WO2008056200A1

WO2008056200A1 - Oral pharmaceutical compositions of simethicone

Info

Publication number: WO2008056200A1
Application number: PCT/IB2006/003194
Authority: WO
Inventors: Ganpat Desai; Rajendra Nagamalla; Natrajan Kumaraperumal; Indrajit Ghosh; Irena Mudri; Vidya Poduval; Supriya Rane
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2006-11-10
Filing date: 2006-11-10
Publication date: 2008-05-15

Abstract

The present invention relates to oral pharmaceutical compositions of simethicone and methods for providing the pharmaceutical compositions.

Description

ORAL PHARMACEUTICAL COMPOSITIONS OF SIMETHICONE

Field of the Invention

The present invention relates to oral pharmaceutical compositions of, and methods for formulating compositions of simethicone that include excipients to improve processing during manufacture of dosage forms of the pharmaceutical compositions.

Background of the Invention

Chemically, simethicone is characterized as being a mixture of fully methylated linear siloxane polymers containing repeating units of polydimethylsiloxane stabilized with trimethylsiloxy end-blocking units, and silicon dioxide. Simethicone contains 90.5-99% of polydimethylsiloxa ne and 4-7% of silicon dioxide. The polydimethylsiloxanes present in simethicone are ess entially inert polymers having a molecular weight of 14,000-21,000. The mixture is a gray, translucent, viscous fluid which is insoluble in water and can be described as being sticky.

Orally adm nistered simethicone is indicated as an adjunct in the symptomatic treatment of fiatule ice, functional gastric bloating, and postoperative gas pains. The clinical use of simethicone is based on its fiinction as an antifoam agent with the silicone antifoams spreading on the surface of aqueous liquids, forming a film of low surface tension and thus causing the collapse of foam bubbles. As a nonprescription, over-the-counter medication, simethicone is used as an anti-flatulent to relieve symptoms commonly referred to as gas, including upper gastrointestinal bloating, pressure, fullness, or stuffed feeling. It is often combined with other gastrointestinal medications, such as antacids, antispasmodics or digestive enzymes. Accordingly, various simethicone formulations are disclosed in the art.

Simethicone is known as a sticky substance that can be difficult to process into tablets. For example, U.S. 6,103,260 discloses formulations of simethicone with anhydrous dibasic or tribasic cilcium phosphate. This patent describes the dosage form as being formulated from a f "ee flowing granular composition of simethicone and anhydrous tribasic calcium phosphate or anhydrous dibasic calcium phosphate. The simethicone is described as being about 10-70% w/w of the admixture combination and the anhydrous calcium phosphate as being 30-90% w/w of the admixture combination. Formulators have found it difficult to prepare free flowing, compressible solid simethicone dosage forms when incorporating substantial quantities of the liquid simethicone in the solid final blend for tableting. The difficulty can be a lack of sufficient cohesion in. the compact for compression, particularly for direct compression tableting, such that the tablet will withstand the rigors of further processing, i.e., film coating, gelatin dipping, printing, packaging and the like. Further, it can be difficult to assure that the viscous liquid simethicone is uniformly distributed throughout the solid formulation and expeditiously dispersed upon administration. In the '260 patent, the simethicone is added to the calcium phosphate at a rate of 200 grams of simethicone per 700 grams of calcium phosphate over five minutes while mixing at a low speed. The result is described as being a free flowing granulation with no large agglomerates.

U.S. 4,906,478 discloses simethicone preparations that include a powdered combination of par iculate calcium silicate and simethicone. The '478 patent discloses the calcium silicate and simethicone as being preferably present in equal parts by weight but as being suitable in a range of 40-60% w/w simethicone to 60-40% w/w calcium silicate.

U.S. 5,073, 384 discloses simethicone preparations that are in the form of combinations of wεter soluble agglomerated maltodextrin and simethicone. The '384 patent states that a preferred embodiment includes an admixture of 30% by weight simethicone and 70% by weight maltodextrin. The weight range ratios of simethicone to maltodextrin is described as being ;τom 10% to 50% simethicone to 90% to 50% maltodextrin.

U.S. 5,458,'* 86 discloses formulations that are characterized as being free-flowing granular compositions of titanium dioxide having specific particle size and surface area in combination with simethicone.

U.S. 7,101,.'»^'73 discloses admixture compositions of simethicone, an adsorbent, and an optional active agent in which the weight ratio of the simethicone to adsorbent is 1 : 1.75 to 1:2.22. As adsorbents substrates, the '573 patent discloses using silicified microcrystalline cellulose and magnesium aluminometasilicate together in combination with simethicone. The simethicone oil or liquid is adsorbed onto the surface of the substrate particles.

