MXPA94008792A - Sustained release formulations for 24 hours of metopro release - Google Patents

Abstract

The present invention relates to: A sustained release oral solid dosage form for pharmaceutical formulation of metoprolol includes a sustained release excipient that includes a gelling agent, a pharmaceutically inert diluent, a cationic covalent bonding agent, and metoprolol providing the release of metoprolol for at least 24 hours. In certain embodiments, the sustained release formulation also includes a hydrophobic material

Description

SUSTAINED RELEASE FORMULATIONS DURING 24 HOURS OF METOPROLOL RELEASE Mr. ANA R. BAICHWAL, JOHN N. STANIFORTH, of American nationality, residing respectively at 5 Kendell Drive, City of Appingers Falls, State of New York; United States of America; and High Trees, 170 Bloomfield Road, town of Bath, BA2 2AT England; inventors, assign, sell and transfer to EDWARD MENDELL CO., INC., American company, with address at 2981 Route 22, Patterson City, State of New York, United States of America, all the rights to the invention that are immediately describes: DISCLOSURE OF THE DISCLOSURE A sustained release oral solid dosage form for pharmaceutical formulation of metoprolol includes a sustained release excipient that includes a gelling agent, a pharmaceutically inert diluent, a cationic covalent bonding agent, and metoprolol providing the release of metoprolol during at least 24 hours In certain embodiments, the sustained release formulation further includes a hydrophobic material.

BACKGROUND OF THE INVENTION The advantages of controlled release products are well known in the pharmaceutical field and include the ability to maintain a desired blood level of a drug. medication over a comparatively longer period of time while increasing patient acceptance by reducing the number of administrations necessary to achieve it. These advantages have been achieved through a wide variety of methods. For example, different hydrogels have been described for use in controlled release medicines, some of which are synthetic, but most of which are semi-synthetic or naturally occurring. A few contain synthetic and non-synthetic material. However, some of the systems require special production processes and equipment and in addition some of these systems are susceptible to variable drug release. The delivery systems of oral controlled release should ideally be adapted to the reasons for release and the profiles can be adapted to the physiological and chronotherapeutic requirements. While many sustained and controlled release formulations are already known, it is often not possible to easily predict whether a particular sustained release formulation will provide the desired sustained release for a particular drug or medicament, and it has generally been found that it is necessary to carry out considerable Experiments to obtain sustained release formulations of such drugs that have the desired release ratio when ingested.

There have been a large number of patents in the prior art that relate to controlled release metoprolol formulations. For example, U.S. Patent No. 5,169,638 discloses a controlled and sustained release pharmaceutical formalin in the form of a capsule filled with powder in which a basic active ingredient exhibits an independent controlled release of the Ph. The powder comprises the active agent , which may be metoprolol, a water-soluble salt of polyuronic acid, a pH-independent hydrocolloid agelatinating agent (e.g., hydroxypropylmethylcellulose, methylcellulose or hydroxypropylcellulose), and a binder (HPMC). The formulation is free of calcium ion and carbon dioxide producing material and is said to float in gastric juices so that it has extended residence time in the stomach. U.S. Patent No. 4,792,452 discloses controlled release pharmaceutical compositions that are said to provide independent pH release for a basic drug such as metoprolol. The formulations include a pH independent polymer which is an alginic acid salt, a pH independent hydrocolloid gelling agent and a binder. The salt of alginic acid is preferably a sodium alginate or potassium alginate. The weight ratio of the alginic acid to the hydrocolloid gelation agent is all within the range of 0.1: 1 to 10: 1, and the formulation is free from calcium ion and carbon dioxide producing material. U.S. Patent No. 4,957,745 also describes a controlled release metoprolol. The preparation includes a plurality of beads comprising metoprolol coated with a polymeric membrane comprising ethylcellulose with or without hydroxypropylmethyl cellulose. U.S. Patent No. 4,871,549 describes a time-controlled exposure system comprising metoprolol, a swelling agent such as a substituted hydroxypropylcellulose, sodium starch glycolate or sodium carboxymethylcellulose, coated with a water-soluble coating material so that Drug release is caused by exposure of the membrane after a defined period of time. U.S. Patent No. 5,081,154, is directed to metoprolol succinate in an oral composition coated with a soluble polymer at a pH above 5.5 and a substituted water-soluble quaternary ammonium substituted with acrylic polymer. Previously, a heterodisperse polysaccharide excipient system and controlled release oral solid dosage forms were described in our U.S. Patent Applications Nos. 4,994,276, 5,128,143 and 5,135,757, all of which are incorporated herein by reference. These systems are commercially available under the trade name TIMEREx ™ of Edward Mendell Co., Inc., N.Y., which is the assignee of the present invention.

