US20190022112A1 - Controlled release and taste masking oral pharmaceutical compositions - Google Patents

Controlled release and taste masking oral pharmaceutical compositions Download PDF

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Publication number
US20190022112A1
US20190022112A1 US16/139,672 US201816139672A US2019022112A1 US 20190022112 A1 US20190022112 A1 US 20190022112A1 US 201816139672 A US201816139672 A US 201816139672A US 2019022112 A1 US2019022112 A1 US 2019022112A1
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Prior art keywords
controlled release
pharmaceutical composition
oral pharmaceutical
composition according
release oral
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Abandoned
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US16/139,672
Inventor
Roberto Villa
Massimo Pedrani
Mauro Ajani
Lorenzo Fossati
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Cosmo Technologies Ltd
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Cosmo Technologies Ltd
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Priority claimed from IT1999MI001317A external-priority patent/ITMI991317A1/en
Priority claimed from IT2000MI000422A external-priority patent/IT1317871B1/en
Application filed by Cosmo Technologies Ltd filed Critical Cosmo Technologies Ltd
Priority to US16/139,672 priority Critical patent/US20190022112A1/en
Assigned to COSMO TECHNOLOGIES LIMITED reassignment COSMO TECHNOLOGIES LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: AJANI, MAURO, FOSSATI, LORENZO, PEDRANI, MASSIMO, VILLA, ROBERTO
Assigned to COSMO TECHNOLOGIES LIMITED reassignment COSMO TECHNOLOGIES LIMITED CHANGE OF ADDRESS Assignors: COSMO TECHNOLOGIES LIMITED
Priority to US16/234,951 priority patent/US20190134061A1/en
Publication of US20190022112A1 publication Critical patent/US20190022112A1/en
Abandoned legal-status Critical Current

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    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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Definitions

  • the present invention relates to controlled release and taste-masking compositions containing one or more active principles incorporated in a three-component matrix structure, i.e. a structure formed by successive amphiphilic, lipophilic or inert matrices and finally incorporated or dispersed in hydrophilic matrices.
  • a three-component matrix structure i.e. a structure formed by successive amphiphilic, lipophilic or inert matrices and finally incorporated or dispersed in hydrophilic matrices.
  • the use of a plurality of systems for the control of the dissolution of the active ingredient modulates the dissolution rate of the active ingredient in aqueous and/or biological fluids, thereby controlling the release kinetics in the gastrointestinal tract, and it also allows the oral administration of active principles having unfavourable taste characteristics or irritating action on the mucosae of the administration site, particularly in the buccal area.
  • compositions of the invention can contain active principles belonging to the therapeutical classes of analgesics, antiinflammatories, cardioactives, tranquilizers, antihypertensives, disinfectants and topical antimicrobials, antiparkinson drugs, antihistamines and are suitable to the oral administration or for acting topically at some areas of the gastrointestinal tract.
  • Inert matrices for example, generally entail non-linear, but exponential, release of the active ingredient.
  • Hydrophilic matrices have a linear behaviour until a certain fraction of active ingredient has been released; then they significantly deviate from linear release.
  • Bioerodible matrices are ideal to carry out the so-called “site-release”, but they involve the problem of finding the suitable enzyme or reactive to degradation. Furthermore, they frequently release in situ metabolites that are not wholly toxicologically inert.
  • EP 375,063 discloses a technique for the preparation of multiparticulate granules for the controlled-release of the active ingredient which comprises co-dissolution of polymers or suitable substances to form a inert matrix with the active ingredient and the subsequent deposition of said solution on an inert carrier which acts as the core of the device.
  • the inert carrier is kneaded with the solution containing the inert polymer and the active ingredient, then the organic solvent used for the their dissolution is evaporated off to obtain a solid residue.
  • the resulting structure is a “reservoir”, i.e. is not macroscopically homogeneous along all the symmetry axis of the final form.
  • EP 0 453 001 discloses a multiparticulate with “reservoir” structure inserted in a hydrophilic matrix.
