CN1285738A - Novel oral dosage form for carvedilol - Google Patents

Abstract

The present invention discloses a matrix formulation containing carvedilol.

Description

New Oral Dosage Form of Carvedilol

field of invention

The present invention relates to a new preparation containing carvedilol or a pharmaceutically acceptable salt thereof and its use in treating and/or preventing certain diseases.

Background of the invention

U.S. Patent 4,503,067 describes a compound known as carvedilol. The compound is a novel drug with multiple activities for the treatment of mild to moderate hypertension. Carvedilol is known to be both a competitive nonselective beta-adrenoceptor antagonist and a vasodilator. When used to treat hypertension, the vasodilator effect of carvedilol is mainly caused by blocking alpha1-adrenergic receptors, while the beta-adrenoceptor blocking activity of the drug prevents reflex tachycardia . This multiple activity of carvedilol is responsible for the drug's antihypertensive efficacy. In addition, due to its antioxidant effect in attenuating lipid peroxidation induced by oxygen free radicals, carvedilol can also be used for organ protection, especially cardioprotection. In addition, carvedilol can also be used to treat congestive heart failure.

The currently used formulation of carvedilol is a conventionally swallowed tablet to be taken twice daily. The formulation is an immediate release dosage form; that is, the formulation is characterized in that when carvedilol leaves the stomach, it is in the form of a solution or a suspension of fine particles, i.e. carvedilol can be rapidly released Absorbed form.

It has now been found that controlled and sustained release formulations containing carvedilol can be administered once daily. These formulations can prolong the duration of action of carvedilol, thereby improving the bioavailability of the drug.

SUMMARY OF THE INVENTION The present invention provides controlled or sustained release formulations comprising carvedilol or a pharmaceutically acceptable salt thereof. Detailed description of the invention

The present invention provides controlled-release or sustained-release preparations containing carvedilol or its pharmaceutically acceptable salts in oral unit dosage forms, carvedilol is (1-(carbazol-4-yloxy) of formula (I) -3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol):

The present invention also provides a matrix formulation containing carvedilol in an oral unit dosage form and an enteric coating preparation containing carvedilol in an oral unit dosage form.

Carvedilol is conveniently prepared as described in U.S. Patent 4,503,067. Reference can be made to said patent in its entirety, the entire disclosure of which is incorporated herein by reference.

According to the formulations of the present invention, carvedilol may be in the form of a free base or a pharmaceutically acceptable salt thereof. Preferably carvedilol is in free base form.

Controlled release refers to any formulation that achieves slow release of drug over a prolonged period of time. In the controlled release formulations of the present invention, a portion of the carvedilol in the formulation may be released as a priming dose and the rest in a sustained manner. An example of a controlled release system is a matrix formulation.

Sustained release refers to any formulation that utilizes repeated, intermittent release of carvedilol from one or more immediate release units incorporated into a single dosage form. Examples of sustained-release systems include repeated-action tablets and capsules, and enteric-coated tablets that are coated with a carrier for timed release.

Examples of controlled release formulations suitable for incorporation of carvedilol are described in:

Sustained Release Medications, Chemical Technology, Review No. 177, edited by J.C. Johnson, Noyes Data Corporation (1980); and

Controlled Drug Delivery, Fundamentals and Applications, 2nd Edition, edited by J.R. Robinson, V.H.L. Lee, Mercel Dekkes Inc., New York (1987).

Examples of sustained release formulations suitable for incorporation of carvedilol are described in:

Remington's Pharmaceutical Sciences, 16th Edition, Ed. A. Osol, Mack Publishing Company (1980).

Examples of other controlled release formulations suitable for incorporation of carvedilol are described in U.S. Patent 4,839,177 (issued June 13, 1989) and U.S. Patent 5,422,123 (issued June 6, 1995) . Matrix-controlled release formulations of carvedilol are described in detail in US Patent 4,389,393 (issued June 21, 1983) and US Patent 4,968,508 (issued November 6, 1990).

In addition, the controlled release formulation containing carvedilol may also be in the form of non-compressed pellets with an enteric coating or a sustained release coating permeable to gastrointestinal fluids. These controlled release formulations can be prepared, for example, as described in U.S. Patent 4,524,060 (issued June 18, 1985) and U.S. Patent 4,983,401 (issued January 8, 1991). Other controlled release formulations are described in US Patent 4,880,830 (issued November 4, 1989) and US Patent 5,068,112 (issued November 26, 1991).

The preferred formulation of the controlled-release formulation is that the release of carvedilol is mainly completed in the process of passing through the stomach and small intestine; the preferred formulation of the controlled-release formulation is to avoid the release of carvedilol in the stomach and allow it to mainly pass through the released in the small intestine.

