CN111297812A - Compound preparation containing losartan potassium and preparation method thereof - Google Patents
Compound preparation containing losartan potassium and preparation method thereof Download PDFInfo
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- CN111297812A CN111297812A CN202010114704.7A CN202010114704A CN111297812A CN 111297812 A CN111297812 A CN 111297812A CN 202010114704 A CN202010114704 A CN 202010114704A CN 111297812 A CN111297812 A CN 111297812A
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- losartan potassium
- hydrochlorothiazide
- preparation
- kollicoat
- compound preparation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- Heart & Thoracic Surgery (AREA)
- Engineering & Computer Science (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Abstract
A compound preparation containing losartan potassium and a preparation method thereof are disclosed, which comprises the following steps: dissolving losartan potassium and kollicoat IR in a methanol water solution, and granulating on auxiliary materials to obtain granules of losartan potassium coated by kollicoat IR; dissolving hydrochlorothiazide in acetone, and granulating on auxiliary materials; mixing the two kinds of granules, and tabletting. The losartan potassium-containing compound preparation prepared by the invention can fully isolate losartan potassium and hydrochlorothiazide, and the medicine is added in a solution state, fully dispersed on the surface of an auxiliary material and quickly dissolved out. The compound preparation containing losartan potassium prepared by the process steps is simple and feasible in process and stable in quality, improves the product quality, and ensures the stability of the product in the long-term storage process.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a losartan potassium-containing compound preparation and a preparation method thereof.
Background
Hypertension is one of the most common cardiovascular diseases in the world nowadays, and is a chronic disease mainly manifested by continuous rise of arterial blood pressure, which often causes the pathological changes of important organs such as heart, brain, kidney and the like and has corresponding consequences. The treatment of hypertension requires long-term administration, generally starting from small doses and gradually increasing doses, and the combination can be selected for patients who receive one drug treatment and have uncontrollable blood pressure, and researches show that 2/3 is the combination in patients with well-controlled blood pressure. When the medicines are used in combination, the synergistic effect is achieved, the effect of reducing blood pressure is improved, and the adverse reaction caused by the excessive dosage of one medicine can be avoided.
Losartan potassium is the angiotensin II receptor antagonist for treating hypertension in the first world and is a powerful vasoconstrictor, angiotensin II receptors are AT1 receptors and AT2 receptors, losartan potassium competitively blocks AT1 receptors to produce a plurality of important biological effects including vasoconstriction and aldosterone release, and losartan potassium is suitable for treating essential hypertension and can also be used together with other antihypertensive drugs.
Hydrochlorothiazide is a diuretic, and sodium discharge reduces the content of sodium ions in blood vessel wall cells, so that a sodium-calcium exchange mechanism is adopted to reduce calcium ions in cells, and thus blood vessel smooth muscles are relaxed; the reduction of intracellular calcium ions reduces the responsiveness of vascular smooth muscle to vasoconstrictors such as norepinephrine and the like. The losartan potassium and hydrochlorothiazide combined drug can have synergistic effect on reducing blood pressure, and has better blood pressure reducing effect compared with the single use of any one of the components.
Chinese patent CN103505460A discloses a preparation method for preparing a losartan potassium hydrochlorothiazide composition, which adopts dry granulation, but easily causes uneven particle size, large difference of tablet weight and dissolution difference. Chinese patent CN101632678A discloses a losartan potassium hydrochlorothiazide composition and a preparation method thereof, wherein losartan potassium and hydrochlorothiazide are respectively subjected to wet granulation with pharmaceutical excipients, and then mixed tabletting and coating are carried out to obtain the losartan potassium hydrochlorothiazide composition. However, the adoption of wet granulation easily causes the degradation of hydrochlorothiazide, so that related substances are increased, and the stability of the preparation is influenced.