  • the basic multiparticulate utilizes two coating membranes to decrease the release rate of the active ingredient, a pH-dependent membrane with the purpose of gastric protection and a pH-independent methacrylic membrane with the purpose of slowing down the penetration of the aqueous fluid.
  • WO 95/16451 discloses a composition only formed by a hydrophilic matrix coated with a gastro-resistant film for controlling the dissolution rate of the active ingredient.
  • compositions of the invention are characterized by the absence of a first phase in which the medicament superficially present on the matrix is quickly solubilized, and by the fact the amphiphilic layer compensate the lack of affinity of the aqueous solvent with the lipophilic compounds forming the inner inert matrix.
  • the invention provides controlled release and taste masking oral pharmaceutical compositions containing an active ingredient, comprising:
  • a particular aspect of the invention consists of controlled release oral compositions containing one or more active ingredients comprising:
  • a further aspect of the invention provides taste masking oral pharmaceutical compositions containing one or more active ingredients comprising:
  • compositions of the invention can be prepared by a method comprising the following steps:
  • the active ingredient is first inglobated by simple kneading or mixing in a matrix or coating consisting of compounds having amphiphilic properties, which will be further specified below.
  • the active principle(s) can be mixed with the amphiphilic compounds without the aid of solvents or with small amounts of water-alcoholic solvents.
  • the matrix obtained in a) is incorporated in a low melting lipophilic excipient or mixture of excipients, while heating to soften and/or melt the excipient itself, which thereby incorporates the active ingredient by simple dispersion. After cooling at room temperature an inert matrix forms, which can be reduced in size to obtain inert matrix granules containing the active ingredient particles.
  • inert matrix granules are subsequently mixed together with one or more hydrophilic water-swellable excipients.
  • the mixture is then subjected to compression or tabletting. This way, when the tablet is contacted with biological fluids, a high viscosity swollen layer is formed, which coordinates the solvent molecules and acts as a barrier to penetration of the aqueous fluid itself inside the new structure. Said barrier antagonizes the starting “burst effect” caused by the dissolution of the medicament inglobated inside the inert matrix, which is in its turn inside the hydrophilic matrix.
  • the lipophilic matrix consists of substances selected from unsaturated or hydrogenated alcohols or fatty acids, salts, esters or amides thereof, fatty acids mono-, di- or triglycerides, the polyethoxylated derivatives thereof, waxes, ceramides, cholesterol derivatives or mixtures thereof having a melting point within the range of 40 to 90° C., preferably from 60 to 70° C.
  • a fatty acid calcium salt may be incorporated in the lipophilic matrix which is subsequently dispersed in a hydrophilic matrix prepared with alginic acid, thus remarkably increasing the hydrophilic matrix viscosity following penetration of the solvent front until contact with the lipophilic matrix granules dispersed inside.
  • an amphiphilic matrix with high content in active ingredient is first prepared by dispersing the active ingredient or the mixture of active ingredients in a mixture of amphiphilic compounds, such as lecithin, other type II polar lipids, surfactants, or in diethylene glycol monoethyl ether; the resulting amphiphilic matrix is then mixed or kneaded, usually while hot, with lipophilic compounds suitable to form an inert matrix, such as saturated or unsaturated fatty acids, such as palmitic, stearic, myristic, lauric, laurylic, or oleic acids or mixtures thereof with other fatty acids with shorter chain, or salts or alcohols or derivatives of the cited fatty acids, such as mono-, di-, or triglycerides or esters with polyethylene glycols, alone or in combination with waxes, ceramides, cholesterol derivatives or other apolar lipids in various ratios so
  • the order of formation of the inert and amphiphilic matrices can be reversed, incorporating the inert matrix inside the amphiphilic compounds.
  • the resulting inert lipophilic matrix is reduced into granules by an extrusion and/or granulation process, or any other known processes which retain the homogeneous dispersion and matrix structure of the starting mixture.
