Title of Invention

"CONTROLLED RELEASE AND TASTE-MASKING PHARMACEUTICAL COMPOSITION"

Abstract

Controlled release and taste-masking pharmaceutical composition containing an active ingredient ranges from 5 to 95%, containing characterized in that: i) a matrix consisting of lipophilic compounds with melting point lower than 90 °C wherein the active ingredient is partially inglobated consisting of C6-C20 alcohols or C8-C20 fatty acids or easters of fatty acids with glycerol or sorbitol or other polyaclcohols with carbon atom chain not higher than six and the said lipophilic matrix compounds selected from unsaturated or hydrogenated alcohols or fatty acids, salts, esters or amides thereof, mono-, di- or triglycerids of fatty acids, the polyethoxylated derivatives thereof, waxes, cholesterol derivatives; ii) an amphiphilic matrix are polar lipids of type I or II (lecithin, phosphatidylcholine, phosphatidyl-ethanolamine), ceramides, glycol alkyl ethers, esters of fatty acids with polyethylene glycols or diethylene glycois; iii) an outer hydrophilic matrix consisting of hydrogels in which the lipophilic matrix and the amphiphilic matrix are dispersed wherein hydrophilic matrix consists of compounds selected from acrylic or methacrylic acid polymers pr copolymers, cellulose, polysaccharides, dextrins, pectins, starches and derivatives, alginic acid, natural or synthetic gums, polyalcohols; iv) optionally a gastro-resistant outer coating of the kind as herein described; and other excipients. 21