While these methods are of some benefit in achieving a simethicone composition suitable for some ccmpression manufacturing process, the present invention provides compositions which may be easily and inexpensively formulated into potent swallowable or chewable tablets of simethicone, alone or with additional active ingredients (e.g., loperamide hydrochloride) and administered, for example, to treat diarrhea and act as an anti-gas/anti- flatulent. While tablets have been specifically named as a suitable or possible dosage form, other dosage forms, also may be made according to the present invention. These additional dosage forms include bi-layer or tri-layer tablets, tablet-in-tablet, film-coated tablets, effervescent tablets;, dispersible tablets, chewable tablets, chewing gums, powders, granules, and capsules. An object of the present invention, therefore, is to provide compositions and processes that permit substantial quantities of liquid simethicone to be incorporated into solid tablet formulations for manufacture by various compression and other manufacturing processes.

Summary of the Invention In one general aspect there is provided an oral pharmaceutical composition that includes simethicone, a pharmaceutically acceptable salt of silicate, at least one adsorbent material that adsorbs simethicone, and optionally one or more pharmaceutically acceptable excipients.

Embodiments of the oral pharmaceutical composition may include one or more of the following features. For example, the pharmaceutically acceptable salt of silicate may be calcium silicate. T] ie pharmaceutically acceptable salt of silicate may be aluminum silicate, magnesium trisilicete, and magnesium aluminum silicate.

The adsorbmt material maybe one or more of powdered cellulose, microcrystalline cellulose, silicifled macrocrystalline cellulose, tribasic calcium phosphate, dibasic calcium phosphate, maltodextrin, precipitated silica, colloidal silica, starch, pregelatinized starch, hydroxypropyl cellulose, magnesium oxide, and magnesium hydroxide. The adsorbent material may be a material that adsorbs simethicone onto the surface of the adsorbent material. The ratio of the simethicone to the calcium silicate and at least one adsorbent material may be between 4:1 to 1:2 on a weight percentage basis. The ratio of the simethicone to the c alcium silicate and at least one adsorbent material may be between 3:1 to 1 :2 on a weight percentage basis. The calcium silicate, the at least one adsorbent material and the simethicone may be characterized as being free flowing.

The oral pharmaceutical composition may further include one or more additional active ingredients. The one or more additional active ingredients may be one or more of H₂ (histamine) receptor inhibitors, gastrointestinal prokinetics, antidiarrheal preparations, adsorbents as active ingredient, antispasmodics, proton pump inhibitors, laxatives, lactase, mesalamine, bismuth compounds, antacids, antibiotics, antiemetics, and glycopyrrolatess. The H₂ (histamine) receptor inhibitors may be one or more of cimetidine, ranitidine, famotidine, and ntz atidine. The gastrointestinal prokinetic may be prucalopride. The antidiarrheal prep&'ation may be loperamide or diphenoxylate. The adsorbents as active ingredient may be pectin, polycarbophil, activated charcoal, and kaolin. The proton pump inhibitor maybe oraeprazole, pantoprazole, lansoprazole, their salts and derivatives. The laxative may be bisacodyl, cascara sagrada, danthron, senna, phenolphtalein, aloe, castor oil, ricinoleic acid, and dehydrocholic acid. The antacids may be calcium carbonate, aluminum hydroxide, magnes: um hydroxide, and magnesium carbonate. The gastrointestinal cytoprotectives may be sucralfate and misoprostol. The antibiotic may be clarithromycin, amoxicillin, other penicillins and cephalosporins, tetracycline, metronidazole, azithromycin, and erythromycin. The antiemetics may be ondansetron. The anticholinergic may be a glycopyrrolate. In particular, the additional active ingredient may be loperamide.

In another general aspect there is provided an oral pharmaceutical composition that includes simethicor e, an adsorbent material, and optionally one or more pharmaceutically acceptable excipients. The ratio of the simethicone to the adsorbent material is between 4:1 to 1 :2 on a weight r. ercentage basis.

Embodimerts of the oral pharmaceutical composition may include one or more of the following features. For example, the adsorbent material may be one or more of powdered cellulose, microcryf.talline cellulose, silicified macrocrystalline cellulose, tribasic calcium phosphate, dibasic c alcium phosphate, maltodextrin, precipitated silica, colloidal silica, starch, pregelatinizcd starch, hydroxypropyl cellulose, magnesium oxide, and magnesium hydroxide. The adsorbent material may be one or more materials that adsorb simethicone onto the surface of Ihe adsorbent material. A mixture of the adsorbent material and the simethicone may be characterized as being free flowing.

The oral phjirmaceutical composition may further include one or more additional active ingredients. The one or more additional active ingredients may be one or more of H₂ (histamine) receptoi inhibitors, gastrointestinal prokinetics, antidiarrheal preparations, adsorbents as active ingredient, antispasmodics, proton pump inhibitors, laxatives, lactase, mesalamine, bismuth compounds, antacids, antibiotics, antiemetics, and anticholinergetics.. In particular, the additional active ingredient may be loperamide. In another general aspect there is provided a process for making a free flowing mixture of simethicone and an adsorbent material, the method comprising; (i) providing an adsorbent material and optional dry excipients in a mixing means; and (ii) adding simethicone to the adsorbent material at a rate of between 0.06 and 0.2 kg of simethicone per kg of adsorbent and dry excipients per minute while using the mixing means to mix the simethicone and adsorbent material.