Since hydrochlorothiazide is susceptible to degradation, the main degradation products: 4-amino-6-chloro-1, 3-benzenedisulfonamide (DSA), and stable hydrochlorothiazide cannot be obtained by wet granulation; the hydrochlorothiazide is unstable in property, and is easy to react in the long-term contact process with the losartan potassium and other auxiliary materials, so that related substances of the medicament are increased; dry granulation is carried out, the particle size is not uniform, and the dissolution is different; the flowability of the direct compression tablet is poor. The invention creatively adopts the following method to prepare: dissolving losartan potassium and kollicoat IR in 70-80% methanol water solution, and granulating on auxiliary materials to obtain granules of losartan potassium coated by kollicoat; dissolving hydrochlorothiazide in acetone, and granulating on the auxiliary materials; mixing the two granules, and tabletting.
Disclosure of Invention
The compound preparation containing losartan potassium and the preparation method thereof provided by the invention have the advantages that the process is simple and feasible, the tablet weight is stable, the product quality of the losartan potassium compound preparation is improved, and the stability of the product in the long-term storage process is ensured.
The purpose of the invention is realized by the following steps:
a compound preparation containing losartan potassium and a preparation method thereof comprise the following steps:
(1) granules containing losartan potassium were prepared.
(2) Granules containing hydrochlorothiazide were prepared.
(3) Mixing the two kinds of granules, and tabletting.
The compound preparation containing losartan potassium and the preparation method thereof, the step (1) comprises the following steps:
dissolving losartan potassium and a coating material kollicoat IR in a specific solvent, and granulating on auxiliary materials to obtain granules containing losartan potassium coated by kollicoat IR.
The compound preparation containing losartan potassium and the preparation method thereof, the step (2) comprises the following steps:
dissolving hydrochlorothiazide in a specific solvent, and granulating the mixture on auxiliary materials to obtain granules containing hydrochlorothiazide.
The compound preparation containing losartan potassium and the preparation method thereof, the specific solvent is 70-80% methanol water solution.
The compound preparation containing losartan potassium and the preparation method thereof, the specific solvent is acetone solution.
The compound preparation containing losartan potassium and the preparation method thereof are characterized in that in the step (1), the weight ratio of losartan potassium, kollicoat IR and hydrochlorothiazide is as follows: 1: 0.1-1: 0.25.
the auxiliary materials are pharmaceutically commonly used auxiliary material fillers, disintegrants and lubricants.
The filler is one or more of lactose, microcrystalline cellulose, starch and mannitol.
The disintegrant is one or more of sodium carboxymethyl starch, crospovidone, croscarmellose sodium and low-substituted hydroxypropyl cellulose.
The lubricant is one or more of magnesium stearate, superfine silica gel powder and talcum powder.
The losartan potassium-containing compound preparation prepared by the invention has the advantages that losartan potassium and hydrochlorothiazide can be fully isolated, and the medicine is added in a solution state, fully dispersed on the surface of an auxiliary material and quickly dissolved out. The compound preparation containing losartan potassium prepared by the process steps is simple and feasible in process, rapid in dissolution and stable in quality, improves the product quality, and ensures the stability of the product in the long-term storage process.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
Example 1
The embodiment provides a losartan potassium-containing compound preparation and a preparation method thereof, wherein the losartan potassium-containing compound preparation is prepared by the following preparation steps:
dissolving losartan potassium and kollicoat IR in 70% methanol water solution, and granulating on microcrystalline cellulose to obtain granules of losartan potassium coated by kollicoat; dissolving hydrochlorothiazide in acetone, and granulating on microcrystalline cellulose; mixing the two granules with sodium carboxymethyl starch and magnesium stearate, and tabletting.
Example 2
The embodiment provides a losartan potassium-containing compound preparation and a preparation method thereof, wherein the losartan potassium-containing compound preparation is prepared by the following preparation steps:
dissolving losartan potassium and kollicoat IR in 75% methanol water solution, and granulating on lactose to obtain granules of losartan potassium coated by kollicoat; dissolving hydrochlorothiazide in acetone, and granulating on microcrystalline cellulose; mixing the two granules with crospovidone and magnesium stearate, and tabletting.
