CZ2000631A3 - Tablet - Google Patents

Abstract

The present solution deals with new therapeutic means for oral administration which comprises compressed a mixture of methylcellulose with a viscosity greater than 1 Pas, preferably more than 3 pas and calcium salt. The resource is fast disintegrating in 0.1N HCl and in water and satisfying USP standards for disintegration. Next, the solution deals with the method of preparation and production of such a composition.

Description

FAST-FADING ORAL ADMINISTRATIVE TABLETS

Technical field

The invention relates to an improved process for the preparation of compressed tablets containing methylcellulose that satisfies USP standards for disintegration.

BACKGROUND OF THE INVENTION

The history of cellulose ethers such as methylcellulose and carboxymethylcellulose suggests that they are effective as bulking agents. Their mechanism of action involves both increasing water content and stool volume, as well as increasing stool lubricity. This will release the constipation.

Cellulose ethers may be administered as bulking agents in dosage forms including tablets, suspensions, bulking powders; sugar-free powders or compositions containing high amounts of sugar.

Cellulose ethers, administered as a suspension in water, may contain high concentrations of sucrose or other sugars and odors. In such compositions, the sugar is competitive with cellulose ethers for available water, thus preventing sufficient hydration of the cellulose ethers to form a gel. The advantage of using a suspension is that the cellulose ether is adequately dispersed to avoid significant clumping in the digestive tract. However, these suspensions are viscous, partially gelatinous and perceptually unacceptable to consumers. Another drawback is the unpleasant taste of the suspension, which relates to the sticky mouth feel and the extreme sweetness of such a suspension. Thus, these dosage forms do not achieve significant consumer acceptance.

Bulk cellulose ether formulations often include clumping of individual particles and gel formation. They remain undissolved during the passage through the digestive tract. Administration of bulk powders

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9 99

9 9 • 9 999 999

Furthermore, it causes convulsive contractions, nausea and vomiting in some patients. Bulk powders are therefore not the preferred dosage form for cellulose ethers.

The tasteful and visually desirable bulk powders are, however, made by adding water or other aqueous liquids to the dry powder mixture of the water-soluble cellulose ethers and the dispersant of the sugar component, typically sugar. This technology is described in South Africa Patent Application No. 84,1044, issued September 26, 1984. The risk of these compositions is a nutritional content of about 4,000 calories per dose, mainly due to the high sugar content. This high calorific value is not acceptable for the average consumer or user suffering from blood sugar disorders, especially diabetics. Older people are normally the normal population, suffering from constipation and more likely to recurrent laxatives. They also usually suffer from blood sugar disorders. Consumption of large amounts of sugar can make these blood sugar disorders worse.

Sugar coated cellulose ethers are offered as alternatives to bulk powders that contain high amounts of sugar. Such compositions have: 1) a minor amount of sugar, such as natural sugar or a combination of sugars such as sucrose, glucose, fructose or a solid portion of corn sugar; 2) lower caloric value; 3) are readily soluble in aqueous liquids.

Citruel® Orange Flavor, a laxative volume containing methylcellulose as an active ingredient, was first introduced in 1986. This product contains 15 g sucrose in a 19 g adult dose, which corresponds to a 2 g methylcellulose dose. In order to reduce the sugar content of this composition, a natural, low-calorie flavoring prescription containing only 1 g of sucrose has been developed in 1988. Further patent protection of this product focuses on the production of sugar-free powders and in fact non-caloric powders. The product has a non-sugar sweetening dispersant, other excipients and fragrance and was put on sale in 1991 as Sugar Free Citruel® Orange Flavor.

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·. · · ··· · ··· · · · · · ♦ · * ·· ·· ···

There remains a need in science to improve solid dosage forms of bulk disintegrants, preferably methylcellulose, which is suitable for acceptance and transport, is sugar-free and easily administered to a consumer having, for example, a blood sugar disorder or diabetics.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for the preparation of methylcellulose tablets that are readily soluble and meet USP standards for disintegration. The methylcellulose is compressed into tablets which contain the edible calcium salt in preferred weight ratios. In particular, the tablets disintegrate in vitro in 0.1N hydrochloric acid and water at 37 ± 0.5 ° C.

It is well known that tabletted cellulose ethers are not readily soluble in the gastrointestinal tract because cellulose ethers are highly hygroscopic. The outer part of the tablet is intended to form gel-like hydrates, which prevent tablet disintegration and greatly retard hydration of the inner part of the tablet. The present invention overcomes these identified problems in the art and includes the preparation of a novel composition and a process for preparing fast disintegrating methylcellulose tablets.

The tablets are prepared in a novel manner, which includes a high shear wet granulation method, followed by a fluidized bed drying, crushing, mixing with other ingredients and compression.

The present invention relates to methylcellulose tablets comprising methylcellulose with a viscosity of greater than 1 PaS and at least one excipient selected from edible calcium salts. It will be appreciated that the composition will also contain diluents and fillers well known to those skilled in the art.

The tablets of the present invention are advantageous for their convenient administration and rapid disintegration as compared to other methylcellulose dosage forms. This is in contrast to tablets · «9999 ·« «9 • 9 9 9 9« 9 9 9 9 9 • 9 999 99 9

9

99 99

9 9 9 9 • 9 9 9 9 9 9 9 9 9

9

999 99 99 with methylcellulose, constituted as 100% by weight of methylcellulose in 0.5 g tablets which did not show disintegration in 0.1N HCl solution after two hours using a conventional dissolution apparatus. The tablets offered will disintegrate in 0.1N HCl after about 20 to 30 minutes, preferably after 10 to 19 minutes, and most preferably less than after 10 minutes. In water, these tablets will disintegrate after 25 to 30 minutes, preferably after 15 to 24 minutes and more preferably less than after 15 minutes.

It is found that the low molecular weight (mw) of methylcellulose is less effective for use as a laxative and hence less desirable for use in the formation of rapidly disintegrating tablets. Thus, higher molecular weight is both desirable and necessary in the present invention. The fibers must have sufficient viscosity to form a gel and retain water in the intestine to provide an increase in stool volume and soften the stool for use as a laxative.