Embodimeits of the process may include one or more of the following features or those described heiein. For example, the simethicone may be added at a rate of between 0.06 and 0.1 kg/kg/min. The mixing means may be one or more of high shear mixers, low shear mixers, non shear mixers, roller compactors, blenders, and blenders with intensifier bars. The process may furthe ^• include using the material of step (ii) in forming a pharmaceutical dosage form.

In another general aspect, there is provided a process for making a free flowing mixture of simethicone and an adsorbent material. The method includes (i) mixing simethicone with a solvent to form a solution or emulsion; (ii) adding the adsorbent material to the solution or emulsion; and (iii) spray drying the material of step (ii).

Embodiments of the process may include one or more of the following features or those described her in. For example, the particle size of the material produced at step (iii) may be reduced. The solvent may be one or more of polar and nonpolar solvents. The solvent may be one or more of methylene chloride, isopropyl alcohol, water and ethanol. The solvent may be selected so as not to dissolve the adsorbent material. The process may further include using the material of step (iii) in forming a pharmaceutical dosage form.

In another general aspect there is provide an oral dosage form that includes loperamide and one or more pharmaceutically acceptable excipients having the function of overwhelming the bitter taste of the loperamide as sensed upon oral administration.

Embodiments of the oral dosage form may include one or more of the following features or those described herein. For example, the pharmaceutically acceptable excipient may be an excipient having one or more of a sweet flavor, a sour flavor, or a salty flavor. The sweetener is prosent in a range of from 1% to about 60% of the tablet weight. The sour flavor may be caused by a pharmaceutically acceptable acid. The pharmaceutically acceptable acid may be one or more of fumaric acid, ascorbic acid, and citric acid. The oral dosage form may be a chewable tablet.

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims. For example, a number of difficulties can be advantageously addressed using the inventions discloses herein. One such difficulty is that of poor flow of the siriethicone and dry excipients as a result of the sticky nature of simethicone. Another such difficulty that may be addressed is the sticky nature of the simethicone causing the material to stick to the punches and equipment, e.g., clogging up the tablet dies and the like. Other difficulties that may be addressed relate to low hardness of the resulting tablets and poor dissolution properties of the tablets.

Detailed Description of the Invention

The inventors have inexpensive and generally trouble-free methods for formulating pharmaceutical compositions that include simethicone. In one aspect, the basis for the methods and resulting compositions relies on the use of calcium silicate and a second adsorbent material i o absorb simethicone to give body to the material for further processing. In general, any phaπnaceutically acceptable salt of silicate of trivalent, divalent and monovalent cation can be used in place of the calcium silicate. In another aspect, the basis for the methods anc resulting compositions relies on the use of dihydrous dibasic or tribasic calcium phosphate ^*vith the simethicone to give body (e.g., higher density) to the mixture and improve the flowability of the mixture during further processing. Finally, in another aspect, microcrystalline cellulose and/or colloidal silicon dioxide can be used to improve the flowability of the mixture during further processing. These three aspects can be used in combination or sep.irately. Further to any of these aspects, the simethicone can be combined with a second active ingredient, such as loperamide hydrochloride. Additional second active ingredients (or third or more active ingredient, is so desired) include H₂ (histamine) receptor inhibitors (e.g., cimetidine, ranitidine, famotidine, nizatidine), gastrointestinal prokinetics (e.g., prucalopride), antidiarrheal preparations (e.g., loperamide, diphenoxylate), adsorbents as active ingredient (e.g., pectin, polycarbophil, activated charcoal, kaolin), antispasmodics, proton pump inhibitors (e.g.. omeprazole, pantoprazole, lansoprazole, their salts and derivatives), laxatives (e.g., bisacodyl, cascara sagrada, danthron, senna, phenolphtalein, aloe, castor oil, ricinoleio acid, dehydrocholic acid), lactase, mesalamine, bismuth compounds, antacids (e.g., calci jm carbonate, aluminum hydroxide, magnesium hydroxide, magnesium carbonate, gastrointestinal cytoprotectives (e.g., sucralfate, misoprostol), antibiotics (e.g., clarithromycin, amoxicillin, other penicillins and cephalosporins, tetracycline, metronidazole, azithromycin, erithromycin, etc.), antiemetics (e.g., ondansetron), and anticholinergics (e.g., a glycopyrrolate). Examples of these formulations, and processes for making them, are described below.

As used herein, an adsorbent material is a substrate that adsorbs a second material, e.g., simethicone, oato the surface of the substrate particles. Thus calcium silicate is an adsorbent material because it adsorbs simethicone onto its surface.