  • the hydrophilic matrix consists of excipients known as hydrogels, i.e. substances which when passing from the dry state to the hydrated one, undergo the so-called “molecular relaxation”, namely a remarkable increase in mass and weight following the coordination of a large number of water molecules by the polar groups present in the polymeric chains of the excipients themselves.
  • hydrogels which can be used according to the invention are compounds selected from acrylic or methacrylic acid polymers or copolymers, alkylvinyl polymers, hydroxyalkyl celluloses, carboxyalkyl celluloses, polysaccharides, dextrins, pectins, starches and derivatives, natural or synthetic gums, alginic acid.
  • polyalcohols such as xylitol, maltitol and mannitol as hydrophilic compounds can also be advantageous.
  • the lipophilic matrix granules containing the active ingredient are mixed with the hydrophilic compounds cited above in a weight ratio typically ranging from 100:0.5 to 100:50 (lipophilic matrix:hydrophilic matrix).
  • Part of the active ingredient can optionally be mixed with hydrophilic substances to provide compositions in which the active ingredient is dispersed both in the lipophilic and the hydrophilic matrix, said compositions being preferably in the form of tablets, capsules and/or minitablets.
  • the compression of the mixture of lipophilic and/or amphiphilic matrix, hydrogel-forming compound and, optionally, active ingredient not inglobated in the lipophilic matrix yields a macroscopically homogeneous structure in all its volume, namely a matrix containing a dispersion of the lipophilic granules in a hydrophilic matrix.
  • a similar result can also be obtained by coating the lipophilic matrix granules with a hydrophilic polymer coating.
  • the tablets obtainable according to the invention can optionally be subjected to known coating processes with a gastro-resistant film, consisting of, for example, methacrylic acids polymers (Eudragit®) or cellulose derivatives, such as cellulose acetophthalate.
  • a gastro-resistant film consisting of, for example, methacrylic acids polymers (Eudragit®) or cellulose derivatives, such as cellulose acetophthalate.
  • Active ingredients which can conveniently be formulated according to the invention comprise:
  • analgesics such as acetaminophen, phenacetin, sodium salicylate
  • antitussives such as dextromethorphan, codeine phosphate
  • bronchodilators such as albuterol, procaterol
  • antipsychotics such as haloperidol, chlorpromazine
  • antihypertensives and coronary-dilators such as isosorbide mono- and dinitrate, captopril;
  • selective ⁇ 2 antagonists such as salbutamol, terbutaline, ephedrine, orciprenaline sulfate;
  • calcium antagonists such as nifedipine, nicardipine, diltiazem, verapamil;
  • antiparkinson drugs such as pergolide, carpidopa, levodopa;
  • non steroid anti-inflammatory drugs such as ketoprofen, ibuprofen, diclofenac, diflunisal, piroxicam, naproxen, ketorolac, nimesulide, thiaprophenic acid, mesalazine (5-aminosalicylic acid); antihistamines, such as terfenedine, loratadine;
  • antidiarrheals and intestinal antiinflammatories such as loperamide, 5-aminosalicylic, olsalazine, sulfasalazine, budenoside;
  • spasmolytics such as octylonium bromide
  • anxiolytics such as chlordiazepoxide, oxazepam, medazepam, alprazolam, donazepam, lorazepan;
  • oral antidiabetics such as glipizide, metformin, phenformin, gliclazide, glibenclamide;
  • cathartics such as bisacodil, sodium picosulfate
  • antiepileptics such as valproate, carbamazepine, phenyloin, gabapentin;
  • antitumorals such as flutamide, etoposide
  • oral cavity disinfectants or antimicrobials such as benzalkonium chloride, cetylpyridinium chloride or tibezonium iodide, and some amino derivatives such as benzydamine and chlorhexidine as well as the salts and derivatives thereof;
  • compositions of the invention can further contain conventional excipients, for example bioadhesive excipients such as chitosans, polyacrylamides, natural or synthetic gums, acrylic acid polymers.