OBJECTIVES AND SUMMARY OF THE INVENTION It is an object of the present invention to provide sustained release oral and solid releases that release metoprolol for a period of time of at least 24 hours, when the formulations are exposed to an environment of use (eg, gastrointestinal tract). It is a further object of the present invention to provide methods for the preparation of sustained release metoprolol formulations which can be administered to patients on a once a day basis, or a longer time interval. The aforementioned and other objects are achieved by virtue of the present invention, which is in prelated to a controlled release formulation comprising a therapeutically effective amount of metoprolol, and a sustained release excipient comprising a heteropolisccharide gum and a gum homopolysaccharide capable of binding covalently to the heteropolysaccharide gum when exposed to a fluid environment, - an inert diluent selected from, for example, a monosaccharide, a disaccharide, a polyhydric alcohol, or mixtures thereof; an effective amount of a water soluble cationic covalent bonding agent pharmaceutically acceptable to provide a sustained release of the medicament for at least 24 hours, when the dosage form is exposed to a fluid environment. In some preferred embodiments of the invention, the gum is included in an amount of from about 30% to about 60%, and more preferably from about 35% to about 50%, by weight of the final product. The ratio of drug to gum can be, for example, from about 1: 1 to about 1: 5. More preferably, the ratio of drug to gum is from about 1: 1.5 to about 1: 4. In some preferred embodiments, the sustained release excipient further comprises a hydrophobic material in an amount effective to decrease the hydration of the gums without altering the hydrophilic matrix formed by the heterodisperse polysaccharide when the formulation is exposed to fluids in an environment of use. The formulations of the present invention are prepared as a pharmaceutically acceptable oral solid dosage form, such as tablets. The present invention is also related to a method for providing a sustained release formulation of metoprolol, comprising preparing a sustained release excipient to (1) dry blending a heteropolysaccharide gum and a homopolysaccharide gum capable of covalently binding to the heteropolysaccharide gum when are exposed to a fluid environment, together with a pharmaceutically acceptable inert diluent in desired proportions; (2) wet granulate the mixture; (3) drying the resulting granulate; and (4) milling the dried granules to obtain a sustained release excipient having a desired particle size. Then, the sustained release excipient is (5) wet granulated with metoprolol or its pharmaceutically acceptable salt, and (6) the resulting granulate is dried. Then, any (7) of the excipients are added (eg, a lubricant) and the resulting mixture is then, for example, (8) compressed into tablets. In some preferred embodiments, the mixture of excipient and sustained release metoprolol is granulated with a solution of hydrophobic material in an amount sufficient to decrease the hydration of the gums without altering them. Then, any of the additional inert excipients (e.g., a lubricant) are added and the resulting mixture is then, for example, compressed into tablets. The present invention further relates to a sustained release oral solid dosage form for the absorption of a therapeutically active drug in the gastrointestinal tract; and the sustained release excipient comprises a gelling agent comprising a heteropolysaccharide gum and a homopolysaccharide gum capable of binding covalently to the heteropolysaccharide gum when exposed to an environmental fluid, and a pharmaceutically inert diluent. The present invention further relates to a method of treating a patient comprising orally administering the sustained release metoprolol tablets to a patient, thereby providing therapeutically effective blood levels of the medicament for at least 24 hours. By "sustained release" it is meant for purposes of the present invention that the active medicament is released from the formulation at a controlled rate such that therapeutically beneficial blood levels (but below the toxic levels) of the medicament are maintained over an extended period of time. time, for example, provided a 24-hour dosage form. The term "environmental fluid" is intended for purposes of the present invention to encompass, for example, an aqueous solution, such as that used for invitro solution tests, or gastrointestinal fluid.