The simethicone as used in the formulations described herein should conform to the United States Pharmacopoeia (USP XXIX) definition: a mixture of fully methylated linear siloxane polymers containing repeating units of the formula (--(CHife SiO~)_n, stabilized with trimethyl siloxy enc -blocking units of the formula (--(CH₃)_S -SiO-) and silicon dioxide,

Typically, antifoam agents such as simethicone are viscous liquid or paste-like materials. At typical ambient conditions, simethicone will be a water-white to gray, translucent, viscous oil-like liquid with a density of 0.965-0.970 grams per cubic centimeter and immiscible with water and alcohol. The amount of simethicone antifoam agent in the solid oral dosage form should be that amount that provides a therapeutic dosage to a patient suffering from gas or flatulence and associated symptoms. A preferred dosage range for simethicone is in the range of about 20 mg to about 125 mg per dosage unit, and generally should not exceed 500 mg/day. The dosage ranges may /ary by age and weight of a patient as well as the severity of symptoms, As noted above, the simethicone is a viscous, sticky liquid that creates difficulties in preparing free-flowing materials suitable for preparing compressible dosage forms that include simethicone, due in part to the lack of sufficient cohesion in the compact for compression such tr at the resulting tablets will withstand the rigors of further processing. The use of an adsorbent material with the simethicone is an attempt to address the difficulties arising from handlir g simethicone and to prepare a free-flowing material of simethicone with at least one adsorbent. Such adsorbent materials include calcium silicate, microcrystalline cellulose, silicifiec microcrystalline cellulose, tribasic or dibasic calcium phosphate, maltodextrin, and other materials that could adsorb silicone on their surface, such as precipitated and cc lloidal silica, starch, pregelatinized starch, hydroxypropyl cellulose, magnesium oxide, magnesium hydroxide, etc. Depending on the adsorbent or adsorbents used, the ratio of adsorbents to simethicone may range from 2 : 1 to 1 :4, and in particular 1 :2 to 1:4

The calciur.1 silicate used in the formulation should conform to the standards of the USP, although calcium silicate that does not conform to that standard also may be suitable and is included within the scope of this application. The amount of calcium silicate used in the formulation cart range from 1 mg to 2000 mg. Although the upper end of this range is higher than the amount currently permitted by the US FDA, there are known procedures in place to show safety of inactive ingredients used at amounts greater than currently accepted levels. Commercial forms of calcium silicate are readily available from numerous suppliers. If loperamide hydrochloride is used in the formulation, the amount of calcium silicate is typically the same iind may be used in an amount of from 1 mg to 2000 mg. The ratio of simethicone to excipients may range from 100:1 to 1:100. A blend of the simethicone and excipients may hava a particle size distribution having a D90 ranging from about 5 microns to about 2000 microns.

The inventors have found that depending upon the weight ratio of simethicone to calcium silicate, an additional adsorbent material should be used to prepare a free-flowing material. Such addrtional adsorbent materials include those in the list above, and specifically microcrystalline cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate, maltodextrin, mannitol, directly compressible sugar, and silicone dioxide. These additional adsorbent materials also have the potential to be used as the sole adsorbent material with simethicone to prepare a free-flowing material. For example, the inventors have conducted experiments and determined that the adsorbent capacity of silicon dioxide for simethicone is about 300% and car be used as the sole adsorbent with simethicone at a 1 :3 weight ratio (silicon dioxide:simsthicone). The inventors also have conducted experiments and determined that the adsorbent capacity of mannitol (Pearlitol 160C) for simethicone is about 2:1, macrocrystalline; cellulose (Unitab 101) for simethicone is about 1:1, and silicified microcrystalline cellulose for simethicone is about 1:1. These experiments demonstrate that these materials have the potential be used as the sole adsorbent in a simethicone dosage form that results from a free-flowing simethicone-adsσrbent mixture. For example, a dosage form can include simethicone and any one of microcrystalline cellulose, silicifϊed microcrystalline cellulose, dibasic c alcium phosphate, maltodextrin, mannitol, and silicone dioxide used at the simethicone:adsorbent ratios described above. Further, an additional adsorbent, such as calcium silicate, also can be used with the above adsorbents in the formulation.

In comparison to the data above, the inventors found that calcium silicate adsorbs up to 56% of its weight, which provides a ratio of adsorbent to simethicone of 2:1. The materials can be used in the following amounts: calcium silicate, from 1 mg to 500 mg, and in particular from ] mg to 182.7 mg; dibasic calcium phosphate, from 1 mg to 1000 mg, and in particular from ] mg to 635.5 mg; microcrystalline cellulose, from 1 mg to 2000 mg, and in particular from 1 mg to 1385.3 mg; and silicon dioxide, from 1 mg to 500 mg, and in particular from 1 rr g to 100 mg.

The tribasic or dibasic calcium phosphate is in the dihydrate form. The amount of the calcium phosphate present in the dosage form typically ranges from about 1 mg to 400 mg but may be suitable at a range of 1 mg to 1000 mg. Commercial forms of dihydrous tribasic or dibasic calcium phosphates are available from numerous suppliers well known to those of skill in the art.

The amount of microcrystalline cellulose present in the dosage form ranges from about 1 mg to 2000 mg. Commercial forms of microcrystalline cellulose are available from numerous suppliers well known to those of skill in the art.

The amount of colloidal silicon dioxide present in the dosage form typically ranges from 1 mg to about 200 mg. Commercial forms of colloidal silicon dioxide are available from numerous sup pliers known to those skilled in the art.

