MXPA00004573A - Novel oral dosage form for carvedilol - Google Patents

Abstract

The present invention discloses a matrix formulation containing carvedilol.

Description

ORAL DOSAGE FORM NOVEDOSA FOR CARVEDILOL FIELD OF THE INVENTION. g / 5 The present invention relates to a novel formulation containing carvedilol, or a pharmaceutically acceptable salt thereof, and to its use in the treatment and / or prophylaxis of certain disorders.

BACKGROUND OF THE INVENTION 10 The patent of E.U.A. No. 4,503,067 describes a compound which is known as carvedilol. This compound is a novel multi-action drug useful in the treatment of mild to moderate hypertension. It is known that carvedilol is both an antagonist of the β-adrenoceptor not competitive selective as a vasodilator. The vasodilatory actions of carvedilol are mainly derived from the blocking of the on-adrenoceptor, while the blocking activity of the β-adrenoceptor of the drug prevents reflex tachycardia when used in the treatment of hypertension. These multiple actions of carvedilol are responsible for the efficacy antihypertensive drug. Likewise, carvedilol, as a consequence of its antioxidant action by attenuating lipid peroxidation initiated by free oxygen radicals, is useful in the protection of organs, in particular, cardioprotection. In addition, carvedilol is useful in the treatment of congestive heart failure. The present formulation of carvedilol is an ingestible tablet Conventional Q, taken twice a day. This formulation is in the form of immediate release; that is to say that the nature of the formulation is such that when carvedilol leaves the stomach, it is either in solution or in the form of a suspension of fine particles, that is, a form from which carvedilol can be easily absorbed. It has now been found that formulations of controlled release and delayed release containing carvedilol give rise to a formulation once a day. These formulations can extend the duration of action of carvedilol, thus improving the bioavailability of this drug.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a controlled release or delayed release formulation containing carvedilol or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE FIGURE Fig. 1 is a flow chart summarizing the manufacturing procedure * for the preparation of controlled release tablets which contain carvedilol.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a controlled release or delayed release formulation comprising carvedilol, which is (1- (carb "azol-4-yloxy-3 - [[2- (o-methoxyphenoxy) -ethyl] amino] -2- propanol), of the formula or a pharmaceutically acceptable salt thereof, in an oral dosage unit form: The present invention also provides a matrix formulation comprising carvedilol in an oral dose unit form and an enteric layer formulation comprising carvedilol in a unit dosage form. oral dose Carvedilol can be prepared conveniently as described in the US patent. No. 4,503,067. Reference should be made to said patent for its full description, which is incorporated herein by reference. In accordance with the formulation of the present invention, carvedilol is suitably in the form of a free base or a pharmaceutically acceptable salt thereof. Preferably, carvedilol is in the form of a free base. By controlled release is meant any formulation that manages to slowly release the medication in an extended period. In the controlled release formulations of the present invention, a portion of the carvedilol in the formulation is available as an initial dose and the remainder is released from a sustained dosage. An example of a controlled release system is a matrix formulation. Delayed release means any formulation that uses repeated doses, carvedilol intermittent of one or more immediate release units incorporated in a single dose form. Examples of delayed-release systems include tablets and capsules of repeated action, and tablets with enteric coating wherein release over time is achieved by a barrier coating. Examples of controlled release formulations that are suitable for incorporating carvedilol are described in: Sustained Relase Medications, Chemical Technol Revision No. 177, Ed. J. O Johnson, Noyes Data Corporation (1980); Y Controlled Drug Delivery, Fundamentáis and Applications, 2a. Edition, Eds. J. R. Robinson, V.H.L. Lee, Mercel Dekkes Inc., New York (1987). Examples of delayed release formulations that are suitable for incorporating carvedilol are described in: Remington's Pharmaceutical Sciences, 16th Edition, Ed. A. Osol, Mack Publishing Company (1980). Other examples of controlled release formulations that are suitable for incorporating carvedilol are described in the U.S.A. No. 4,839,177, issued June 13, 1989, and the US patent.

No. 5,422,123, issued June 6, 1995. The formulations of • *. ^ "- 's controlled release of matrix for carvedilol are detailed in the patent of E.U.A. No. 4,389,393, issued June 21, 1983, and the US patent.