DETAILED DESCRIPTION Metoprolol is an adrenoceptor blocking agent (cardioselective) eta! -selective. It reduces the oxygen demand of the heart, decreases the reason of the heart and reduces cardiac output at rest and in exercise; it also reduces systolic blood pressure among other things. Any salt Pharmaceutically acceptable of metoprolol can be used according to the present invention. Metoprolol is commercially available in the United States as the tartrate salt and succinate salt. Metoprolol tartrate (Lopressor®, Geigy Pharmaceuticals), is available as 50 mg, 100 mg and 200 mg prolonged-release tablets which can be dosed once a day. As previously reported in our US Patents Nos. 4,994,276, 5,128,143 and 5,135,757, the heterodisperse excipient of the present invention comprises both hetero- and homo-polysaccharides that exhibit synergism, for example, the combination of two or more polysaccharide gums produces a high viscosity. and hydration faster than could be expected by any of the gums alone, the resulting gel being formed faster and more rigid. In the present invention, it has been found that a sustained release excipient comprising only the heterodisperse polysaccharide, for example, xanthan gum and locust bean gum, may not be sufficient to provide a sustained release of an insoluble drug to provide a 24 hour formulation. hours, nor to avoid an initial "burst" of drug release from the formulation when the formulation is exposed to a fluid in an environment of use, for example, an aqueous solution or gastrointestinal fluid. The term "heteropolysaccharide" as used in the present invention is defined as a water soluble polysaccharide containing two or more kinds of sugar units, the heteropolysaccharide has a branched or helical configuration, and has excellent branching properties in water and immense thickening properties. An especially preferred heteropolysaccharide is xanthan gum, which is a high molecular weight polysaccharide (> 106). Other preferred heteropolysaccharides include xanthan gum derivatives, the carboxymethyl ether, and the glycol propylene ester. Homopolysaccharides useful in the present invention include galactomannan and galactose gums. Preferred galactomannan gums are those capable of covalent binding to the heteroposaccharide. Galactomannan having higher proportions of insubstituted mannose regions has been found to achieve greater interaction with the hetepolysaccharide when exposed to a fluid environment. The locust bean gum, which has a higher ratio of the maganese to the galactose, is especially preferred in comparison with other galactomannose such as guar and guar hydroxypropyl. The combination of xanthan gum with locust bean gum is an especially preferred rubber blend. It has now been surprisingly discovered that the synergistic combination of heteropolysaccharide / homopolysaccharide gums, when incorporated in a form of Oral dosage contains metoprolol as the active ingredient together with an effective amount of a cationic covalent bonding agent to obtain to obtain an increased and desired gel strength due to the covalent bond of the heteropolysaccharide, provides a sustained release of metoprolol from the initial product which is appropriate for one administration once a day. In the preferred embodiments, the controlled release properties of the final product are optimized when the ratio of the heteropolysaccharide gum to the galactomannan gum is from about 3: 1 to about 1: 3, and more preferably about 1: 1. However, the sustained-release excipient of the invention may comprise from about 1% to about 99% by weight of heteropolysaccharide gum and from about 99% to about 1% by weight of homopolysaccharide gum. The chemistry of some of the ingredients comprising the excipients of the present invention such as xanthan gum is such that the excipients are considered to be self-regulating agents that are substantially insensitive to the solubility of the medicament and equally insensitive to changes in pH along the length of the gastrointestinal tract. In this way, the formulations of the present invention are pH independent. The cationic covalent bonding agent can be monovalent or multivalent metal cations. The preferred salts are the inoganic salts, including various alkali metal and / or alkaline earth metal sulphates, chlorides, borates, bromides, citrates, acetates, lactates, etc. Specific examples of cationic covalent bonding agents include calcium sulfate, sodium chloride, potassium sulfate, sodium carbonate, lithium chloride, tripotassium phosphate, sodium borate, potassium bromide, potassium fluoride, sodium bicarbonate, calcium chloride, magnesium chloride, and sodium fluoride. However, the preferred cationic covalent bonding agents are bivalent. Particularly preferred salts are calcium sulfate and sodium chloride. In preferred embodiments, the cationic covalent bonding agent includes the sustained release excipient of the present invention in an amount of about 1 to about 20% by weight of the sustained release excipient, and in an amount of about 1% to about 20% by weight of the final dosage form. In the preferred embodiments of the present invention, the cationic covalent bonding agent comprises about 10% by weight of the sustained release excipient. The inert diluent of the sustained release excipient preferably comprises a pharmaceutically acceptable saccharide, which includes a monosaccharide, a disaccharide, or a polyhydric alcohol, cellulose derivatives, and / or mixtures of some of the above Examples of suitable pharmaceutically inert diluents include sucrose, dextrose, lactose, microcrystalline cellulose, hydroxypropylmethylcellulose, fructose, xylotol, sorbitol, mixtures thereof and the like. However, it is preferred that a pharmaceutically soluble diluent such as lactose, dextrose, sucrose or mixtures thereof be used. In some preferred embodiments of the invention, the sustained release excipient further comprises a hydrophobic material in an amount effective to decrease the hydration of the gums without altering the hydrophobic matrix formed by the heterodisperse polysaccharide when the formulation is exposed to fluids in an environment of use. The sustained-release excipients of the invention have uniform packing characteristics over a range of different particle size distributions and are capable of being processed into tablets using either direct compression, followed by the addition of the drug and the lubricating powder or either by wet granulation. The properties and characteristics of a specific excipient system prepared in accordance with the present invention depends in part on the individual characteristics of the homo- and hetero-polysaccharide constituents, in terms of polymer solubility, glass transition temperatures, etc. as well as in the synergism between the different homopolysaccharides and the constituent (s) of the inert saccharide in the modification of dissolution interactions of the excipient in fluid. The sustained release excipients of the present invention are preferably prepared via a wet granulation method: However, the excipients prepared according to the present invention can be prepared according to any agglomeration technique to give an acceptable excipient product. In wet granulation techniques, the desired amounts of the heteropolysaccharide gum, the homopolysaccharide gum, the cationic covalent bonding agent and the inert diluent are mixed together and then a humidifying agent, such as water, propylene glycol, glycerol, alcohol or the similar is added to prepare a moistened mass. Then, the moistened mass is dried. The dry mass is then ground with conventional equipment to obtain the desired particle size. Once the sustained release excipient of the present invention has been prepared, it is then possible to mix it with metoprolol, for example, in a V mixer or via wet granulation. An effective amount of any pharmaceutically accepted lubricant, including calcium or magnesium soaps may be added to the aforementioned ingredients of the excipient at the time the medicament is added, or in any case before compression in a solid dosage form. An example of a lubricant Appropriate is magnesium stearate in an amount of about 0.5% to about 3% by weight of the solid dosage form. An especially preferred lubricant is sodium stearyl fumarate, NF, commercially available under the tradename Pruv®, from Edward Mendell Co., Inc. In some variants of the embodiment a hydrophobic material is added to the formulation. This can be carried out by granulating the sustained release excipient with a solution or dispersion of hydrophobic material prior to incorporation of the medicament. The hydrophobic material may be selected from ethylcellulose, acrylic, and / or polymers of metracrylic acid, hydrogenated vegetable oils, zein, as well as other pharmaceutically acceptable hydrophobic materials known to those skilled in the art. Other hydrophobic cellulosic materials such as other alkyl celluloses can also be used. The amount of hydrophobic material incorporated in the sustained release excipient is such that it is effective to encourage the hydration of the gums without disturbing the hydrophilic matrix formed under exposure to a fluid environment. In some embodiments of the present invention, the hydrophobic material may be included in the sustained release excipient in an amount of about 1% to about 20% by weight. More preferably, the hydrophobic material can be included in the sustained release excipient in an amount of about 3% to about 12% by weight of the final formulation. The hydrophobic material may be dissolved in an organic solvent or dispersed in an aqueous solution for incorporation into the formulation. The dosage forms of the present invention are preferably tablets. However, the ingredients can also be formulated in a capsule, extruded and spheronized with an active drug to form pills, etc. In some embodiments, the complete mixture in an amount sufficient to make a uniform batch of tablets is then subjected to tableting in a conventional production scale tablet machine at a normal compression pressure, eg, 2000-1600 psi. However, the mixture should not be compressed to such a degree that there is subsequent difficulty in achieving hydration when exposed to a gastric fluid. The average tablet weight can be from about 300 mg to 950 mg. For metoprolol tablets which are to contain about 100 mg of drug, the weight of the tablet is preferably from about 450 mg to 950 mg. The average particle size of the granulated excipient of the present invention is in the range of about 50 microns to about 400 microns and preferably from about 185 microns to about 265 microns. The particle size of the granulation is not extremely critical, the important parameter being that the average particle size should allow the formulation of a directly compressible excipient which forms pharmaceutically acceptable tablets. The derivatization and bulk densities of the granulation of the present invention are typically between about 0.3 to about 0.8 g / ml, with an average density of about 0.5 to about 0.7 g / ml. For best results, tablets formulated from the granulations of the present invention are from about 6 to about 8 kg of hardness. The average flow of the granulations prepared according to the present invention are from about 25 to about 40 g / sec. Tablets compacted using an instrumented rotary tablet machine have been found to possess the strength profiles that are largely independent of the inert saccharide component. Electron scanning photomicrographs of the tablet surfaces have enormously provided qualitative evidence of extensive plastic deformation in compaction, both on the surface of the tablet and across the fracture surface, and also show pore evidence of surfaces through which the initial solvent enters and the discharge of the solution may occur. The amount of metropolol or its salt incorporated into the dosage unit formulations (e.g., tablets) of the present invention can be 50 mg, 100 mg or 200 mg, based on the tartrate salt. Of course, if other salts of metoprolol are to be used, the weight of the particular metoprolol salt to be included can be calculated based on a weight equivalent to the tartrate salt.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES The following examples illustrate various aspects of the present invention. These have not been constructed to limit the claims in any way.