The preferred formulation of the preparation is that carvedilol is mainly released 1.5-3 hours after digestion.

The small intestine refers to the duodenum, ileum or jejunum.

The formulations of the invention can be administered once daily.

Preferred formulations of carvedilol are enteric coated tablets or caplets, wax or polymer coated tablets or caplets or time release matrix tablets or combinations thereof. The oral route of administration of the formulations of the invention is preferred.

According to the present invention, the controlled release formulation may be a matrix formulation. The formulation may comprise a plurality of carvedilol-containing matrix cores having different drug release rates. A preferred formulation includes an immediate release phase of carvedilol as well as a sustained release phase. The sustained-release matrix cores may be uncoated or coated with a sustained-release substance. When the matrix core is coated with a sustained-release substance, the content of the sustained-release substance is preferably 2-30% (w/w) of the matrix core. More preferably, the sustained-release substance is present in an amount of 5-25% (w/w).

The sustained-release substance of the present invention is a coating agent or a mixture of coating agents, which can prevent carvedilol from being rapidly degraded in the stomach. Depending on the desired release rate, the outer coating can be continuous release, slow release or delayed release. The preferred slow-release substance is enteric coating, that is, it can make the pharmaceutical preparation disintegrate in the intestine without changing when passing through the stomach.

The matrix-removing agents of the present invention can be prepared from three types of materials: insoluble plastics, hydrophilic polymers or fatty compounds. Plastic matrices include acrylate-methacrylate, polyvinyl chloride, and polyethylene. Hydrophilic polymers include methylcellulose, hydroxypropylmethylcellulose (HMPC) and sodium carboxymethylcellulose. Fatty compounds include various waxes such as carnauba wax and glyceryl tristearate. The most common method of preparation is to mix carvedilol with a base material and compress the mixture into tablets. In the case of a wax matrix, carvedilol is gradually dispersed in molten wax which is then solidified, granulated and compressed into tablet cores. In matrix formulations containing carvedilol, the priming dose (the portion of carvedilol in the formulation that can be released immediately) is placed in the coating of the tablet. The coating can be achieved by punch coating or by conventional pan or air suspension coating methods.

In one embodiment of the invention, the carvedilol matrix tablet contains a mixture of HMPC and carbopol. In another embodiment of the present invention, the carvedilol matrix tablet contains a mixture of HMPC, carbopol and mannitol. The flow chart below outlines the process for the manufacture of controlled release tablets containing carvedilol.

According to the present invention, carvedilol, mannitol and HPMC are granulated with purified water, wet sieved and then dried. The dried granules are sieved. The resulting inner granules were mixed with pre-screened Carbomer 941 until homogeneous. The pre-screened magnesium stearate is blended with the blend to obtain a tableting blend. Tablets were compressed into round cores and then coated with ^Opadry® white solution to a weight gain of about 3%, and then coated with ^Opadry® clear solution to a weight gain of about 0.5%.

The invention also provides various combinations of immediate release and controlled release forms. For example, uncoated sustained release matrix cores may be combined with an immediate release form of carvedilol and/or a coated matrix form. The matrix core may contain a number of pellets coated independently of each other with different slow-release substances, all of which may be combined with uncoated or immediate-release forms of carvedilol.

Sustained-release formulations containing carvedilol can be prepared by coating carvedilol-coated granules or granules with slowly dissolving polymers of various thicknesses, or by microencapsulation. In formulations using microencapsulation, a hydrophilic substance is used as a coating material around the microcapsules. The hydrophilic material may be selected from various natural and synthetic polymers including shellac, waxes, starches, cellulose acetate phthalate or butyrate, polyvinylpyrrolidone and polyvinylchloride. When the coating material dissolves, all carvedilol in the microcapsules can be dissolved and absorbed immediately. Therefore, the release of carvedilol can be controlled by adjusting the thickness and dissolution rate of the coating. By varying the amount of coating material within the range of 3-30% by total weight, the thickness can be varied from less than 1 micromolar to 200 micromolar. If only a few different thicknesses (usually three or four) are used, carvedilol will be released at different predetermined times to produce a sustained release effect, ie, repeated action. A more uniform blood level of carvedilol can be obtained if a range of different thicknesses is used. The coated granules can be directly compressed into tablets, or placed in capsules.

Carvedilol in controlled-release or sustained-release formulations is used in the treatment of hypertension, angina pectoris, and congestive heart failure. The formulations of the invention may also be used for organ protection, for example, for cardioprotection.

