WO2008056200A1 - Compositions pharmaceutiques orales de siméthicone - Google Patents

Compositions pharmaceutiques orales de siméthicone Download PDF

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Publication number
WO2008056200A1
WO2008056200A1 PCT/IB2006/003194 IB2006003194W WO2008056200A1 WO 2008056200 A1 WO2008056200 A1 WO 2008056200A1 IB 2006003194 W IB2006003194 W IB 2006003194W WO 2008056200 A1 WO2008056200 A1 WO 2008056200A1
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Prior art keywords
simethicone
oral
adsorbent material
pharmaceutical composition
composition
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PCT/IB2006/003194
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English (en)
Inventor
Ganpat Desai
Rajendra Nagamalla
Natrajan Kumaraperumal
Indrajit Ghosh
Irena Mudri
Vidya Poduval
Supriya Rane
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Ranbaxy Laboratories Limited
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Priority to PCT/IB2006/003194 priority Critical patent/WO2008056200A1/fr
Publication of WO2008056200A1 publication Critical patent/WO2008056200A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/80—Polymers containing hetero atoms not provided for in groups A61K31/755 - A61K31/795
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • it can be difficult to assure that the viscous liquid simethicone is uniformly distributed throughout the solid formulation and expeditiously dispersed upon administration.
  • 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 w ⁇ ter 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 ; ⁇ om 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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 H 2 (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 H 2 (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.
  • the additional active ingredient may be loperamide.
  • 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.
  • 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 H 2 (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.
  • the additional active ingredient may be loperamide.
  • a process for making a free flowing mixture of simethicone and an adsorbent material 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.
  • 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.
  • a process for making a free flowing mixture of simethicone and an adsorbent material 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.
  • 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.
  • 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.
  • 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 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.
  • any pha ⁇ naceutically acceptable salt of silicate of trivalent, divalent and monovalent cation can be used in place of the calcium silicate.
  • 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.
  • 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.
  • the simethicone can be combined with a second active ingredient, such as loperamide hydrochloride.
  • Additional second active ingredients include H 2 (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...
  • H 2 (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
  • 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
  • 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
  • anticholinergics e.g., a glycopyrrol
  • an adsorbent material is a substrate that adsorbs a second material, e.g., simethicone, oato the surface of the substrate particles.
  • a second material e.g., simethicone
  • calcium silicate is an adsorbent material because it adsorbs simethicone onto its surface.
  • 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 (--(CH 3 ) S -SiO-) and silicon dioxide,
  • 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,
  • 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.
  • 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.
  • an additional adsorbent material should be used to prepare a free-flowing material.
  • 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.
  • 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.
  • a dosage form can include simethicone and any one of microcrystalline cellulose, silicif ⁇ ed microcrystalline cellulose, dibasic c alcium phosphate, maltodextrin, mannitol, and silicone dioxide used at the simethicone:adsorbent ratios described above.
  • an additional adsorbent such as calcium silicate, also can be used with the above adsorbents in the formulation.
  • 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.
  • 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.
  • 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;.
  • 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.
  • 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
  • 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
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • step 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.
  • step 3 The screened material of step 3 was blended with calcium silicate that had been screened through a #30 mesh screen.
  • 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.
  • step 6 stearic acid that had been screened through a #40 mesh screen was added ⁇ nd blended and set aside.
  • 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 ⁇ 5°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).
  • 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.
  • Table 1 discloses a loperamide-simethicone tablet formulation
  • the inventions disclosed herein can pertain equally to a tablet that includes simethicone but not loperamide.
  • 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.
  • Tablets of the formulation of Table 5 can be made as follows:
  • step 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.
  • 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.
  • step 5 stearic acid that had been screened through a #40 mesh screen was added and blended and set aside.
  • step 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.
  • 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.
  • 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.
  • 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.
  • 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-simeth ⁇ cone combination may form a solution or emulsion but the solvent should be selected such th ⁇ t the adsorbent does not dissolve in the solvent.
  • the processes described herein can be used to formulate chewable tablets of loperamide and/or simethicone.
  • 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.
  • 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.
  • 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.
  • 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.
  • step 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.
  • ingredient nos. 14 colloidal silicon dioxide
  • anc 15 calcium silicate
  • Ingredient no. 19 (colloidal silicon dioxide) was screened, added to the blend of step 8 and mixed.
  • step 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.
  • organopolysiloxane antifoarn agents are known in the art and may be used as the active ingredient in place cf simethicone.
  • 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.
  • the ability to use simethicone with a smaller amount of an adsorbent material allows the formulation of a smaller tablet.
  • Example 1 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).
  • the tablet contains 311.5 mg ?f adsorbent material with the simethicone.
  • 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.
  • 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.
  • 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.

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Abstract

La présente invention concerne des compositions pharmaceutiques orales de siméthicone et des procédés de fabrication des compositions pharmaceutiques.
PCT/IB2006/003194 2006-11-10 2006-11-10 Compositions pharmaceutiques orales de siméthicone WO2008056200A1 (fr)