EXAMPLES 1-3 In Examples 1-3, the sustained release excipients according to the present invention are prepared first, the medicament being subsequently added, and the final mixture is then tabletted. The sustained release excipient is prepared by dry blending the required amounts of xanthan gum, locust bean gum, calcium sulfate, and dextrose in a high speed mixer / granulator for two minutes. While the shredders / impellers are running, water is added to the dry mix, and the mixture is granulated for another 2 minutes. The granulation is then dried in a fluid bed granulator at a dr loss (PES) of less than about 10% by weight. In examples 1-3 the PES it is between 4-7%. The granulation is then ground using 20 mesh screens. The ingredients of the sustained release excipient of Examples 1-3 are disclosed in Table 1 below: TABLE 1 PREPARATION OF SUSTAINED RELEASE EXCIPIENT Component% Xanthan Gum 25 Gum of locust bean 25 Dextrose 40 Calcium Sulphate 10 Water 10 * * removed during processing Then, the sustained release excipient prepared as detailed above is dry blended with the desired amount of metoprolol, provided as the tartrate salt, in a blender / high speed granulator for 2 minutes. While rotating / propelling switches are running, a solution of ethylcellulose in ethanol is added to the mixture, and the mixture is granulated during others 2 minutes. The granulation is then dried in a fluid bed dryer at a dryness loss between 4-7%. Then, the granulation is ground using 20 mesh screens. An appropriate tabletting lubricant (Pruv®, sodium stearyl fumarate, NF, commercially available from Edward Mendell Co., Inc.) is then added, and the mixture is mixed during others minutes. This final mixture is compressed into tablets, each Tablet contains 100 mg of metoprolol. The tablets of Example 1 weighed 486 mg. The tablets of Example 2 weighed 642 mg. The Tablets of Example 3 weighed 753 mg. The drug ratio: gum of the tablets of Example 1 was 1: 1.77. The drug ratio: gum of the tablets of Example 2 was 1: 2.57. The ratio of drug: gum of the tablets of Example 3 was 1: 3. The ingredients of the tablets of Examples 1-3 are disclosed in Table 2 below: TABLE 2 TABLET FORMULATION - EXAMPLES 1-3 Component% -Eiem. .1% -Eje. .2% -Eiem.3 1. Excipient of release 7 722..88 79.1 81.3 sustained 2. Metoprolol 20.6 15.8 13.5 3. Ethylcellulose 5.1 5.1 5.2 4. Pruv 1.5 1.5 1.5 5. Ethanol 30 * 30 * 30 * * Removed during processing Dilution tests were carried out on the tablets of examples 1-3. The dissolution tests are conducted in USP automatic dissolution apparatuses (Paddie type II, pH 6.8 buffer, 100 rpm). The results are reported in Table 3 below.