Using the test procedures for methylcellulose under standard conditions such as those found in USP XXII, p. 894, Apparent Viscosity method for methylcellulose or discussed in the Handbook of Pharmaceutical Excipients, AphA, preferred methylcellulose for use will have a viscosity of more than 1 PaS, preferably more than 2 PaS, more preferably more than 3 PaS and most preferably more than 4 PaS. A higher molecular weight of methylcellulose than those described is also desirable, however, the technical availability of methylcellulose types will be limited by the limiting properties. Currently, the upper limit of technical availability is 6 PaS, which is included within the scope of the invention. One currently available methylcellulose product is Methocel A4M, prepared by Dow Chemical Company, Midland Michigan as Dow Methocel A4M, which has a viscosity of about 3 PaS to 5.6 PaS, which is 75 to 140% of the target viscosity desired herein.

Some of the auxiliary diluents or fillers for use in the composition are preferably swelling agents and may include, but are not limited to, various types of microcrystalline cellulose, such as " 0 " · · · «Φ 0 0 00 00 0 0 Φ 0 ·

0 000 0 «» * 00 00 0

0 00 0 0000

00 00 00 00 00 00

Avicel PH 101, Avicel PH 102 and Avicel PH 200; maize starch or

Starch 1500.

Edible calcium salts for use include, but are not limited to, dibasic calcium phosphate dihydrate, anhydrous dicalcium phosphate and dicalcium phosphate, or mixtures thereof.

A preferred edible calcium salt is dibasic calcium phosphate dihydrate which also provides good compressibility.

If microcrystalline cellulose is added, it is preferably about 50-180 microns in diameter, more preferably about 50. Avicel PH 101 has a mean particle diameter of about 50; Avicel PH 102 has a mean particle diameter of about 100 and Avicel PH 200 has a mean particle diameter of about 190 microns. Preferably, the microcrystalline cellulose is Avicel PH 101.

It is noted that the ratio of methylcellulose to edible calcium salt and co-diluents will depend on the diluent selected and is determined by those skilled in the art with the accuracy of the necessary ratios.

Suitable ratios for each diluent are described below:

Methylcellulose: dibasic calcium phosphate dihydrate 2 to 4: 1, preferably 2.6 to 3.1: 1;

Methylcellulose: anhydrous calcium phosphate 2 to 4: 1, preferably

3.1: 1

Methylcellulose: calcium phosphate, WG® 2 to 4: 1, preferably 3.1: 1

Methylcellulose: microcrystalline cellulose 2: 1 to 14: 1. Preferably for

Avicel PH 101 2.2 to 13.5: 1; for Avicel PH 102 2.4 to 8.3: 1 and for

Avicel PH 200 2.4 to 4: 1.

Methyl cellulose: maize starch 7.5 to 15, preferably 13.5: 1

Methyl cellulose: Starch 1500, 2.0 to 5.0: 1, preferably 2.4: 1 · 9999 99 ··· · 99 · 99 1 9 9 9 9 9 9 9 9

9 9 9 9 9 9 1

09 90 009 99 09

6 Methyl cellulose: Explotab, 5 to 25: 1, preferably 8.1 to 21.3: 1

It is found that the composition must also have, with the edible calcium salt, a component that holds the granule together, i. binder. A preferred binder is PVP or alternative agents listed below.

The composition may contain, in addition to the edible calcium salt (s) or diluents or fillers and binders described above, adjuvants such as, but not limited to, wetting agents, (super) disintegrants, other binders, dyes or pigments and lubricants which are: preferably used to prepare a tablet that is easily wetted and rapidly degrades in 0.1N hydrochloric acid and water, a USP test standard, tested for methylcellulose.

A preferred wetting agent is sodium lauryl sulfate.

A preferred lubricant is magnesium stearate.

A preferred binder is polyvinylpyrrolidone, or PVP, such as Povidone 29K / 32. The PVP is preferably present in an amount of about 4 to 6.5% by weight.

A preferred disintegrant is a sodium starch glycolate such as Explotab®. The sodium starch glycolate is preferably present in an amount of about 3 to 8% by weight.

Since various excipients and diluents will be formulated together and used in combination herein, the proposed weight percent ratios for the various compounds are given below.

While not all of these ratios include edible calcium salts, they merely illustrate the invention, and those skilled in the art will readily understand how to make an article of the invention with the addition of edible calcium salts.

Sodium lauryl sulfate: Explotab: dibasic calcium phosphate dihydrate: Povidone 29K / 32: magnesium stearate includes: 0.380.40: 3.5-7.9: 20.6-24.8: 4.0-6.5: 0.5- 1.0 • · φ · · φ

Sodium Lauralsulphate: Explotab: Calcium phosphate WG®: Povidone 29K / 32: Magnesium stearate includes: 0.40: 3.5: 21.6: 6.4: 1.0

Sodium lauryl sulfate: Explotab: anhydrous calcium phosphate: Povidone 29K / 32: magnesium stearate includes: 0.40: 3.5: 21.6: 6.4: 1.0

Methylcellulose: sodium lauryl sulfate (SLS) 60 to 170: 1, preferably 155: 1 to 170: 1;

Methylcellulose: Povidone, preferably PVP 29K / 32, 8 to 22: 1, preferably

10.4: 1 to 16.7: 1;

Methylcellulose: magnesium stearate 50 to 150: 1, preferably 58 to 132: 1;

Sodium lauryl sulfate: Explotab: Avicel PH 101®: Povidone 29K / 32: magnesium stearate include: 0, 35-0, 46: 3.05-6, 17: 4.38-27.13: 4.38-6, 66: 0.7 61.14

Sodium lauryl sulfate: Explotab: Avicel PH 102®: Povidone 29K / 32: magnesium stearate includes: 0.35-0.46: 4.9-6, 17: 9.21-25.53: 4.38-6, 66 : 0.761.14

Sodium lauryl sulfate: Avicel PH 200®: Povidone 29K / 32: magnesium stearate includes: 0.38-0.42: 19.27-25.53: 5.99-6, 66: 0, 94-1.04

Sodium lauryl sulfate: Explotab: corn starch: Povidone 29K / 32: magnesium stearate include: 0.36-0.38: 3.66-7.07: 4.35-4.68: 4.35-4.68: 0,880,95

Sodium lauryl sulfate: Explotab: Starch 1500®: Povidone 29K / 32: magnesium stearate includes: 0.36-0.38: 3.66-7.07: 24.05-25.89: 4.354.68: 0.88- 0.95

It is not desirable to limit certain excipients listed above, alternative agents may also be used.

