WO2005030201A1 - Sustained release preparation containing hydrochlorothiazide - Google Patents

Abstract

The invention relates to a sustained release preparation for the treatment of hypertension, congestive cardiac failure and angina pectoris, in which contains hydrochlorothiazide, and carvedilol in free base form, or atenolol or a pharmaceutically acceptable salt thereof.

Description

 FIELD OF THE INVENTION The present invention relates to a free base containing dihydrochlorothiazide and carvedilol or atenolol or atenolol or a pharmaceutically acceptable salt thereof. Compound slow-release formula, especially the dissolution method of compound slow-release formula containing dihydrochlorothiazide and carvedilol free base or atenolol or a pharmaceutically acceptable salt thereof, so it is more convenient to take, has low side effects, and Has better tolerance and patient compliance.

 technical background:

U.S. Patent No. 4,503,067 discloses carvedilol common tablet formulations. Carvedilol (trade name Core _g ), which is currently sold in the United States, is a commonly used oral tablet, and the dosage is twice a day. C ₀ reg is currently the only approved light can be used to reduce moderate to severe heart failure patients at risk of death β- blockers. It is also approved for treating patients with hypertension accompanied by diabetes and high cholesterol. Core is also the only beta-blocker currently approved to reduce the risk of death in patients who have had a recent heart attack and who have low heart function, whether or not they have symptoms of heart failure. 0) 1 "^ includes 4.125mg, 6.25mg, 12.5mg and 25mg four dose tablets.

 Carvedilol can be quickly and widely absorbed through the oral route, and its bioavailability is approximately 25-35% due to first-pass metabolism. The oral half-life of carvedilol is usually 7 to 10 hours.

 Patent W099 / 24017 discloses a controlled release (sustained release) matrix tablet of carvedilol. The preparation consists of two parts, one is the immediate release part in the coating film, and the other is the controlled or sustained release part in the tablet core. This matrix tablet contains excipients such as hydroxypropyl methylcellulose (HPMC), Kappabo, and mannitol. Sodium carboxymethyl starch This disintegrant is commonly used in the formulation of immediate release formulations or pH-dependent coating formulations. Disintegrants allow tablets to accelerate drug release through disintegration. And too fast release of the drug may have side effects. Tablets are usually prepared with a coating method (pH-dependent or slow-release coating film), but once a coating problem occurs, such a operation cannot make a complete tablet. Specific viscosity is usually not described in detail in the description of hydrophilic polymers such as HPMC. HPMC with different viscosities will release the drug in an immediate or slow release manner. The present invention does not specifically describe data on the release rate of carvedilol matrix tablets in vitro or in vivo pharmacokinetics.

U.S. Patent Nos. 4,389,393 and 4,968,508 also disclose the invention of Carvedilol controlled release or sustained release matrix tablets. Other related Carvedilol controlled-release or sustained-release formulations in U.S. patents Nos. 4524060, 4943401, 4880830 and 5068112 are introduced. However, these formulations are not suitable for making daily doses.

 Atenolol is a synthetic selective beta ΐ (cardioselective) adrenergic blocker. Atenolol has a molecular weight of 266, a solubility of 26.5mg ml at 37 ° C, a partition coefficient of 0.23 (octanol / 7jO, easily soluble in 1N HCL (25 ° C, 300mg / ml), and chloroform (25 ° C, 3 mg / mO slightly soluble.

 TENORMIN is the trade name of atenolol. The drug is available in 25 mg, 50 mg and 100 mg oral tablets.

 In the human body, atenolol's oral tablets are rapidly absorbed, and approximately 50% of the oral dose is absorbed, and the remaining original drug is excreted in the feces. After 2 to 4 hours of administration, the plasma drug concentration reached a peak. The half-life of oral TENORMIN is approximately 6-7 hours. Slow administration can maintain the same pharmacokinetic profile of 50 mg and 100 mg oral tablets—both blocking and hypotensive effects are maintained for at least 24 hours.