Full Text

The presence of the amphiphilic matrix inside the lipophilic matrix inert allows to prevent any unevenness of the release profile of the active ingredient. The surfactants present in the amphiphilic portion promote wettability of the porous canaliculuses which cross the inert matrix preventing or reducing resistance to penetration of the solvent inside the inert matrix. To obtain taste masking tablets, the components of the hydrophilic matrix are carefully selected to minimize the active substance release time through penetration accelerated by the canalization induced by the hydrophilic compound. STATEMENT OF THE INVENTION In accordance with the present invention it is associated to Controlled release and taste-masking pharmaceutical compositions containing an active ingredient ranges from 5 to 95%, containing characterized in that: i) a matrix consisting of lipophilic compounds with melting point lower than 90 °C wherein the active ingredient is partially inglobated consisting of C6-C20 alcohols or C8-C20 fatty acids or easters of fatty acids with glycerol or sorbitol or other polyaclcohols with carbon atom chain not higher than six and the said lipophilic matrix compounds selected from unsaturated or hydrogenated alcohols or fatty acids, salts, esters or amides thereof, mono-, di- or triglycerids of fatty acids, the polyethoxylated derivatives thereof, waxes, cholesterol derivatives; ii) an amphiphilic matrix are polar lipids of type I or II (lecithin, phosphatidylcholine, phosphatidyl-ethanolamine), ceramides, glycol alkyl ethers, esters of fatty acids with polyethylene glycols or diethylene glycols; iii) an outer hydrophilic matrix consisting of hydrogels in which the lipophilic matrix and the amphiphilic matrix are dispersed wherein hydrophilic matrix consists of compounds selected from acrylic or methacrylic acid polymers pr copolymers, cellulose, polysaccharides, dextrins, pectins, starches and derivatives, alginic acid, natural or synthetic gums, polyalcohols; iv) optionally a gastro-resistant outer coating of the kind as herein described; and other excipients. The following Examples illustrate the invention in greater detail. EXAMPLE 1 500 g of 5-aminosalicylic acid and 20 g of octylonium bromide are mixed with 10 g of soy lecithin dissolved in 50 g of a water: ethyl alcohol 1: 3 mixture at about 50°C. After homogenization and drying, the granules of the resulting matrix are treated in a kneader with 20 g of carnauba wax and 50 g of stearic acid, heating until homogeneous dispersion, then cold-extruded into small granules. The inert matrix granules are loaded into a mixer in which 30 g of carbopol 971 P and 65 g of hydroxypropyl methylcellulose are sequentially added. After a first mixing step for homogeneously dispersing the powders, 60 g of microcrystalline cellulose and 5 g of magnesium stearate are added. After mixing, the final mixture is tabletted to unitary weight of 760 mg/tablet. The resulting tablets are film-coated with cellulose acetophthalate or polymethacrylates and a plasticizer to provide gastric resistance and prevent the early release of product in the stomach. The resulting tablets, when subjected to dissolution test in simulated enteric juice, have shown a release of the active principles having the following profile: after 60 minutes no more than 30%, after 180 minutes no more than 60%, after 5 hours no more than 80%. EXAMPLE 2 50 g of diethylene glycol monoethyl ether are homogeneously distributed on 500 g of microcrystalline cellulose; then 100 g of Budesonide are added, mixing to complete homogenization. This mix is further added with 400 g of Budesonide, then dispersed in a blender containing 100 g of carnauba wax and 100 g of stearic acid preheated at a temperature of 60°C. After kneading for 5 minutes, the mixture is cooled to room temperature and extruded in granules of size below 1 mm. A suitable mixer is loaded with the matrix granules prepared as above and the following amounts of hydrophilic excipients: 1500 g of hydroxypropyl methylcellulose and 500 g of policarbophil. The components are mixed until homogeneous dispersion of the matrices, then added with 2450 g of microcrystalline cellulose, 400 g of lactose, 100 g of colloidal silica and 50 g of magnesium stearate. After further 5 minute mixing, the mix is tabletted to unitary weight of 250 mg/tablet. EXAMPLE 3 850 g of metformin are dispersed in a granulator/kneader with 35 g of diethylene glycol monoethyl ether previously melted with 100 g of stearic acid and 55 g of carnauba wax. The system is heated to carry out the granulation of the active ingredient in the inert matrTx. The resulting 1040 g of formulation are added with 110 g of hydroxypropyl methylcellulose and 20 g of magnesium stearate. The final mixture is tabletted to unitary weight of 1170 mg/tablet equivalent to 850 mg of active ingredient. The resulting tablets, when subjected to dissolution test in simulated enteric juice, have shown a release of the active principles having the following profile: after 60 minutes no more than 35%, after 180 minutes no more than 60%, after 5 hours no more than 80%. EXAMPLE 4 120 g of octylonium bromide are dispersed in a granulator/kneader with 30 g of stearic acid and 15 g of beeswax in which 10 g of diethylene glycol monoethylene had previously been melted. The system is heated to carry out the granulation of the active ingredient in the inert matrix. The resulting 10 g of formulation are added with 5 g of hydroxypropyl methylcellulose and 5 g of policarbophyl, 2 g of magnesium stearate and 3 g of microcrystalline cellulose. The final mixture is tabletted to unitary weight of 200 mg/tablet equivalent to 120 mg of active ingredient. The resulting tablets, when subjected to dissolution test in simulated enteric juice, have shown a release of the active principles having the following profile: after 60 minutes no more than 25%; after 180 minutes no more than 50%; after 5 hours no more than 70%. EXAMPLE 5 12 g of diethylene glycol monoethyl ether are loaded on 6 g of microcrystalline cellulose and 6 grams of calcium carbonate, then 100 g of Gabapentin are added and the mixture is homogenized. After that, 800 g of Gabapentin are added which are dispersed in a granulator/kneader with 4.5 g of white wax and 5 g of stearic acid. The system is heated to carry out the granulation of the active ingredient in the inert matrix. The resulting 916.5 g of formulation are added with 39.5 g of hydroxypropyl methylcellulose, 10 g of alginic acid, 11 g of magnesium stearate and 6 g of syloid. The final mixture is tabletted to unitary weight of 1000 mg/tablet equivalent to 900 mg of active ingredient. EXAMPLE 6 50 g (25 g) of carbidopa and 200 g (100 g) of levodopa are dispersed in a granulator/kneader with 60 g (30 g) of stearic acid and 30 g (15 g) of yellow wax, in which 10 (5) g of diethylene glycol monoethyl ether had previously been melted. The system is heated to carry out the granulation of the active ingredient in the inert matrix. The resulting 340 g (170 g) of formulation are added with 20 g (10 g) of hydroxypropyl methylcellulose, 10 g (5 g) of xantangum, 16 g (8 g) of microcrystalline cellulose, 4 g (2 g) of magnesium stearate. The final mixture is tabletted to unitary weight of 400 (200) mg/tablet equivalent to 50(25) mg of carbidopa and 200 (100) mg di levodopa. EXAMPLE 7 4 g of Nimesulide are solubilised in 50 g of diethylene glycol monoethyl ether, then 100 g of microcrystalline cellulose are added to obtain a homogeneous mixture. The resulting mixture is added in a granulator/kneader with 196 g of Nimesulide, 50 g of stearic acid and 25 g of carnauba wax. The system is heated to carry out the granulation of the active ingredient in the inert and amphiphilic matrix system. 