Alternative lubricants to magnesium stearate include, but are not limited to, calcium stearate, sodium stearate, Cab-O-Sil,

Syloid, stearic acid and talc.

Alternative binders to PVP include, but are not limited to, hydroxypropylcellulose, hydroxypropylmethylcellulose, acacia, gelatin, tragacanth, pregelatinized starch, and starch.

Alternative disintegrants to Explotab® include, but are not limited to, sodium carboxymethylcellulose, AC-di-sol®, carboxymethylcellulose, veegum, alginates, agar, guar, tragacanth, locust, karaya, pectin, and cross-linked polyvinylpyrrolidone.

Alternative wetting agents to sodium lauryl sulfate include, but are not limited to, magnesium lauryl sulfate.

All of these compositions can be prepared with or without sugar. The advantage of a sugar-free composition is that it can be administered without fear to consumers with blood sugar disorders or diabetics if they need such a composition.

Another advantageous feature of the present invention is that the compositions comprise calcium as well as calcium hydrogen phosphate dihydrate. These formulations will, for example, contain about 80 mg per dose, an expected formulation of 0.5g per tablet X 2 tablets per dose of methylcellulose. If desired, the amount of calcium in these tablets may be increased to provide increased therapeutic value to the consumer.

The amount of methylcellulose present in each dose, as well as the amount of doses of daily laxative, will depend somewhat on the age, sex, weight of the patient, severity of the individual patient's problems, the judgment of the attending physician, the individual taste and habits of the patient. Accordingly, the tablets of the invention are preferably administered in a single dose which may contain 500 to 1000 mg methylcellulose per tablet, or in multiple small doses containing less than 250 mg per tablet. Each tablet will, for laxative effect, most preferably contain about 500 mg methylcellulose and the patient may take 1 to 2 tablets.

per dose. This dosage of 1000 mg will adequately provide an optimal laxative effect. Thus, the preferred range of methylcellulose in the tablet is optimally 450 to 550 mg, preferably about 500 mg; or alternatively 200 to 300 mg for a smaller tablet, preferably about 250 mg, or even in additions of about 125 mg per tablet, i. 75 to

150 mg per tablet.

While preferably compressed tablets are uncoated, if desired, they may be coated with a suitable coating well known in the art. Suitable coatings are used for direct release and will be dissolved in gastric juice. Such coatings are well known to those skilled in the art and include, but are not limited to, hydroxypropyl methylcellulose or methylcellulose or 20% by weight of Opadry II, an orange flavor.

As will be seen in the examples, there are various combinations of intra and extragranular compositions that can be used as ingredients. All are included within the scope of the invention. Generally, a high viscosity methylcellulose such as Methocel A4M will first be granulated with a binder such as polyvinylpyrrolidone, a wetting agent such as sodium lauryl sulfate and a suitable colorant to form an intragranular mixture which is then granulated. These granules! the ingredients are mixed with auxiliary wetting and disintegrating agents and finally mixed with the lubricant. The resulting granules! the mixture is then mixed and compressed into tablets according to the invention.

Thus, an aspect of the present invention is a method of preparing tablets comprising:

(a) Blend highly viscous methylcellulose of more than 3 PaS, a wetting agent, polyvinylpyrrolidone or sodium starch glycolate and an edible calcium salt until the intragranular mixture is formed;

b) Add an aqueous PVP solution to the mixture of step (a) or spray the mixture of step (a) with an aqueous PVP solution;

0 0 0 0 0 0 0 0 0 0 0

00 a granulate is prepared;

c) blending the extragranular mixture of the edible calcium salt, wetting agent, lubricant, polyvinylpyrrolidone or sodium starch glycolate or a mixture thereof;

d) Compress the granulate of step (b) with the extragranular mixture of step (c).

Another aspect of the present invention is a method of releasing constipation by increasing the water content of the stool or providing a laxative effect on the stool in mammals in need thereof. The method comprises administering to said mammal an effective amount of highly viscous methylcellulose, compressed into tablets with a suitable diluent.

DETAILED DESCRIPTION OF THE INVENTION

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 times of the compositions described were obtained using conventional disintegration devices.

EXAMPLE 1

TABLE

Tablets with methylcellulose for oral administration

Prescription g / tablet

Component

Phase A% by weight

Methocel A4M

Hydrogen phosphate dihydrate

0.5000

0,0370

67.27

4.98

calcium Sodium lauryl sulfate 0.0015 0.20 Dye / pigment 0,0010 0.13 Povidone 29K / 32 0,0480 6.46 Deionized water according to need according to need Phase B Phase A 0.5875 79.04 Sodium lauryl sulfate 0.0015 0.20 Sodium starch glycolate 0,0260 3.50 Hydrogen phosphate dihydrate calcium 0.1245 16, 75 Magnesium stearate 0.0038 0.51 TOTAL 0.7433 100.00

The method for preparing rapidly disintegrating methylcellulose tablets is carried out using the determined amounts of the ingredients as mentioned in Table 1 above, using the following steps.

1. Preparation of Povidone K29 / 32 (PVP) solution

The determined amount of PVP is weighed and added to the weighed amount of water and mixed until all PVP is completely dissolved.

2. Preparation of phase A

Precisely weighed amounts of Methocel A4M, dibasic calcium phosphate dihydrate, sodium lauryl sulfate and dye, as well as some suitable FD&C aluminum paints, are transferred to the Key-Hi shear granulator and mixed for about 10 minutes while rotating the impeller at 135 rpm and speed interrupter at 10%. The PVP solution is sprayed onto the mixture in the granulator at

Rates of more than 200 ml / min. When the addition of the PVP solution is complete, the device stops. Stirring is continued in the granulator up to a resistance value of about 130-135 watts and the time to reach this value is recorded. A sample is taken from the wet granulation to record the loss on drying (% LOD). The wet granule is dried in portions in the fluidized bed air dryer up to a% LOD of a probable value of 1.0-3.0%. The air temperature in the fluidized bed dryer is maintained at about 90-95 ° C and the sample is subjected to drying at an ambient air temperature of about 32-35 ° C. The dried granule is crushed through a 12 mesh sieve at high speed in a Fitz mill. The granules are weighed and the percentage is calculated. The water content is measured for dry granules. A sample is taken from the granules to distribute the particle size, volume and density, the flow rate indicator and the moisture examination. The granules are weighed and the phase B components are calculated based on the weight of the remaining granules.