TABLE 2 TABLET FORMULATION - EXAMPLES 1-3 Time Example 1 Example 2 Example 3 0 0.0 0.0 0.0 2 52.7 37.7 29.7 4 69.7 50.9 41.9 8 80.9 71.1 61.5 12 86.7 86.4 74.8 16 90.6 90.3 85.1 20 94.4 98.1 94.1 24 100.0 100.0 100.0 From the results provided in Table 3, it can be seen that as the amount of gum in the formulations is increased, the rate of release of the drug (metoprolol) is decreased. It is evident that the tablets of Examples 1-3 provided appropriate oral solid dosage forms for 24 hours for metoprolol.

EXAMPLES 4-6 In Examples 1-3, the sustained release excipients according to the present invention are prepared first, the drug being added accordingly, and the final mixture is then tabletted. The sustained-release excipient is prepared by dry mixing the required amounts of xanthan gum, locust bean gum, calcium sulfate, and dextrose in a high speed mixer / granulator for two minutes.

While the rotary / booster switches are running, water is added to the dry mix, and the mixture is pelletized for another 2 minutes. The granulation is then dried in a fluid bed granulator at a drying loss (PES) between 4-7% by weight. The granulation is then ground using 20 mesh screens. The ingredients of the sustained release excipient of Examples 4-6 are disclosed in Table 4 below: TABLE 4 PREPARATION OF SUSTAINED RELEASE EXCIPIENT Component% Xanthan Gum 30 Gum of carob 30 Dextrose 30 Calcium Sulphate 10 Water 10 * * withdrawal during processing Then, the sustained release excipient prepared as detailed above is dry blended with the desired amount of metoprolol, provided as the tartrate salt, in a high speed mixer / granulator for 2 minutes. While rotating / propelling switches are running, a solution of ethylcellulose in ethanol is added to the mixture, and the mixture is granulated for another 2 minutes. The granulation is then dried in a bed dryer fluid at a loss by dryness between 4-7%. Then, the granulation is ground using 20 mesh screens. An appropriate tabletting lubricant (Pruv®, sodium stearyl fumarate, NF, commercially available from Edward Mendell Co., Inc.) is then added, and the mixture is mixed during another 5 minutes. This final mixture is compressed into tablets, each tablet contains 100 mg of metoprolol. The tablets of Example 4 weighed 552 mg. The tablets of Example 5 weighed 642 mg. The Tablets of Example 6 weighed 731 mg. The drug ratio: gum of the tablets of Example 4 was 1: 2.5. The drug ratio: gum in the tablets of Example 5 was 1: 3.0. The drug ratio: gum of the tablets of Example 6 was 1: 3.5. The ingredients of the tablets of Examples 4-6 are disclosed in Table 5 below: TABLE 5 TABLET FORMULATION - EXAMPLES 4-6 Component% -E? Em. .4% -Eiem. , 5% -Eiem.6 1. Excipient of release 7 755..44 77.9 79.8 sustained 2. Metoprolol 18.6 15.6 13.7 3. Ethylcellulose 5.0 5.0 5.0 4. Pruv 1.5 1.5 1.5 5. Ethanol 30 * 30 * 30 * * Removed during processing Dilution tests were carried out on the tablets of Examples 4-6. Dissolution tests are conducted in USP automatic dissolution apparatus (Paddie type II, buffer pH 6.8, 100 rpm). The results are disclosed in Table 6 below.