425 g of the resulting granulate are added with 60 g of hydroxypropyl methylcellulose, 5 g of policarbophil" and 10 g of magnesium stearate. The final mixture is tabletted to unitary weight of 500 mg/tablet equivalent to 200 mg of active ingredient. The resulting tablets, when subjected to dissolution test in simulated enteric juice, have shown a release of the active principles having the following profile: after 1 hour no more than 25%, after 2 hours no more than 40%, after 4 hours no more than 60%, after 8 hours no more than 90%. EXAMPLE 8 500 g of propionyl carnitine are dispersed in a granulator/kneader with 90 g of stearic acid and 40 g of carnauba wax, in which 20 g of diethylene glycol monoethyl ether had previously been melted. The system is heated to carry out the granulation of the active ingredient in the inert/amphiphilic matrix. The resulting 650 g of formulation are added with 60 g of hydroxypropyl methylcellulose and 10 g of magnesium stearate. The final mixture is tabletted to unitary weight of 720 mg/tablet equivalent to 500 mg of active ingredient. The resulting tablets, when subjected to dissolution test in simulated enteric juice, have shown a release of the active principles having the following profile: after 60 minutes no more than 40%, after 180 minutes no more than 60%, after 4 hours no more than 80%, after 8 hours no more than 90%. ••, EXAMPLE 9 One kg of Nimesulide is placed in a high rate granulator, pre-heated to about 70°, together with 200 g of cetyl alcohol and 25 g of glycerol palmitostearate; the mixture is kneaded for about 15 minutes and stirred while decreasing temperature to about 30°C. The resulting inert matrix is added, keeping stirring and kneading during cooling, with 50 g of soy lecithin and 50 g of ethylene glycol monoethyl ether. The granulate is extruded through a metallic screen of suitable size and mixed with 50 g of hydroxypropyl methylcellulose, 1320 kg of maltodextrins, 2 kg of lactose-cellulose mixture, 50 g of colloidal silica, 40 g of aspartame, 150 g of citric acid, 75 g of flavour and 65 g of magnesium stearate. The final mixture is tabletted to unitary weight of about 500 mg, having hardness suitable for being dissolved in the mouth and a pleasant taste. EXAMPLE 10 Operating as in the preceding example, chewable tablets are prepared replacing dextrin with mannitol and the lactose-cellulose mixture with xylitol. The resulting tablets ahve pleasant taste and give upon chewing a sensation of freshness enhancing the flavour. EXAMPLE 11 Operating as described in example 9, but with the following components: active ingredient: ibuprofen mg 100 lipophilic/inert matrix component: cetyl alcohol mg 15 amphiphilic matrix component: soy lecithin mg 8 hydrophilic matrix components: mannitol mg 167 maltodextrins mg 150 methylhydroxypropylcellulose mg 30 adjuvants: aspartame mg 15 flavour mg 5 colloidal silica mg 5 magnesium stearate mg 5 500 mg unitary weight tablets are obtained, which undergo progressive erosion upon buccal administration, and effectively mask the bitter, irritating taste of the active ingredient. " EXAMPLE 12 Operating as described in example 9, but with the following components: active ingredient: diclofenac sodium mg 25 lipophilic/inert matrix component: cetyl alcohol mg 5 glycerol palmitostearate mg 5 amphiphilic matrix component: soy lecithin mg 7 17 hydrophilic matrix components: xylitol mg 168 maltodextrins mg 150 hydroxypropylmethylcellulose mg 20 adjuvants: aspartame mg 5 flavour mg 5 colloidal silica mg 5 magnesium stearate mg 5 400 mg unitary weight tablets are obtained, which undergo progressive erosion upon buccal administration, and effectively mask the irritating taste of the active ingredient. EXAMPLE 13 Operating as described in example 9, but with the following components: active ingredient: chlorhexidine mg 2, 5 lipophilic/inert matrix component: cetyl alcohol mg 0.5 -•. glycerol palmitostearate mg 0 . 5 amphiphilic matrix component: diethylene glycol monoethyl ether mg 0.3 hydrophilic matrix components: xylitol mg 38 maltodextrins mg 96 hydroxypropyl methylcellulose mg 10 adjuvants: aspartame mg 3 flavour mg 5 colloidal silica mg 2 magnesium stearate mg 2 150 mg unitary weight tablets are obtained, which undergo progressive erosion upon buccal administration, and effectively mask the irritating taste of the active ingredient. EXAMPLE 14 One Kg of Nimesulide is placed in a high rate granulator, pre-heated to about 70°, together with g 125 of cetyl alcohol: the mixture is kneaded for about 15 minutes and stirred while decreasing temperature to about 30°C, then added with g 30 of lecithin. The resulting matrix is then extruded through a metallic screen of suitable size and mixed with 2.415 kg of lactose, 1.0 kg of maltodextrins, 50 g of hydroxypropyl methylcellulose, 50 g of colloidal silica, 40 g of aspartame, 150 g of citric acid, 75 g of flavour and 65 g of magnesium stearate. The final mixture is tabletted to about 500 mg tablets, having hardness suitable for being dissolved in the mouth and pleasant taste. We Claim: 1. Controlled release and taste-masking pharmaceutical compositions containing an active ingredient ranges from 5 to 95%, containing characterized in that: a) a matrix consisting of lipophilic compounds with melting point lower than 90 °C wherein the active ingredient is partially inglobated consisting of C6-C20 alcohols or C8-C20 fatty acids or easters of fatty acids with glycerol or sorbitol or other polyaclcohols with carbon atom chain not higher than six and the said lipophilic matrix compounds selected from unsaturated or hydrogenated alcohols or fatty acids, salts, esters or amides thereof, mono-, di- or triglycerids of fatty acids, the polyethoxylated derivatives thereof, waxes, cholesterol derivatives; b) an amphiphilic matrix are polar lipids of type I or II (lecithin, phosphatidylcholine, phosphatidyl-ethanolamine), ceramides, glycol alkyl ethers, esters of fatty acids with polyethylene glycols or diethylene glycols; c) an outer hydrophilic matrix consisting of hydrogels in which the lipophilic matrix and the amphiphilic matrix are dispersed wherein hydrophilic matrix consists of compounds selected from acrylic or methacrylic acid polymers pr copolymers, cellulose, polysaccharides, dextrins, pectins, starches and derivatives, alginic acid, natural or synthetic gums, polyalcohols; d) optionally a gastro-resistant outer coating of the kind as herein described; and e) other excipients. 2. Compositions as claimed in claim 1, in which the gastro-resistant coating consists of methacrylic acid polymers or cellulose derivatives. 3. Compositions as claimed in claim 1, in which the active ingredient is wholly contained in the inert amphiphilic matrix, in the form of pharmaceutical formulations such as herein described. 4. Compositions as claimed in claim 1, wherein the active ingredient is dispersed both in the hydrophilic matrix and in the lipophilic/amphiphilic matrix, in the form of pharmaceutical formulations such as herein described. 5. Compositions as claimed in claim 1, in which the active ingredient belongs to the therapeutical classes of analgesics, antitussives, bronchodilators, antipsychotics, selective & 2 antagonists, calcium antagonists, antiparkinson drugs, non-steroidal anti- inflammatory drugs, antihistamines, antidiarrheals and intestinal antiinflammatories, spasmolytics, anxiolytics, oral antidiabetics, cathartics, antiepileptics, topical antimicrobials. 6. Compositions as claimed in claim 1, in which the active ingredient is selected from mesalazine (5-aminosalicylic acid), budesonide, metformin, octylonium bromide, gabapentin, carbidopa, namesulide, propionylilcarnitine, isosorbide mono- and dinitrate, naproxen, ibuprofen, ketoprofen, diclofenac, thiaprophenic acid, nimesulide, chlorhexidine, benzydamine, tibezonium iodide, cetylpyridinium chloride, benzalkonium chloride, sodium fluoride. 7. Compositions as claimed in the above claims, containing bioadhesive substances. 8. Compositions as claimed in the above claims, in the form of pharmaceutical formulation such as herein described in the buccal cavity or in the first portion of the gastrointestinal tract. 9. Controlled-release and taste-masking pharmaceutical compositions substantially as herein described with reference to the foregoing description and the accompanying examples.