3. Preparation of final mixtures

The weighed crushed granule produced in phase A, the determined amount of sodium lauryl sulfate, sodium starch glycolate (Explotab) ® and dibasic calcium phosphate dihydrate is added to the V-blender and mixed for about 10 minutes. Magnesium stearate is then added to the mixture and mixed for about an additional 3 minutes. Samples from different parts of the mixer are removed and subjected to a homogeneity analysis of the mixture. The sample from the final blend is analyzed for particle size distribution, volume and density, flow rate and moisture analysis. The granules are then weighed.

4. Compressing tablets with methylcellulose

The final blend is filled into a one-punch Stokes tabletting press hopper F and compressed into tablets. The final hardness is desired between 10 to 25, preferably 8-12 SCU and the preferred final weight of each tablet is less than 750 mg; a determined friability of less than 2.0%, more preferably less than 1.0%, and a final disintegration time of less than 30 minutes in water and acid (shorter times are preferred) 'A' a aaa a aaa a 12 _ a. Disintegration, less than 10 minutes, more preferably less than 8 minutes in

0.1N HCl and less than 15 minutes in water, more preferably about 8 minutes).

The tablets are packed in Ziplock sachets. The tablets are tested for weight variation, hardness, acid and water degradation, friability, water content (% LOD), thickness, viscosity and uniformity of content.

The composition in Table 1 shows a disintegration time of less than 5 minutes in 0.1N HCl and less than 9 minutes in water, by the conventional USP method, using a disintegrator with disks.

The disintegration time for the composition in Table 1, Example 1, was less than 5 minutes in 0.1N HCl and less than 9 minutes in water.

It is noted that Examples 2 to 6 and 11 to 15 are Avicel-based compositions and Examples 7 to 10 are starch-based compositions that do not contain edible calcium salt excipients. These are for illustrative purposes only and can be formed until the edible calcium salts of the invention and Examples 1 and 16 to 23 are contained.

• • •

EXAMPLE 2

A composition comprising both Avicel PH 101® and Explotab®, intra and extragranular, as shown in Table II below, has an average disintegration time of less than 1 minute in 0.1N HCl at 37 ± 0.5 ° C, using an automatic disintegrator.

TABLE II

Tablets with methylcellulose for oral administration % by weight Regulation Component g / tablet Phase A Methocel A4M 0.5000 60.31 Avicel PH 101® 0,0370 4.46 Sodium lauryl sulfate 0.0015 0.18 Povidone 29K / 32 0,0370 4.46 Explotab® 0,0300 3.62 Deionized water according to need according to need Phase B Phase A 0.6055 73.03 Sodium lauryl sulfate 0.0017 0.21 Sodium starch glycolate 0.0253 3.05 Avicel PH 101® 0.1880 22.67 Magnesium stearate 0.0086 1.04 TOTAL 0.8291 100.00

• · · · · · · · · · · · · ·

I · 4 · 4 · 4 · 4 · 4 4

4 * 4 4 · · <

EXAMPLE 3

PH 101® intragranular, and Explotab®, intra a

Avicel

The 102® extragranular, as shown in Table III below, has an average disintegration time of less than 3 minutes in 0.1N HCl at 37 ± 0.5 ° C, using an automatic disintegrator.

Extragranular composition containing Avicel PH

TABLE III

Tablets with methylcellulose for oral administration % by weight Regulation Component g / tablet Phase A Methocel A4M 0.5000 59.24 Avicel PH 101® 0,0370 4.38 Sodium lauryl sulfate 0.0015 0.18 Povidone 29K / 32 0,0370 4.38 Explotab® 0,0300 3.56 Dye / pigment 0.0040 0.47 Deionized water according to need according to need Phase B Phase A 0.6095 72.21 Sodium lauryl sulfate 0.0015 0.18 Sodium starch glycolate 0.0220 2, 61 Avicel PH 102® 0.2035 24.11 Magnesium stearate 0.0075 0.89 TOTAL 0.8440 100.00

• 4 · 4

- 16 EXAMPLE 4

Means containing Avicel PH 101® intragranular, extragranular Avicel PH 102® a Explotab®, intra and extragranular, as shown Table IV below, has an average time disintegration less than 2 minutes in 0.1N HCl at 37 ± 0.5 ° C, using automatic disintegrator. TABLE IV Tablets with methylcellulose for oral administration Regulation g / tablet % by weight Component Phase A Methocel A4M 0.5000 59.52 Avicel PH 101® 0,0370. 4.41 Sodium lauryl sulfate 0.0015 0.18 Povidone 29K / 32 0,0370 4.41 Explotab® 0,0300 3.57 Deionized water according to need according to need Phase B Phase A 0.6055 72.08 Sodium lauryl sulfate 0.0015 0.18 Sodium salt of glycolate starch 0.0220 2.62 Avicel PH 102® 0.2035 24.23 Magnesium stearate 0.0075 0.89 TOTAL 0.8400 100.00

In an alternative embodiment of Example 4, the coated variant of the composition of Table IV was tested for disintegration time. A 20% Opadryl I coating solution, orange flavor, was used. The average disintegration time of the coated tablets was less than 1 min. in 0.1N HCl at 37 ± 0.5 ° C, using an automatic disintegrator.

PH 101® intragranular, and Explotab®, intra a

EXAMPLE 5 containing Avicel PH

Extragranular extragranular,

Avicel

102®, as shown in Table V below, has an average disintegration time of less than one minute in 0.1N HCl at 37 ± 0.5 ° C, using an automatic disintegrator.

TABLE V

Tablets with methylcellulose for oral administration % by weight Regulation Component g / tablet Phase A Methocel A4M 0.5000 60.24 Avicel PH 101® 0,0370 4.46 Sodium lauryl sulfate. 0.0015 0.18 Povidone 29K / 32 0,0370 4.46 Explotab® 0,0300 3, 62 Deionized water according to need according to need Phase B Phase A 0.6055 72.95 Sodium lauryl sulfate 0.0015 0.18 Sodium starch glycolate 0.0110 1.33 Avicel PH 102® 0.2045 24.64 Magnesium stearate 0.0075 0.90 TOTAL 0.8300 100.00

• · · · «

PH 101® and not containing average time

EXAMPLE 6

The composition comprising Avicel intragranular, extragranular Avicel PH 102® Explotab®, as shown in Table VI below, has a disintegration of less than 3 minutes in 0.1N HCl and less than 2 minutes in water at 37 ± 0.5 ° C, using an automatic, disintegrant machines. The disintegration times using a conventional disintegrator were about 1 minute in acid and 2 minutes in water.