 TENORMIN can be taken alone or daily with a diuretic. TENORJiHN can effectively control blood pressure. It can be used alone or in combination with other antihypertensive drugs, especially thiazide diuretics. TENORMIN has a long-term effect on patients with angina pectoris and also has an effect on acute myocardial infarction.

Dihydrochlorothiazide is a thiazide (diuretic) that is taken once a day. It has been reported using both β-blockers and thiazides treatment of hypertension, congestive heart failure and angina has a good effect (McTavish et al, 1993, Drugs45 (2):. 232-258) 0 but The compound formula has not been greatly improved in dosage form. In the experimental study, it was only just to mix two single-drug tablets for patients to take. US Patent No. 6403579 has disclosed a synthesis and production process of carvedilol and dichlorochlorothiazide compound preparations. This patent describes a compound immediate release formulation of carvedilol and dihydrochlorothiazide.

 A variety of evidence has demonstrated the advantages of using a sustained release dosage form. One of the goals in developing sustained-release preparations is to increase patient compliance and reduce the incidence of side effects. It is reported that other beta-blockers are made into sustained-release oral solid dosage forms, and their multiparticulate structure can increase bioavailability and maintain the effective concentration of the drug in the blood for at least 24 hours. For example, Toprol—XL ~~ Metoprolol Succinate Sustained Release Tablets and Inderal LA——Pronolol Hydrochloride Sustained Release Tablets.

The present invention relates to a compound sustained-release preparation of carvedilol free base, a main component of dihydrochlorothiazide and CoregTt, or atenolol or a pharmaceutically acceptable salt thereof. Summary of the invention:

 The novelty of the present invention is to propose a compound sustained-release formulation containing dihydrochlorothiazide and carvedilol free base or atenolol or a pharmaceutically acceptable salt thereof.

 The purpose of the present invention is to greatly improve the therapeutic effect of treating hypertension, congestive heart failure and angina pectoris with low side effects.

 The invention also proposes a specific formula, namely a compound slow-release formula containing dihydrochlorothiazide and carvedilol free base or atenolol or its pharmaceutically acceptable salts, which can effectively improve the treatment of hypertension and congestive heart failure And the efficacy of angina pectoris.

 The object of the present invention is also to propose a new administration method and dosage form of carvedilol base or atenolol, so as to significantly improve the clinical efficacy of daily dosage of hypertension, congestive heart failure and angina pectoris. .

 detailed description:

 The present invention aims to prepare dihydrochlorothiazide and carvedilol base or atenolol or atenolol as a compound sustained-release preparation.

 The compound sustained-release solid dosage form of dihydrochlorothiazide and carvedilol or atenolol or atenolol medicinal salts according to the present invention can be operated according to conventional procedures, including granulation, mixing, ebullating bed, Granulation, tableting, dry granulation, crushing, packaging into capsules and coating.

 The compound sustained-release preparations of dihydrochlorothiazide and carvedilol or atenolol or atenolol medicinal salts according to the present invention include two dosage forms of tablets and capsules.

 The matrix sustained-release tablets of the present invention can be made of two materials: (1) polymers of all hydrophilic cellulose derivatives, and / or (2) various aliphatic compounds such as various waxes (such as Brazil Palm wax), glyceryl tristearate, etc.

 The capsule dosage form of the present invention can be made by techniques such as granulation, spray granulation, polymer coating and the like.

 Compound sustained-release preparations of dihydrochlorothiazide and carvedilol or atenolol or atenolol medicinal salts can be enteric-coated (enteric polymer) drug particles, granules, pellets, or tablets Method made. These enteric polymers are acid-resistant but easily soluble in solvents with a basic pH, such as hypromellose phthalate, cellulose acetate monophthalate or cellulose butyrate monoacetate, and polyvinyl acetate phthalate Formate, acrylic polymer Eudragit L and Eudragit S. The coated granules can be filled into capsules or compressed into tablets.

The invention particularly proposes a compound drug release library containing dihydrochlorothiazide and carvedilol or atenolol. Although the formulation of the dosage form is compatible with various other drugs or active ingredients such as various soluble, slightly soluble and difficult Soluble ingredients are also effective when mixed together. The present invention is not limited to these identified components, and / or the drug substance or other active ingredients that can be released under certain conditions.

