Solid dosage form of someticone for oral administration

Description of the invention

The present invention relates to a solid dosage form containing simethicone and an adsorbent for oral administration.

Active agents, e.g. drugs and nutritional therapeutics and the like, for oral administration, are often prepared in the form of solid preparations such as tablets, capsules, pills, lozenges or granules. Oral dosage forms are swallowed whole, chewed in the mouth, bitten in the mouth and swallowed or dissolved under the tongue.

When administered orally, simethicone is used as an additive in the symptomatic treatment of flatulence, functional bloating associated with gastrointestinal disorders, and postoperative gas aches. The clinical use of simethicone is based on its anti-foam properties. Silicone has an anti-foaming effect when it is spread over the surface of a watery liquid to form a film with low surface tension, which causes the foam bubbles to collapse. Thus, for self-administration by the patient, in over-the-counter preparations, simethicone is used as an anti-flatulent agent to relieve symptoms commonly associated with gas accumulation, such as bloating in disorders of the upper gastrointestinal tract, feeling of tightness, fullness, and overeating. It is often combined with other gastrointestinal agents such as antacids, antispasmodics, or digestive enzymes; Various simethicone preparations have already been described.

Simethicone can be administered orally in the form of liquid or solid preparations, for example capsules, chewable tablets or tablets for swallowing. Tablets have advantages over liquid forms due to their ease of handling. Swallow tablets have the advantage over chewable tablets that they are easy to swallow and no taste is felt. Among the swallowable tablets, film-coated tablets are preferred.

In the past, difficulties have been encountered in the preparation of solid simethicone dosage forms when attempting to incorporate a substantial amount of liquid simethicone into the final solid tableting mixture. The difficulty has been to achieve sufficient ductility for processing and sufficient compression cohesion, especially in direct compression tableting, so that the tablet can withstand further processing such as coating, gelatin dipping, printing, packaging and the like. Difficulties have also been encountered in ensuring uniform distribution of the viscous, liquid simethicone throughout the solid preparation and rapid dispersion after administration.

Japanese patent SHO 39 [1961] - 46451, issued in the name of Kitsusho Yakuhin Kogyo KK, describes a method of making simethicone tablets by mixing and granulating simethicone with aluminum silicate, magnesium aluminum metasilicate and magnesium silicate. In particular, the formulation described in this Japanese patent requires the use of at most 25% simethicone and 75% or more silicate, a binder and dispersant. Starch and lactose are described as binders. Carboxymethyl cellulose is described as the dispersing agent. Moreover, this Japanese patent describes that when the amount of simethicone exceeds 25%, some of the simethicone may separate, which adversely affects the workability of the tablet.

JP 5 097 681, issued in the name of Horii Yakuhin Kogyo KK, describes a preparation in which simethicone is adsorbed to magnesium aluminum metasilicate and dextrin. The excipient is then added and the mixture is tableted. After tableting, a hydroxypropyl methylcellulose phthalate coating is added followed by additional simethicone and gelatin. The simethicone content in the final tablet produced is about 15%.

U.S. Patent No. 4,906,478 describes a simethicone formulation containing a powdered combination of calcium silicate particles and simethicone.

US Patent No. 5,073,384 describes simethicone formulations containing combinations of water-soluble agglomerated maltodextrin and simethicone.

US Patent No. 5,458,886 describes a plastic, granular composition containing titanium dioxide with a particular size and particle surface area in combination with simethicone.

U.S. Patent No. 6,103,260 describes the use of a mixture of simethicone and granular, anhydrous, tribasic calcium phosphate or dibasic calcium, or both, where the admixture of the unitary granular composition does not exceed 1000 microns, which is preferred for solid compression. dosage form for administration

Orally. The amount of simethicone in the final tablet was reported to be 10-50%, however the final weight of this tablet exceeded 1000 mg.

There is therefore a need for a malleable compressible simethicone composition for the preparation of a solid dosage form into which a larger amount of simethicone or smaller dosage forms can be incorporated containing the same amount of simethicone.

It has surprisingly been found that such a composition can be obtained by using silicified microcrystalline cellulose and magnesium aluminum metasilicate as substrates onto which simethicone or other oily or liquid active ingredient is adsorbed. Thus, the object of the present invention is a solid simethicone dosage form containing a higher percentage of simethicone while maintaining substantially the same amount as previously obtained or the same percent simethicone in a smaller dosage form size, manufactured from a plastic compressible mixture of simethicone and an adsorbent agent. .

The subject of the present invention is therefore a solid dosage form containing a compressed mixture of appropriate amounts of simethicone adsorbed on a mixture of magnesium aluminum metasilicate and siliconized microcrystalline cellulose, wherein the weight ratio between simethicone, magnesium aluminum metasilicate and siliconized microcrystalline cellulose is 1: 0.5-0, respectively. 85: 0.9-1.30 per unit of solid dosage form, for oral administration.