TABLE VI

Tablets with methylcellulose for oral administration

Prescription g / tablet% by weight

Component

Phase A

Methocel A4M 0.5000 67.94 Avicel PH 101® 0,0370 5.03 Sodium lauryl sulfate 0.0015 0.20 Povidone 29K / 32 0,0370 5.03 Dye / pigment 0,0010 0.14 Deionized water according to need according to need Phase B Phase A 0.5765 78.34 Sodium lauryl sulfate 0.0011 0.15 Avicel PH 102® 0.1527 20.75 Magnesium stearate 0.0056 0.76 TOTAL 0.7359 100.00

• · · · * · * · * *....... ·. 19 - ·· · * ·· · · ··

EXAMPLE 7

A composition comprising corn starch intragranular, extragranular Starch 1500 and not containing Explotab®, as shown in Table VII below, has an average disintegration time of less than 16 minutes in 0.1N HCl at 37 ± 0.5 ° C, using an automatic disintegrator.

TABLE VII

Tablets with methylcellulose for oral administration

Prescription g / tablet% by weight

Component

Phase A

Methocel A4M 0.5000 63.29 Cornstarch 0,0370 4.68 Sodium lauryl sulfate 0.0015 0.19 Povidone 29K / 32 0,0370 4.68 Dye / pigment 0,0010 0.13 Deionized water according to need according to need Phase B Phase A 0.5765 72.97 Sodium lauryl sulfate 0.0015 0.19 Starch 1500 0.2045 25.89 Magnesium stearate 0.0075 0.95 TOTAL 0.7900 100.00

• fefefe • fefe • fefe • fefe • fefe fe • fefe • fefe • fefe • fe · • fe • fe fefe • fe fefe • fefe · fe fefe fe fefe • fe fefe

EXAMPLE 8

The composition comprising corn starch intragranular, extragranular Starch 1500 and intragranular Explotab®, as shown in Table VIII below, has an average disintegration time of less than 14 minutes in 0.1N HCl at 37 ± 0.5 ° C, using an automatic disintegrator.

TABLE VIII

Tablets with methylcellulose for oral administration

Prescription g / tablet% by weight

Component

Phase A

Methocel A4M 0.5000 61,00 Cornstarch 0,0370 4.51 Sodium lauryl sulfate 0.0015 0.18 Povidone 29K / 32 0,0370 4.51 Dye / pigment 0,0010 0.12 Explotab® 0,0300 3.66 Deionized water according to need according to need Phase B Phase A 0.6065 73.98 Sodium lauryl sulfate 0.0015 0.18 Starch 1500® 0.2045 24.93 Magnesium stearate 0.0075 0.91 TOTAL 0.8200 100.00

• 9 9

Composition containing corn starch intragranular, extragranular Starch 1500 and intra as well as extragranular

Explotab®, as shown in Table IX below, has an average disintegration time of less than 13 minutes in 0.1N HCl at 37 ± 0.5 ° C, using an automatic disintegrator.

9 «99 99 •• 1 2 3 4 5 6

9

9,999 9 9 9

9

99 99 9 99 9 9 9

998 9 99 9

9

9 9 9 *

999 99 99

EXAMPLE 9

TABLE IX

Tablets with methylcellulose for oral administration

Prescription g / tablet% by weight

Component

Phase A

Methocel A4M 0.5000 59.88 Cornstarch 0,0370 4.43 Sodium lauryl sulfate 0.0015 0.18 Povidone 29K / 32 0,0370 4.43 Dye / pigment 0,0010 0.12 Explotab® 0,0300 3.59 Deionized water according to need according to need Phase B Phase A 0.6065 72.63 Sodium lauryl sulfate 0.0015 0.18 Starch 1500® 0.2045 24.49 Explotab® 0.0150 1.80 Magnesium stearate 0.0075 0.90 TOTAL 0.8350 100.00

• 0 0 • 999 9 9 9 9 9 9 9 • 00 00 00 000 000 0 0 00 00 000 000 0 0 0 0 ·· ·· * ·

EXAMPLE 10

The corn starch formulation intragranular, extragranular Starch 1500 and intra as well as extragranular Explotab® (in higher amounts than Example 9, Table IX), as shown in Table X below, has 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 an automatic disintegrator.

TABLE X

Methylcellulose tablets for oral use

Prescription g / tablet% by weight

Component

Phase A Methocel A4M 0.5000 58.82 Cornstarch 0,0370 4.35 Sodium lauryl sulfate 0.0015 0.18 Povidone 29K / 32 0,0370 4.35 Dye / pigment 0,0010 0.12 Explotab® 0,0300 3.53 Deionized water according to need according to need Phase B Phase A 0.6065 71.35 Sodium lauryl sulfate 0.0015 0.18 Starch 1500® 0.2045 24.05 Explotab® 0,0300 3, 54 Magnesium stearate 0.0075 0.88 TOTAL 0.8500 100.00

* · Φφ · ·

Φ φ φ · · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

EXAMPLE 11

Various formulations containing Avicel PH 101® intragranular and different levels of extragranular Avicel PH 102® (as shown in Examples 6,7 and 8 above) were made to monitor their effect on tablet disintegration time.

The composition in Table XI below has an average disintegration time of less than 1 minute in 0.1N HCl and less than 2 minutes in water at 37 + 0.5 ° C, using an automatic disintegrator. With a conventional disintegrator, less than 1 minute is obtained in both acid and water.

