WO2008101375A1

WO2008101375A1 - A gastric retentive sustained-release pharmaceutical composition comprising irbesartan

Info

Publication number: WO2008101375A1
Application number: PCT/CN2007/002833
Authority: WO
Inventors: Qingsheng Bei
Original assignee: Guangzhou Pui's Pharmaceutical Factory Ltd.
Priority date: 2007-02-16
Filing date: 2007-09-28
Publication date: 2008-08-28
Also published as: CN101011393B; CN101011393A

Abstract

A gastric retentive sustained-release pharmaceutical composition comprising irbesartan and pharmaceutically acceptable excipients for effectively controlling the retention time of the drug in the stomach to obtain stable blood concentration in patients after administration and increase security and efficacy of the drug, and the preparative method thereof.

Description

Irbesartan gastric retention type sustained release pharmaceutical composition

Technical field

The invention relates to a gastric retention type sustained release pharmaceutical composition, in particular to a gastric retention type sustained release pharmaceutical composition for antihypertensive drug irbesartan and a preparation method thereof. Background technique

Irbesartan has the chemical name: 2-butyl-3_[4-[2-(1H-tetrazol-5-yl)phenyl]benzyl]-1,3-diazaspiro- [4. 4] 壬-1-en-4-one. It is a novel angiotensin II receptor antagonist that specifically antagonizes angiotensin II (Ang II) receptor ΑΊ\. For AT, the selectivity of the receptor is 8500 times that of ΑΤ ₂ , by selectively Antagonizes the binding of Ang II to ΑΊ\receptor, inhibits vasoconstriction and aldosterone release, and produces antihypertensive effect. Suitable for a variety of levels of essential hypertension. Compared with other antihypertensive drugs, irbesartan is similar or slightly superior to enalapril, amlodipine, atenolol, losartan, and valsartan. With the deepening of the research, it has also been found that irbesartan has the effects of treating left ventricular hypertrophy, congestive heart failure, and diabetic nephropathy.

Irbesartan can be rapidly absorbed after oral administration, and the bioavailability is 60-80%, which is not affected by food. The plasma peak time is 1. 5~2 hours, the elimination half-life is 11~15 hours, and the steady state is reached within 3 days. A dose of 50 mg or more can significantly reduce the patient's blood pressure and is dose-related. Irbesartan is mainly metabolized by cytochrome P450 2C9. The plasma protein binding rate is 90%, and the average volume of distribution is 53~93L. It is excreted by the biliary tract and kidneys with the original drug form and metabolites. It is suitable for liver and kidney dysfunction. patient.

At present, irbesartan dosage forms sold on the domestic and international markets include ordinary tablets, capsules, dispersible tablets, etc., because of its long biological half-life, it can produce a 24-hour antihypertensive effect once a day. However, since the antihypertensive effect of irbesartan is dose-dependent, the blood pressure can be controlled 24 hours a day, but the blood pressure is highly volatile. Studies have shown that blood pressure fluctuations on the heart, blood vessels and target organs are more harmful than hypertension itself. Therefore, it can be used to control blood pressure fluctuations and reduce blood pressure by making a slow-release preparation with small fluctuations in blood concentration. The peak-to-valley ratio is achieved, and a 24-hour smooth buck can be achieved.

The usual slow-release preparations have limited action time in the human body due to the effects of gastric emptying and intestinal transit, and the advantages of the controlled release preparation cannot be fully exerted. As a targeted local drug delivery system, the gastric retention-type sustained release preparation can prolong the residence time of the drug in the gastrointestinal tract (mainly the stomach), increase the drug concentration in the adsorption-absorption site, and promote the site. The driving force of passive absorption of cells, thereby increasing the absorption of drugs in the stomach or duodenum, and improving the bioavailability of drugs; slow release of drugs can avoid fluctuations in blood concentration, reduce systemic side effects, and improve drug safety. The drug can be absorbed immediately after it is released, thereby avoiding the possible degradation of the drug in the channel fluid and the decrease in solubility caused by the increase in intestinal pH, improving the effectiveness of the drug and reducing the cost.

