance significantly increase this difficult problem, and the medicine stripping is fast.Have higher stability and high bioavailability.
Summary of the invention
The object of the present invention is to provide a kind of compound preparation of forming by Losartan Potassium and hydrochlorothiazide and preparation method thereof.Compound preparation by this prepared has advantages of higher stability.
According to an aspect of the present invention; The compound preparation that provides Losartan Potassium and hydrochlorothiazide to form; Comprise label and film-coat layer; It is characterized in that said label is that medicament active composition and pharmaceutically acceptable auxiliaries are formed with Losartan Potassium and hydrochlorothiazide, said pharmaceutically acceptable auxiliaries is microcrystalline Cellulose, lactose, low-substituted hydroxypropyl cellulose and magnesium stearate.
In the label prescription of the present invention, Losartan Potassium, hydrochlorothiazide are principal agent, and microcrystalline Cellulose, lactose are diluent, and low-substituted hydroxypropyl cellulose is a disintegrating agent, and magnesium stearate is a lubricant.
Among the present invention, the prescription of said label is following:
Label according to the invention, its optimization formula is following:
(in 1000)
According to another aspect of the present invention, a kind of method for preparing of the compound preparation of being made up of Losartan Potassium and hydrochlorothiazide is provided, may further comprise the steps:
1) with Losartan Potassium, hydrochlorothiazide pulverize separately, sieve, subsequent use;
2) take by weighing supplementary material by recipe quantity respectively;
3) with 2) middle supplementary material mix homogeneously, tabletting;
4) with 3) sample that obtains puts in the coating pan, and coating promptly gets.
Wherein, sieving in the step 1) crossed 100 mesh sieves for the Losartan Potassium after will pulverizing and hydrochlorothiazide.
Advantage of the present invention is simple to operate, is fit to industrial large-scale production; The losastan potassium/hydrochlorothiazide tablets stripping that makes is fast, good stability, and bioavailability is high.
The specific embodiment
Below in conjunction with embodiment the present invention is done further explain, but should understand the non-scope that only limits to these embodiment of scope of the present invention.
Embodiment 1
(1) prescription
(in 1000)
Coating is formed
Opadry (stomach dissolution type) 7g
Water 100ml
(2) method for preparing
1) with Losartan Potassium, hydrochlorothiazide pulverize separately, sieve, subsequent use; Microcrystalline Cellulose, lactose, low-substituted hydroxypropyl cellulose, magnesium stearate are sieved respectively, subsequent use;
2) take by weighing supplementary material by recipe quantity respectively;
3) with 2) middle supplementary material mix homogeneously, tabletting;
4) with 3) sample that obtains puts in the coating pan, and coating promptly gets.
Embodiment 2 (Comparative Examples)
(1) prescription
(in 1000)
Coating is formed
Opadry (stomach dissolution type) 7g
Water 100ml
(2) method for preparing
1) with Losartan Potassium, hydrochlorothiazide pulverize separately, sieve, subsequent use; Microcrystalline Cellulose, lactose, low-substituted hydroxypropyl cellulose, magnesium stearate are sieved respectively, subsequent use;
2) take by weighing the supplementary material mix homogeneously by recipe quantity respectively;
3) hypromellose is dissolved in 80% ethanol water;
4) with step 2) and the product mix homogeneously that obtains of step 3), adopt 20 eye mesh screens to granulate, 60 ℃ of dryings, 18 eye mesh screen granulate add magnesium stearate, tabletting;
5) with 4) sample that obtains puts in the coating pan, and coating promptly gets.
Embodiment 1 adopts the direct pressed powder prepared of the present invention, and embodiment 2 adopts the traditional wet method of granulating to prepare sample.Relatively two embodiment are with the dissolution and the stability test data of sample.
With reference to 2 appendix XC first methods of Chinese Pharmacopoeia version in 2010, embodiment 1 and embodiment 2 are carried out the test of dissolution in vitro respectively, and carry out assay, the result sees table 1.