No. 4,968,508, issued November 6, 1990. In addition, the controlled release formulations containing carvedilol may be in the form of an uncompressed pellet, with an enteric layer or a sustained release layer permeable to gastrointestinal juices. These controlled release formulations are prepared, for example, as described in U.S. Pat. No. 4,524,060, issued June 18, 1985, and the US patent. No. 4,983,401, issued January 8, 1991. Other controlled release formulations are described in the US patent. No. 4,880,830, issued November 14, 1989, and the patent of E.U.A. No. 5,068,112, issued November 26, 1991. Said controlled release formulations are preferably formulated in such a way that the release of carvedilol is affected. predominantly during the passage through the stomach and the small intestine, and the delayed-release formulations are preferably formulated in such a way as to prevent the release of carvedilol in the stomach and it is predominantly affected during the passage through the small intestine . (10) Such formulations are preferably formulated in such a way that "... the release of carvedilol is predominantly 1 1/2 to 3 hours after ingestion. ideally the duodenum, the ileum or the jejunum 15 The formulations of the present invention allow once-a-day dosages The preferred formulations for carvedilol are tablets or tablets with enteric coating, tablets or tablets with a wax or polymer coating. release matrices over time, or combinations of the same Oral route of administration of the formulation of the present invention is preferred In accordance with the present invention, the controlled release formulation can be a matrix formulation. it can comprise a plurality of matrix cores containing carvedilol, said matrix cores having different release rates of the drug. omprende a phase of ^ immediate release of carvedilol, as well as a sustained release phase.

The sustained release phase matrix core may or may not have a layer of a substance that delays the release. Preferably, when the matrix core is coated with a substance that retards the release, said substance is present in an amount of 2 to 30% (w / w) relative to the matrix core. Most preferably, the substance that retards the release / 10 is present in an amount of 5 to 25% (w / w). The substance that delays the release of the present invention is a coating agent or a mixture of agents thereof, which protects carvedilol from immediate degradation in the stomach. The top coating, depending on the desired release rate, can allow a continuous release, or slow release, or delayed release. A substance that retards the preferred release is the enteric layer, that is, a medicinal preparation treated to pass through the stomach without being altered, which disintegrates in the intestines. The matrix formulations of the present invention can be prepare using three types of materials: insoluble plastics, hydrophilic polymers or fatty compounds. Plastic matrices include methyl acrylate-methacrylate, polyvinyl chloride and polyethylene. Hydrophilic polymers include methylcellulose, hydroxypropylmethylcellulose (HMPC) and sodium carboxymethylcellulose. The fatty compounds include various waxes such as carnauba wax and glyceryl tristearate. The most common preparation method is to mix the carvedilol with the matrix material and then ^ jjjfc compress the mixture to form tablets. In the case of wax matrices, Generally, carvedilol is dispersed in molten wax, which is then frozen, granulated and compressed to form nuclei. In the matrix formulation containing carvedilol, the initial dose (the portion of carvedilol that is immediately available in the formulation) is placed in a layer of the tablet. The layer can be applied by pressing coating or by conventional tray coating or air suspension. "In one embodiment of the invention, the carvedilol matrix tablet formulation comprises a mixture of HMPC and Carbopol In another embodiment of the invention, the carvedilol matrix tablet formulation comprises a mixture of HMPC, Carbopol and mannitol, Figure 1 summarizes the manufacturing process for the preparation of controlled release tablets containing carvedilol. In accordance with the present invention, carvedilol, mannitol, and HPMC are granulated with purified water, sieved wet, and then dried. The dried granules are sieved. The internal granulated material The resulting mixture is mixed with Carbomer 941 pretreated until homogeneous. The pre-tainted magnesium stearate is incorporated into the mixture to create the compression mixture. The tablets are compressed as round cores and coated at a weight gain of approximately 3% with an Opadry® white solution, followed by a weight gain of approximately 0.5% with a clear Opadry® solution. The present invention also provides various combinations of immediate release and controlled release forms. For example, the uncoated sustained release matrix core may be in combination with an immediate release form of carvedilol and / or a coated matrix form. The matrix core may comprise many independently coated pellets with different retarding substances, all of which may be combined with immediate release forms not coated with carvedilol. Delayed release formulations containing carvedilol can be prepared either by coating particles or granules of carvedilol with various thicknesses of slowly soluble polymers, or by microencapsulation. In formulations employing microencapsulation, a hydrophilic substance acts as the coating material around a microcapsule. The hydrophilic substance can be selected from a variety of natural and synthetic polymers including lacquers, waxes, starches, phthalate 0 cellulose acetate butyrate, polyvinylpyrrolidone and polyvinyl chloride. Once the coating material dissolves, all the carvedilol in the microcapsule is immediately available for dissolution and absorption. Therefore, the release of carvedilol can be controlled by adjusting the thickness and dissolution rate of the coating. The thickness can vary from less than 1 micromolar to 200 micromolar changing the amount of coating material from 3 to 30% of the total weight. If only a few different thicknesses are used, usually 3 or 4, the carvedilol will be released at different predetermined times to provide a delayed release effect, i.e., repeated action. If a spectrum of different thicknesses is used, can get a more uniform blood level of carvedilol. The coated particles can be compressed directly to form a tablet, or they can be placed in capsules. Carvedilol in the form of a controlled release or delayed release formulation can be used to treat hypertension, angina and congestive heart failure. The formulations of the present invention can also be used in the protection of organs, for example, in cardioprotection. The present invention provides a method for treating hypertension, angina and congestive heart failure by administering a The effective amount of a controlled release or delayed release formulation containing carvedilol or a pharmaceutically acceptable salt of the _ same, to a person suffering from any of the aforementioned diseases and who needs such treatment. Also, the present invention provides the use of a A controlled release or delayed release formulation containing carvedilol or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating hypertension, angina and congestive heart failure.