The surprising discovery of the present invention is that irbesartan is stable under acidic conditions and is readily soluble and absorbable, with reduced solubility in alkaline buffers. To this end, the present invention utilizes its unique characteristics to prepare a sustained-release drug for gastric retention, which is mainly absorbed in the stomach and exerts its efficacy, and is further formulated by a sustained-release pharmaceutical composition for irbesartan gastric retention type. Screening, found the appropriate formula composition, so that the obtained irbesartan gastric retention type sustained release tablets obtained a good gastric retention effect and complete drug release, significantly reduced blood drug concentration fluctuations, improved bioavailability Degree and medication safety. Summary of the invention

SUMMARY OF THE INVENTION An object of the present invention is to provide an irbesartan gastric retention type sustained release pharmaceutical composition which has a drug release property and a safe and effective drug administration. It has the characteristics of complete absorption, stable and long-lasting effect and high safety.

The irbesartan gastric continuous release sustained-release pharmaceutical composition of the present invention comprises irbesartan or a physiologically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable excipient Acceptable excipients are selected from the group consisting of hydrophilic polymeric gel materials, bleaching aids, gas generating agents, surfactants, swelling materials, fillers, lubricants, wetting agents or binders, and packages. A coating agent or the like may be used in combination of one or more of them. Wherein the hydrophilic polymer gel material is selected from one or more of hypromellose, alginate, chitosan, and the like having a viscosity of 4000 to 10000 centipoise. The bleaching agent is selected from one or more of a mixture of cetyl alcohol, stearyl alcohol, cetyl alcohol and stearyl alcohol.

The gas generating agent is one or more selected from the group consisting of sodium hydrogencarbonate, magnesium carbonate, calcium carbonate and the like. The surfactant is selected from one or more of poloxamer, sodium dodecyl sulfate, magnesium decyl sulfate or Tween 80.

The swelling material is selected from one or more of croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, cross-linked polyvinylpyrrolidone, and the like.

The filler is selected from one or more of microcrystalline cellulose, lactose, starch, mannitol, sorbitol, dextrin, etc., preferably microcrystalline cellulose, lactose.

The wetting agent or binder may be one or more selected from the group consisting of water, ethanol, starch slurry, povidone, low viscosity hypromellose or other cellulose solution, and may or may not be needed. selected.

The lubricant is selected from one or more of stearic acid, magnesium stearate, talc, micronized silica gel, starch, paraffin, etc., preferably magnesium stearate, talc.

The coating agent is preferably gastric-soluble Opadry.

The active ingredient and the pharmaceutically acceptable excipient used in the preparation of the irbesartan gastric retention type sustained release pharmaceutical composition of the present invention are composed of the following ratios (weight ratio of the core): irbesartan 1 -90%

Hydrophilic polymer gel material 0-50%

Bleaching agent 0-50%

Gas generating agent 0. 5-50%

Surfactant 0-20%

Intumescent material 0-10%

Filler 0-90%

Adhesive 0-10%

Lubricant 0. 1-10%

Coating agent 0-5%

The preferred ratio of the active ingredient and the pharmaceutically acceptable excipient used in the preparation of the irbesartan gastric retention type sustained release pharmaceutical composition of the present invention (weight ratio of the core) is composed of: Irbesartan 40-80%

Hydrophilic polymer gel material 5-30%

Bleaching agent 0-15%

Gas generating agent 0. 5-20%

Surfactant 0-5%

Expanded material 0-5%

Filler 15-50%

Adhesive 0-5%

Lubricant 0. 1-2%

Coating agent 0-3%

The invention also provides a preparation method of the irbesartan gastric retention type sustained release pharmaceutical composition. Method 1: The original amount and the auxiliary material of the prescription amount are separately sieved, fully mixed, and compressed into tablets. Method 2: Mix the prescription raw materials and auxiliary materials separately, mix them thoroughly, add granules by adding wetting agent or binder, add lubricant or flow aid after drying, mix well, and press into tablets.

Method 3: The prescription raw materials and auxiliary materials are separately sieved, uniformly mixed, and pressed into a tablet core; a coating liquid is prepared; and the obtained core is coated with a coating liquid according to a conventional process. The configuration of the coating liquid can be as follows:

Coating liquid prescription (1000 tablets)

Oubaday 5g

85% ethanol

The appropriate amount refers to the amount of addition required to meet the formulation requirements according to conventional techniques of pharmacy, and can be added according to the requirements of the textbook.

Particularly preferred formulations of the present invention are listed in the examples of the present invention. These most preferred formulations are screened and have a longer gastric retention time, a stable and complete release, and a stable blood concentration compared to the prior art. Small fluctuations.

In order to investigate the in vitro retention performance and release effect of the present invention, we have determined the irbesartan stomach prepared in Example 3 of the present invention according to the first method of the dissolution test method according to the first method of the Chinese Pharmacopoeia 2005 edition two appendix XD. The floating time of the internal retention type sustained release tablets Continued floating time and in vitro release.