Test of table 1 dissolution in vitro and assay result
Embodiment 1 and embodiment 2 are carried out accelerated tests respectively under 40 ℃, 75% damp condition, and respectively at 0 day, the 1st, 2,3,6, December sampling and measuring related substance and content, the result sees table 2.
Table 2 accelerated test result
Therefore, can find out from the result of table 1 and table 2, the tablet that pharmaceutical composition of the present invention adopts technique of direct powder compression to process, hydrochlorothiazide has stripping preferably, and stability is better, and the stability of Losartan Potassium is also better simultaneously.
Claims (5)
1. compound preparation of forming by Losartan Potassium and hydrochlorothiazide; Comprise label and film-coat layer; It is characterized in that; Said label is that medicament active composition and pharmaceutically acceptable auxiliaries are formed with Losartan Potassium and hydrochlorothiazide, and said pharmaceutically acceptable auxiliaries is microcrystalline Cellulose, lactose, low-substituted hydroxypropyl cellulose, magnesium stearate.
2. the compound preparation of being made up of Losartan Potassium and hydrochlorothiazide according to claim 1 is characterized in that, the prescription of said label is following:
3. the compound preparation of being made up of Losartan Potassium and hydrochlorothiazide according to claim 2 is characterized in that:
(in 1000)
Coating is formed
Opadry (stomach dissolution type) 7g
Water 100m.l
4. the compound preparation of being made up of Losartan Potassium and hydrochlorothiazide according to claim 3 is characterized in that the method for preparing of this compound preparation comprises the steps:
1) with Losartan Potassium, hydrochlorothiazide pulverize separately, sieve, subsequent use;
2) take by weighing supplementary material by recipe quantity respectively;
3) with 2) middle supplementary material mix homogeneously, tabletting;
4) with 3) sample that obtains puts in the coating pan, and coating promptly gets.
5. the compound preparation of being made up of Losartan Potassium and hydrochlorothiazide according to claim 4 is characterized in that, sieving in the step 1) crossed 100 mesh sieves for the Losartan Potassium after will pulverizing and hydrochlorothiazide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012100380463A CN102526063A (en) | 2012-02-20 | 2012-02-20 | Compound preparation containing losartan potassium and hydrochlorothiazide and preparation method for compound preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012100380463A CN102526063A (en) | 2012-02-20 | 2012-02-20 | Compound preparation containing losartan potassium and hydrochlorothiazide and preparation method for compound preparation |
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| CN102526063A true CN102526063A (en) | 2012-07-04 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2012100380463A Pending CN102526063A (en) | 2012-02-20 | 2012-02-20 | Compound preparation containing losartan potassium and hydrochlorothiazide and preparation method for compound preparation |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103006566A (en) * | 2012-12-27 | 2013-04-03 | 惠州市九惠制药股份有限公司 | Osmotic pump controlled release tablet of losartan potassium and hydrochlorothiazide solid dispersion or inclusion compound |
| CN105982901A (en) * | 2015-03-05 | 2016-10-05 | 南京从医药科技有限公司 | Propranolole hydrochloride and hydrochlorothiazide tablets and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101327195A (en) * | 2008-06-20 | 2008-12-24 | 海南锦瑞制药有限公司 | Losartan potassium and hydrochlorothiazide tablets and preparation method thereof |
-
2012
- 2012-02-20 CN CN2012100380463A patent/CN102526063A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101327195A (en) * | 2008-06-20 | 2008-12-24 | 海南锦瑞制药有限公司 | Losartan potassium and hydrochlorothiazide tablets and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103006566A (en) * | 2012-12-27 | 2013-04-03 | 惠州市九惠制药股份有限公司 | Osmotic pump controlled release tablet of losartan potassium and hydrochlorothiazide solid dispersion or inclusion compound |
| CN105982901A (en) * | 2015-03-05 | 2016-10-05 | 南京从医药科技有限公司 | Propranolole hydrochloride and hydrochlorothiazide tablets and preparation method thereof |
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Application publication date: 20120704 |