TABLE 6 TABLET FORMULATION - EXAMPLES 4-6 Time for Employment 4 Year 5 Year 6 0 0.0 0.0 0.0 2 18.3 20.6 14.2 4 28.2 32.4 22.4 8 43.0 49.0 34.2 12 54.2 59.9 42.5 16 67.5 66.6 51.5 20 80.4 72.8 60.5 24 83.8 83.2 75.6 From the results provided in Table 6, it can be seen that as the amount of gum in the formulations is increased, the rate of release of the drug (metoprolol) is decreased. The tablets of Examples 4-6 provide an even slower release rate compared to the formulations of Examples 1-3, and are suitable for a sustained release of metoprolol of 24 hours or greater.

EXAMPLES 7-9 In Examples 1-3, sustained release metoprolol formulations are prepared according to the present invention without including the hydrophobic material (e.g., methylcellulose). The sustained release excipient is prepared by dry blending the required amounts of xanthan gum, locust bean gum, calcium sulfate, and dextrose in a high speed mixer / granulator for two minutes. While the rotary / booster switches are running, water is added to the dry mix, and the mixture is pelletized for another 2 minutes. The granulation is then dried in a fluid bed granulator at a drying loss (PES) between 4-7% by weight. The granulation is then ground using 20 mesh screens. The ingredients of the sustained release excipient of Examples 7-9 are disclosed in Table 7 below: TABLE 7 PREPARATION OF SUSTAINED RELEASE EXCIPIENT Component% Xanthan Gum 25 Gum of carob 25 Dextrose 40 Calcium Sulphate 10 Water 10 * * withdrawal during processing Then, the sustained release excipient prepared as detailed above is dry blended with the desired amount of metoprolol, provided as the salt of tartrate, in a high speed mixer / granulator for 2 minutes. While rotating / propelling switches are running, a solution of ethylcellulose in ethanol is added to the mixture, and the mixture is granulated for another 2 minutes. The granulation is then dried in a fluid bed dryer at a dryness loss between 4-7%. Then, the granulation is ground using 20 mesh screens. An appropriate tabletting lubricant (Pruv®, sodium stearyl fumarate, NF, commercially available from Edward Mendell Co., Inc.) is then added, and the mixture is mixed during another 5 minutes. This final mixture is compressed into tablets, each tablet contains 100 mg of metoprolol. The tablets of Example 7 weighed 508 mg. The tablets of Example 8 weighed 711 mg. The Tablets of Example 9 weighed 914 mg. The ratio of drug: gum of the tablets of Example 7 was 1: 2. The drug ratio: gum of the tablets of Example 8 was 1: 3. The drug ratio: gum of the tablets of Example 9 was 1: 4. The ingredients of the tablets of Examples 7-9 are disclosed in Table 8 below: TABLE 8 TABLET FORMULATION - EXAMPLES 7-9 Component% -Eiem. , 7% -Eiem. 8% -Exem.9 1. Release agent 7788..88 84.4 87.6 sustained 2. Metoprolol 19.7 14.1 10.9 3. Pruv 1.5 1.5 1.5 5. Water 10 * 10 * 10 * * Removed during processing Dilution tests were carried out on the tablets of examples 7-9. The dissolution tests are conducted in USP automatic dissolving devices (Paddie type II, buffer pH 7.5, 100 rpm). The results are disclosed in Table 9 below.

TABLE 9 TABLET FORMULATION - EXAMPLES 7-9 Time Example 7 Example 8 Example 9 0 0.0 0.0 0.0 2 32.9 25.0 21.3 4 47.0 36.4 32.3 8 65.6 53.2 49.0 12 77.5 65.9 61.4 16 85.1 75.0 71.0 20 89.7 81.9 78.7 24 93.4 86.2 84.8 From the results provided in Table 9, it can be seen that as the amount of gum in the formulations is increased, the rate of release of the drug (metoprolol) is decreased. The tablets of Examples 7-9 (which do not include methylcellulose) provide an even slower release rate compared to the formulations of Examples 1-3, (which included 10% ethylcellulose) and are suitable for a release sustained dose of metoprolol 24 hours or greater.