Using 1000 ml of 0.1 mol/L hydrochloric acid as the solvent, the rotation speed is 100 rpm, and it is operated according to law. 10 ml of the solution was taken at the specified time point, filtered, and 10 ml of the same solvent at the same temperature was immediately added to the operating container. The results showed that the sustained-release tablets had been bleached within 2 minutes in vitro, and the floating time was more than 12 hours. The results of the release assay are shown in Table 1.

Table 1 The release rate of irbesartan sustained-release tablets prepared according to Example 3

The release profile of the irbesartan gastric retention type sustained release tablet prepared according to Example 3 is shown in Fig.-1.

The results showed that the irbesartan sustained-release tablets had significant release characteristics and was completely released within 12 hours.

In order to further verify the efficacy of irbesartan gastric retention-type sustained-release tablets, 6 healthy beagle dogs were divided into two groups, and the eubesartan sustained release sustained-release was prepared by single dose cross-administration method. Tablets and commercially available irbesartan tablets were each 150 mg. The concentration of irbesartan in plasma at different times after administration was determined by high performance liquid chromatography, and the blood concentration-time curve was plotted. The AUC value was calculated using the trapezoidal method based on the plasma concentration-time data. The results are shown in Table -2.

Table -2 AUC of irbesartan sustained-release tablets T and ordinary tablets R ( ug. h/ml ) cycle AUC cycle AUC

1 1 1. 203 2 1. 097

2 1 0. 607 2 0. 467

3 1 1. 082 2 0. 965

4 2 0. 985 1 1. 103

5 2 0. 742 1 0. 594

6 2 0. 864 1 0. 758 Sum - 5. 483 - 4. 984 Average - 0. 914 - 0. 831 Irbesartan sustained-release sustained-release tablets and reference preparations prepared according to Example 3 The plasma concentration-time curve of the besartan tablet is shown in Figure-2. The results showed that the relative bioavailability of the irbesartan sustained-release tablet prepared according to Example 3 was 11.0% compared with the reference preparation of the irbesartan. It can be seen from the blood drug concentration-time graph that the irbesartan gastric retention type sustained release tablet of the present invention has a stable blood concentration and a small fluctuation compared with the ordinary tablet.

DRAWINGS

Figure -1 Ursaartan sustained-release sustained release tablets

Figure -2 Urbesartan sustained-release tablets and irbesartan tablets blood concentration - time curve

detailed description

The invention is further described in detail below by way of embodiments, without restricting the invention. Example 1

Irbesartan 75g

Hypromellose g

Cetyl alcohol 7g

Calcium carbonate 20g

Microcrystalline cellulose 30g

Lactose 20g

Magnesium stearate 1. 8R

Made into 1000 pieces

Preparation:

Weigh the above-mentioned raw materials and auxiliary materials separately and sieve them thoroughly, then mix them well and press them into tablets.

Example 2

(1) core prescription

Irbesartan 150g Hypromellose 20g

Mixture of cetyl alcohol and stearyl alcohol lOg

Magnesium carbonate 20g

Polosham 2g

Microcrystalline cellulose 40g

Talc powder 2. 5g

Made into 1000 pieces

(2) Prescription of coating liquid (1000 tablets)

Oubaday 5g

85% ethanol

Preparation:

1. Weigh the original and auxiliary materials according to the core prescription, mix them separately after sieved, and press into tablets;

2. Prepare the coating solution: Slowly add Opadry to an appropriate amount of 85% ethanol solution, stir evenly and continue to stir for a few minutes, and set aside;

3. The obtained core is coated with the above coating liquid according to a conventional process.

Example 3

Irbesartan 150g

Hypromellose 20g

Mixture of cetyl alcohol and stearyl alcohol 12g

Calcium carbonate 20g

Microcrystalline cellulose 45g

Povidone 4g

Magnesium stearate 2. 5g

50% ethanol

Made into 1000 pieces

Preparation: Weigh the above-mentioned raw materials and excipients except magnesium stearate, mix them thoroughly, mix them thoroughly, add granules of povidone 50% ethanol solution, add magnesium stearate after drying, mix thoroughly, and compress into tablets. That is.