The solid dosage form also contains at least one active agent selected from the group consisting of bisacodyl, famotidine, prucalopride, diphenoxylate, loperamide, lactase, mesalamine, and bismuth.

According to the invention, the solid dosage form comprises 19% to 27% by weight of silicified microcrystalline cellulose and 31% to 39% by weight of magnesium aluminum metasilicate, preferably 23% to 27% by weight of silicified microcrystalline cellulose and 33% to 37% by weight of metasilicate. magnesium aluminum.

According to the invention, the compressed mixture constitutes a tablet with a hardness ranging from 2 to 15 kp / cm², preferably with a hardness of between 5 and 10 kp / cm².

Bisacodyl is a laxative; famotidine is an H 2 receptor antagonist marketed by McNeil-PPC, Inc. under the name Pepcid; prucalopride is an agent that increases the kinetics of the gastrointestinal tract; diphenoxylate and loperamide marketed by McNeil-PPC, Inc. under the name Imodium are anti-diarrheal agents; mesalamine is a pain reliever.

As used herein, the term "simethicone" refers to the broader class of polydimethylsiloxanes, including simethicone and dimethicone. These compounds are disclosed in U.S. Patent Nos. 4,906,478, 5,275,822, and 6,103,260, which are hereby incorporated by reference.

Preferred lactases for use in the present invention are: lactase isolated from Saccharomyces lactis, available from Gist-Brocade, Delft, The Netherlands, sold by Enzyme Development Corporation, New York, NY, United States; a lactase from Aspergillus oryzae, Lactase Y-400, from KK Yakult Honsha; a lactase from Aspergillus oryzae Plexazym LA1 from Roehm GmbH; a lactase from Aspergillus oryzae from Shinnihon Kagaku Kogyo Co .; a lactase from Kluyveromyces fragilis from Sturges Enzymes, Selby, North Yorkshire, England; Aspergillus oryzae lactase - Takamine lactase from Miles Laboratories, Inc., Elkhart, IN, United States; a lactase from Kluyveromyces fragilis from Novo Enzymes, Bagsvaerd, Denmark and a lactase from Aspergillus oryzae, for example, Lactase F "Amano" 100 from Amano Pharmaceutical Co., Ltd., Naka-ku, Nagoya, Japan. These and other companies typically offer a lactase composition, containing a diluent, with a potency of between 14,000 and 100,000 FCC lactase units per gram.

The active agent may be used in the form of a fine powder, granules, or large crystals, and the average particle size is from about 1 µm to about 1000 µm, sometimes from about 150 µm to about 500 µm. Typically the active agent of the present invention has an average size of greater than 50 µm.

If the active agent has an unpleasant taste, it may be coated with a taste-masking coating as known in the art. Examples of suitable taste-masking coatings are described in US Patent Nos. 4,851,226, 5,075,114, and 5,489,436. Commercial taste-masking actives can also be used. For example, acetaminophen particles encapsulated in ethyl cellulose or other polymers by coacervation may be used in accordance with the present invention. Acetaminophen encapsulated in capsules using the coacervation technique can be purchased

From Eurand America, Inc., Vandalia, Ohio, United States or at Circa Inc., Dayton, Ohio, United States.

As used herein, all ranges given include at least all numbers between both ends of the range.

As used herein, simethicone corresponds to the definition in the United States Pharmacopoeia (USP XXII), that is, it is a mixture of fully methylated linear siloxane polymers containing polydimethylsiloxane repeating units stabilized with trimethylsiloxyl end blocking units and silicon dioxide. As used herein, dimethicone may be used instead of simethicone. Simethicone contains about 90.5-99% polydimethylsiloxane and about 4-7% silicon dioxide. The polydimethylsiloxanes present in simethicone are practically inert polymers with a molecular weight of 14,000-21,000. The mixture is a gray, transparent, viscous liquid, insoluble in water.

Conventional excipients preferred according to the present invention include fillers or dry binders such as water-soluble simple and complex carbohydrates (e.g., sucrose, glucose, fructose, maltose, lactose, maltodextrins, starch, modified starch, mannitol, sorbitol, maltite). , xylitol and erythritol), cellulose and cellulose derivatives (e.g. microcrystalline cellulose, carboxymethyl cellulose and hydroxyethyl cellulose), wet binders, such as polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, xanthan gum, carrageenan gum, locust bean gum, alginates and acacia; disintegrants such as sodium starch glycolate, crospovidone, croscarmellose, microcrystalline cellulose, starch and the like, lubricants such as magnesium stearate, stearic acid and pharmaceutically acceptable salts thereof, talc, vegetable oils and waxes, colloidal silicon dioxide, sweeteners, including aspartame, acesulfame potassium, sucralose and saccharin, fragrances, acidulants, antioxidants, preservatives, surfactants, wetting agents and dyes and mixtures thereof.

As used herein, the term "adsorbent" means a solid or combination of solids capable of adsorbing and transporting oily or liquid substances such as simethicone while retaining sufficient plasticity for content uniformity and sufficient compatibility to be made into tablets. by direct pressing methods.

