MXPA00001857A - Rapidly disintegrating methylcellulose tablets - Google Patents

Abstract

The present invention relates to a novel pharmaceutical composition and process for preparing swallowable methylcellulose tablets that disintegrate rapidly and meet USP standards in 0.1 N hydrochloric acid as well as water.

Description

ETILCELÜLOSA TABLETS THAT ARE QUICKLY DISINTEGRATED FIELD OF THE INVENTION The present invention relates to an improved process for preparing tablets containing compressed methylcellulose, which comply with the USP disintegration standards.

BACKGROUND OF THE INVENTION The history of cellulose ethers, such as methylcellulose and carboxymethylcellulose, suggests that these agents are effective as bulk laxatives. Its mechanism of action involves increasing both the water content of, as well as the volume content of, the evacuation, as well as lubricate the evacuation; relieving constipation in this way. The cellulose ethers have been administered as bulk laxatives in dosage forms comprising tablets, suspensions, and bulk powders; the latter are free of sugar, or in compositions containing high amounts of sugar. The cellulose ethers administered as suspensions in water may contain high concentrations of sucrose or other sugars and flavorings. In these formulations, the sugar competes with the cellulose ether for the available water, thus preventing the cellulose ether from hydrating sufficiently to form a gel. The advantages of using a suspension formulation are that the cellulose ether disperses sufficiently to avoid any significant swelling in the digestive tract. However, these suspensions are viscous, semi-gelatinous, and visually unpleasant to the consumer. Another drawback is the bad taste of the suspensions, due to the sluggish feeling in the mouth, and the extreme sweetness of these suspensions. Accordingly, these dosage forms have not had significant consumer acceptance. Bulk powders of cellulose ethers often exhibit bulking of the individual particles and gelation, and therefore, remain undissolved as they pass through the digestive tract. Additionally, the administration of bulk powders has caused cramps, nausea, and vomiting in some patients. Accordingly, bulk powders are not the preferred dosage form for cellulose ethers. However, good tasting and visually pleasing bulk powders have been made by the addition of water or other aqueous liquid to a dry powder mixture of a water soluble cellulose ether, and a dispersing agent / sweetening component, typically sugar. This technology is disclosed in South African Patent Number 84, 1044, published September 26, 1984. The trap with these compositions is that they contain approximately 400 calories of nutritional value per dose, primarily because of the high sugar content. This caloric value is not acceptable for average consumers or for users suffering from blood sugar disorders, including diabetics. Elderly people are usually the common stratum of the population suffering from constipation, and the most frequent users of laxatives, and are commonly also suffering from blood sugar disorders. The consumption of large amounts of sugar would aggravate blood sugar disorders. Cellulose ethers embedded in sugar have been proposed as alternatives for bulk powders containing high amounts of sugar. These formulations have 1) less sugar, such as natural sugar, or a combination of sugars, such as sucrose, glucose, fructose, or corn syrup solids; 2) a lower caloric value; and 3) they are easily dispersed in cold aqueous liquids. ® The Orange Flavor Citrucel, a volume-forming laxative containing methylcellulose as its active ingredient, was first introduced to the market in 1986. This product contains 15 grams of sucrose in an adult dose of 19 grams, corresponding to one dose of 2 grams of methylcellulose. To decrease the sugar content of this product, a natural flavored formula with a lower caloric value was developed, and which contains only 1 gram of sucrose, and was introduced in 1988. The additional patent protection for this product has focused on producing a powder free of sugar and virtually free of calories. The product has a sugar-free sweetener, a dispersing agent, other excipients, and flavorings, and was marketed in 1991 as Sugar Free Citrucel Orange Flavor (Taste of ® Orange Citrucel Exempt of Sugar). There remains a need in the art to develop a solid dosage form that rapidly disintegrates from a bulk agent, preferably methylcellulose, that is convenient to take and transport, free of sugar, and easily administered to the consumer having sugar disorders. in blood or diabetics, for example.

SUMMARY OF THE INVENTION The present invention relates to an improved process for the preparation of methylcellulose tablets which can be easily dispersed, and which comply with the disintegration standards of Pharmacopoeia of the United States. The methylcellulose is compressed into tablets containing an edible calcium salt, in preferred weight / weight ratios. Preferably, the tablets disintegrate rapidly, in vi tro, in hydrochloric acid 0. IN and water at 37 + 0.5 ° C.

