CN102028663A - Stable olmesartan medoxomil solid preparation - Google Patents

Abstract

The invention provides a stable olmesartan medoxomil solid preparation and a preparation method thereof. Olmesartan medoxomil is unstable within a certain pH range and is easy to undergo hydration reaction. The hydrolysis product as an impurity is retained in the medicine, thereby influencing the safety effectiveness of the medicine. A pH adjusting agent and a stabilizing agent are added in a prescription, active components of the preparation are ensured to be free from undergoing the hydration reaction in the production process, the impurities are avoided, and the quality of the products and the medicine application safety of patients can be ensured.

Description

A kind of stable olmesartan medoxomil solid preparation

Technical field

The present invention relates to a kind of stable medical solid preparation, particularly relate to olmesartan medoxomil solid preparation and preparation method thereof, belong to field of pharmaceutical preparations.

Background technology

The impurity of medicine is to be present in not have therapeutical effect in the medicine, human body had harm or influences the material of drug quality, and be one of key factor that influences drug safety.The impurity source is many-sided, can bring in the feedstock production process, and is impure as raw material, and the part material reaction not exclusively; Intermediate that produces in the course of reaction or by-product do not eliminate when refining; Or in the processing technology process, may bring impurity etc. into.Impurity also can produce in the preparation production process, brings adjuvant and active component interaction etc. into as adjuvant; Also may produce impurity in storage and the transportation, as be subjected to the influence of external condition, cause that physical and chemical properties of drugs changes and generation etc.Therefore, in drug production process, must strictly control each link, guarantee drug safety.

As everyone knows, ester type compound is unstable in specific PH scope, can separate reaction with the waterishlogging unboiled water and generate corresponding acid and pure, and the preparation production process generally all will be gone through the main ingredient mixing, heating, processes such as granulation may contain slant acidity or meta-alkalescence composition in the adjuvant, if the acid-base value of material forms the unsettled PH scope of ester just, in heating process, ester will be separated reaction with the waterishlogging unboiled water, and hydrolyzate continues to be retained in the product as impurity, causes the medicine impurity level to accumulate, after particularly living through secular storage and transportation, impurity content is constantly accumulated, and causes product quality defective, and then has a strong impact on patient's drug safety.

Olmesartan medoxomil is a kind of non-peptide class angiotensin ii receptor antagonist, can suppress angiotensin and its receptors bind effectively, thereby suppresses feritin, is used for hypertensive treatment, and its structural formula is

As ester type compound, olmesartan medoxomil character instability, can be in sour environment stable existence, then unstable in alkaline environment, facile hydrolysis, in the formulation preparation process, adjuvant is bigger to its influence, causes its hydrolysis as the basic auxiliary environment, generates corresponding acid and pure, impurity increases, and influences drug quality; Though can stable existence in sour environment, need strict control PH, adjuvant acidity is too weak can't to play a protective role, too strong then might with the hydroxyl generation esterification in the molecule, generate new impurity.

By retrieval, find in the past academic documents and patent documentation in about suppressing the report of Olmesartan ester hydrolysis reaction.

Summary of the invention

The invention provides a kind of olmesartan medoxomil solid preparation and preparation method thereof, hydrolysis does not take place in active component in the preparation production process, guarantees the safety of medicine, and concrete technical scheme is as follows:

A kind of stable olmesartan medoxomil solid preparation comprises olmesartan medoxomil or its hydrate, and stabilizing agent and PH regulator, stabilizing agent are BHA, and one or both among the BHT, PH regulator are citric acid, one or more in malic acid, the fumaric acid, optimization citric acid; This solid preparation also comprises diluent, disintegrating agent, and binding agent, lubricant, diluent are one or more in lactose, starch, microcrystalline Cellulose, the pregelatinized Starch; Disintegrating agent is carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, one or more of crospolyvinylpyrrolidone; Binding agent is a polyvidone, one or both in the hypromellose; Lubricant is micropowder silica gel, one or both in the magnesium stearate, and the each component ratio is olmesartan medoxomil 15-25 part, stabilizing agent 0.8-1.5 part, PH regulator 1.5-2.6 part, diluent 140-180 part, disintegrating agent 5-25 part, binding agent 3-6 part, lubricant 5-8 part.

Preparation method is following steps

(1) takes by weighing the olmesartan medoxomil of recipe quantity and diluent, disintegrating agent mix homogeneously;

(2) with stabilizing agent, PH regulator, binding agent are dissolved in the dehydrated alcohol, make binder solution;

(3) in (1) gained mixture, add binding agent, granulate, granulate, after the drying, the adding mix lubricant is even;

(4) measure granule content, tabletting.