In the present invention, the silicified microcrystalline cellulose may be Prosolv brand materials (PenWest Pharmaceuticals, Patterson, NY, USA).

In the present invention, the magnesium aluminum metasilicate may be substances of the Neusilin brand, followed by SI, FH2, US2 and UFL2 (Fuji Chemical Industries (USA) Inc., Robbinsville, NJ, USA).

In one embodiment of the present invention, simethicone is mixed with magnesium aluminum metasilicate to produce a uniform, plastic, granular mixture. The silicified microcrystalline cellulose is then added, as well as any optional additional active ingredients and any additional excipients. The composition is then mixed until a uniform mass is obtained. The resultant granular composition is then compressed to give the dosage form of the invention.

In embodiments where one or more additional active agents are employed, the additional active agent may optionally be mixed with simethicone prior to adsorption onto the magnesium aluminum metasilicate and silicified microcrystalline cellulose. The resulting mixture is then further mixed with any additional active agents and additional excipients and compressed into tablets.

It is generally preferred that the composition comprises a proportionate amount of simethicone, magnesium aluminum metasilicate and silicified microcrystalline cellulose to give a plastic, granular composition. According to the invention, the proportion by weight of the components of the granular mixture (simethicone: magnesium aluminum metasilicate and silicified microcrystalline cellulose) is 1: 0.5 to 0.85: 0.9 to 1.30 per solid dosage unit.

The weight ratio of simethicone to the total adsorbent agent is at least 1: 2.22, such as at least 1: 2.00, or at least 1: 1.80. In one embodiment, the weight ratio of simethicone to the total weight of the adsorbent is at least 1 part simethicone to 1.75 parts adsorbent.

The solid dosage forms of the present invention can be shaped, or shaped, in a number of ways known in the art. The dosage form according to the present invention, with

With or without the active agent, it can be cast, deposited or pressed by methods known in the art.

The solid dosage forms of the invention may be prepared by direct compression. Using this method, solid dosage forms are prepared by direct compression of a mixture of the active ingredient and any other suitable inactive ingredients, i.e., excipients (e.g. fragrances, binders, lubricants, etc.). Any compression method known in the art may be used to produce chewable dosage forms to form the soft core of the present invention. These methods include, but are not limited to, dry granulation followed by compression and wet granulation and drying and pressing. Pressing methods which may be used in accordance with the present invention are rotary pressing, pressing by a press roller, such as a chilsonator or drop roller, or by casting or extrusion. These methods are known in the art and are described in detail in, for example, Lachman et al., The Theory and Practice of Industrial Pharmacy, Chapter 11 (3rd edition, 1986).

In one of these methods, a predetermined volume of particles or ingredients is placed in a die blank of a rotary tablet press, which is continuously imaged as part of the die table from the filling position to the compression position. In the pressing position, the particles are pressed between the upper and lower punches. The die table then rotates to an ejection position in which the produced tablet is pushed out of the die blank by the lower punch and guided to the discharge chute by the stationary start bolt.

One aspect of the present invention is a compressed solid dosage form, for example a tablet or a caplet. The hardness of a solid dosage form is up to about 20 kiloponds per square centimeter (kp / cm²), e.g. about 2-15 kp / cm² or about 4-10 kp / cm². As used herein, the term "hardness" means diameter breaking strength as measured by conventional pharmaceutical hardness test equipment, such as the Schleuniger Hardness Tester. In order to compare the values ​​for tablets of different sizes, the breaking strength is standardized to the breaking surface area (which can be roughly measured as the diameter of the tablet times its thickness). This standardized value, expressed in kp / cm², is sometimes referred to in the literature as the tensile strength of the tablet. For a general discussion of tablet hardness testing, see Leiberman et al., Pharmaceutical Dosage Forms - Tablets, Vol. 2, 2nd Edition, Marcel Dekker Inc., 1990, pp. 213-217, 327-329.

The solid oral dosage form of the present invention can be made into tablets, caplets, gelcaps, chewable tablets, lozenges, fast dissolving wafers, and other known and effective methods of oral administration.

A typical solid dosage form of the present invention may include a formulation containing the individual components as specified below:

Simetikon

Silicified microcrystalline cellulose Magnesium Aluminum Metasilicate Additional active agent

Lubricant

Dry filler / binder

Wet Binder from about 1 to about 75% from about 5 to about 40% from about 5 to about 30% from about 0 to about 89% from about 0 to about 5% from about 0 to about 35% from about 0 to about 10% from about 0 to about 5%

Flavorings / Sweeteners / Colorants All% were given as weight to weight (%).

The following examples illustrate specific embodiments of the present invention. The invention is not limited to the specific limitations given in these examples, but only to the scope.