DETAILED DESCRIPTION OF THE INVENTION There is a common belief that cellulose ethers in tablets do not readily dissolve in the digestive tract, because these cellulose ethers are highly hygroscopic. The outer portion of the tablet is said to form a gel-type hydrate that prevents the tablet from breaking, and greatly retards hydration of the inner portion of the tablet. The present invention overcomes this problem recognized in the art, and involves the preparation of a novel composition, and a manufacturing process, by which a rapidly dissolving methylcellulose tablet is prepared. The tablets are prepared by a novel process involving a high shear wet granulation method, followed by fluidized bed drying, milling, mixing with the other ingredients, and compression. The present invention is for a methylcellulose tablet comprising methylcellulose having a viscosity of > 1000 centipoise, and at least one excipient selected from an edible calcium salt. It is recognized that the formulation will also include diluents and fillers well known to the skilled artisan. The tablet formulations of the present invention are convenient over other dosage forms of methylcellulose, because of their convenience of administration and their rapid disintegration. This contrasts with the methylcellulose tablets, formulated as 100 percent weight / weight methylcellulose in a 0.5 gram caplet, which has been found not to disintegrate in a 0.1N HCl solution, using a conventional dissolution apparatus, including after 2 hours . The present tablets should disintegrate in HCl 0. IN from about 20 to about 30 minutes, preferably from about 10 to about 19 minutes, and more preferably less than 10 minutes; and in water, the tablets should disintegrate in about 25 to about 30 minutes, preferably about 15 to about 24 minutes, and more preferably less than 15 minutes. Low molecular weight methylcellulose (mw) has been found to be less effective for use as a laxative, and therefore less desirable for use in a rapidly disintegrating tablet formulation. Accordingly, the higher molecular weight methylcellulose is both desirable and necessary in the present invention. The fibers should have a viscosity sufficient to gel and retain water in the intestine, in order to provide volume and softening evacuation for use as laxatives. By using the test methods for methylcellulose under standard conditions, such as those found in USP XXII, page 894, Apparent Viscosity'Method for Methylcellulose, or as discussed in Handbook of Pharmaceutical Excipient, APhA, a preferred methylcellulose for use in the present must have a viscosity of > 1000 centipoise (cps), preferably > 2000 centipoise, more preferably > 3000 centipoises, and very preferably > 4000 centipoises. However, a methylcellulose of higher molecular weight than those described is also desirable, the commercial availability of this grade of methylcellulose being the limiting characteristic. At present, the commercially available upper limit is about 6,000 cps, which is encompassed within the scope of this invention. A methylcellulose product currently available for use herein is Methocel A4M, made by Dow Chemical Company, Midland Michigan, as Dow Methocel A4M, having a viscosity of about 3,000 to about 5,600 cps, which is within 75 to 140 percent of the desired target viscosity herein. Some of the additional diluents or fillers for use in this formulation are preferably swallowing agents, and may include, but are not limited to, different grades of microcrystalline cellulose, such as Avicel PH 101, Avicel PH 102, and Avicel PH 200; cornstarch; or starch 1500. Edible calcium salts suitable for use herein include, but are not limited to, dibasic calcium phosphate dihydrate, anhydrous calcium phosphate, and tribasic calcium phosphate; or mixtures thereof. A preferred edible calcium salt is the dibasic calcium phosphate dihydrate salt, which salt also provides a good possibility of compression. If microcrystalline cellulose is added, it is preferably of a size of about 50 to 180 microns, more preferably about 50. Avicel PH 101 has an average particle size of about 50; Avicel PH 102 has an average particle size of approximately 100; and Avicel PH 200 has an average particle size of approximately 190 microns. Preferably, the preferred microcrystalline cellulose is Avicel PH 101. - It is noted that the proportion of methylcellulose to the edible calcium salt, and additional diluents, will depend on the diluent selected, and it is within the skill of the art to accurately determine the proportions