  • bioadhesive excipients such as chitosans, polyacrylamides, natural or synthetic gums, acrylic acid polymers.
  • compositions of the invention can contain more than one active ingredient, each of them being optionally contained in the hydrophilic matrix or in the inert amphiphilic matrix, and are preferably in the form of tablets, capsules or minitablets.
  • contact with water or aqueous fluids causes the immediate penetration of water inside the more superficial layer of the matrix which, thanks to the presence of the aqueous solvent, swells due to the distension of the polymeric chains of the hydrogels, giving rise to a high viscosity hydrated front which prevents the further penetration of the solvent itself linearly slowing down the dissolution process to a well determined point which can be located at about half the thickness, until the further penetration of water would cause the disintegration of the hydrophilic layer and therefore the release of the content which, consisting of inert matrix granules, however induces the diffusion mechanism typical of these structures and therefore further slows down the dissolution profile of the active ingredient.
  • 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.
  • 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.
  • microcrystalline cellulose 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%.
  • 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.
  • metformin 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 matrix.
  • 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%.
  • 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%.
  • 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 xantan gum, 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.
  • Nimesulide 4 g 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.
  • 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%.
  • propionyl carnitine 500 g 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%.
  • 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.
  • chewable tablets are prepared replacing dextrin with mannitol and the lactose-cellulose mixture with xylitol.
  • the resulting tablets have pleasant taste and give upon chewing a sensation of freshness enhancing the flavour.
  • active ingredient ibuprofen mg 100 lipophilic/inert matrix component: mg 15 cetyl alcohol 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.
  • active ingredient diclofenac sodium mg 25 lipophilic/inert matrix component: mg 5 cetyl alcohol glycerol palmitostearate mg 5 amphiphilic matrix component: mg 7 soy lecithin 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.
  • active ingredient chlorhexidine mg
  • 2.5 lipophilic/inert matrix component mg 0.5 cetyl alcohol glycerol palmitostearate mg
  • amphiphilic matrix component mg 0.3 diethylene glycol monoethyl ether 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.
  • 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.
  • 2.7 kg of budesonide, 3.0 kg of lecithin (amphiphilic matrix forming material) and 3.0 kg of stearic acid (lipophilic matrix forming material) are mixing after sieving till an homogeneous mixture is obtained; then add 39.0 kg of inert, functional excipients and 9.0 kg of low viscosity hydroxypropylcellulose (binder) and mix for 10 minutes before adding purified water and kneading to a suitable consistence. Then pass the granulate through a rotating granulator equipped with the suitable screen and transfer the granulate to the fluid bed drier to lower the residual moisture content under 3%.
  • the granulate is added of 9.0 kg of hydroxypropylcellulose (hydrophilic matrix forming material) and the suitable amount of functional excipients (in particular, microcrystalline cellulose, lactose and silicon dioxide) and, after 15 minutes of mixing, magnesium stearate in a suitable quantity to act as lubricant is added.
  • hydroxypropylcellulose hydrophilic matrix forming material
  • functional excipients in particular, microcrystalline cellulose, lactose and silicon dioxide
  • the core are then subjected to be coated with a suspension obtained introducing into a stainless steel container 5.8 kg of EudragitTM (methacrylate copolymers), 0.6 kg of triethylcitrate and 3.0 kg of dyes and talc, using alcohol as solvent.
  • the mean dissolution percentage (as average of six or more tablets) obtained with this tablet formulation were around 10-20% at second hour sampling, in the range 25% to 65% at fourth hour and a dissolution greater than 80% was achieved at 8 th hour sampling.
  • coated tablets individually weighing about 220 mg are obtained.
  • Budesonide (3.0 kg) is mixed with soybean Lecithin (5.0 kg) till an homogeneous mixture is obtained. Then carnauba wax (2.0 kg) and stearic acid (2.0 kg) sieved through a fine screen are added. After mixing, the powders are added with other functional excipients and kneaded with a binder solution obtained by dissolving medium viscosity polyvinylpirrolidone in water. After drying in a fluid bed and milling throughout a suitable screen, hydroxypropylmethylcellulose (35.0 kg) and other excipients, including magnesium stearate as lubricant, in a suitable quantity are added and the mixture is blended till an homogeneous powder dispersion is obtained.