In addition to the above formulation ingredients, one or more additional pharmaceutically acceptable excipients may be used including fillers, binders, sweeteners, artificial sweeteners, lubricants, glidants, disintegrants, colors, adsorbents, acidifying agents, and flavoring agents;. The choice of excipient will depend on the solid oral dosage form employed (i.e., tablets, caplets, capsules, bi-layer or tri-layer tablets, tablet-in-tablet, film- coated tablets, effervescent tablets, dispersible tablets, chewing gums, powders, and granules) and whether the dosage form is chewable or a swaliowable formulation. For example, pharmaceutically excipients chosen from the following list may be employed: (a) diluents such as lactose, kaolin, mannitol, crystalline sorbitol, additional dibasic or calcium phosphates, calciuri carbonate, calcium sulfate, powdered and microcrystalline cellulose, magnesium carbonate, magnesium oxide, maltodextrin, sucrose, pregelatinized starch, starch, and the like; (b) binders such as sugars, microcrystalline cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, acacia, alginic acid, Carbomer, ethyl cellulose, guar gun: , hydroxypropyl methylcellulose, magnesim aluminum silicate, maltodextrin, meth/lcellulose, polymethacrylates, sodium alginate, zein, polyvinylpyrrolidone and the like; (c) lubricants such as magnesium stearate, talc, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, leucine, glycerides, hydrogenated castor oil, polyethylene glycols and sodium stearyl fumarate; (d) disintegrants such as starches, croscarmellose sodium, methylcellulose, agar, bentonite, alginic acid, carboxymethylcelli lose, polyvinylpyrrolidone, carboxymethylcellulose calcium, carboxymethylcelklose sodium, crospovidone, guar gum, magnesium aluminum silicate, polacrillin potassium, sodium alginate and the like; (e) scavengers such as charcoal, silicon dioxide, anhydrous calcium phosphates; (f) flavoring agents such as mannitol, dextrose, fructose, sorbitol, εcesulfame potassium, aspartame, citric acid, fumaric acid, lactic acid, malic acid, saccharin sodium, tartaric acid, xylitol and the like; (g) glidants such as silicon dioxide (precipitated and colloidal) and talc; and (h) coloring agents. Additional suitable excipients can be found, for example, in the Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association, herein incorporated by reference.

The solid oril dosage forms of the present invention may be prepared in the form of tablets, e.g., single layer, bi-layer or tri-layer tablets, tablet-in-tablet, film-coated tablets, effervescent tablets, dispersible tablets; caplets; gelcaps; capsules; chewable tablets and gums; lozenges; fas: dissolving wafers; powders; granules; and other known and effective delivery modes. For example, a multilayer tablet can be formed that includes a first loperamide layers, a second simethicone layer and a third layer between the first and second layers. Similarly, a tablet-in-tablet dosage form can include either the loperamide or simethicone and the inner tablet and the unused active ingredient in the outer tablet.

In one aspect, the process of manufacturing the dosage form includes preparing a loperamide hydrochloride blend, preparing a simethicone blend, and compressing into a tablet. Table 1 provides an example of a formulation made according to this aspect. Table 1. Loperamide-Simethicone Formulation

* indicates that the quantity of this ingredient may he adjusted based on an Assay percentage of loperamide hydrochloride.

Tablets of tfce formulation of Table 1 were made as follows:

1. The i ngredients of Layer A were variously blended and screened through a #40 mesh screen to form a first blend. This blend was set aside.

2. The calcium silicate, microcrystalline cellulose, and dibasic calcium phosphate dihydrate of the granulation of Layer B were screened through a #30 mesh screen and blended. 3. Tht: blend of step 2 was granulated in a high shear mixer with simethicone and then screened through a #20 mesh screen.

4. The screened material of step 3 was blended with calcium silicate that had been screened through a #30 mesh screen.

5. The blend material of Layer B (microcrystalline cellulose; dibasic calcium phosphate, dihydr∑te; sodium starch glycolate; and colloidal silicon dioxide) was screened through a #30 mesi screen and blended with the material of step 4.

6. To ihe blend of step 5, stearic acid that had been screened through a #40 mesh screen was added ∑nd blended and set aside.

7. The blends of steps 1 and 6 were compressed to form a tablet.

Tablets formulated according to the Table 1 (Test Product) and the above process steps were tested for in vitro dissolution against the currently-marketed loperamide- simethicone product, Imodium® Advanced Tablets (Reference Product), which contains 2 mg of loperamide HCl and 125 mg of simethicone per tablet. The dissolution test was conducted in an USP-2 test apparatus in 0.1 N HCl, volume 900 mL, 75 rpm, and a temperature of 37±λ5°C. Table 2 demonstrates the similarity between the dissolution rate of tablets according to Table 1 (test product) and the currently-marketed product (reference product).

Table 2. ID Vitro Dissolution of Test Product Compared to Reference Product

In addition to in vitro dissolution testing, the tablets of Table 1 were subjected to a bioequivalence stud/ with the Imodium® Advanced caplets being the reference product. The bioequivalence stud / was a single dose, randomized, two-period, two-treatment, two- sequence crossover .itudy design with 23 patients tested. The results of the bioequivalence study, presented in table form in Table 3, demonstrate the bioequivalen.ee of the test product relative to the reference product.