Example 3
The embodiment provides a losartan potassium-containing compound preparation and a preparation method thereof, wherein the losartan potassium-containing compound preparation is prepared by the following preparation steps:
dissolving losartan potassium and kollicoat IR in 80% methanol water solution, and granulating on starch to obtain granules of losartan potassium coated by kollicoat; dissolving hydrochlorothiazide in acetone, and granulating on microcrystalline cellulose; mixing the two granules with sodium carboxymethyl starch, magnesium stearate, and silica gel micropowder, and tabletting.
Comparative example 1
The embodiment provides a losartan potassium-containing compound preparation and a preparation method thereof, wherein the losartan potassium-containing compound preparation is prepared by the following preparation steps:
| name (R) | Weight (g) |
| Losartan potassium | 50 |
| kollicoat IR | 75 |
| Hydrochlorothiazide | 12.5 |
| To obtain | 1000 tablets |
Dissolving losartan potassium and kollicoat IR in 75% methanol water solution, and granulating on auxiliary materials to obtain granules of losartan potassium coated by kollicoat; dissolving hydrochlorothiazide in acetone, and granulating on the auxiliary materials; mixing the two kinds of granules, and tabletting. COMPARATIVE EXAMPLE 2 (REFERENCE CN103505460A EXAMPLE 2)
The present embodiment provides a losartan potassium-containing formulation and a preparation method thereof, wherein the losartan potassium-containing formulation is obtained by the following preparation steps:
uniformly mixing losartan potassium, microcrystalline cellulose, lactose and croscarmellose sodium, and performing dry granulation to obtain granules A containing losartan potassium. The hydrochlorothiazide, the pregelatinized starch, the microcrystalline cellulose, the povidone and the carboxymethyl starch sodium are uniformly mixed, and dry granulation is carried out to obtain the hydrochlorothiazide-containing granules B. Dissolving a proper amount of methylcellulose in water to prepare a coating solution; and (3) placing the granules B containing hydrochlorothiazide in a coating machine, spraying coating liquid when the temperature in the coating machine reaches 40-45 ℃, and screening the granules to obtain the granules C. And finally, uniformly mixing the granules A and the granules C, adding magnesium stearate, and tabletting to obtain the tablet.
COMPARATIVE EXAMPLE 3 (REFERENCE CN101632678A EXAMPLE 1)
The present embodiment provides a losartan potassium-containing formulation and a preparation method thereof, wherein the losartan potassium-containing formulation is obtained by the following preparation steps:
respectively crushing the losartan potassium and the hydrochlorothiazide for later use; sieving microcrystalline cellulose, lactose, croscarmellose sodium, pregelatinized starch and magnesium stearate; and (3) respectively granulating the raw materials and auxiliary materials in the components 1 and 2 by using 50% ethanol solution, drying, uniformly mixing with magnesium stearate, tabletting and coating.
Verification examples
The tablets obtained by applying the invention in examples 1-3 were compared with comparative examples 1-3 in terms of quality, and subjected to accelerated and long-term stability test investigation, and the comparison results were as follows:
stability test results Table-1
Stability test results Table-2
From the results, it can be seen that the tablets of examples 1 to 3 of the present invention were rapidly dissolved, and the substances involved were significantly superior to those of comparative example 1 and others. In comparative example 2, dry granulation is adopted, but uneven particle size and large tablet weight difference are easily caused, so that the dissolution is slow; in comparative example 3, the wet granulation is adopted, but hydrochlorothiazide is easily degraded, related substances are increased, and the stability is not as good as that of the invention.