necessary. However, suitable proportions for the particular diluents are described below: For Methylcellulose: dibasic calcium phosphate dihydrate, from about 2 to about 4: 1, preferably from about 2.6-3 1: 1; For Methylcellulose: anhydrous calcium phosphate, from about 2 to about 4: 1, preferably about 3.1: 1; Methylcellulose: tribasic calcium phosphate, G, from about 2 to about 4: 1, preferably about 3.1: 1; For Methylcellulose: microcrystalline cellulose, from about 2: 1 to about 14: 1. Preferably for Avicel PH 101, of approximately 2.2-13.5: 1; for Avicel PH 102, of approximately 2.4-8.3: 1; and for Avicel PH 200 of approximately 2.4-4: 1; For Methylcellulose: corn starch, from about 7.5 to about 15, preferably about 13.5: 1; For Methylcellulose: starch 1500, from about 2.0 to about 5.0: 1, preferably from about 2.4: 1; For Methylcellulose: Explotab, from about 5 to about 25: 1, preferably from about 8.1 to about 21.3: 1. It is recognized that, with the edible calcium salt, the formulation must also have an ingredient that holds the granules together, i.e., a binding agent. PVP, or the alternative agents mentioned below, is a preferred binding agent. In addition to the aforementioned edible calcium salts, optional diluents or fillers, and binding agents, the formulation may also include additional components, such as, but not limited to, a wetting agent (super) disintegrants, a second binding agent. , dyes or coloring agents, and lubricants, which are preferably used to prepare a tablet that is easily moistened, and rapidly disintegrate in 0. NIN hydrochloric acid and water, the standard test of the USP test for methylcellulose. A preferred wetting agent is sodium lauryl sulfate. A preferred lubricant is magnesium stearate. A preferred binding agent is polyvinylpyrrolidone, or PVP, such as Povidone 29K / 32. Preferably, the PVP is present in an amount from about 4 to about 6.5 weight percent / weight. A preferred disintegrating agent is sodium starch glycolate, such as, Explotab. Preferably, the sodium starch glycolate is present in an amount from about 3 to about 8 weight percent / weight. Because different excipients and diluents will be formulated together, and will be used in combination herein, the suggested weight / weight ratios for different formulations are presented below. Although not all of these proportions include the edible calcium salts, these are merely illustrative of the invention, and the skilled artisan will readily recognize the manner of formulating the product of this invention with the addition of the edible calcium salts. Sodium lauryl sulfate: Explotab: Dibasic calcium phosphate dihydrate: povidone 29K / 32: Magnesium stearate, include: 0.38-0.40: 3.5-7.9: 20.6-24.8: 4.0-6.5.-0.5-1.0; Sodium Lauryl Sulfate: Explotab: Trisodic Calcium Phosphate G ®.-Povidone 29K / 32: Magnesium Stearate, include: 0. 40: 3.5: 21.6: 6.4: 1.0; Sodium lauryl sulfate: Explotab: Anhydrous calcium phosphate: Povidone 29K / 32: Magnesium stearate, include: 0.40: 3.5: 21.6: 6.4: 1.0; Methylcellulose: sodium lauryl sulfate (SLS), from about 60 to about 170: 1, preferably from about 155: 1-170: 1; Methylcellulose: Povidone, preferably PVP 29K / 32, from about 8 to about 22: 1, preferably about 10.4: 1-16.7: 1; Methylcellulose: Magnesium stearate, from about 50 to about 150: 1, preferably from about 58-132: 1; Sodium lauryl sulfate: Explotab: vicel PH 101.-Povidone 29K / 32: Magnesium stearate, include: 0.35-0.46: 3.05-6.17: 4.38-27.13: 4.38-6.66: 0.76-1.14; Sodium lauryl sulphate: Explotab: Avicel PH 102 ®: Povidone 29K / 32: Magnesium stearate, include: 0.35-0.46: 4.9-6.17: 9.21-25.53: 4.38-6.66: 0.76-1.14; ® Sodium Lauryl Sulfate: Av? Cel PH 200: Povidone 29K / 32: Magnesium stearate, include: 0.38-0.42: 19.27-25.53: 5.99-6.66: 0.94-1.04. Sodium lauryl sulfate: Explotab: cornstarch: Povidone 29K / 32 Magnesium stearate, include: 0.36-0.38: 3.66-7.07: 4.35-4.68: 4.35-4.68: 0.88-0.95; Sodium Lauryl Sulfate: Explotab: Starch 1500 ®: Pov? Dona 29K /, 32: Magnesium stearate, include: 0.36-0.38: 3.66-7.07: 24.05-25.89: 4.35-4.68: 4.35-4.68: 0.88-0.95. Without wishing to be limited to the explicit excipients mentioned above, the following alternative agents may also be used herein. Alternative lubricants for magnesium stearate include, but are not limited to, calcium stearate, sodium stearate, Cab-O-Sil, Syloid, stearic acid, and talc. Alternative binders for PVP include, but are not limited to, hydroxypropylcellulose, hydroxypropylmethylcellulose, acacia, gelatin, tragacanth, pregelatinized starch, and starch.