The present invention also provides a pharmaceutical composition for use in the treatment of hypertension, angina and congestive heart failure comprising a formulation of ? controlled release or delayed release, preferably a formulation of matrix, which contains carvedilol or a pharmaceutically acceptable salt thereof. Unacceptable toxicological effects are not expected when carvedilol is used in accordance with the present invention. The following examples do not attempt to limit the scope of this invention, but are provided to illustrate the same. Many other modalities will be readily apparent to those skilled in the art.

EXAMPLES Description of the manufacturing process _ Mixing Step 1 Exact amounts of carvedilol, mannitol, hydroxypropylmethylcellulose, and purified water are weighed. 20 Step 2. Carvedilol, mannitol and hydroxypropylmethylcellulose are transferred to a mixing bowl of high shear stress. Step 3. Pre-mix the ingredients for 2 minutes with the propeller and blade at a low speed setting.

Granulation Step 4. Granulate with purified water at low speed until the appearance of desired granules is achieved. Step 5. The granulated material is discharged in a stainless steel container for the wet grinding process. Step 6. The wet granules are slowly added through the Quadro Cornil (with sieve) in a stainless steel container. Step 7. Transfer the ground granulated material to the bowl / 10 of preheated fluid bed. Step 8.-Dry the granules maintaining the target inlet temperature V of about 70 ° C (65 ° C-75 ° C) until the temperature of the product reaches the target temperature (40-47 ° C) and the loss during the drying is within the target range (0.5-15%). Step 9. The Quadro Cornil (variable speed) is mounted and the sieve for grinding is attached. Step 10. Dry granules are added through the Quadro Cornil (with sieve) in pre-cut polyethylene bags.

Mixture of unlubricated granulated material Step 11. Sift an excessive amount of Carbomer 941 (Carbopol 971 P) to disintegrate by passing through a # 20 mesh stainless steel screen by hand. Step 12. The exact amount of Carbomer 941 is weighed (Carbopol 971 P) pre-adjusted on the weighted paper. Step 13. The exact amount of internal carvedilol granulate material is weighed in appropriately labeled polyethylene bags. Step 14. A V-mixer of adequate size is assembled. Step 15. - One third of the internal granulated material of carvedilol is transferred to the "V" mixer. Step 16. One third of Carbomer 941 (Carbopol 971 P) is added to the mixer 'V. Step 17. Repeat steps 15 through 16 until all internal granulated material and Carbomer 941 (Carbopol 971 P) are in mixer "V". Step 18. Mix for 30 minutes or until homogeneous. Step 19. Samples are removed for testing in the procedure.

Mixture of lubricated granulated material Step 20. Sift an excessive amount of magnesium stearate (to disaggregate) by passing through a # 40 mesh stainless steel screen by hand. Step 21. The exact amount of magnesium stearate pre-ground on the weighted paper is weighed. Step 22. Magnesium stearate is charged into the mixer (containing the non-lubricated granulated material) and mixed for 3 minutes.

* Compression - Step 23. Transfer the compression mixture to the hopper of a rotary tablet press using standard round tools of 1.11 cm x 1.58 cm. 15 Step 24. Compress the tablets to meet the physical properties objectives. Step 25. Samples are removed for testing in the procedure throughout the operation.