Example 1

<td>Ingredients</td><td>Unit weight (mg)</td><td>% (by weight)</td><td>Batch weight (g)</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td>

<td>Simetikon **</td><td> 135</td><td> 33,75</td><td> 337,5</td>

<td>Magnesium Aluminum Metasilicate (Neusilin, US-2, Fuji Chemical Ltd.)</td><td> 77</td><td> 19,25</td><td> 192,5</td>

PL 204 141 B1 cont. table

<td> 1</td><td> 2</td><td> 3</td><td> 4</td>

<td>Siliconized microcrystalline cellulose (Prosolv HD-90, PenWest Co.)</td><td> 150</td><td> 37,5</td><td> 375,0</td>

<td>Loperamide USP</td><td> 2</td><td> 0,5</td><td> 5,0</td>

<td>Sodium starch glycolate NF</td><td> 32</td><td> 8,0</td><td> 80,0</td>

<td>NF stearic acid</td><td> 4</td><td> 1,0</td><td> 10,0</td>

<td colspan="3">Together</td><td> 1000</td>

**: note: excess cargo 10%

In a Hobart mixer 4, the fourths were combined magnesium aluminum metasilicate and half the amount per batch of siliconized microcrystalline cellulose with simethicone by initially placing a layer of simethicone between the magnesium aluminum metasilicate layer on the bottom and the siliconized microcrystalline cellulose layer on top and mixed at speed setting "1" by about 5 minutes.

Loperamide was screened through a 40 mesh screen. After screening, loperamide, sodium starch glycolate and the remainder of the siliconized microcrystalline cellulose were added to the Hobart mixer and mixed at speed setting "1" for about 5 minutes.

The stearic acid was sieved through a 30 mesh screen. After sieving, the stearic acid was added to a Hobart mixer and mixed for about 5 minutes to form a plastic, compressible powder.

The powder was then compressed into individual units, e.g. tablets, on a Manesty Beta Press with a standard caplet shape concave setting (diameter = 6.092 mm, length = 19.995 mm) by pre-pressing at 5 kN followed by main compression. The target weight per unit was 400 mg. For each unit, the total weight, thickness (mm) and hardness (Kp) were determined at various compression forces. These data are presented below.

<td>Basic pressing force (kN)</td><td>Weight 10 units (g)</td><td>Average thickness (mm)</td><td>Medium hardness (kp / cm²)</td>

<td> 5,0</td><td> 4,0370</td><td> 5,135</td><td> 5,75</td>

<td> 10,0</td><td> 3,9900</td><td> 4,943</td><td> 6,64</td>

<td> 12,5</td><td> 3,9470</td><td> 4,814</td><td> 7,50</td>

<td> 15,0</td><td> 3,9060*</td><td> 4,743</td><td> 5,88</td>

<td> 20.0</td><td> 3,0912*</td><td> 4,687</td><td> 5,95</td>

* changing after ironing

Example 2

Caplets containing simethicone (120 mg) and loperamide (2 mg):

<td>Ingredients</td><td>Unit weight (mg)</td><td>% (by weight)</td><td>Batch weight (g)</td>

<td>Simetikon</td><td> 135</td><td> 33,75</td><td> 33,75</td>

<td>Magnesium Aluminum Metasilicate (Neusilin, US-2, Fuji Chemical Ltd.)</td><td> 85</td><td> 21,25</td><td> 21,25</td>

<td>Siliconized microcrystalline cellulose (Prosolv HD-90, PenWest Co.)</td><td> 150</td><td> 37,50</td><td> 37,50</td>

<td>Loperamide USP</td><td> 2</td><td> 0,50</td><td> 0,50</td>

<td>Sodium starch glycolate NF</td><td> 26</td><td> 6,50</td><td> 6,50</td>

<td>NF stearic acid</td><td> 2</td><td> 0,50</td><td> 0,50</td>

<td>Together</td><td></td><td></td><td> 100</td>

PL 204 141 B1

In a glass mortar, the simethicone was wet milled and sedimentation fractionated to make magnesium aluminum metasilicate. The silicified microcrystalline cellulose was added to the dry simethicone / magnesium aluminum metasilicate mixture and mixed thoroughly. Loperamide and sodium starch glycolate were added while mixing until uniform. Stearic acid was added and mixing was continued for approximately five minutes.

The powder was then compressed into separate units, e.g. tablets, on a Manesty Beta Press with a standard caplet shape concavity setting (diameter = 6.092 mm, length = 19.995 mm) by pre-pressing at 5 kN followed by main compression. The target weight per unit was 400 mg. For each unit, the total weight, thickness (mm) and hardness (Kp) were determined at various compression forces. These data are presented below.