® Alternative disintegrants for Explotab include, but are not limited to, sodium carboxymethylcellulose, ® Ac-di-sol, carboxymethylcellulose, veegum, alginates, agar, guar, tragacanth, locust bean, carayá, pectin, and crospovidone. Alternative wetting agents for sodium lauryl sulfate include, but are not limited to, magnesium lauryl sulfate. All these formulations can be prepared with and without sugar. A sugar-free formulation has the advantage that it can be easily administered to consumers with blood sugar disorders, or to diabetics who need these preparations. Another convenient property of the present invention is that the formulations contain calcium, such as dibasic calcium phosphate dihydrate. These formulations, for example, will contain approximately 80 milligrams / dose, anticipating the formulation of 0.5 grams / tablet X 2 tablets / dose of methylcellulose. If desired, the amount of calcium can be increased in these tablets to provide a greater therapeutic value to the consumer. The amount of methylcellulose present in each dose, as well as the number of doses of laxative taken per day, will depend a little on the age, sex, size of the patient, severity of the patient's particular problem, the advice of the treating physician, case, and the particular taste and habits of the patient. Accordingly, the tablets of this invention are conveniently administered in a single dose, which may contain as much as 500 to 1000 milligrams of methylcellulose per tablet, or in a plurality of smaller doses containing as little as 250 milligrams. per tablet. More preferably, for the laxative effect, each tablet will contain approximately 500 milligrams of methylcellulose, and the patient may take 1 to 2 tablets per dose. This dosage, of 1000 milligrams, should adequately provide an optimal laxative efficacy. Accordingly, a preferred scale of methylcellulose per tablet is optimally about 450 to 550 milligrams, preferably about 500 milligrams.; or alternatively, from about 200 to about 300 milligrams for a smaller tablet, preferably about 250 milligrams; or even in increments of approximately 125 milligrams per tablet, that is, from 75 to 175 milligrams per tablet. Although preferably the compressed tablets are not coated, if desired, they can be coated with any suitable coating agent well known in the art. Suitably, the coating agents are those used for immediate release purposes, and will dissolve in the gastric juices. These coating agents are well known to those skilled in the art, and include, but are not limited to hydroxypropylmethylcellulose, or methylcellulose, or Orange Opadry II at 20 weight percent / weight in water. As will be readily seen from the working examples, there are several combinations of intra- and extra-granular mixing that are possible using the ingredients herein. All are encompassed within the scope of this invention. In general, high viscosity methylcellulose, such as Methocel A4M, will first be granulated with a binder, such as povidone, a wetting agent, such as sodium lauryl sulfate, and a suitable coloring agent to form the intragranular mixture, which is then granulate Then these granular components are mixed with additional wetting agents, and disintegrating agents, and finally mixed with lubricant. This final granular mixture is then mixed and compressed into the tablets of the present invention. Accordingly, an aspect of the present invention is a process for the preparation of a tablet formulation, which comprises: a) mixing together to form an intragranular, high viscosity methylcellulose blend of > 3000 cps, a wetting agent, povidone or sodium starch glycolate, and an edible calcium salt; and b) adding to the mixture of step a), an aqueous solution of PVP, or alternatively spraying the mixture of step (a) with an aqueous solution of PVP; and prepare granulates; and c) mixing together an extragranular mixture of an edible calcium salt, a wetting agent; a lubricating agent; povidone or sodium starch glycolate, or a mixture thereof; and d) compacting the granulates of step (b) with the extragranular mixture of step (c).