Table 3. Bioequivalence of Test Product Compared to Reference Product

In addition :o the formulation provided in Table 1, the inventors have developed other formulations of simethicone with an adsorbent material that also have desirable characteristics. Those formulations are provided below in Table 4.

Table 4. Various Formulations of Loperamide and Simethicone

Although Table 1 discloses a loperamide-simethicone tablet formulation, the inventions disclosed herein can pertain equally to a tablet that includes simethicone but not loperamide. For example, the inventors believe that a simethicone tablet can be formulated as disclosed in Table 5. Formulations 2 and 3, while acceptable, had slight sticking of the material to the tabbt punches.

Table 5. Simethicone Formulation

Tablets of the formulation of Table 5 can be made as follows:

10 1. The calcium silicate, microcrystalline cellulose, and dibasic calcium phosphate dihydrate of the grsuiulation were screened through a #30 mesh screen and blended.

2. The blend of step 1 was granulated in a high shear mixer with simethicone and then screened through a #20 mesh screen. 3. The screened material of step 2 was blended with calcium silicate that had been screened through a #30 mesh screen.

4. The blend material (microcrystalline cellulose; dibasic calcium phosphate, dihydrate; sodium starch glycolate; and colloidal silicon dioxide) was screened through a #30 mesh screen and blsnded with the material of step 3.

5. To the blend of step 4, stearic acid that had been screened through a #40 mesh screen was added and blended and set aside.

6. The blend of step 6 was compressed to form a tablet.

The above process of making the loperamide simethicone tablets can be varied and controlled to improve the processing. For example, the inventors have found that it is advantageous to co itrol the rate of addition of simethicone in the process of mixing with a mixing means the simethicone with the adsorbent and optional additional dry excipients. In particular, the inventors believe that simethicone can be added at a rate that is up to approximately 0.2 kg of simethicone per kg of dry excipients per minute with an increase in rate of addition of s imethicone being controlled, at least in part, by increasing the speed of the mixer. Thus, to increase the processing rate of the product, the rate of addition of simethicone can be in the range of 0.06 to 0.1 or 0.06 to 0.2 kg of simethicone added per kg of dry excipients pe r minute. Suitable mixing means include high-shear mixers, low shear mixers, non shear mixers, roller compactors, blenders, blenders with intensifier bars and other mixing means.

The simethicone also can be combined with the adsorbent in a spray drying process. In this process, the simethicone is mixed in a solvent, the adsorbent material is added, the combination is mix 3d and then spray dried. The spray dried material can be used in the process of making tablets of simethicone. Suitable solvents to use in this process include polar and nonpolar solvents, e.g., methylene chloride, isopropyl alcohol, water and ethanol. The solvent-simethαcone combination may form a solution or emulsion but the solvent should be selected such thεt the adsorbent does not dissolve in the solvent.

In addition to the tablets described above, the processes described herein can be used to formulate chewable tablets of loperamide and/or simethicone. For example, the processes for mixing the simethicone with the adsorbent and dry excipients are generally the same for chewable tablets an for the tablets described above. The tablets can be, for example, a single layer, bi-layer, or tri-layer tablets.

The excipients also may differ to provide a pharmaceutically acceptable excipient or means to overwhelm the bitter taste of the loperamide or other bitter tasting active substance. In contrast, the prior art uses taste masking to cover the bitter taste of loperamide in a process that generally masks the taste by physically coating or covering the bitter tasting active ingredient. The inventors have found that using one or more sweeteners overwhelms the bitter taste. For ex anple, a sweetener can be used at a range of 1% to 60% of the tablet weight. At the low end of this range, 1% sucralose will overwhelm the loperamide and, at the high end of this rarge, 60% sucrose will overwhelm the loperamide. Additional sweeteners and other excipient 5, such as acids, that have the potential to overwhelm the bitter taste of loperamide include fumaric acid, ascorbic acid, citric acid, and other pharmaceutically acceptable sour flavors and acids. Besides using a sour or sweet tasting excipient or flavor to overwhelm the bitter flavor, a salty flavor can be imparted to provide the overwhelming function to cause the individual taking the chewable tablet to sense the flavor (e.g., sweet, sour, salty) rather than the bitter taste of loperamide.

One example of a dosage form of a chewable tablet of loperamide and simethicone is provided in Table 6.

Table 6. Formulation for a Chewable Tablet of Loperamide and Simethicone

Process

Simethicone Blenc

1. Ingredients no. 11 (calcium silicate), 12 (MCC, Avicel) and 13 (MCC, Unitab) were screened. 2. The screened items were blended and then loaded into a high shear mixer.

3. Simethicone (ingredient no. 10) was added to the materials in the high shear mixer and blended until a free flowing mixture was formed, and then set aside. Loperamide Blend

4. Ingredients no. 2 (MCC, Avicel), 1 (loperamide), 3 (sodium saccharin), 6 (crospovidone), and 9 (D of C Blue Lake #1) were screened and loaded into a blender.