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012130351A1 (fr) * 2011-03-25 2012-10-04 Maria Clementine Martin Klosterfrau Vertriebsgesellschaft Mbh Composition destinée à une application dans des troubles digestifs
WO2013095111A1 (fr) 2011-12-14 2013-06-27 Disphar International B.V. Formulation de siméthicone
US8580302B2 (en) 2000-11-20 2013-11-12 Warner Chilcott Company, Llc Pharmaceutical dosage form with multiple coatings for reduced impact of coating fractures
CN106038585A (zh) * 2016-05-27 2016-10-26 郑州思辩科技有限公司 一种胶体果胶铋片剂及其制备方法
WO2016200345A1 (fr) 2015-06-12 2016-12-15 Santa Farma İlaç Sanayi̇ A. Ş. Composition pharmaceutique orale comprenant du bromure d'otilonium et de la siméthicone présentant une certaine densité en vrac et des caractéristiques de dissolution améliorées
EP3173076A1 (fr) 2015-05-14 2017-05-31 Abdi Ibrahim Ilac Sanayi ve Ticaret A.S. Composition pharmaceutique comprenant de la siméthicone et de l'otilonium
WO2018109693A1 (fr) * 2016-12-14 2018-06-21 Siegfried Rhein, S.A. De C.V. Composition améliorée de lansoprazol et de siméticone et procédé de préparation de cette dernière
CN111003836A (zh) * 2019-10-31 2020-04-14 黄冈师范学院 从甲硝唑精制废水中回收甲硝唑的装置及方法
CN111132667A (zh) * 2017-09-29 2020-05-08 强生消费者公司 固体西甲硅油颗粒及其剂型
RU2790260C2 (ru) * 2017-09-29 2023-02-15 Джонсон энд Джонсон Консьюмер Инк. Твердые частицы симетикона и их дозированная форма
CN116139165A (zh) * 2023-02-13 2023-05-23 南京艾德加生物制药科技有限公司 铝镁西甲硅油咀嚼片及其制备方法

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US5716641A (en) * 1992-05-21 1998-02-10 Mcneil-Ppc, Inc. Simethicone containing pharmaceutical compositions
EP1297825A1 (fr) * 2001-09-28 2003-04-02 McNEIL-PPC, INC. Forme orale solide de siméthicone

Patent Citations (2)

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US5716641A (en) * 1992-05-21 1998-02-10 Mcneil-Ppc, Inc. Simethicone containing pharmaceutical compositions
EP1297825A1 (fr) * 2001-09-28 2003-04-02 McNEIL-PPC, INC. Forme orale solide de siméthicone

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8580302B2 (en) 2000-11-20 2013-11-12 Warner Chilcott Company, Llc Pharmaceutical dosage form with multiple coatings for reduced impact of coating fractures
US9089492B2 (en) 2000-11-20 2015-07-28 Warner Chilcott Company, Llc Pharmaceutical dosage form with multiple coatings for reduced impact of coating fractures
WO2012130351A1 (fr) * 2011-03-25 2012-10-04 Maria Clementine Martin Klosterfrau Vertriebsgesellschaft Mbh Composition destinée à une application dans des troubles digestifs
WO2013095111A1 (fr) 2011-12-14 2013-06-27 Disphar International B.V. Formulation de siméthicone
US20150119422A1 (en) * 2011-12-14 2015-04-30 Disphar International B.V. Simethicone formulation
AU2012327176B2 (en) * 2011-12-14 2015-08-13 Disphar International B.V. Simethicone formulation
RU2602745C2 (ru) * 2011-12-14 2016-11-20 Дисфар Интернэшнл Б.В. Состав с симетиконом
EP3173076A1 (fr) 2015-05-14 2017-05-31 Abdi Ibrahim Ilac Sanayi ve Ticaret A.S. Composition pharmaceutique comprenant de la siméthicone et de l'otilonium
WO2016200345A1 (fr) 2015-06-12 2016-12-15 Santa Farma İlaç Sanayi̇ A. Ş. Composition pharmaceutique orale comprenant du bromure d'otilonium et de la siméthicone présentant une certaine densité en vrac et des caractéristiques de dissolution améliorées
CN106038585A (zh) * 2016-05-27 2016-10-26 郑州思辩科技有限公司 一种胶体果胶铋片剂及其制备方法
WO2018109693A1 (fr) * 2016-12-14 2018-06-21 Siegfried Rhein, S.A. De C.V. Composition améliorée de lansoprazol et de siméticone et procédé de préparation de cette dernière
CN111132667A (zh) * 2017-09-29 2020-05-08 强生消费者公司 固体西甲硅油颗粒及其剂型
JP2020535200A (ja) * 2017-09-29 2020-12-03 ジョンソン・アンド・ジョンソン・コンシューマー・インコーポレイテッドＪｏｈｎｓｏｎ ＆ Ｊｏｈｎｓｏｎ Ｃｏｎｓｕｍｅｒ Ｉｎｃ． 固体シメチコン粒子及びその剤形
RU2790260C2 (ru) * 2017-09-29 2023-02-15 Джонсон энд Джонсон Консьюмер Инк. Твердые частицы симетикона и их дозированная форма
JP7282753B2 (ja) 2017-09-29 2023-05-29 ジョンソン アンド ジョンソン コンシューマー インコーポレイテッド 固体シメチコン粒子及びその剤形
EP3687502B1 (fr) * 2017-09-29 2023-06-07 Johnson & Johnson Consumer Inc. Particules solides de siméthicone et leur forme posologique
EP4215187A1 (fr) * 2017-09-29 2023-07-26 Johnson & Johnson Consumer Inc. Particules solides de siméthicone et leur forme pharmaceutique
AU2018343214B2 (en) * 2017-09-29 2023-10-05 Johnson & Johnson Consumer Inc. Solid simethicone particles and dosage form thereof
CN111003836A (zh) * 2019-10-31 2020-04-14 黄冈师范学院 从甲硝唑精制废水中回收甲硝唑的装置及方法
CN111003836B (zh) * 2019-10-31 2022-05-13 黄冈师范学院 从甲硝唑精制废水中回收甲硝唑的装置及方法
CN116139165A (zh) * 2023-02-13 2023-05-23 南京艾德加生物制药科技有限公司 铝镁西甲硅油咀嚼片及其制备方法

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