<td>Basic pressing force (kN)</td><td>Average weight of 3 units (mg)</td><td>Average thickness of 3 units (mm)</td><td>Average hardness of 3 units (kp / cm²)</td>

<td> 3,5</td><td> 421,0</td><td> 5,602</td><td> 10,16</td>

<td> 5,0</td><td> 424,0</td><td> 5,290</td><td> 9,62</td>

<td> 7,0</td><td> 410,0</td><td> 4,601</td><td> 5,71</td>

<td> 10,0</td><td> 418,3</td><td> 5,129</td><td> 7,68</td>

<td> 18,0</td><td> 402,7</td><td> 4,890</td><td> 5,37</td>

Example 3

Caplets containing simethicone (120 mg) and loperamide (2 mg):

<td>Ingredients</td><td>Unit weight (mg)</td><td>% (by weight)</td><td>Batch weight (g)</td>

<td>Simetikon</td><td> 135</td><td> 31,0340</td><td> 62,1</td>

<td>Magnesium Aluminum Metasilicate (Neusilin, US-2, Fuji Chemical Ltd.)</td><td> 105</td><td> 24,1380</td><td> 48,3</td>

<td>Siliconized microcrystalline cellulose (Prosolv HD-90, PenWest Co.)</td><td> 170</td><td> 39,0800</td><td> 78,2</td>

<td>Loperamide USP</td><td> 2</td><td> 0,4598</td><td> 0,9</td>

<td>Sodium starch glycolate NF</td><td> 20</td><td> 4,5977</td><td> 9,2</td>

<td>NF stearic acid</td><td> 3</td><td> 0,6897</td><td> 1,4</td>

<td>Together</td><td></td><td></td><td> 200</td>

In a Hobart mixer 4, the fourths were combined magnesium aluminum metasilicate and half the amount per batch of siliconized microcrystalline cellulose with simethicone by initially placing a layer of simethicone between the magnesium aluminum metasilicate layer on the bottom and the siliconized microcrystalline cellulose layer on top and mixed at speed setting "1" by about 5 minutes.

Loperamide was screened through a 40 mesh screen. After screening, loperamide, sodium starch glycolate and the remainder of the siliconized microcrystalline cellulose were added to the Hobart mixer and mixed at speed setting "1" for about 5 min.

The stearic acid was sieved through a 30 mesh screen. After sieving, the stearic acid was added to a Hobart mixer and mixed for about 5 minutes to form a plastic, compressible powder.

The powder was then compressed into individual units, e.g. tablets, on a Manesty Beta Press with a standard caplet shape concave setting (diameter = 6.092 mm, length = 19.995 mm) by pre-pressing at 5 kN followed by main compression. The target weight per unit was 400 mg. For each unit, the total weight, thickness (mm) and hardness (Kp) were determined at various compression forces. These data are presented below.

PL 204 141 B1

<td>Basic pressing force (kN)</td><td>Average weight 5 units (mg)</td><td>Average thickness 5 units (mm)</td><td>Medium hardness 5 units (kp / cm²)</td>

<td> 1,0</td><td> 405,0</td><td> 5,9940</td><td> 11,50</td>

<td> 3,4</td><td> 404,4</td><td> 5,7522</td><td> 15,24</td>

<td> 5,0</td><td> 371,6</td><td> 5,1290</td><td> 15,87</td>

<td> 6,0</td><td> 390,2</td><td> 5,1450</td><td> 17,23</td>

<td> 7,5</td><td> 394,0</td><td> 5,1640</td><td> 15,26</td>

<td> 10,0</td><td> 390,6</td><td> 4,8740</td><td> 13,13</td>

<td> 13,0</td><td> 386,4</td><td> 4,7630</td><td> 10,30</td>

<td> 20,0</td><td> 397,8</td><td> 4,7950</td><td> 8,18</td>

Although the target unit weight was 435 g, with the available equipment (caplet BB 604 x 224 x 052), i.e. with maximum filling of the die, it was only possible to obtain a weight of about 400 mg.

Example 4

A water disintegration test was carried out comparing the unit of example 1 (5 kN pre-compression and 5 kN main compression) and the units of example 3 (3 kN pre-compression and 5 kN main compression). The results showed that the unit of example 1 disintegrated in less than 2 minutes after being placed in water, while the unit of example 3 remained intact and floated in the water for about 2.5 minutes.

Example 5

Caplets containing simethicone (120 mg) and loperamide (2 mg):

<td>Ingredients</td><td>Unit weight (mg)</td><td>% (by weight)</td><td>Batch weight (g)</td>

<td>Simetikon *</td><td> 135</td><td> 33,75</td><td> 67,5</td>

<td>Magnesium Aluminum Metasilicate (Neusilin, US-2, Fuji Chemical Ltd.)</td><td> 90</td><td> 22,50</td><td> 45,0</td>

<td>Siliconized microcrystalline cellulose (Prosolv HD-90, PenWest Co.)</td><td> 150</td><td> 37,50</td><td> 75,0</td>

<td>Loperamide USP</td><td> 2</td><td> 0,50</td><td> 1,0</td>

<td>Sodium starch glycolate NF</td><td> 20</td><td> 5,00</td><td> 10,0</td>

<td>NF stearic acid</td><td> 3</td><td> 0,75</td><td> 10,0</td>

<td>Together</td><td></td><td></td><td> 200</td>

note: 10% overload

In a Hobart 4 mixer bowl, the quarters were slowly added simethicone to about half the amount of magnesium aluminum metasilicate per batch and paddle mixed for about 5 minutes.