5. Ingredients no. 7 (peppermint flavor) and 8 (D of C Yellow Lake #10) were screened and loaded into the blender of step 4, blended with the ingredients from step 4, and screened.

6. To the screened material of step 5, ingredient nos. 4 (mannitol) and 5 (DIPAC) were added after screening and then blended together. 7. The blend from step 3 was put into a blender to which ingredient nos. 14 (colloidal silicon dioxide) anc 15 (calcium silicate) were added after screening, and the combined was mixed.

8. Ingredient nos. 16 (mannitol), 17 (DIPAC), 18 (SSG)₅ 20 (peppermint flavor), and 22 (plasdone) were screened and added to the blend of step 7 and the combined was mixed with the blend of step 6.

9. Ingredient no. 19 (colloidal silicon dioxide) was screened, added to the blend of step 8 and mixed.

10. Ingredient no. 21 (stearic acid) was screened, added to the blend of step 9 and mixed until uniform. 11. The mix of step 10 was compressed into tablets.

The resulting tablets were found to be processed with good yield and of suitable hardness and friabil ty.

While several particular forms of the inventions have been described, it will be apparent that various modifications and combinations of the inventions detailed in the text can be made without departing from the spirit and scope of the inventions. For example, other organopolysiloxane antifoarn agents are known in the art and may be used as the active ingredient in place cf simethicone. Various organopolylosiloxane amifoam agents are disclosed, for example, in U.S. 5,458,886 and the references disclosed in that patent, all of which are hereby incorporated by reference. In another aspect, the ability to use simethicone with a smaller amount of an adsorbent material allows the formulation of a smaller tablet. For example, the formulation of Example 1 includes 128.75 mg simethicone with three adsorbents, calcium silicate (70.00 mg), microcrystalline cellulose, (41.50 mg), and dibasic calcium phosphate, dihydrate (200.00 mg). Thus, for 128 mg of simethicone, the tablet contains 311.5 mg ?f adsorbent material with the simethicone. As described above, if only silicon dioxide is used as the absorber with simethicone, and is used at a 1 :3 weight ratio, then it is necessary to use approximately 40-50 mg. This results in a reduction in approximately 260- 270 mg from the tablet weight, which can be reduced to approximately 700 mg. Similarly, based on the inventors' experiments, if mannitol is the sole adsorbent it can be used in the cuantity of between 250-260 mg with 128 mg of simethicone, resulting in a tablet weight that is reduced by approximately 50 mg over the formulation of Example 1. Under the same basis, approximately 125-130 mg of microcrystalline cellulose or silificied microcrystalline ce] lulose may be used with 128 mg of simethicone, resulting in a tablet weight that is reduced by approximately 170-180 mg over the formulation of Example 1. Accordingly, it is not intended that the inventions be limited, except as by the appended claims.

Claims

We Claim 1. An oral ph.irmaceutical composition comprising simethicone, a pharmaceutically acceptable salt of silicate, at least one adsorbent material that adsorbs simethicone, and optionally one or n lore pharmaceutically acceptable excipients.

2. The oral pharmaceutical composition of claim 1 wherein the pharmaceutically acceptable salt of silicate comprises calcium silicate.

3. The pharmaceutical composition of claim 1 wherein the pharmaceutically acceptable salt of silicate comprises aluminum silicate, magnesium trisilicate, and magnesium aluminum silicate.

4. The oral pharmaceutical composition of claim 1 wherein the adsorbent material comprises one or rr ore of powdered cellulose, microcrystalline cellulose, silicified microcrystalline ce .lulose, tribasic calcium phosphate, dibasic calcium phosphate, maltodextrin, precipitated silica, colloidal silica, starch, pregelatinized starch, hydroxypropyl cellulose, magnesium oxide, and magnesium hydroxide.

5. The oral pharmaceutical composition of claim 1 wherein the adsorbent material is a material that adsorb s simethicone onto the surface of the adsorbent material.

6. The oral phsirmaceutical composition of claim 1 wherein the ratio of the simethicone to the calcium silicate and at least one adsorbent material is between 4: 1 to 1 :2 on a weight percentage basis.

7. The oral pharmaceutical composition of claim 1 wherein the ratio of the simethicone to the calcium silicate and at least one adsorbent material is between 3: 1 to 1 :2 on a weight percentage basis.

8. The oral pharmaceutical composition of claim 1 wherein the calcium silicate, the at least one adsorbent material and the simethicone are characterized as being free flowing

9. The oral pharmaceutical composition of claim 1, further comprising one or more additional active ingredients.

10. The oral pha rmaceutical composition of claim 9 wherein the one or more additional active ingredients comprise one or more OfH₂ (histamine) receptor inhibitors, gastrointestinal prokinetics, antidiar -heal preparations, adsorbents as active ingredient, antispasmodics, proton pump inhibitors, laxatives, lactase, mesalamine, bismuth compounds, antacids, antibiotics, antiem sties, and anticholinergics.