EXAMPLES 10-11 In Examples 10-11, sustained release metoprolol formulations are prepared according to Examples 7-9. The ingredients of the sustained release excipient of Examples 10-11 are identical to those of Examples 7-9. The sustained release excipient is dry blended with the desired amount of metoprolol, provided as the tartrate salt, wet granulated with water, tabletted as disclosed in Examples 7-9. The ingredients and the amounts of these in the tablets of Examples 10-ll are identical with those of Example 7. In Example 10, the tablets were compressed to a tablet size of 1.27 cm. In example 11 the tablets were compressed to a tablet size of 1.11 cm (7/16"). Dilution tests were carried out in the tablets of the examples «10-11. Dilution tests are conducted in an automatic UPS dissolution apparatus (Paddie type II, buffer pH 7.5, 100 rpm). The results are disclosed in Table 10 below.

TABLE 10 Percentage released Time Example 10 Example 11 0 0.0 0.0 2 32.9 29.9 4 47.0 44.0 8 65.6 63.9 12 77.5 76.9 16 85.1 85.2 20 89.7 90.1 24 93.4 94.1 From the results provided in Table 10 it can be seen that for tablets of the same composition and weight, small changes in diameter and thickness have no significant effects on the rate of drug release. The tablets of Examples 10-11 could be suitable to provide a sustained release of metoprolol for 24 hours or longer. The examples provided above do not mean they are exclusive. Many other variations of the present invention could be obvious to those skilled in the art, and are contemplated to be within the scope of the invention.

Claims (30)