The remainder of the magnesium aluminum metasilicate was added to the mixture and mixing was continued until a homogeneous mass was obtained, scraping the sides of the bowl.

Loperamide was screened through a 40 mesh screen. After screening, loperamide, sodium starch glycolate and silicified microcrystalline cellulose were added. The resulting mixture was mixed at speed setting "1" for about 5 minutes.

The stearic acid was sieved through a 30 mesh screen. After sieving, stearic acid was added and mixed for approximately 5 minutes to form a plastic, compressible powder.

The powder was then compressed into individual units, e.g. tablets, on a Manesty Beta Press with a standard caplet shape concave setting (diameter = 6.092 mm, length = 19.995 mm) by pre-pressing at 3 kN followed by main compression. The target weight per unit was 400 mg. For each unit, the total weight, thickness (mm) and hardness (kp) were determined at various compression forces. These data are presented below.

PL 204 141 B1

<td>Basic pressing force (kN)</td><td>Average weight 5 units (mg)</td><td>Average thickness 5 units (mm)</td><td>Medium hardness 5 units (kp / cm²)</td>

<td> 1,0</td><td> 397,4</td><td> 5,920</td><td> 6,60</td>

<td> 3,0</td><td> 396,6</td><td> 5,572</td><td> 9,66</td>

<td> 5,0</td><td> 396,6</td><td> 5,263</td><td> 9,67</td>

<td> 6,0</td><td> 399,6</td><td> 5,156</td><td> 9,30</td>

<td> 7,0</td><td> 395,6</td><td> 5,018</td><td> 8,37</td>

<td> 90,0</td><td> 396,2</td><td> 4,974</td><td> 8,45</td>

<td> 12,5</td><td> 389,4</td><td> 4,806</td><td> 7,24</td>

<td> 20,0</td><td> 372,4</td><td> 4,655</td><td> &lt; 4,94</td>

Example 6

Caplets containing simethicone (120 mg) and loperamide (2 mg):

<td>Ingredients</td><td>Unit weight (mg)</td><td>% (by weight)</td><td>Batch weight (g)</td>

<td>Simetikon</td><td> 135</td><td> 33,75</td><td> 67,5</td>

<td>Magnesium Aluminum Metasilicate (Neusilin, US-2, Fuji Chemical Ltd.)</td><td> 100</td><td> 25,00</td><td> 50,5</td>

<td>Siliconized microcrystalline cellulose (Prosolv HD-90, PenWest Co.)</td><td> 140</td><td> 35,00</td><td> 70,0</td>

<td>Loperamide USP</td><td> 2</td><td> 0,50</td><td> 1,0</td>

<td>Sodium starch glycolate NF</td><td> 20</td><td> 5,00</td><td> 10,0</td>

<td>NF stearic acid</td><td> 3</td><td> 0,75</td><td> 10,0</td>

<td>Together</td><td></td><td></td><td> 200</td>

In a Hobart 4 mixer bowl, the quarters were slowly added simethicone to about half the amount of magnesium aluminum metasilicate per batch and paddle mixed for about 5 minutes.

The remainder of the magnesium aluminum metasilicate was added to the mixture and mixing was continued until a homogeneous mass was obtained, scraping the sides of the bowl.

Loperamide was screened through a 40 mesh screen. After screening, loperamide, sodium starch glycolate and silicified microcrystalline cellulose were added. The resulting mixture was mixed at speed setting "1" for about 5 minutes.

The stearic acid was sieved through a 30 mesh screen. After sieving, stearic acid was added and mixed for approximately 5 minutes to form a plastic, compressible powder.

The powder was then compressed into individual units, e.g. tablets, on a Manesty Beta Press with a standard caplet shape concave setting (diameter = 6.092 mm, length = 19.995 mm) by pre-pressing at 3 kN followed by main compression. The target weight per unit was 400 mg. For each unit, the total weight, thickness (mm) and hardness (kp) were determined at various compression forces. These data are presented below.

<td>Basic pressing force (kN)</td><td>Average weight 5 units (mg)</td><td>Average thickness 5 units (mm)</td><td>Medium hardness 5 units (kp / cm²)</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td>

<td> 1,0</td><td> 395,6</td><td> 5,7730</td><td> 6,94</td>

<td> 2,0</td><td> 398,2</td><td> 5,6720</td><td> 8,57</td>

<td> 3,0</td><td> 400,0</td><td> 5,2630</td><td> 10,23</td>

<td> 4,0</td><td> 395,8</td><td> 5,2960</td><td> 7,81</td>

PL 204 141 B1 cont. table

<td> 1</td><td> 2</td><td> 3</td><td> 4</td>

<td> 5,0</td><td> 390,8</td><td> 5,1128</td><td> 8,48</td>

<td> 10</td><td> 397,6</td><td> 4,9750</td><td> &lt; 7,26</td>

<td> 20</td><td> 374,8</td><td> 4,6710</td><td> 7,10</td>

Example 7

Caplets containing simethicone (120 mg) and loperamide (2 mg):