The present invention provides a method for treating hypertension, angina pectoris and congestive heart failure, the method comprising, administering an effective amount of a controlled-release or sustained-release formulation containing carvedilol or a pharmaceutically acceptable salt thereof to a patient in need of said treatment .

The present invention also provides the use of the controlled-release or sustained-release preparation containing carvedilol or a pharmaceutically acceptable salt thereof in the production of medicines for treating hypertension, angina pectoris and congestive heart failure.

The present invention also provides a pharmaceutical composition for treating hypertension, angina pectoris and congestive heart failure. The composition contains a controlled-release or sustained-release preparation, preferably a matrix preparation, containing carvedilol or a pharmaceutically acceptable salt thereof.

No unacceptable toxicological effects are expected when carvedilol is used in accordance with the present invention.

The following examples are used to illustrate the present invention and are not intended to limit the scope of the present invention. Many other embodiments will be apparent to those skilled in the art.

Example Production Method Description Mixing

step 1. Weigh accurate amounts of carvedilol, mannitol, hypromellose, and purified water.

Step 2. Transfer carvedilol, mannitol, and hypromellose to the product drum of the high shear mixer.

Step 3. Premix ingredients with impeller and chopper on low speed for 2 minutes. granulation

Step 4. Granulate with purified water at low speed until the desired granule appearance is obtained.

Step 5. The pellets were discharged in a stainless steel vessel for wet grinding.

Step 6. The wet granules were slowly added through the Quadro Comil (with screen) into the stainless steel vessel.

Step 7. The milled particles are transferred to a preheated fluid bed product drum.

Step 8. The target inlet temperature was maintained at about 70°C (65°C-75°C) to dry the granules until the product temperature reached the target temperature (40-47°C) and the loss on drying was within the target range (0.5-1.8%).

Step 9. Properly installed Quadro Comil (variable speed) and connected to the sieve for grinding.

Step 10. The dry granules were passed through a Quadro Comil (with screen) into pre-tared polyethylene bags. Unlubricated granulation mix

Step 11. Sieve the excess carbomer 941 (carbomer 971P), and press it through a 20-mesh stainless steel sieve by hand to depolymerize it.

Step 12. Weigh an accurate amount of pre-screened Carbomer 941 (Carbopol 971P) on weighing paper.

Step 13. Weigh out the exact amount of carvedilol granules in appropriately labeled polyethylene bags.

Step 14. Properly fitted V-blender of appropriate size.

Step 15. Transfer 1/3 of the carvedilol granules to the 'V' blender.

Step 16. Add 1/3 of Carbomer 941 (Carbopol 971P) to the 'V' mixer.

Step 17. Repeat steps 15 and 16 until all inner granules and Carbomer 941 (Carbopol 971P) are added to the 'V' mixer.

Step 18. Blend for 30 minutes or until smooth.

Step 19. Samples were removed for in-process testing. Lubricating Granulation Mixing

Step 20. Excess magnesium stearate was sieved (deagglomerated) by hand pressing through a 40 mesh stainless steel screen.

Step 21. Weigh an exact amount of pre-screened magnesium stearate on weighing paper.

Step 22. Magnesium stearate was added to the mixer (with the unlubricated granules) and mixed for 3 minutes. tablet

Step 23. The tableting mixture was transferred to the hopper of the rotary tablet press using a 7/16" x 5/8" round standard tool.

Step 24. Tablets that meet the physical property specifications are compressed.

Step 25. Samples were taken for testing during operation. coating

Step 26. Precise amounts of carvedilol round active cores, ^Opadry_White and ^Opadry_Clear were weighed separately in polyethylene bags. If necessary, the round active cores can be extended with oval placebo cores to achieve the batch size needed to fill the coating pan.

Step 27. To a suitable, tared clean container, add the required amount of purified water to produce a solids concentration of 12% ^Opadry_White .

Step 28. Slowly add ^Opadry_White to purified water with vortex stirring. Continue stirring until no solids are visible. Use this solution within 24 hours of preparation.

Step 29. To a suitable, tared clean container, add the required amount of purified water to produce a solids concentration of 5% ^Opadry_Clear .

Step 30. Slowly add ^Opadry_Clear to purified water with vortex stirring. Continue stirring until no solids are visible. Use this solution within 24 hours of preparation.

Step 31. Properly fitted Accela Coater coating pan. The pump set to deliver the white and clear coating solution was sprayed at a rate of approximately 35 g/min.