TABLE XI

Tablets with methylcellulose for oral administration

Prescription g / tablet% by weight

Component

Phase A Methocel A4M 0.5000 62.42 Avicel PH 101® 0,0370 4.62 Sodium lauryl sulfate 0.0015 0, 19 Povidone 29K / 32 0,0480 5, 99 Dye / pigment 0,0010 0.12 Deionized water according to need according to need Phase B Phase A 0.5875 73.34 Sodium lauryl sulfate 0.0015 0.19 Avicel PH 102® 0.2045 25.53 Magnesium stearate 0.0075 0.94 TOTAL 0.8010 100.00

* 0 0000

00

0 0 0 0 0

0 0 0 0 0

0 000 0 0 • 0 0 0 0 »0 00« 0 0 0 0 0 0

000 0 00 0

0 0 0 0 0 * 0 0 0 0

0 * 0 0 0 0

EXAMPLE 12

The composition in Table XII below has an average disintegration time of less than 5 minutes in 0.1N HCl and less than 7 minutes in water at 37 ± 0.5 ° C, using an automatic disintegrator. With a conventional disintegrator, less than 5 minutes are obtained in both acid and water.

TABLE XII

Tablets with methylcellulose for oral administration

Prescription g / tablet% by weight

Component

Phase A

Methocel A4M 0.5000 69.35 Avicel PH 101® 0,0370 5.13 Sodium lauryl sulfate 0.0015 0.21 Povidone 29K / 32 0,0480 6, 66 Dye / pigment 0,0010 0.14 Deionized water according to need according to need Phase B Phase A 0.5875 81.48 Sodium lauryl sulfate 0.0015 0.21 Avicel PH 102® 0.1245 17.27 Magnesium stearate 0.0075 1.04 TOTAL 0.7210 100.00

• · · · · · · · · · ···

EXAMPLE 13

The composition in Table XIII below has an average disintegration time of less than 10 minutes in 0.1N HCl and less than 14 minutes in water at 37 ± 0.5 ° C, using an automatic disintegrator. With a conventional disintegrator, less than 14 minutes in acid and less than 22 minutes in water are obtained.

TABLE XIII

Tablets with methylcellulose for oral administration

Prescription g / tablet% by weight

Component

Phase A

Methocel Ά4Μ

Avicel PH 101® Sodium lauryl sulfate Povidone 29K / 32

Dye / pigment Deionized water

0.5000

0,0370

0.0015

0,0480

0.0010 as needed

Phase B

Phase A

Sodium lauryl sulfate Avicel PH 102® TOTAL magnesium stearate

0.5875

0.0015

0.0605

0.0075

0.6570

76.10 5, 63 0.23 7.31 0.15 as needed

89, 42

0.23

9.21

1.14

100,00 ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- ** * ·

EXAMPLE 14

Two formulations containing Avicel PH 101® intragranular with different levels of extragranular Avicel PH 200® (as shown in Table XIV and XV below) were made to monitor the effect on tablet disintegration times.

The composition in Table XIV below has 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 an automatic disintegrator. With a conventional disintegrator, less than 8 minutes in acid and less than 13 minutes in water are obtained.

TABLE XIV

Tablets with methylcellulose for oral administration

Prescription g / tablet% by weight

Component

Phase A

Methocel A4M 0.5000 62.42 Avicel PH 101® 0,0370 4.62 Sodium lauryl sulfate 0.0015 0.19 Povidone 29K / 32 0,0480 5, 99 Dye / pigment 0,0010 0.12 Deionized water according to need according to need Phase B Phase A 0.5875 73.34 Sodium lauryl sulfate 0.0015 0.19 Avicel PH 200® 0.2045 25.53 Magnesium stearate 0.0075 0.94 TOTAL 0.8010 100.00

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

EXAMPLE 15

The composition in Table XV below has an average disintegration time of less than 4 minutes in 0.1N HCl and less than 7 minutes in water at 37 ± 0.5 ° C, using an automatic disintegrator. With a conventional disintegrator, less than 5 minutes in acid and less than 9 minutes in water are obtained.

TABLE XV

Tablets with methylcellulose for oral administration

Prescription g / tablet% by weight

Component

Phase A

Methocel A4M 0.5000 69.35 Avicel PH 101® 0,0370 5.13 Sodium lauryl sulfate 0.0015 0.21 Povidone 29K / 32 0,0480 6.66 Dye / pigment 0,0010 0.14 Deionized water according to need according to need Phase B Phase A 0.5875 81.48 Sodium lauryl sulfate 0.0015 0.21 Avicel PH 200® 0.1245 17.27 Magnesium stearate 0.0075 1.04 TOTAL 0.7210 100.00

• 9 · · 9 · · ···· · 9 9 9 9.99 9 99 ·

9,999,999,999,999 9

9 · · 9 9 9 9 9

99 99 99 99 99

EXAMPLE 16

A calcium-containing composition, derived from intragranular and extragranular excipients, calcium hydrogen phosphate dihydrate with extragranular Explotab®, as shown in Table XVI.

The composition in Table XVI below has 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 an automatic disintegrator. With a conventional disintegrator, less than 5 minutes in acid and less than 12 minutes in water are obtained.

TABLE XVI

Tablets with methylcellulose for oral administration

Prescription g / tablet% by weight

Component

Phase A

Methocel A4M 0.5000 66, 93 Hydrogen phosphate dihydrate 0,0370 4.95 calcium Sodium lauryl sulfate 0.0015 0.20 F, D and C yellow (mesh) 6 0,0010 0.13 Povidone 29K / 32 0,0480 6, 43 Deionized water according to need according to need Phase B Phase A 0.5875 78.65 Sodium lauryl sulfate 0.0015 0.20 Sodium starch glycolate 0,0260 3.48 Hydrogen phosphate dihydrate 0.1245 16, 67 calcium Magnesium stearate 0.0075 1.00 TOTAL 0.7470 100.00

9 9 φ 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

- 29 EXAMPLE 17

The calcium-containing composition of the extragranular calcium hydrogen phosphate auxiliary Explotab® is shown in Table XVII below.

of an intragranular origin and a composition, the dihydrate with the larger in Example 17, an amount as shown

The composition in Table XVII below, an average disintegration time of less than 9 minutes in O, 1N HCl and less than 14 minutes in water at 37 ± 0.5 ^G C using automated disintegration apparatus. With a conventional disintegrator, less than 6 minutes in acid and less than 12 minutes in water are obtained.