  • the powder mixture is subjected to compression in a rotating tabletting machine and the tablets so obtained are coated in a pan coat with a gastroresistant composition containing EudragitTM, plasticizers, dyes and pigments.
  • coated tablets individually weighing around 105 mg are obtained.
  • 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 PolicarbophilTM are added. 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.
  • Tablets are then subjected to coating using a suspension n containing polyacrylate and poly methacrilate copolymers in addition to other dyes, plasticizers and colouring agents in solvent (ethylic alcohol).
  • solvent ethylic alcohol

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Abstract

The invention relates to tablet comprising granules dispersed in at least one hydrophilic compound or matrix. The granules contain an active agent, at least one amphiphilic compound and at least one lipophilic compound. The tablet may include a gastro-resistant film coating.

Description

    CROSS REFERENCE TO RELATED APPLICATIONS
  • This application is a continuation of application Ser. No. 15/646,330, filed on Jul. 11, 2017, which is a continuation of application Ser. No. 15/369,296, filed on Dec. 5, 2016, now U.S. Pat. No. 10,064,878, which is a continuation of application Ser. No. 14/308,305, filed on Jun. 18, 2014, now U.S. Pat. No. 9,532,954, which is a continuation of application Ser. No. 13/617,138, filed on Sep. 14, 2012, now U.S. Pat. No. 8,784,888, which is a continuation of application Ser. No. 13/462,409, filed on May 2, 2012, now U.S. Pat. No. 8,293,273, which is a continuation of Ser. No. 13/249,839, filed on Sep. 30, 2011, now abandoned, which is a continuation of application Ser. No. 12/210,969, filed on Sep. 15, 2008, which reissued as U.S. Pat. No. RE43,799 from U.S. Pat. No. 8,029,823, which is a continuation-in-part of application Ser. No. 10/009,532, filed on Dec. 12, 2001, now U.S. Pat. No. 7,431,943, which is the 35 U.S.C. 371 national stage of International application PCT/EP00/05356, filed on Jun. 9, 2000, which claimed priority to Italian applications MI2000A000422 and MI99A001317 filed Mar. 3, 2000 and Jun. 14, 1999, respectively. The entire contents of each of the above-identified applications are hereby incorporated by reference.
  • The present invention relates to controlled release and taste-masking compositions containing one or more active principles incorporated in a three-component matrix structure, i.e. a structure formed by successive amphiphilic, lipophilic or inert matrices and finally incorporated or dispersed in hydrophilic matrices. The use of a plurality of systems for the control of the dissolution of the active ingredient modulates the dissolution rate of the active ingredient in aqueous and/or biological fluids, thereby controlling the release kinetics in the gastrointestinal tract, and it also allows the oral administration of active principles having unfavourable taste characteristics or irritating action on the mucosae of the administration site, particularly in the buccal area.
  • The compositions of the invention can contain active principles belonging to the therapeutical classes of analgesics, antiinflammatories, cardioactives, tranquilizers, antihypertensives, disinfectants and topical antimicrobials, antiparkinson drugs, antihistamines and are suitable to the oral administration or for acting topically at some areas of the gastrointestinal tract.
    • TECHNOLOGICAL BACKGROUND
  • The preparation of a sustained, controlled, delayed or anyhow modified release form can be carried out according to different known techniques:
      • 1. The use of inert matrices, in which the main component of the matrix structure opposes some resistance to the penetration of the solvent due to the poor affinity towards aqueous fluids; such property being known as lipophilia.
      • 2. The use of hydrophilic matrices, in which the main component of the matrix structure opposes high resistance to the progress of the solvent, in that the presence of strongly hydrophilic groups in its chains, mainly branched, remarkably increases viscosity inside the hydrated layer.