Example 4

Irbesartan 150g

Hypromellose 12g

Cetyl alcohol 6g

Calcium carbonate 20g

Microcrystalline cellulose 30g

Cross-linked sodium carboxymethyl cellulose 3g

Povidone 3. 5g

Magnesium stearate 2. 5g

50% ethanol

Made into 1000 pieces

Preparation method: Same as Example 3.

Example 5

Irbesartan 300g

Hypromellose 40g

Mixture of cetyl alcohol and stearyl alcohol 20g

Calcium carbonate 40g

Microcrystalline cellulose 90g

Povidone 8g

Magnesium stearate 5g

50% ethanol

Made into 1000 pieces

Preparation method: same as the third embodiment Note: The appropriate amount described in the formulation of the above examples refers to the amount of addition required to meet the formulation requirements according to the conventional pharmacy technique, and may be added according to the requirements of the textbook, generally 0.01% to 30%, preferably 1%, of the total weight. 10% ₀

Claims

Rights request

What is claimed is: 1. An irbesartan gastric retention type sustained release pharmaceutical composition, wherein the weight ratio of each component of the composition is:

Irbesartan 1-90%

Hydrophilic polymer gel material 0-50%

Bleaching agent 0-50%

Gas generating agent 0. 5-50%

Surfactant 0-20%

Intumescent material 0-10%

Filler 0-90%

Adhesive 0-10%

Lubricant 0. 1-10%

Coating agent 0-5%

2. The composition of claim 1 wherein the weight ratio of each component is:

Irbesartan 40-80%

Hydrophilic polymer gel material 5-30%

Bleaching agent 0-15%

Gas generating agent 0. 5-20%

Surfactant 0-5%

Expanded material 0-5%

Filler 15-50%

Adhesive 0-5%

Lubricant 0. 1-2%

Coating agent 0-3%.

3. The composition of claim 1 wherein:

Wherein the hydrophilic polymer gel material is selected from the group consisting of hypromellose, alginate, and chitosan; Wherein the bleaching agent is selected from the group consisting of cetyl alcohol, stearyl alcohol, cetyl alcohol and stearyl alcohol; wherein the gas generating agent is selected from the group consisting of sodium hydrogencarbonate, magnesium carbonate, and calcium carbonate;

Wherein the surfactant is selected from the group consisting of poloxamer, sodium dodecyl sulfate, magnesium lauryl sulfate or Tween 80;

Wherein the swelling material is selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone;

Wherein the filler is selected from the group consisting of microcrystalline cellulose, lactose, starch, mannitol, sorbitol, dextrin;

Wherein the wetting agent or binder is selected from the group consisting of water, ethanol, starch-pulp, povidone, low viscosity hypromellose or other cellulosic solutions;

Wherein the lubricant is selected from the group consisting of stearic acid, magnesium stearate, talc, micronized silica gel, starch, and paraffin;

Wherein the coating agent is selected from the group consisting of gastric-soluble Opadry.

The composition according to claim 1, wherein the hydrophilic polymer gel material has a viscosity of from 4,000 to 10,000 centipoise.

5. The composition of claim 1 wherein the composition is:

Irbesartan 75g

Hypromellose 14g

Cetyl alcohol 7g

Calcium carbonate 20g

Microcrystalline cellulose 30g

Lactose 20g

Magnesium stearate 1. 8g.

6. The composition of claim 1 wherein the composition is - (1) core prescription

Irbesartan 150g

Hypromellose 20g

Mixture of cetyl alcohol and stearyl alcohol 10g

Magnesium carbonate 20g Polosham 2g

Microcrystalline cellulose 40g

Talc powder 2. 5g

(2) Prescription of coating liquid (1000 tablets)

Oubaday 5g

85% ethanol.

The composition according to claim 1, wherein the composition is: irbesartan 150 g

Hypromellose 20g

Mixture of cetyl alcohol and stearyl alcohol 12g

Calcium carbonate 20g

Microcrystalline cellulose 45g

Povidone 4g

Magnesium stearate 2. 5g

50% ethanol

The composition of claim 1 wherein the composition is: irbesartan 150g

Hypromellose 12g

Cetyl alcohol 6g

Calcium carbonate 20g

Microcrystalline cellulose 30g

Cross-linked sodium carboxymethyl cellulose 3g

Povidone 3. 5g

Magnesium stearate 2. 5g

50% ethanol.

The composition according to claim 1, wherein the composition is: irbesartan 300 g

Hypromellose 40g

Mixture of cetyl alcohol and stearyl alcohol 20g Calcium carbonate microcrystalline cellulose povidone magnesium stearate

50% ethanol