Step 32. Transfer cores to coating pan. Preheat the tablet cores: set the inlet temperature at 55°C (40°C-70°C) and shake the coating pan periodically. Start spraying when the temperature of the product reaches about 42°C (37°C-45°C). The entire amount of white coating solution was sprayed to obtain a coating that gave a weight gain of about 3%. The clear coating solution was then sprayed to obtain a coating with a weight gain of about 0.5%.

Step 33. Transfer the coated tablets from the coating pan to a double polyethylene lined cylinder. If placebo cores are used to scale up to the coating batch size, a sort/inspection process will be required after the coating process to separate the oval placebo cores from the round active cores.

Example 1

Table 1: Unit formulations for controlled-release carvedilol formulations Concentration Formula Components summary 50mgBC 50mg BD amount mg/tablet 50mgBE Carvedilol Mannitol Hypromellose Carbomer 934P Magnesium Stearate Opadry White (OY-S-9603) Opadry Clear (YS-1-19025A) Purified Water USPUSPNFNF or PF.Eur.NCNCUSP or PF.Eur. 50.0152.537.57.52.57.51.25 appropriate amount 50.0366.2575.03.755.015.02.5 appropriate amount 50.0360.075.010.05.015.02.5 appropriate amount Total piece weight 258.75 517.5 517.5

Example 2

Table 1: Typical Batch Formulations for Controlled Release Carvedilol Formulations Concentration Formula Components summary 50mgBC 50mg BD amount kg/batch 50mgBE Carvedilol Mannitol Hypromellose Carbomer 934P Magnesium Stearate Opadry White(OY-S-9603)Opadry Clear(YS-1-19025A) NCUSPUSPNFNF or PF.Eur.NCNC 1.364.141.010.200.070.200.03 0.684.961.010.050.070.200.03 0.684.871.010.140.070.200.03

实施例3(立即释放片芯上的pH敏感性包衣)片芯            ％w/w卡维地洛        11.45乳糖            64.05微晶纤维素      20.0淀粉甘醇酸钠    4.0硬脂酸镁        0.5总量            100.0片剂包衣(涂覆片芯重量的约6-10％)    ％w/w羟丙甲基纤维素邻苯二甲酸酯          90.0甘油三乙酸酯                        10.0实施例4(立即释放片芯上的pH敏感性包衣)

Example 3 (pH Sensitive Coating on Immediate Release Core) Tablet Core % w/w Carvedilol 11.45 Lactose 64.05 Microcrystalline Cellulose 20.0 Sodium Starch Glycolate 4.0 Magnesium Stearate 0.5 Total 100.0 Tablets Coating (approximately 6-10% by weight of coated core) % w/w hypromellose phthalate 90.0 triacetin 10.0 Example 4 (pH sensitive on immediate release core) sexual coating)

Tablet core is the same as embodiment 3 tablet coating (approximately 6-10% of coating tablet core weight) %w/w

Cellulose acetate phthalate 90.0

Diethyl phthalate 10.0 Example 5 (Controlled release coating on immediate release tablet core)

Tablet core is the same as embodiment 3 tablet coating (approximately 5-12% of coating tablet core weight) %w/w

Eudragit RS 100 86.0

Dibutyl phthalate 10.0

Talc 4.0

FD&C Yellow No. 6 0.01 Example 6 (pH Sensitive Coating on Controlled Release Tablet Cores)

Tablet core is the same as embodiment 3

Tablet coating is the same as Example 3 Example 7 (encapsulated controlled release coated beads) pellets %w/w (approximately)

Non Pareil Seed 30

Carvedilol 40

Gelatin 8

Lactose 20

Talc 2 Coating % w/w Glyceryl Monostearate 36.6 Glyceryl Distearate 53.4 White Wax 10.0

The above is the description of the present invention. However, the invention is not intended to be limited to the particular embodiments described herein, but it is intended to cover all modifications within the scope of the appended claims.

Various journals, patents, and other publications cited herein contain prior art content and are hereby incorporated by reference in their entirety.

Claims (8)

1. A matrix formulation for oral dosage unit form containing carvedilol. 2. The formulation of claim 1, which contains a hydrophilic polymer. 3. The formulation of claim 2, wherein the hydrophilic polymer is hydroxypropylmethylcellulose (HMPC). 4. The formulation of claim 1, which contains a mixture of HMPC and carbopol. 5. The formulation of claim 1, which contains a mixture of HMPC, carbopol and mannitol. 6. An enteric-coated formulation containing carvedilol in oral dosage unit form. 7. A method of treating hypertension, angina pectoris or congestive heart failure comprising administering carvedilol in a matrix formulation. 8. A method of treating hypertension, angina pectoris or congestive heart failure comprising administering carvedilol in an enteric coated formulation.