TABLE XVI

Tablets with methylcellulose for oral administration

Prescription g / tablet% by weight

Component

Phase A

Methocel A4M 0.5000 65.19 Hydrogen phosphate dihydrate 0,0370 4.82 calcium Sodium lauryl sulfate 0.0015 0.20 F, D and C yellow '(mesh) 6 0,0010 0, 13 Povidone 29K / 32 0,0480 6.26 Deionized water according to need according to need Phase B Phase A 0.6105 79, 60 Sodium lauryl sulfate 0.0015 0.20 Sodium starch glycolate 0,0230 3.00 Hydrogen phosphate dihydrate 0.1245 16, 23 calcium Magnesium stearate 0.0075 0, 97 TOTAL 0.7670 100.00

• ·

Calcium-containing composition originating from intragranular a

EXAMPLE 18 dihydrate levels of the composition, with various extragranular calcium hydrogen phosphate co-phosphate extragranular Explotab®, in combination with a similar amount of intragranular Explotab® as shown in Tables XVIII and XIX below (Example XIX).

The composition in Table XVIII below has an average disintegration time of less than 6 minutes in 0.1N HCl and less than 11 minutes in water at 37 ± 0.5 ° C, using an automatic disintegrator.

TABLE XVIII

Tablets with methylcellulose for oral administration

Prescription g / tablet% by weight

Component

Phase A

Methocel A4M 0.5000 65.19 Hydrogen phosphate dihydrate 0,0370 4.82 calcium Sodium lauryl sulfate 0.0015 0.20 Sodium starch glycolate 0,0230 3.00 F, D and C yellow (mesh) 6 0,0010 0.13 Povidone 29K / 32 0,0480 6.26 Deionized water according to need according to need Phase B Phase A 0.6105 79.60 Sodium lauryl sulfate 0.0015 0.20 Sodium starch glycolate 0,0230 3.00 Hydrogen phosphate dihydrate 0.1245 16.23 calcium Magnesium stearate 0.0075 0, 97 TOTAL 0.7670 100.00

• ······ · «·· · · · · · · · ·

- 31 EXAMPLE 19

The composition in Table XIX below has 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 an automatic disintegrator.

TABLE XVIII

Tablets with methylcellulose for oral administration % by weight Regulation Component g / tablet Phase A Methocel A4M 0.5000 63.86 Hydrogen phosphate dihydrate 0,0370 4.73 calcium Sodium lauryl sulfate 0.0015 0.19 Sodium starch glycolate 0,0230 2.94 F, D and C yellow (mesh) 6 0,0010 0.13 Povidone 29K / 32 0,0480 6.13 Deionized water according to need according to need Phase B Phase A 0.6105 77.97 Sodium lauryl sulfate 0.0015 0.19 Sodium starch glycolate 0,0390 4.98 Hydrogen phosphate dihydrate 0.1245 15.90 calcium Magnesium stearate 0.0075 0.96 TOTAL 0.7830 100.00

9 9 9 9 9 9

9 9 9 9 9 999 99 9 · · 9 9999

99 99 99 99

EXAMPLE 20

A calcium-containing composition, derived from intragranular and extragranular excipients, calcium hydrogen phosphate dihydrate with extragranular Explotab®, as shown in Tables XX and XXI (Example 21) below.

The composition in Table XX below has 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 an automatic disintegrator.

TABLE XX.

Tablets with methylcellulose for oral administration

Prescription g / tablet. % by weight

Component

Phase A

Methocel A4M 0.5000 66, 89 Hydrogen phosphate dihydrate 0,0370 4.95 calcium Sodium lauryl sulfate 0.0015 0.20 F, D and C yellow (mesh) 6 0,0010 0.13 Povidone 29K / 32 0,0300 4.01 Deionized water according to need according to need Phase B Phase A 0.5695 76.19 Sodium lauryl sulfate 0.0015 0.20 Sodium starch glycolate 0,0445 5.95 Hydrogen phosphate dihydrate 0.1245 16, 66 calcium Magnesium stearate 0.0075 1.00 TOTAL 0.7475 100.00

• 4 · O · · 9 9 9 9

9 9 · · 0 0 0 0 • 0 0 · 9 9 · ·

0 0 0 0

9 9 000 000

0 1 · · »

9 ·

EXAMPLE 21

The composition in Table XXI below has 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 a conventional disintegrator.

TABLE XVIII_

Tablets with methylcellulose for oral administration

Prescription g / tablet% by weight

Component

Phase A

Methocel A4M

Calcium hydrogen phosphate dihydrate

Sodium lauryl sulfate

F, D and C yellow (mesh) 6

Povidone 29K / 32

Deionized water

Phase B

Phase A

Sodium lauryl sulfate

Sodium starch glycolate Calcium hydrogen phosphate dihydrate

Magnesium stearate

TOTAL

0.5000 64.52 0,0370 4.77 0.0015 0.19 0,0010 0.13 0,0480 6.19 according to need according to need 0.5875 75, 81 0.0015 0.19 0,0235 3.03 0.1550 20,00 0.0075 0.97 0.7750 100.00

• ·

EXAMPLE 22

The calcium-containing composition, derived from an intragranular and extragranular excipient, anhydrous calcium phosphate with extragranular Explotab®, as shown in Table XXII below.

The composition in Table XXII below has an average disintegration time of less than 11 minutes in 0.1N HCl and less than 19 minutes in water at 37 ± 0.5 ° C, using a conventional disintegrator.

TABLE XVIII

Tablets with methylcellulose for oral administration % by weight Regulation Component g / tablet Phase A Methocel A4M 0.5000 66, 93 Anhydrous calcium phosphate 0,0370 4.95 Sodium lauryl sulfate 0.0015 0.20 F, D and C yellow (mesh) 6 0,0010 0.13 Povidone 29K / 32 0,0480 6.43 Deionized water according to need according to need Phase B Phase A 0.5875 78.65 Sodium lauryl sulfate 0.0015 0.20 Sodium starch glycolate 0,0260 3.48 Anhydrous calcium phosphate 0.1245 0, 67 Magnesium stearate 0.0075 1.00 TOTAL 0.7470 100.00

• · · ·

EXAMPLE 23

The calcium-containing composition, derived from intragranular and extragranular excipient, calcium phosphate WG® with extragranular Explotab®, as shown in Table XXIII below.

The composition in Table XXIII below has an average disintegration time of less than 13 minutes in 0.1N HCl and less than 24 minutes in water at 37 ± 0.5 ° C, using a conventional disintegrator.