 The ideal dosage forms in tablets and capsules, that is, the sustained-release dosage forms according to the present invention include (1) immediate-release dosage forms containing 0% -50% of dihydrochlorothiazide and carvedilol or atenolol ( 2) The sustained release dosage form contains the remaining ingredients of the drug.

 The ideal dosage form in tablets and capsules is the carvedilol sustained-release dosage form of the present invention, which does not release more than 50% in the first hour, 30% -90% in the first 8 hours, and release in the first 16 hours. The total amount will not be less than 80%.

 Example 1 Matrix tablets

 Ingredients

1 carvedilol or atenolol 25.0 mg

2 dihydrochlorothiazide 25.0mg

3 hydroxypropyl methylcellulose (HPMC) 50.0 mg

4 Microcrystalline cellulose 113.0 mg

5 Polymicroketone K-30 8.0 mg

6 colloidal silica 2.0 mg

7 Magnesium stearate 2.0 mg Total 225.0 mg Put the appropriate amount of the above components 1-5 in a high-efficiency shear mixer granulator or planetary mixer granulator, and then mix with water or other suitable liquid. Granules and dried in a drying cabinet. After drying the granules, add the additional components 6 and 7 to it. 0iiig 的 片。 The lubricated granules were made into a tablet with a tablet weight of 225. 0iiig. The above steps are performed according to the traditional tablet manufacturing process. Such tablets can also be made into coated tablets. Example 2 PH-coated pellets

 Component content

1 carvedilol or atenolol 25.0 mg

2 Dihydrochlorothiazide 12.5mg

3 sucrose pellets (60-40 mesh) 50.0 mg

4 Polymicroketone K-30 25.0 mg

5 Eudragit L30D 20.0 mg

6 PEG-fine 3.0 mg 1.1 · 135.5 mg Dissolve appropriate amounts of carvedilol and polymicroketone K-30 in water or organic solvents. Fill the ebullated bed dryer with an appropriate amount of sucrose pellet core. The drug substance solution or suspension is slowly sprayed on the surface of the sucrose pellet core and dried. After spraying is complete, the particles are sieved. The sieved drug-containing granules are then filled into an ebullating bed dryer, coated with acrylic resin, coated with acrylic resin, or coated with plasticizer. The granules can be mixed with other ingredients into tablets or directly capsule. The above steps are performed according to the traditional tablet manufacturing process. ■ Example 3 Insoluble polymer-coated pellets

 Such pellets can be prepared by the method described in Example 2 and coated with an ethyl cellulose solution. The ethylcellulose solution formulation is detailed in the table below. The coated pellets are mixed with other ingredients and used for tabletting or direct filling into capsules.