<td>Ingredients</td><td>Unit weight (mg)</td><td>% (by weight)</td><td>Batch weight (g)</td>

<td>Simetikon</td><td> 135</td><td> 33,75</td><td> 67,5</td>

<td>Magnesium Aluminum Metasilicate (Neusilin, US-2, Fuji Chemical Ltd.)</td><td> 110</td><td> 27,50</td><td> 55,0</td>

<td>Siliconized microcrystalline cellulose (Prosolv HD-90, PenWest Co.)</td><td> 125</td><td> 31,25</td><td> 62,5</td>

<td>Loperamide USP</td><td> 2</td><td> 0,50</td><td> 1,0</td>

<td>Sodium starch glycolate NF</td><td> 25</td><td> 6,25</td><td> 12,5</td>

<td>NF stearic acid</td><td> 3</td><td> 0,75</td><td> 1,5</td>

<td>Together</td><td></td><td></td><td> 200</td>

In a Hobart 4 mixer bowl, the quarters were slowly added simethicone to about half the amount of magnesium aluminum metasilicate per batch and paddle mixed for about 5 minutes.

The remainder of the magnesium aluminum metasilicate was added to the mixture and mixing was continued until a homogeneous mass was obtained, scraping the sides of the bowl.

Loperamide was screened through a 40 mesh screen. After screening, loperamide, sodium starch glycolate and silicified microcrystalline cellulose were added. The resulting mixture was mixed at speed setting "1" for about 5 minutes.

The stearic acid was sieved through a 30 mesh screen. After sieving, stearic acid was added and mixed for approximately 5 minutes to form a plastic, compressible powder.

The powder was then compressed into individual units, e.g. tablets, on a Manesty Beta Press with a standard caplet shape concave setting (diameter = 6.092 mm, length = 19.995 mm) by pre-pressing at 3 kN followed by main compression. The target weight per unit was 400 mg. For each unit, the total weight, thickness (mm) and hardness (kp) were determined at various compression forces. These data are presented below.

<td>Basic pressing force (kN)</td><td>Average weight 5 units (mg)</td><td>Average thickness 5 units (mm)</td><td>Medium hardness 5 units (kp / cm²)</td>

<td> 1,0</td><td> 399,0</td><td> 5,9350</td><td> 7,47</td>

<td> 2,0</td><td> 398,8</td><td> 5,8980</td><td> 7,68</td>

<td> 3,0</td><td> 404,2</td><td> 5,7090</td><td> 8,74</td>

<td> 4,0</td><td> 408,0</td><td> 5,4380</td><td> 9,60</td>

<td> 5,0</td><td> 408,8</td><td> 5,3440</td><td> 9,46</td>

<td> 10,0</td><td> 408,6</td><td> 5,0900</td><td> 5,80</td>

<td> 15,0</td><td> 405,8</td><td> 4,9440</td><td> &lt; 4,45</td>

<td> 20,0</td><td> 400,8</td><td> 4,8716</td><td> &lt; 4,04</td>

PL 204 141 B1

Example 8

Caplets containing simethicone (120 mg) and loperamide (2 mg):

<td>Ingredients</td><td>Unit weight (mg)</td><td>% (by weight)</td><td>Batch weight (g)</td>

<td>Simetikon **</td><td> 135</td><td> 35,065</td><td> 140,3</td>

<td>Magnesium Aluminum Metasilicate (Neusilin, US-2, Fuji Chemical Ltd.)</td><td> 90</td><td> 23,377</td><td> 93,5</td>

<td>Siliconized microcrystalline cellulose (Prosolv HD-90, PenWest Co.)</td><td> 146</td><td> 37,922</td><td> 151,7</td>

<td>Loperamide USP</td><td> 2</td><td> 0,520</td><td> 2,1</td>

<td>Sodium starch glycolate NF</td><td> 10</td><td> 2,597</td><td> 10,4</td>

<td>NF stearic acid</td><td> 2</td><td> 0,520</td><td> 2,1</td>

<td>Together</td><td></td><td></td><td> 400</td>

note: 10% overload

In a Hobart 4 mixer bowl, the quarters were slowly added simethicone to about half the amount of magnesium aluminum metasilicate per batch and paddle mixed for about 5 minutes.

The remainder of the magnesium aluminum metasilicate was added to the mixture and mixing was continued until a homogeneous mass was obtained, scraping the sides of the bowl.

Loperamide was screened through a 40 mesh screen. After screening, loperamide, sodium starch NF glycolate and silicified microcrystalline cellulose were added. The resulting mixture was mixed at speed setting "1" for about 5 minutes.

The stearic acid was sieved through a 30 mesh screen. After sieving, stearic acid was added and mixed for about 5 minutes to form a plastic, compressible powder.