Increased the PH regulator in the olmesartan medoxomil solid preparation prescription provided by the invention, guarantee that material is in the faintly acid state, thereby the hydrolysis that suppresses olmesartan medoxomil, in the selection of PH regulator, the inventor tests respectively several PH regulators commonly used such as citric acid, malic acid, fumaric acid, the faintly acid that all can effectively keep material, wherein citric acid best results; In order to guarantee its stability more, realize " dual fail-safe " that added a spot of stabilizing agent BHA in the prescription, BHT has inhibitory action to the hydrolysis of olmesartan medoxomil, because BHA and BHT have the antioxidative effect, has avoided olmesartan medoxomil oxidized simultaneously.In the preparation production process; replace water to granulate with dehydrated alcohol, avoided the influence of moisture, prevent the generation of hydrolysis active substance; guarantee the stability of active component more; in addition, because stabilizing agent, PH regulator consumption is less relatively; it is dissolved in the dehydrated alcohol with binding agent; make binder solution,, guarantee that mixing of materials is even again with olmesartan medoxomil and mixing diluents.

The specific embodiment

Following embodiment but does not limit scope of invention in order to explanation the present invention

Embodiment 1

Olmesartan medoxomil 20g, BHA0.5g, BHT0.5g, citric acid 2g, lactose 60g, microcrystalline Cellulose 100g, carboxymethyl starch sodium 10g, micropowder silica gel 5g, magnesium stearate 2g, dehydrated alcohol 60ml, polyvidone 4.5g.

Preparation method:

(1) takes by weighing the olmesartan medoxomil of recipe quantity, lactose, microcrystalline Cellulose, carboxymethyl starch sodium, mix homogeneously;

(2) with BHA, BHT, citric acid, polyvidone are dissolved in the dehydrated alcohol, make binder solution;

(3) add binder solution in (1) gained mixture, granulate, granulate after the drying, adds silicon dioxide and magnesium stearate mix homogeneously;

(4) measure granule content, tabletting.

Embodiment 2

Olmesartan medoxomil 17g, BHA0.3g, BHT0.6g, citric acid 1.6g, lactose 54g, microcrystalline Cellulose 98g, low-substituted hydroxypropyl cellulose 14g, micropowder silica gel 5g,, dehydrated alcohol 60ml, polyvidone 4g.

Preparation method embodiment 1

Embodiment 3

Olmesartan medoxomil 20g, BHA0.8g, malic acid 2.4g, lactose 30g, microcrystalline Cellulose 115g, cross-linking sodium carboxymethyl cellulose 10g, crospolyvinylpyrrolidone 5g, magnesium stearate 4g, dehydrated alcohol 70ml, polyvidone 5g.

Preparation method such as embodiment 1

Embodiment 4

Olmesartan medoxomil 18g, BHT0.4g, BHA0.6g, fumaric acid 2.2g, lactose 30g, microcrystalline Cellulose 130g, cross-linking sodium carboxymethyl cellulose 19g, magnesium stearate 4g, dehydrated alcohol 50ml, hypromellose 4g.

Preparation method such as embodiment 1

Embodiment 5

Olmesartan medoxomil 20g, starch 40g, microcrystalline Cellulose 110g, carboxymethyl starch sodium 20g, micropowder silica gel 4g, dehydrated alcohol 65ml, polyvidone 5g.

Preparation method such as embodiment 1

The said goods is carried out influence factor's test, and carry out related substance and detect

Prescription 1

Prescription 2

Prescription 3

Prescription 4

Prescription 5

Claims (8)

1. a stable olmesartan medoxomil solid preparation is characterized in that comprising olmesartan medoxomil, stabilizing agent and PH regulator.

2. solid preparation according to claim 1 is characterized in that, described stabilizing agent is BHA, one or both among the BHT.

3. solid preparation according to claim 1 is characterized in that, described PH regulator is a citric acid, one or more in malic acid, the fumaric acid.

4. solid preparation according to claim 3 is characterized in that, described PH regulator is a citric acid.

5. solid preparation according to claim 1 is characterized in that, described olmesartan medoxomil solid preparation also comprises diluent, disintegrating agent, binding agent, lubricant.

6. solid preparation according to claim 5 is characterized in that, described diluent is one or more in lactose, starch, microcrystalline Cellulose, the pregelatinized Starch; Disintegrating agent is carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, one or more of crospolyvinylpyrrolidone; Binding agent is a polyvidone, one or both in the hypromellose; Lubricant is micropowder silica gel, one or both in the magnesium stearate.

7. according to claim 5 or 6 described solid preparations, it is characterized in that the each component ratio is olmesartan medoxomil 15-25 part, stabilizing agent 0.8-1.5 part, PH regulator 1.5-2.6 part, diluent 140-180 part, disintegrating agent 5-25 part, binding agent 3-6 part, lubricant 5-8 part.

8. according to the arbitrary described solid preparation of claim 1-7, its preparation method is following steps

(1) takes by weighing the olmesartan medoxomil of recipe quantity and diluent, disintegrating agent mix homogeneously;

(2) with stabilizing agent, PH regulator, binding agent are dissolved in the dehydrated alcohol, make binder solution;

(3) in (1) gained mixture, add binder solution, granulate, granulate, after the drying, the adding mix lubricant is even;

(4) measure granule content, tabletting.