Another aspect of the present invention is a process for the manufacture of a pharmaceutical tablet, which process comprises mixing: a) granulates comprising high viscosity methylcellulose of > 3000 cps, a wetting agent, povidone or sodium starch glycolate, an edible calcium salt; and b) mixing together an extragranular mixture of an edible calcium salt, a wetting agent; a lubricating agent; povidone or sodium starch glycolate, or a mixture thereof; and c) compacting the granulates of step (b) with the granular mixture of step (a); and d) compressing into a tablet.

Another aspect of the present invention is the method for relieving constipation, by increasing the water content of the evacuation, or by providing a lubricating effect to the evacuation in a mammal in need thereof, which method comprises administering to this mammal an effective amount of a high viscosity methylcellulose compressed in a tablet with a suitable diluent. METHODS OF PREPARATION The following examples illustrate the invention, but are not intended to limit its scope. All parts and percentages are by weight, unless otherwise indicated. The disintegration time of the formulations described in the following tables was obtained using a conventional disintegration apparatus.

EXAMPLE 1 TABLE I The process for preparing the rapidly disintegrating methyl cellulose tablet is performed using specified amounts of ingredients, such as those mentioned in TABLE I above, using the following steps: 1. Preparation of Povidone K29 / 32 Solution (PVP) The amount Specified PVP was weighed and added to the weighed amount of water, and stirred until all the PVP was completely dissolved. 2. Preparation of Phase A Exactly heavy amounts of Methocel A4M, dibasic calcium phosphate dihydrate, sodium lauryl sulfate, and coloring agent, such as any Aluminum FD &C lacquer, were transferred to a high shear granulator Key Hi-shear , and mixed for about 10 minutes, with a speed of the propeller of 135 rpm, and a speed of the chopper at 10 percent. The PVP solution was sprayed onto the mixture in the granulator at a rate of about > 200 milliliters / minute. Once the addition of PVP solution was finished, the chopper was stopped. The mixing was continued in the granulator until the resistance was read at approximately 130-135 watts, and it was observed that the time reached this wattage. A sample of the wet granulation was removed to record the loss on drying (% LOD). The wet granules were dried in the Aeromatic Fluid bed dryer in portions until the percentage loss reading on drying approached 1.0-3.0 percent. The temperature of the air in the fluid bed dryer was maintained at about 90-95 ° C, and the sample was found to be dry at an outlet air temperature of about 32-52 ° C. The dried granules were milled through a # 12 mesh in the Fitz Mill at a high speed. The granules were weighed, and the percent yield was calculated. The moisture content was measured for the dry granules. A sample of the granules was removed, and analyzed for particle size distribution, bulk and tap density, flow rate, and moisture studies. The granules were weighed, and the ingredients of phase B were calculated based on the weight of the remaining granules. 3. Preparation of the Final Mixture To the ground and heavy granules produced in Phase A above, the specified amounts of sodium lauryl sulfate, sodium starch glycolate, were added.

® (Explotab), and dibasic calcium phosphate dihydrate, in mixer V, and mixed for approximately 10 minutes. Magnesium stearate was then added to the mixture, and mixed for an additional 3 minutes. Samples were removed from different sections of the mixer V, and subjected to analyze the uniformity of the mixture. A sample of the final mixture was analyzed to determine particle size distribution, bulk and tap density, flow rate, and moisture studies. Then the granules were weighed 4. Compression of Methylcellulose Tablets The final mixture was loaded into the hopper of a single-hole 'F' Stokes tablet press, and compressed into caplets with a suitable tool. The desired target hardness is between 10 and 25, preferably from 8 to 12 SCU, a preferred target weight of each tablet of less than 750 milligrams; an estimated brittleness of less than 2.0 percent, more preferably less than 1.0 percent, and objective disintegration times of less than 30 minutes in water and acid (shorter disintegration times, less than 10 minutes, more preferably less than 8, are preferred minutes, in 0.1 N HCl, and less than 15 minutes in water, more preferably approximately 8 minutes). The tablets were packed in Ziplock bags. The tablets were tested to determine weight variation, hardness, acid and water disintegration, brittleness, moisture (percent loss on drying), thickness, viscosity, and uniformity of contents. The formulation of TABLE I exhibited a disintegration time of less than 5 minutes in HCl 0. IN, and less than 9 minutes in water, by the conventional USP method, using the disintegrating apparatus with disks. The disintegration time for the formulation of TABLE I, Example 1, was less than 5 minutes in HCl 0. IN, and was less than 9 minutes in water. It is noted that Examples 2 to 6, and 11 to 15, are formulations based on Avicel, and Examples 7 to 10 are starch-based formulations, which do not contain edible calcium salt excipients. These are merely for purposes of illustration, and may be formulated to include the edible calcium salts as desired, using the teachings of this invention, and working examples 1, and 16 through 23. EXAMPLE 2 ® A formulation containing both Avicel PH 101 and ® Exploit, m- and extra-granularly, as shown in the TABLE II below, exhibited an average disintegration time of less than 1 minute in HCl 0. IN at 37 + 0.5 ° C, using the automated disintegration apparatus.

TABLE II EXAMPLE 3 A formulation containing Avicel PH 101 ® ® intragranularly, Avicel PH 102 extragranular, and Explotab intra- and extra-granularly, as shown below in TABLE III, exhibited an average disintegration time of less than 3 minutes in HCl 0. IN at 37 + 0.5 ° C, using the automated disintegration apparatus. TABLE III EXAMPLE 4 ® A formulation containing Avicel PH 101 ® mtragranularly, Avicel PH 102 extragranular, and Explotab intra- and extra-granularly, as shown in TABLE IV below, exhibited an average disintegration time of less than 2 minutes in 0.1N HCl a 37 ± 0.5 ° C, using the automated disintegration apparatus. TABLE IV In an alternative embodiment of Example 4, a coated version of the formulation shown in TABLE IV was tested to determine the disintegration time. The coating solution used was Orange Opadry II at 20 percent weight / weight in water. The average disintegration time of the coated tablets was less than 1 minute in HCl 0. IN at 37 + 0.5 ° C using the automated disintegration apparatus. EXAMPLE 5 ® A formulation containing Avicel PH 101 ® ® mtragranularly, Avicel PH 102 extragranular, and Explotab intra- and extra-granularly, as shown in TABLE V below, exhibited a lower average disintegration time of 1 minute in 0.1N HCl at 37 + 0.5 ° C, using the automated disintegration apparatus. TABLE V EXAMPLE 6 ® A formulation containing Avicel PH 101 ® intragranularly, Avicel PH 102 extragranular, and nothing of ® Explotab, as shown in TABLE VI below, exhibited an average disintegration time of less than 3 minutes in HCl 0. 1N, and less than 2 minutes at 37 + 0.5 ° C, using the automated disintegration apparatus. Disintegration times using the conventional apparatus were about 1 minute in acid, and less than 2 minutes in water.