Coating Step 26. The exact amount of round active cores of carvedilol, Opadry® White and Transparent Opadry® is weighed separately in polyethylene bags. If necessary, round active cores can be augmented using oval placebo cores to achieve the batch size needed to fill the liner tray. Step 27. The required amount of purified water is transferred to a tared, clean, and suitable container to produce a concentration of solid materials at 12% Opadry® White. Step 28. With a vortex mixing action, Opadry® White is slowly added to the purified water. Continue mixing until there are no visible solid components. This solution is used within 24 hours after its manufacture. Step 29. Transfer to a tared, clean, and suitable container the amount of purified water required to produce a 5% solids concentration of Transparent Opadry®. Step 30. With a vortex mixing action, the Transparent Opadry® is slowly added to the purified water. Continue mixing until there are no visible solid components. This solution is used within 24 hours after its manufacture. Step 31. The Accela Coater tray is mounted The pump is mounted to provide the clear and white coating solution for spraying at a rate of approximately 35 g / minute. Step 32. Transfer the cores to the coating tray. The cores are preheated: the inlet temperature is adjusted to 55 ° C (40 ° C -70 ° C) while shaking the pan periodically.

When the temperature of the product reaches approximately 42 ° C (37 ° C - 45 ° C) begins to spray. The entire amount of the white coating solution is sprayed to obtain approximately a 3% weight gain coating. It continues with the coating solution ^ transparent to obtain approximately a gain coating of weight of 0.5%. Step 33. The coated tablets are removed from the coating tray and placed in a double polyethylene lined cylinder. If placebo cores were used to increase the size of the coating batch, a sorting / inspection procedure is carried out after the coating operation is completed, in order to separate the nuclei from "... place". or ovals of round active nuclei. rp EXAMPLE 1 TABLE 1 (Unit formulations for controlled release carvedilol formulations) Concentration 50 mg 50 mg 50 mg Formula BD BD BE Component Compendium Amount mg / tablet Carvedilol 50.0 50.0 50.0 Manitol USP 152.5 366.25 360.0 Hydroxypropylmethyl- USP 37.5 75.0 75.0 Cellulose. ,, Carbomer 934P '' and 'NF 7.5 3.75 10.0 NF stearate or Ph. Eur. 2.5 5.0 5.0 Magnesium White Opadry (OY-NC 7.5 15.0 15.0 S-9603) Transparent Opadry NC 1.25 2.5 2.5 (YS-1-19025A) Purified water USP or Ph.Eur. is. is. is.

Total weight of the 258.75 517.5 517.5 tablet EXAMPLE 2 TABLE 2 Typical batch formulations for controlled release carvedilol formulations i 10 fifteen EXAMPLE 3 (pH sensitive coating in immediate release core) Tablet core% p / p Carvediol 11.45 Lactose 64.05 Microcrystalline cellulose 20.0 Sodium starch glycolate 4.0 Magnesium stearate 0.5 TOTAL 100.0 Tablet coating (apply approximately 6-10% of tablet core weight)% w / w Hydroxypropylmethylcellulose phthalate 90.0 Triacetin 10.0 EXAMPLE 4 V (pH sensitive coating in immediate release core) Tablet core as in example 3 Tablet coating (apply approximately 6-10% of the weight of tablet core)% w / w Cellulose acetate phthalate 90.0 Diethyl phthalate 10.0 EXAMPLE 5 (Controlled release coating in immediate release core) ^^ Tablet core as in example 3 Tablet coating (apply approximately 5-12% of tablet core weight)% w / w Eudragit RS IOO 86.0 Dibutyl Phthalate 10.0 Talcum 4.0 FD &C Yellow No.6 0.01 C 10 EXAMPLE 6 (pH sensitive coating in controlled release core) Tablet core as in example 3 15 Tablet coating as in example 3 EXAMPLE 7 (Encapsulated controlled release coated granules) Pella% w / w (approx.) Granules 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 foregoing illustrates this invention. However, this invention is not limited to the precise embodiments described herein, but includes all modifications within the scope of the following claims. The various references to journals, patents and other publications referred to herein comprise the most advanced and are incorporated herein by reference as if they were set forth in their entirety.

Claims (8)

NOVELTY OF THE INVENTION CLAIMS

1. - A matrix formulation comprising carvedilol in a unit dose oral form.,

2. The formulation according to claim 1 comprising a hydrophilic polymer.

3. The formulation according to claim 2, further characterized in that the hydrophilic polymer is hydroxypropyl methylcellulose (HMPC).

4. The formulation according to claim 1 comprising a mixture of HMPC and Carbopol.

5. The formulation according to claim 1 comprising a mixture of HMPC, Carbopol and mannitol.

6. An enteric layer formulation comprising carvedilol in a unit dose form orally.

7. The use of carvedilol for the manufacture of a matrix formulation for the treatment of hypertension, angina or congestive heart failure.

8. The use of carvedilol for the manufacture of an enteric-coated formulation for the treatment of hypertension, angina, or congestive heart failure.