      • 3. The use of bioerodible matrices, which are capable of being degraded by the enzymes of some biological compartment.
  • All the procedures listed above suffer, however, from drawbacks and imperfections.
  • Inert matrices, for example, generally entail non-linear, but exponential, release of the active ingredient.
  • Hydrophilic matrices have a linear behaviour until a certain fraction of active ingredient has been released; then they significantly deviate from linear release.
  • Bioerodible matrices are ideal to carry out the so-called “site-release”, but they involve the problem of finding the suitable enzyme or reactive to degradation. Furthermore, they frequently release in situ metabolites that are not wholly toxicologically inert.
  • A number of formulations based on inert lipophilic matrices have been described: Drug Dev. Ind. Pharm. 13 (6), 1001-1022, (1987) discloses a process making use of varying amounts of colloidal silica as a porization element for a lipophilic inert matrix in which the active ingredient is incorporated.
  • The same notion of canalization of an inert matrix is described in U.S. Pat. No. 4,608,248 in which a small amount of a hydrophilic polymer is mixed with the substances forming an inert matrix, in a non sequential compenetration of different matrix materials.
  • EP 375,063 discloses a technique for the preparation of multiparticulate granules for the controlled-release of the active ingredient which comprises co-dissolution of polymers or suitable substances to form a inert matrix with the active ingredient and the subsequent deposition of said solution on an inert carrier which acts as the core of the device. Alternatively, the inert carrier is kneaded with the solution containing the inert polymer and the active ingredient, then the organic solvent used for the their dissolution is evaporated off to obtain a solid residue. The resulting structure is a “reservoir”, i.e. is not macroscopically homogeneous along all the symmetry axis of the final form.
  • The same “reservoir” structure is also described in Chem. Pharm. Bull. 46 (3), 531-533, (1998) which improves the application through an annealing technique of the inert polymer layer which is deposited on the surface of the pellets.
  • To the “reservoir” structure also belong the products obtained according to the technique described in WO 93/00889 which discloses a process for the preparation of pellets in hydrophilic matrix which comprises:
      • dissolution of the active ingredient with gastro-resistant hydrophilic polymers in organic solvents;
      • drying of said suspension;
      • subsequent kneading and formulation of the pellets in a hydrophilic or lipophilic matrix without distinction of effectiveness between the two types of application.
  • EP 0 453 001 discloses a multiparticulate with “reservoir” structure inserted in a hydrophilic matrix. The basic multiparticulate utilizes two coating membranes to decrease the release rate of the active ingredient, a pH-dependent membrane with the purpose of gastric protection and a pH-independent methacrylic membrane with the purpose of slowing down the penetration of the aqueous fluid.
  • WO 95/16451 discloses a composition only formed by a hydrophilic matrix coated with a gastro-resistant film for controlling the dissolution rate of the active ingredient.
  • When preparing sustained-, controlled-release dosage forms of a medicament topically active in the gastrointestinal tract, it is important to ensure a controlled release from the first phases following administration, i.e. when the inert matrices have the maximum release rate inside the logarithmic phase, namely the higher deviation from linear release.
  • Said object has been attained according to the present invention, through the combination of an amphiphilic matrix inside an inert matrix, the latter formulated with a lipophilic polymer in a superficial hydrophilic matrix. The compositions of the invention are characterized by the absence of a first phase in which the medicament superficially present on the matrix is quickly solubilized, and by the fact the amphiphilic layer compensate the lack of affinity of the aqueous solvent with the lipophilic compounds forming the inner inert matrix.
    • DISCLOSURE OF THE INVENTION
  • The invention provides controlled release and taste masking oral pharmaceutical compositions containing an active ingredient, comprising:
      • a) a matrix consisting of lipophilic compounds with melting point lower than 90° C. and optionally by amphiphilic compounds in which the active ingredient is at least partially incorporated;
      • b) optionally an amphiphilic matrix;
      • c) an outer hydrophilic matrix in which the lipophilic matrix and the optional amphiphilic matrix are dispersed;
      • d) optionally other excipients.