TABLE VI EXAMPLE 7 A formulation containing corn starch intragranularly, extragranular 1500 starch, and none of ® Explotab, as shown in Table VII, exhibited an average disintegration time of less than 16 minutes in HCl 0. ÍN a 37 + 0.5 ° C, using the automated disintegration apparatus. TABLE VII EXAMPLE 8 A formulation containing mtragranular corn starch, 1500 extragranular starch, and Explotab ® intragranular, as shown in Table VIII, exhibited an average disintegration time of less than 14 minutes in HCl 0. IN at 37 + 0.5 ° C, using the automated disintegration apparatus. TABLE VIII EXAMPLE 9 A formulation containing mtragranularly corn starch, extragranular 1,500 starch, and intra- as well as extra-granular Explotab®, as shown in Table IX, exhibited an average disintegration time of less than 13 minutes in 0.1 N HCl. at 37 + 0.5 ° C, using the automated disintegration apparatus. TABLE IX EXAMPLE 10 A formulation containing corn starch metatranularly, extragranular 1500 starch, and intra- as well as extra-granular explootab (in higher amounts than those shown above in Example 9, TABLE IX), as shown in TABLE X , exhibited an average disintegration time of less than 11 minutes in 0.1N HCl, and less than 18 minutes in water at 37 + 0.5 ° C, using the automated disintegration apparatus. TABLE X EXAMPLE 11 Various formulations containing Avicel were made ®. PH 101 mtragranularly, and different levels of Avicel PH ® Extragranular ® 102 (as shown in Examples 6, 7, and 8 above), to observe its effect on the disintegration time of the tablets. The formulation of the following Table XI, exhibited an average disintegration time of less than 1 minute in HCl 0. IN, and less than 2 minutes in water at 37 +. 0.5 ° C, using the automated disintegration apparatus. The conventional disintegration apparatus yielded less than 1 minute in both acid and water.

TABLE XI EXAMPLE 12 The formulation of TABLE XII exhibited an average disintegration time of less than 5 minutes in HCl 0. IN, and less than 7 minutes in water at 37 + 0.5 ° C, using the automated disintegration apparatus. The conventional disintegration apparatus yielded less than 5 minutes in acid, and less than 8 minutes in water. TABLE XII EXAMPLE 13 The formulation of TABLE XIII exhibited an average disintegration time of less than 10 minutes in 0.1 N HCl, and less than 14 minutes in water at 37 + 0.5 ° C, using the automated disintegration apparatus. The conventional disintegration apparatus yielded less than 14 minutes in acid, and less than 22 minutes in water. TABLE XIII EXAMPLE 14 Two formulations containing Avicel PH were made ® 101 intragranularly, with different levels of Avicel PH ® Extragranular ® 200 (shown in TABLES XIV and XV below), to observe the effect on the disintegration time of the tablets. The formulation of TABLE XIV exhibited an average disintegration time of less than 7 minutes in 0.1N HCl, and less than 9 minutes in water at 37 + 0.5 ° C, using the automated disintegration apparatus. The conventional disintegration apparatus yielded less than 8 minutes in acid, and less than 13 minutes in water. TABLE XIV EXAMPLE 15 The formulation of TABLE XV exhibited an average disintegration time of less than 4 minutes in 0.1 N HCl, and less than 7 minutes in water at 37 ± 0.5 ° C, using the automated disintegration apparatus. The conventional disintegration apparatus yielded less than 5 minutes in acid, and less than 9 minutes in water. TABLE XV EXAMPLE 16 TABLE XVI shows a formulation containing a calcium source from the intragranular and extragranular excipient, calcium phosphate dihydrate dibasic, with extragranular Explotab. The formulation of TABLE XVI exhibited an average disintegration time of less than 6 minutes in 0.1N HCl, and less than 9 minutes in water at 37 + 0.5 ° C, using the automated disintegration apparatus. The conventional disintegration apparatus yielded less than 5 minutes in acid, and less than 12 minutes in water. TABLE XVI Methylcellulose traable tablets Formula g / tablet (% w / w) Ingredient Phase A Methocel A4M 0.5000 66.93 Dibasic calcium phosphate dihydrate 0.0370 4.95 Sodium lauryl sulfate 0.0015 0.20 Yellow F, D, and C # 6 0.0010 0.13 Povidone 29K / 32 0.0480 6.43 Deionized water c.s. c.s.