11. The oral ph armaceutical composition of claim 10 wherein the H₂ (histamine) receptor inhibitors comprises cimetidme, ranitidine, famotidine, and nizatidine, the gastrointestinal prokinetic comprises prucalopride, the antidiarrheal preparation comprises loperamide or diphenoxylate, the adsorbents as active ingredient comprises pectin, polycarbophil, activated charcoal, and kaoliα, the proton pump inhibitor comprises omeprazole, pantoprazole, lansoprazole, their salts and derivatives, the laxative comprises bisacodyl, cascara sagrada, danthron, senna, phenolphtalein, aloe, castor oil, ricinoleic acid, and dehydrocholic acid, the antacids comprises calcium carbonate, aluminum hydroxide, magnesium hydroxide, magnesium carbon ite, the gastrointestinal cytoprotectives comprises sucralfate and misoprostol, the antibiotic comprises clarithromycin, amoxicillin, penicillins and cephalosporins, tetracycline, metronidazole, azithromycin, and erythromycin, the antiemetic comprises ondanseiron, and the anticholinergic comprises a glycopyrrolate.

12. The oral pharmaceutical composition of claim 9 wherein the additional active ingredient comprises loperamide HCl.

13. An oral pharmaceutical composition comprising simethicone, an adsorbent material, and optionally one or more pharmaceutically acceptable excipients, wherein the ratio of the simethicone to the adsorbent material is between 4: 1 to 1 :2 on a weight percentage basis.

14. The oral pfoirmaceutical composition of claim 13 wherein the adsorbent material comprises one or more of powdered cellulose, rnicrocrystalline cellulose, silicified microcrystalline eel lulose, tribasic calcium phosphate, dibasic calcium phosphate, maltodextrin, precipitated silica, colloidal silica, starch, pregelatinized starch, hydroxypropyl cellulose, magnesiu m oxide, and magnesium hydroxide.

15. The oral phεrmaceutical composition of claim 13 wherein the adsorbent material is one or more materi∑ Is that adsorbs simethicone onto the surface of the adsorbent material.

16. The oral pharmaceutical composition of claim 13 wherein a mixture of the adsorbent material and the shr ethicone is characterized as being free flowing.

17. The oral pha rmaceutical composition of claim 13 , further comprising one or more additional active ingredients.

18. The oral pharmaceutical composition of claim 17 wherein the one or more additional active ingredients comprise one or more of H₂ (histamine) receptor inhibitors, gastrointestinal prokinetics, antidiarrheal preparations, adsorbents as active ingredient, antispasmodics, proton pump inhibitors, laxatives, lactase, mesalamine, bismuth compounds, antacids, antibiotics, antiemetics, and anticholinergics.

19. The oral phirmaceutical composition of claim 17 wherein the additional active ingredient comprises loperamide HCl.

20. A process for making a free flowing mixture of simethicone and an adsorbent material, the method comprising: (i) providing an adsorbent material and optional dry excipients in a mixing means; and (ii) adding i imethicone to the adsorbent material at a rate of between 0.06 and 0.2 kg of simethicone per leg of adsorbent and dry excipients per minute while using the mixing means to mix the simethicone and adsorbent material.

21. The process of claim 20, wherein the simethicone is added at a rate of between 0.06 and 0.1 kg/kg/min.

22. The process of claim 20, wherein the mixing means comprise one or more of high shear mixers, low shear mixers, non shear mixers, roller compactors, blenders, and blenders with intensifier bars .

23. The process of claim 20, further comprising using the material of step (U) in forming a pharmaceutical dosage form.

24. A process fcr making a free flowing mixture of simethicone and an adsorbent material, the method comprising: (i) mixing simethicone with a solvent to form a solution or emulsion; (ii) adding the adsorbent material to the solution or emulsion; and (iϋ) spray drying the material of step (ii).

25. The process of claim 24 wherein the particle size of the material produced at step (iii) is reduced.

26. The process of claim 24 wherein the solvent comprises one or more of polar and nonpolar solvents.

27. The process of claim 24 wherein the solvent comprises one or more of methylene chloride, isopropyl alcohol, water and ethanol.

28. The process, of claim 24 wherein the solvent is selected so as not to dissolve the adsorbent material.

29. The process of claim 24, further comprising using the material of step (iii) in forming a pharmaceutical dosage form.

30. An oral dosage form comprising loperamide and one or more pharmaceutically acceptable excipier. ts having the function of overwhelming the bitter taste of the loperamide HCl as sensed upor. oral administration.

31. The oral dosage form of claim 30, wherein the pharmaceutically acceptable excipient comprises an excip' ent having one or more of a sweet flavor, a sour flavor, or a salty flavor.

32. The oral do∑;age form of claim 31, wherein the sweetener is present in a range of from 1 % to 60% of the tablet weight.

33. The oral dosage form of claim 31 , wherein the sour flavor is caused by a pharmaceutically a< ceptable acid.

34. The oral do. age form of claim 33, wherein the pharmaceutically acceptable acid comprises one or more of fumaric acid, ascorbic acid, and citric acid.

35. The oral dos age form of claim 30, wherein the oral dosage form comprises a chewable tablet.