TABLE XXIII_

Tablets with methylcellulose for oral administration

Prescription · g / tablet% by weight

Component

Phase A

Methocel A4M 0.5000 66, 93 Calcium phosphate WG® 0,0370 4.95 Sodium lauryl sulfate 0.0015 0.20 F, D and C yellow (mesh) 6 0,0010 0.13 Povidone 29K / 32 0,0480 6, 43 Deionized water according to need according to need Phase B Phase A 0.5875 78.65 Sodium lauryl sulfate 0.0015 0.20 Sodium starch glycolate 0,0260 3.48 Calcium phosphate WG® 0.1245 16, 67 calcium Magnesium stearate 0.0075 1.00 TOTAL 0.7470 100.00

• 0

• 9

0

···

0 0

99 9

All publications included, but not limited to, the patents and patent applications cited in the specification are incorporated by reference.

The above description discloses the invention, including a preferred embodiment thereof. Modifications and improvements to the embodiments, particularly described herein, are within the scope of the claims. Without further elaboration, it is believed that those skilled in the art, using the foregoing description, can fully utilize the present invention. Thus, the examples are set forth for illustrative and non-limiting purposes of the present invention in any way.

Represented by:

• φ φφφφ φ φ φ φ φφφφ

Claims (3)

PATENT CLAIMS φ φφ φφ ' A fast disintegrating tablet for oral administration comprising a compressed mixture of methylcellulose with a viscosity greater than 1 PaS and an edible calcium salt. A tablet according to claim 1 wherein the edible calcium salt is calcium dihydrogen phosphate, anhydrous calcium phosphate, calcium phosphate, or mixtures thereof. A tablet according to claim 1 or 2 comprising a binder. A tablet according to claim 3 wherein the binder is PVP, hydroxypropylcellulose, hydroxypropylmethylcellulose, acacia, gelatin, tragacanth, pregelatinized starch or starch. The tablet of claim 4 wherein the binder is PVP. The tablet of claim 1 or 2 further comprising a disintegrant. The tablet of claim 6 wherein the disintegrant is sodium starch glycolate, sodium carboxymethylcellulose, Ac-di-sol®, carboxymethylcellulose, veegum, alginates, agar, guar, tragacanth, locust, karaya, pectin or cross-linked polyvinylpyrrolidone. . A tablet according to claim 7 wherein the disintegrant is sodium starch glycolate. Tablet according to claim 8, characterized in that »9 9 9 9 9 9 9 9 9 • ftft ftft ft ftft ft ft 99 99 99 999 The sodium starch glycolate is present in an amount of from 3 to 8% by weight. 10. A tablet according to claim 1 further comprising a wetting agent. 11. A tablet according to claim 10 wherein the surfactant is sodium lauryl sulfate. The tablet of claim 1, further comprising a lubricant. 13. A tablet according to claim 12 wherein the lubricant is magnesium stearate. 14. The tablet of claim 1 wherein the methylcellulose has a viscosity of more than 2 PaS. 15. A tablet according to claim 14 wherein the methylcellulose has a viscosity of more than 3 PaS. 16. A tablet according to claim 15 wherein the methylcellulose has a viscosity of more than 4 PaS. 17. A tablet according to claim 1 wherein the methylcellulose is Methocel A4M. 18. A tablet according to claim 1 wherein the edible calcium salt is calcium hydrogen phosphate dihydrate and is present in a 2: 4: 1 methylcellulose to calcium ratio. 19. A tablet according to claim 1 wherein the edible calcium salt is anhydrous calcium phosphate and is present in a 2 to 4: 1 methylcellulose to calcium ratio. 20. A tablet according to claim 1 wherein the edible calcium salt is calcium phosphate and is present in a 2 to 4: 1 ratio of methylcellulose to calcium phosphate. 9 9 9 9 99 9 9 9 9 9 9 9 9 9 8 · «···· * 9 9 99 99 9 9 9 9 9 • 99 9 · 9 9 9 9 9 9 9 9 999 99 99 The tablet of claim 1, further comprising excipients and diluents in the ratio: Sodium lauryl sulfate: Explotab: Calcium phosphate: Povidone 29K / 32: Magnesium stearate includes 0.40: 3.5: 21.6: 6 , 4: 1.0 or Sodium lauryl sulfate: Explotab: Anhydrous calcium phosphate: Povidone 29K / 32: Magnesium stearate includes 0.40: 3.5: 21.6: 6.4: 1.0. 22nd Tablet according to claim 1 or 2, mark í c and with E m, ž 550 mg. e methylcellulose is present in an amount around 450 to 23. Tablet according to claim 1 or 2, mark í c and with E m, ž e methylcellulose is present in an amount around 200 to 300 mg. 24. A fast disintegrating tablet for oral administration, characterized in that the tablet comprises methylcellulose with a viscosity higher than 3 PaS; dibasic calcium phosphate, sodium lauryl sulfate, polyvinylpyrrolidone, sodium starch glycolate and magnesium stearate. 25. A process for preparing a tablet, comprising compressing a mixture obtained by compression (a) mixing methylcellulose with a high viscosity of more than 3 PaS, a wetting agent, polyvinylpyrrolidone or sodium starch glycolate and an edible calcium salt to form an intragranular mixture; b) adding an aqueous solution of PVP to the mixture of step (a) or spraying the mixture of step (a) with an aqueous solution of PVP and preparing a granulate; c) mixing an extragranular mixture of edible calcium salt, wetting agent, lubricant, polyvinylpyrrolidone or sodium starch glycolate or a mixture thereof; Fefe fefe fefe fefe fefe fefe fefe fefe d). the granulate of step (b) is compressed with the extragranular mixture of step (c). The method of claim 25, wherein the edible calcium salt is dibasic calcium phosphate dihydrate, anhydrous dicalcium phosphate, dicalcium phosphate, or mixtures thereof. The process according to claim 26, wherein the edible calcium salt is dibasic calcium phosphate. 3. A process for the manufacture of a pharmaceutical tablet which is mixed (a) granules containing methylcellulose with a high viscosity of more than 3 PaS, a wetting agent, polyvinylpyrrolidone or sodium starch glycolate, edible calcium salt; and (b) mixing an extragranular mixture of edible calcium salt, wetting agent, lubricant, polyvinylpyrrolidone or sodium starch glycolate, or a mixture thereof; and c) compressing the granulate of step (b) with the granular mixture of step (a) and d) compress into tablets.