Phase B Phase A 0.5875 78.65 Sodium lauryl sulfate 0.0015 0.20 Sodium starch glycolate 0.0260 3.48 Dibasic calcium phosphate dihydrate 0.1245 16.67 Magnesium stearate 0.0075 1.00 TOTAL 0.7470 100.00 EXAMPLE 17 The following TABLE XVII shows a formulation containing a calcium source from the intra- and extra-granular excipient, dibasic calcium phosphate dihydrate, with a higher amount of extragranular Explotab ® than in the Example 17. The formulation of TABLE XVII exhibited an average disintegration time of less than 9 minutes in 0.1N HCl, and less than 14 minutes in water at 37 + 0.5 ° C, using the automated disintegration apparatus. The conventional disintegration apparatus yielded less than 6 minutes in acid, and less than 12 minutes in water. TABLE XVII EXAMPLE 18 In the following TABLES XVIII and XIX (Example 19) are shown formulations containing a source of calcium from the intra- and extra-granular excipient, dibasic calcium phosphate dihydrate, with different levels of extragranular explotab, in combination with a similar amount of ® Mtragranular explotab. The formulation of TABLE XVIII exhibited an average disintegration time of less than 6 minutes in HCl 0. IN, and less than 11 minutes in water at 37 + 0.5 ° C, using the automated disintegration apparatus. TABLE XVIII Traceable Methylcellulose Tablets Formula g / tablßta (% w / w) Ingredient Phase A Methocel A4M 0.5000 65.19 Dibasic calcium phosphate dihydrate 0.0370 4.82 Sodium lauryl sulfate 0.0015 0.20 Sodium starch glycolate 0.0230 3.00 Yellow F, D, and C # 6 0.0010 0.13 Povidone 29K / 32 0.0480 6.26 Deionized water C.S. c.s.

Phase B Phase A 0.6105 79.60 Sodium lauryl sulfate 0.0015 0.20 Sodium starch glycolate 0.0230 3.00 Dibasic calcium phosphate dihydrate 0.1245 16.23 Magnesium stearate 0.0075 0.97 TOTAL 0.7670 100.00 EXAMPLE 19 The formulation of TABLE XIX exhibited an average disintegration time of less than 9 minutes in HCl 0. IN, and less than 14 minutes in water at 37 + 0.5 ° C, using the automated disintegration apparatus.

TABLE XIX EXAMPLE 20 In the following TABLES XX and XXI (Example 21) are shown formulations containing a calcium source from the intra- and extra-granular excipient, dibasic calcium phosphate dihydrate, with extragranular Explotab. The formulation of TABLE XX exhibited an average disintegration time of less than 5 minutes in 0.1N HCl, and less than 13 minutes in water at 37 + 0.5 ° C, using the automated disintegration apparatus. TABLE XX EXAMPLE 21 The formulation of TABLE XXI exhibited an average disintegration time of less than 7 minutes in 0.1N HCl, and less than 9 minutes in water at 37 + 0.5 ° C, using the conventional disintegration method. TABLE XXI EXAMPLE 22 TABLE XXII indicates a formulation containing a calcium source from the intra-and extra-granular excipient, anhydrous calcium phosphate with extragranular Explotab. The formulation of TABLE XXII exhibited an average disintegration time of less than 11 minutes in HCl 0. IN, and less than 19 minutes in water at 37 + 0.5 ° C, using the conventional disintegration apparatus. TABLE XXII EXAMPLE 23 TABLE XXIII indicates a formulation containing a calcium source from the intra-and ® ® extra-granular excipient, tribasic calcium phosphate WG, with extragranular Explotab. The formulation of TABLE XXIII exhibited an average disintegration time of less than 13 minutes in HCl 0. IN, and less than 24 minutes in water at 37 + 0.5 ° C, using the conventional disintegration apparatus. TABLE XXIII All publications, including, but not limited to, patents and patent applications, cited in this specification, are hereby incorporated by reference as if each individual publication were specifically and individually indicated as being incorporated by reference herein, as if fully stipulated. The foregoing description fully discloses the invention, including its preferred embodiments. Modifications and improvements of the modalities specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art can, using the above description, utilize the present invention to its fullest extent. Accordingly, the examples herein should be interpreted merely as illustrative and not as a limitation of the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed, are defined as follows.