 Component content

1 ethyl cellulose lOcps 65.0 g

2 Hydroxypropylmethylcellulose (HPMC) 15.0 g

3 Acetyl tributyl citrate 9.0 g

4 Dichloromethane 1500g

/ OAV Tosssooi / D /: d000S0¾I> S8

+ 56ι6ε · β-

Claims

Claim 1. Compound slow-release formulations containing dihydrochlorothiazide and carvedilol free base or atenolol or its pharmaceutically acceptable salts, which release no more than 50% of the dose within one hour after daily administration. The dose released in 8 hours is between 30% and 90%, and the dose released in the first 16 hours is not less than 80%. 1 至 15 之间。 The weight ratio of dihydrochlorothiazide and carvedilol free base or atenolol is between 0.1 to 15.  2. A compound sustained-release tablet containing dihydrochlorothiazide and carvedilol free base or atenolol or a pharmaceutically acceptable salt thereof according to claim 1, wherein the tablet is The dose released in one hour does not exceed 50%, the dose released in the first 8 hours is between 30% and 90%, and the dose released in the first 16 hours is not less than 80%.  3. The tablet according to claim 2, using at least one hydrophilic polymer, such as hydroxypropylmethyl fiber, hydroxypropylethyl fiber, hydroxypropyl fiber, hydroxyethyl fiber, methyl fiber, Xanthan gum, alginate, polyethylene oxide, carboxyvinyl polymer or a carboxymethyl cellulose salt. The gel polymer is dissolved in an aqueous solution at a ratio of 2% by mass at 25 ° 0, and is measured with a Brookfield LV viscometer. The ideal viscosity range is between 60 and 15,000 centipoise. The ideal viscosity of HPMC is about 100-120,000 centipoise, the ideal viscosity of HPC is about 100-1,500,000 centipoise, and the ideal viscosity of HEC is about 100-1,300,000 centipoise. Available PE0 molecular weights between 200 and 7,000.  4. The tablet according to claim 2, comprising at least any one of waxes of aliphatic compounds, such as palm wax and glyceryl tristearate.  The tablet according to claim 2, comprising at least one artificially insoluble polymer such as acrylic resin (Eudragit®) or a modified natural polymer such as ethyl acrylic acid.  6. The tablet according to claim 2, comprising at least one pellet, and the drug-containing pellet may be coated or uncoated.  The drug-containing granule according to claim 6, which is coated with an enteric polymer and / or a polymer which is poorly soluble in water.  The sustained-release capsule according to claim 1, containing dihydrochlorothiazide and carvedilol free base or atenolol, once a day, the drug release amount does not exceed 50% within the i hour, after taking the medicine The first 8 hours of drug release was 30% -90%, and the first 16 hours did not exceed 80%. 9. The capsule according to claim 8, comprising at least one coated or uncoated active pellet. The coating of active pellets according to claim 8, which is made of an enteric polymer and / or a polymer which is poorly soluble in water.  The compound sustained-release formulation (tablet or capsule) according to claim 1, containing one or more release rates of dichlorochlorothiazide and carvedilol or atenolol or atenolol salt. Immediate and sustained release ingredients are included in dosage forms containing multiple release rates. The immediate-release ingredients contain at least one retarder, such as the hydrophilic polymers, waxes, and water-insoluble polymers mentioned earlier. The amount of retarder is between 0.5% to 30% by weight.  12. The compound sustained-release formulation (tablets and capsules) according to claim 1, containing one or more release rates of dichlorochlorothiazide and carvedilol or atenolol or atenolol salt. The slow-release component contains at least one aliphatic wax, such as palm wax and glyceryl tristearate, and the amount is between 0.51% and 30% by weight.  13. A compound sustained-release tablet containing dihydrochlorothiazide and carvedilol free base or atenolol or a pharmaceutically acceptable salt thereof according to claim 1, under the same daily dosage conditions, The minimum plasma concentration and the area under the plasma concentration-time curve of the two controlled-release and immediate-release dosage forms are equal.  14. A compound sustained-release tablet containing dihydrochlorothiazide and carvedilol free base or atenolol or a pharmaceutically acceptable salt thereof according to claim 1, under the same daily dosage conditions, The maximum plasma concentration of a controlled release dosage form is lower than the maximum plasma concentration of an immediate release dosage form that is taken twice daily.  15. A compound sustained-release tablet containing dihydrochlorothiazide and carvedilol free base or atenolol or a pharmaceutically acceptable salt thereof according to claim 1, the maximum plasma concentration of which is immediate and sustained release The time ratio is between 1: 3-1: 6.  16. A compound sustained-release tablet containing dihydrochlorothiazide and carvedilol free base or atenolol or a pharmaceutically acceptable salt thereof according to claim 1, under the same daily dosage conditions, The controlled release dosage form has the same effect as the immediate release dosage form.  17. A compound sustained-release tablet containing dihydrochlorothiazide and carvedilol free base or atenolol or a pharmaceutically acceptable salt thereof according to claim 1, under the same daily dosage condition, The safety and tolerability of the controlled release dosage form is equal to or better than the immediate release dosage form.  18. A compound slow-release tablet containing dihydrochlorothiazide and carvedilol free base or atenolol or a pharmaceutically acceptable salt thereof according to claim 1, which is used for treating hypertension , Congestive heart failure and angina.  19. The range of weight ratio of dichlorochlorothiazide and carvedilol or atenolol according to claim 1 is from 0.1 to 15.