The data show that the losartan potassium-containing compound preparation prepared by the invention can fully isolate losartan potassium and hydrochlorothiazide, and the medicine is added in a solution state, fully dispersed on the surface of an auxiliary material and rapidly dissolved out. And the process is simple and feasible, the quality is stable, the product quality is improved, and the stability of the product in the long-term storage process is ensured.
Claims (10)
1. A compound preparation containing losartan potassium and a preparation method thereof are characterized by comprising the following steps:
(1) granules containing losartan potassium were prepared.
(2) Granules containing hydrochlorothiazide were prepared.
(3) Mixing the two kinds of granules, and tabletting.
2. The method according to claim 1, wherein the step (1) comprises the steps of:
dissolving losartan potassium and kollicoat IR in a specific solvent, and granulating on auxiliary materials to obtain granules containing losartan potassium coated by kollicoat IR.
3. The method according to claim 1, wherein the step (2) comprises the steps of:
dissolving hydrochlorothiazide in a specific solvent, and granulating the mixture on auxiliary materials to obtain granules containing hydrochlorothiazide.
4. The method according to claim 2, wherein the specific solvent is 70-80% methanol aqueous solution.
5. The method according to claim 3, wherein the specific solvent is an acetone solution.
6. The process according to claim 1, characterized in that the weight ratio of losartan potassium, kollicoat IR and hydrochlorothiazide in step (1) is 1: 0.1-3: 0.25.
7. the adjuvant according to claim 1 or 2, characterized by being a filler, a disintegrant and a lubricant which are commonly used in pharmacy.
8. The auxiliary material according to claim 7, wherein the filler is one or more of lactose, microcrystalline cellulose, starch, and mannitol.
9. The adjuvant according to claim 7, wherein the disintegrant is one or more of sodium carboxymethyl starch, crospovidone, croscarmellose sodium, and low substituted hydroxypropyl cellulose.
10. The adjuvant according to claim 7, wherein the lubricant is one or more of magnesium stearate, aerosil and talc.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010114704.7A CN111297812A (en) | 2020-02-25 | 2020-02-25 | Compound preparation containing losartan potassium and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010114704.7A CN111297812A (en) | 2020-02-25 | 2020-02-25 | Compound preparation containing losartan potassium and preparation method thereof |
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| Publication Number | Publication Date |
|---|---|
| CN111297812A true CN111297812A (en) | 2020-06-19 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010114704.7A Pending CN111297812A (en) | 2020-02-25 | 2020-02-25 | Compound preparation containing losartan potassium and preparation method thereof |
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| Country | Link |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090304755A1 (en) * | 2005-10-27 | 2009-12-10 | Raghu Rami Reddy Kasu | Pharmaceutical formulation of losartan |
| CN101632678A (en) * | 2009-09-01 | 2010-01-27 | 严洁 | Losartan potassium hydrochlorothiazide composition and preparation method thereof |
| CN103505460A (en) * | 2012-06-19 | 2014-01-15 | 北京万生药业有限责任公司 | Method for preparing losartan potassium and hydrochlorothiazide composition |
| CN104887633A (en) * | 2014-03-04 | 2015-09-09 | 山东新时代药业有限公司 | Rivaroxaban tablets and preparation method thereof |
-
2020
- 2020-02-25 CN CN202010114704.7A patent/CN111297812A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090304755A1 (en) * | 2005-10-27 | 2009-12-10 | Raghu Rami Reddy Kasu | Pharmaceutical formulation of losartan |
| CN101632678A (en) * | 2009-09-01 | 2010-01-27 | 严洁 | Losartan potassium hydrochlorothiazide composition and preparation method thereof |
| CN103505460A (en) * | 2012-06-19 | 2014-01-15 | 北京万生药业有限责任公司 | Method for preparing losartan potassium and hydrochlorothiazide composition |
| CN104887633A (en) * | 2014-03-04 | 2015-09-09 | 山东新时代药业有限公司 | Rivaroxaban tablets and preparation method thereof |
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Application publication date: 20200619 |
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