Claims (28)

1. CLAIMS 1. A rapidly disintegrating tablet for oral administration, which tablet comprises a compacted mixture of methyl cellulose having a viscosity of > 1000 centipoise, and an edible calcium salt. The tablet according to claim 1, wherein the edible calcium salt is dibasic calcium phosphate dihydrate, anhydrous calcium phosphate, tribasic calcium phosphate; or mixtures thereof. 3. The tablet according to claim 1 or 2, which further comprises a binder. 4. The tablet according to claim 3, wherein the binding agent is PVP, hydroxypropylcellulose, hydroxypropylmethylcellulose, acacia, gelatin, tragacanth, pregelatinized starch, or starch. 5. The tablet according to claim 4, wherein the binder is PVP. 6. The. tablet according to claim 1 or 2, which further comprises a disintegrating agent. The tablet according to claim 6, wherein the disintegrating agent is sodium starch glycolate, sodium carboxymethyl cellulose, Ac-di-sol, carboxymethyl cellulose, veegum, alginates, agar, guar, tragacanth, locust bean seed, karaya, pectin, or crospovidone. 8. The tablet according to claim 7, wherein the disintegrating agent is sodium starch glycolate. 9. The tablet according to claim 8, wherein the sodium starch glycolate is present in an amount of about 3 to about 8 weight percent / weight. 10. The tablet according to claim 1, which further comprises a wetting agent. 11. The tablet according to claim 10, wherein the wetting agent is sodium lauryl sulfate. 12. The tablet according to claim 1, which further comprises a lubricating agent. 13. The tablet according to claim 12, wherein the lubricating agent is magnesium stearate. The tablet according to claim 1, wherein the methylcellulose has a viscosity of > 2000 centipoises. 15. The tablet according to claim 14, wherein the methylcellulose has a viscosity of > 3000 centipoises. The tablet according to claim 15, wherein the methylcellulose has a viscosity of > 4000 centipoises. 17. The tablet according to claim 1, wherein the methylcellulose is Methocel A4M. The tablet according to claim 1, wherein the edible calcium salt is dibasic calcium phosphate dihydrate, and is present in a ratio of methylcellulose to calcium of from about 2 to about 4: 1. 19. The tablet according to claim 1, wherein the edible calcium salt is anhydrous calcium phosphate, and is present in a proportion of methylcellulose to calcium of about 2 to about 4.1. The tablet according to claim 1, wherein the edible calcium salt is tribasic calcium phosphate, and is present in a ratio of the methylcellulose to the tribasic calcium phosphate, from about 2 to about 4: 1. The tablet according to claim 1, which further comprises additional excipients and diluents, in the proportion of: sodium lauryl sulfate: Explotab: Tribasic calcium phosphate: Povidone 29K / 32: Magnesium stearate, include: 0.40: 3.5 : 21.6: 6.4: 1.0; or sodium lauryl sulfate: Explotab: Anhydrous calcium phosphate: Povidone 29K / 32: Magnesium stearate, include: 0. 40: 3.5: 21.6: 6.4: 1.0. 22. The tablet according to claim 1 or 2, wherein the methylcellulose is present in an amount of about 450 to about 550 milligrams. 23. The tablet according to claim 1 or 2, wherein the methylcellulose is present in an amount of about 200 to about 300 milligrams. 24. A rapidly disintegrating tablet for oral administration, whose tablet comprises methylcellulose having a viscosity of >; 3000 centipoises; dibasic calcium phosphate, sodium lauryl sulfate, Povidone; Sodium starch glycolate, and magnesium stearate. 25. A process for preparing a tablet formulation, which comprises compacting a mixture of: a) mixing together to form an intragranular mixture, high viscosity methylcellulose of > 3000 cps, a wetting agent, povidone or sodium starch glycolate, and an edible calcium salt; and b) adding to the mixture of step (a), an aqueous solution of PVP, or alternatively spraying the mixture of step (a) with an aqueous solution of PVP; and prepare granulates; and c) mixing together an extragranular mixture of an edible calcium salt, a wetting agent; a lubricating agent; povidone or sodium starch glycolate, or a mixture thereof; and d) compacting the granulates of step (b) with the extragranular mixture of step (c). 26. The process according to claim 25, wherein the edible calcium salt is dibasic calcium phosphate dihydrate, anhydrous calcium phosphate, tribasic calcium phosphate; or mixtures thereof. 27. The process according to claim 26, wherein the edible calcium salt is dibasic calcium phosphate. 28. A process for the manufacture of a pharmaceutical tablet, which process comprises mixing: a) granulates comprising high viscosity methylcellulose of > 3000 cps, a wetting agent, povidone or sodium starch glycolate, an edible calcium salt; and b) mixing together an extragranular mixture of an edible calcium salt, a wetting agent; a lubricating agent; povidone or sodium starch glycolate, or a mixture thereof; and c) compacting the granulates of step (b) with the granular mixture of step (a); and d) compressing into a tablet.