1. scope of the attached annexes. NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and, therefore, the content of the following is claimed as property: CLAIMS 1. A solid sustained oral dosage form of metoprolol or a salt thereof, comprising: metoprolol or a pharmaceutically acceptable salt thereof in an amount necessary to produce a therapeutic effect in a human patient, - a release excipient sustained comprising a heteropolysaccharide gum and a homopolysaccharide gum capable of covalently bonding to said heteropolysaccharide gum when exposed to an ambient fluid; a pharmaceutically inert diluent; and a pharmaceutically acceptable cationic covalent linker capable of covalently bonding with said gums and increasing the gel firmness of said gums when the dosage form is exposed to an ambient fluid; the ratio of metoprolol to said gums being from about 1: 1 to about 1: 5, said dosage form providing a substance releasing metoprolol for at least 24 hours approximately when it is exposed to an environmental fluid.
2. 2. A solid sustained oral dosage form of metoprolol or a salt thereof, comprising: metoprolol or a pharmaceutically acceptable salt thereof in an amount necessary to produce a therapeutic effect in a human patient for about 24 hours; from about 30% to about 60% xanthan gum matrix and a locust bean gum in a ratio of about 1: 3 to about 3: 1; from about 1 to about 20% by weight of a people with pharmaceutically acceptable cationic covalent bond capable of covalently bonding said gums and increasing the gel firmness of said gums when the dosage form is exposed to an ambient fluid; and a pharmaceutically inert diluent.
3. 3. The oral solid dosage form of clauses 1 or 2, wherein said heteropolysaccharide comprises xatan gum and the homopolysaccharide gum comprises locust bean gum in a ratio of about 1: 3 to about 3: 1.
4. 4. The oral solid dosage form of clauses 1-3, wherein said cationic covalent bonding agent comprises from about 1 to about 20 weight percent of said formulation.
5. 5. - The oral solid dosage form of clauses 1-4, wherein the ratio of drug to gum is from about 1: 1.5 to about 1: 4.
6. 6. The oral solid dosage form of clauses 1-5, wherein said agent with cationic covalent bond comprises a sulfate, chloride, borate, bromide, citrate, acetate or lactate of alkali metal or alkaline earth metal. 1 .
7. The oral solid dosage form of clauses 1-6, wherein said agent with cationic covalent bond comprises a calcium sulfate.
8. 8. The oral solid dosage form of clauses 1-6, wherein said cationic covalent agent comprises about 10% by weight of said formulation.
9. 9. The oral solid dosage form of clauses 1-8, further comprises a hydrophobic polymer selected from the group consisting of alkalinecellulose, an acrylic copolymer or methacrylic esters, and a mixture thereof, prior to the incorporation of said medicament, the hydrophobic polymer being included in said dosage form in an amount effective to retard the hydration of said gums when exposed to an ambient fluid.
10. 10. The oral solid dosage form of clause 9, wherein said hydrophobic polymer comprises ethylcellulose.
11. 11. The oral solid dosage form of clause 9-10 wherein said hydrophobic material comprises from about 1 to 20 percent of said dosage form, by weight.
12. 12. The oral solid dosage form of clauses 9-11, wherein said hydrophobic polymer comprises from about 5 to 10 weight percent of said dosage form.
13. 13. The oral solid dosage form of clauses 1-12, which is a tablet.
14. 14. The oral solid dosage form of clauses 1-13, which comprises 50 mg, 100 mg, or 200 mg of metoprolol.
15. 15. The oral solid dosage form of clauses 1-14, wherein said metoprolol or pharmaceutically acceptable salt thereof is selected from the group consisting of metoprolol tartrate, metoprolol succinate or a combination thereof.
16. 16. The oral solid dosage form of clauses 1-15, wherein said pharmaceutically inert diluent is selected from the group consisting of a monosaccharide, a disaccharide, a polyhydric alcohol, cellulose derivatives and mixtures thereof.
17. 17. The oral solid dosage form of clauses 1-15, wherein said diluent is pharmaceutically Inert is selected from the group consisting of sucrose, dextrose, lactose, microcrystalline cellulose, hydroxypropylmethylcellulose, hydroxypropyl cellulose, carboxymethylcellulose, fructose, xylitol, sorbitol and mixtures thereof.
18. 18. The oral solid dosage form of clauses 1-17, wherein said pharmaceutically inert diluent is soluble.
19. 19. A method of preparing a 24-hour formulation of metoprolol, comprising: preparing a sustained release excipient comprising a heteropolysaccharide gum capable of covalently binding said heteropolysaccharide gum when exposed to an ambient fluid; a cationic covalent bonding agent capable of covalently bonding with said guming agents to increase the firmness of the gel when said gums are exposed to an environmental fluid, and a pharmaceutically inert diluent; combining the sustained release excipient with metoprolol or a pharmaceutically acceptable salt to provide a medicament: gum ratio of about 1: 1 to about 1: 5; and forming tablets with the result of the mixture such that each tablet includes a sufficient dose of metoprolol to provide a therapeutic effect for at least 24 hours.
20. 20. - The method of clause 19, further comprises wet granulating the heteropolysaccharide gum, the homopolysaccharide gum, the cationic covalent bonding agent, and the inert diluent before incorporating said metoprolol.
21. 21. - A method of treating a patient with metoprolol comprising preparing a sustained release excipient comprising a heteropolysaccharide gum; a homopolysaccharide gum capable of covalently binding to said heteropolysaccharide gum when exposed to an environmental fluid; an agent with cationic covalent bond capable of covalently binding with said gum agents to increase the firmness of the gel when said gums are exposed to an environmental fluid, and a pharmaceutically inert diluent combining said sustained release excipient with metoprolol or a pharmaceutically acceptable salt for provide a drug ratio: gum from about 1: 1 to about 1: 5; forming tablets with the result of the mixture such that each tablet includes a sufficient dose of metoprolol to provide a therapeutic effect for at least 24 hours or more, and administering said tablets to a patient at appropriate dose ranges.
22. 22. The method according to claims 18-21, characterized in that it further comprises adding a hydrophobic material to the mixture of the sustained release excipient and to the metoprolol before the tabletting in an amount effective to decrease the hydration of the gums when they are exposed to a fluid environment.
23. 23. - The method according to claims 18-22, characterized in that it comprises wet granulating the mixture of sustained release excipient, metoprolol, and hydrophobic material before forming tablets.
24. 24. - The method according to claims 18-23, characterized in that the heteroplissaccharide is a xanthan gum, said homopolysaccharide gum is a locust bean gum and the ratio of xantan gum to locust bean gum is from about 1: 3 to about 3 :1.
25. 25. - The method according to claims 18-24, characterized in that it further comprises providing a cationic covalent bonding agent in an amount of about 1 to about 20 percent by weight of the tablet formulation.
26. 26. - The method according to claims 18- 25, characterized in that it further comprises providing said formulation in tablets with a medicine to gum ratio of from about 1: 1.5 to about 1: 4.
27. 27. - The method according to claims 18-26, characterized in that the cationic covalent bonding agent comprises a sulfate, chloride, bromate, bromide, citrate, acetate, or alkali metal or alkaline earth metal lactate and the hydrophobic polymer is select from the group consisting of alkyl cellulose, an acrylic copolymer and methacrylic esters and a mixture of the foregoing.
28. 28. - The method according to claims 18-27, characterized in that the hydrophobic polymer comprises ethylcellulose and the cationic covalent bonding agent comprises a calcium sulfate.
29. 29. - The method according to claims 18-28, characterized in that the hydrophobic material comprises from about 1 to 10 percent by weight of said dosage form.
30. 30. - The method according to claims 18-29, characterized in that it further comprises shaping the mixture of sustained release excipient and metoprolol such that each tablet contains from about 50 to about 200 mg of metoprolol or a pharmaceutically acceptable salt thereof. IN WITNESS WHEREOF, I have signed the above description and novelty of the invention, as attorney of EDWARD MENDELL CO./ INC., In the city of Mexico, on November 11, 1994. p.p. EDWARD MENDELL CO., INC.