  • A particular aspect of the invention consists of controlled release oral compositions containing one or more active ingredients comprising:
      • a) a matrix consisting of amphiphilic compounds and lipophilic compounds with melting point below 90° C. in which the active ingredient is at least partially incorporated;
      • b) an outer hydrophilic matrix in which the lipophilic/amphiphilic matrix is dispersed;
      • c) optional other excipients.
  • A further aspect of the invention provides taste masking oral pharmaceutical compositions containing one or more active ingredients comprising:
      • an inert or lipophilic matrix consisting of C6-C20-alcohols or C8-C20 fatty acids or esters of fatty acids with glycerol or sorbitol or other polyalcohols with carbon atom chain not higher than six;
      • an amphiphilic matrix consisting of polar lipids of type I or II or glycols partially etherified with C1-C4 alkyl chains;
      • an outer hydrophilic matrix containing the above matrices, mainly formed by saccharide, dextrin, polyalcohol or cellulose compounds or by hydrogels;
      • optional excipients to give stability to the pharmaceutical formulation.
    DETAILED DISCLOSURE OF THE INVENTION
  • The compositions of the invention can be prepared by a method comprising the following steps:
  • a) the active ingredient is first inglobated by simple kneading or mixing in a matrix or coating consisting of compounds having amphiphilic properties, which will be further specified below. The active principle(s) can be mixed with the amphiphilic compounds without the aid of solvents or with small amounts of water-alcoholic solvents.
  • b) The matrix obtained in a) is incorporated in a low melting lipophilic excipient or mixture of excipients, while heating to soften and/or melt the excipient itself, which thereby incorporates the active ingredient by simple dispersion. After cooling at room temperature an inert matrix forms, which can be reduced in size to obtain inert matrix granules containing the active ingredient particles.
  • c) The inert matrix granules are subsequently mixed together with one or more hydrophilic water-swellable excipients. The mixture is then subjected to compression or tabletting. This way, when the tablet is contacted with biological fluids, a high viscosity swollen layer is formed, which coordinates the solvent molecules and acts as a barrier to penetration of the aqueous fluid itself inside the new structure. Said barrier antagonizes the starting “burst effect” caused by the dissolution of the medicament inglobated inside the inert matrix, which is in its turn inside the hydrophilic matrix.
  • The amphiphilic compounds which can be used according to the invention comprise polar lipids of type I or II (lecithin, phosphatidylcholine, phosphatidylethanolamine), ceramides, glycol alkyl ethers such as diethylene glycol monomethyl ether (Transcutol®).
  • The lipophilic matrix consists of substances selected from unsaturated or hydrogenated alcohols or fatty acids, salts, esters or amides thereof, fatty acids mono-, di- or triglycerides, the polyethoxylated derivatives thereof, waxes, ceramides, cholesterol derivatives or mixtures thereof having a melting point within the range of 40 to 90° C., preferably from 60 to 70° C.
  • If desired, a fatty acid calcium salt may be incorporated in the lipophilic matrix which is subsequently dispersed in a hydrophilic matrix prepared with alginic acid, thus remarkably increasing the hydrophilic matrix viscosity following penetration of the solvent front until contact with the lipophilic matrix granules dispersed inside.
  • According to an embodiment of the invention, an amphiphilic matrix with high content in active ingredient, typically from 5 to 95% w/w, is first prepared by dispersing the active ingredient or the mixture of active ingredients in a mixture of amphiphilic compounds, such as lecithin, other type II polar lipids, surfactants, or in diethylene glycol monoethyl ether; the resulting amphiphilic matrix is then mixed or kneaded, usually while hot, with lipophilic compounds suitable to form an inert matrix, such as saturated or unsaturated fatty acids, such as palmitic, stearic, myristic, lauric, laurylic, or oleic acids or mixtures thereof with other fatty acids with shorter chain, or salts or alcohols or derivatives of the cited fatty acids, such as mono-, di-, or triglycerides or esters with polyethylene glycols, alone or in combination with waxes, ceramides, cholesterol derivatives or other apolar lipids in various ratios so that the melting or softening points of the lipophilic compounds mixtures is within the range of 40 to 90° C., preferably from 60 to 70° C.