Documents:

2815-delnp-2005-description (complete)-28-08-2008.pdf

IN-PCT-2001-01113-DEL-Abstract-(27-08-2008).pdf

IN-PCT-2001-01113-DEL-Abstract-18-11-2008.pdf

in-pct-2001-01113-del-abstract.pdf

IN-PCT-2001-01113-DEL-Claims-(27-08-2008).pdf

IN-PCT-2001-01113-DEL-Claims-18-11-2008.pdf

in-pct-2001-01113-del-claims.pdf

IN-PCT-2001-01113-DEL-Correspondence-Others-(27-08-2008).pdf

IN-PCT-2001-01113-DEL-Correspondence-Others-18-11-2008.pdf

in-pct-2001-01113-del-correspondence-others.pdf

IN-PCT-2001-01113-DEL-Description (Complete)-18-11-2008.pdf

in-pct-2001-01113-del-description (complete).pdf

IN-PCT-2001-01113-DEL-Form-1-18-11-2008.pdf

in-pct-2001-01113-del-form-1.pdf

in-pct-2001-01113-del-form-13.pdf

in-pct-2001-01113-del-form-18.pdf

IN-PCT-2001-01113-DEL-Form-2-18-11-2008.pdf

in-pct-2001-01113-del-form-2.pdf

in-pct-2001-01113-del-form-3.pdf

in-pct-2001-01113-del-form-5.pdf

in-pct-2001-01113-del-form-6.pdf

in-pct-2001-01113-del-pct-210.pdf

in-pct-2001-01113-del-pct-306.pdf

in-pct-2001-01113-del-pct-409.pdf

in-pct-2001-01113-del-pct-416.pdf