The powder was then compressed into individual units, e.g. tablets, on Manesty Beta Press with a standard caplet shape concavity setting (diameter = 6.092 mm, length = 19.995 mm) by pre-pressing at 3 kN followed by main compression (the asterisk * marks the units whose was not pre-pressed). The target weight per unit was 385 mg. For each unit, the total weight, thickness (mm) and hardness (kp) were determined at various compression forces. These data are presented below.

<td>Basic pressing force (kN)</td><td>Average weight 5 units (mg)</td><td>Average thickness 5 units (mm)</td><td>Medium hardness 5 units (kp / cm²)</td>

<td> 1,0</td><td> 382,8</td><td> 5,460</td><td> 9,56</td>

<td> 2,0</td><td> 383,4</td><td> 5,395</td><td> 9,31</td>

<td> 3,0</td><td> 382,0</td><td> 5,356</td><td> 7,60</td>

<td> 4,0</td><td> 379,8</td><td> 5,123</td><td> 8,78</td>

<td> 5,0</td><td> 382,8</td><td> 4,993</td><td> &lt; 6,58</td>

<td> 10,0</td><td> 383,6</td><td> 4,841</td><td> &lt; 4,07</td>

<td> 1,5*</td><td> 384,8</td><td> 5,439</td><td> 7,12</td>

<td> 3,0*</td><td> 382,4</td><td> 5,306</td><td> 7,61</td>

Example 9

Caplets containing simethicone (120 mg) and acetaminophen (250 mg):

<td>Ingredients</td><td>Unit weight (mg)</td>

<td> 1</td><td> 2</td>

<td>Simetikon **</td><td> 135</td>

PL 204 141 B1 cont. table

<td> 1</td><td> 2</td>

<td>Magnesium Aluminum Metasilicate (Neusilin, US-2, Fuji Chemical Ltd.)</td><td> 90</td>

<td>Siliconized microcrystalline cellulose (Prosolv HD-90, PenWest Co.)</td><td> 150</td>

<td>Acetaminophen USP</td><td> 250</td>

<td>Sodium starch glycolate NF</td><td> 20</td>

<td>NF stearic acid</td><td> 5</td>

<td>Together</td><td> 650</td>

**: note: excess cargo 10%

In a Hobart 4 mixer bowl, the quarters were slowly added simethicone to about half the amount of magnesium aluminum metasilicate per batch and paddle mixed for about 5 minutes.

The remainder of the magnesium aluminum metasilicate was added to the mixture and mixing was continued until a homogeneous mass was obtained, scraping the sides of the bowl.

Acetaminophen was screened through a 40 mesh screen. After screening, acetaminophen, sodium starch glycolate NF and silicified microcrystalline cellulose were added. The resulting mixture was mixed at speed setting "1" for about 5 minutes.

The stearic acid was sieved through a 30 mesh screen. After sieving, stearic acid was added and mixed for approximately 5 minutes to form a plastic, compressible powder.

Example 10

Caplets containing simethicone (120 mg) and ibuprofen (200 mg):

<td>Ingredients</td><td>Unit weight (mg)</td>

<td>Simetikon **</td><td> 135</td>

<td>Magnesium Aluminum Metasilicate (Neusilin, US-2, Fuji Chemical Ltd.)</td><td> 90</td>

<td>Siliconized microcrystalline cellulose (Prosolv HD-90, PenWest Co.)</td><td> 150</td>

<td>Ibuprofen USP</td><td> 200</td>

<td>Sodium starch glycolate NF</td><td> 20</td>

<td>NF stearic acid</td><td> 5</td>

<td>Together</td><td> 600</td>

**: note: excess cargo 10%

In a Hobart 4 mixer bowl, the quarters were slowly added simethicone to about half the amount of magnesium aluminum metasilicate per batch and paddle mixed for about 5 minutes.

The remainder of the magnesium aluminum metasilicate was added to the mixture and mixing was continued until a homogeneous mass was obtained, scraping the sides of the bowl.

Ibuprofen was screened through a 40 mesh screen. After screening, ibuprofen, sodium starch glycolate NF and silicified microcrystalline cellulose were added. The resulting mixture was mixed at speed setting "1" for about 5 minutes.

The stearic acid was sieved through a 30 mesh screen. After sieving, stearic acid was added and mixed for approximately 5 minutes to form a plastic, compressible powder.

The remainder of the magnesium aluminum metasilicate was added to the mixture and mixing was continued until a homogeneous mass was obtained, scraping the sides of the bowl.

Mesalamine was screened through a 40 mesh screen. After screening, mesalamine, sodium starch glycolate NF and silicified microcrystalline cellulose were added. The resulting mixture was mixed at speed setting "1" for about 5 minutes.

The stearic acid was sieved through a 30 mesh screen. After sieving, stearic acid was added and mixed for approximately 5 minutes to form a plastic, compressible powder.