  • Alternatively, the order of formation of the inert and amphiphilic matrices can be reversed, incorporating the inert matrix inside the amphiphilic compounds.
  • The resulting inert lipophilic matrix is reduced into granules by an extrusion and/or granulation process, or any other known processes which retain the homogeneous dispersion and matrix structure of the starting mixture.
  • The hydrophilic matrix consists of excipients known as hydrogels, i.e. substances which when passing from the dry state to the hydrated one, undergo the so-called “molecular relaxation”, namely a remarkable increase in mass and weight following the coordination of a large number of water molecules by the polar groups present in the polymeric chains of the excipients themselves.
  • Examples of hydrogels which can be used according to the invention are compounds selected from acrylic or methacrylic acid polymers or copolymers, alkylvinyl polymers, hydroxyalkyl celluloses, carboxyalkyl celluloses, polysaccharides, dextrins, pectins, starches and derivatives, natural or synthetic gums, alginic acid.
  • In case of taste-masking formulations, the use of polyalcohols such as xylitol, maltitol and mannitol as hydrophilic compounds can also be advantageous.
  • The lipophilic matrix granules containing the active ingredient are mixed with the hydrophilic compounds cited above in a weight ratio typically ranging from 100:0.5 to 100:50 (lipophilic matrix:hydrophilic matrix). Part of the active ingredient can optionally be mixed with hydrophilic substances to provide compositions in which the active ingredient is dispersed both in the lipophilic and the hydrophilic matrix, said compositions being preferably in the form of tablets, capsules and/or minitablets.
  • The compression of the mixture of lipophilic and/or amphiphilic matrix, hydrogel-forming compound and, optionally, active ingredient not inglobated in the lipophilic matrix, yields a macroscopically homogeneous structure in all its volume, namely a matrix containing a dispersion of the lipophilic granules in a hydrophilic matrix. A similar result can also be obtained by coating the lipophilic matrix granules with a hydrophilic polymer coating.
  • The tablets obtainable according to the invention can optionally be subjected to known coating processes with a gastro-resistant film, consisting of, for example, methacrylic acids polymers (Eudragit®) or cellulose derivatives, such as cellulose acetophthalate.
  • Active ingredients which can conveniently be formulated according to the invention comprise:
  • analgesics, such as acetaminophen, phenacetin, sodium salicylate; antitussives, such as dextromethorphan, codeine phosphate;
  • bronchodilators, such as albuterol, procaterol;
  • antipsychotics, such as haloperidol, chlorpromazine;
  • antihypertensives and coronary-dilators, such as isosorbide mono- and dinitrate, captopril;
  • selective β2 antagonists such as salbutamol, terbutaline, ephedrine, orciprenaline sulfate;
  • calcium antagonists, such as nifedipine, nicardipine, diltiazem, verapamil;
  • antiparkinson drugs, such as pergolide, carpidopa, levodopa;
  • non steroid anti-inflammatory drugs, such as ketoprofen, ibuprofen, diclofenac, diflunisal, piroxicam, naproxen, ketorolac, nimesulide, thiaprophenic acid, mesalazine (5-aminosalicylic acid); antihistamines, such as terfenedine, loratadine;
  • antidiarrheals and intestinal antiinflammatories, such as loperamide, 5-aminosalicylic, olsalazine, sulfasalazine, budenoside;
  • spasmolytics such as octylonium bromide;
  • anxiolytics, such as chlordiazepoxide, oxazepam, medazepam, alprazolam, donazepam, lorazepan;
  • oral antidiabetics, such as glipizide, metformin, phenformin, gliclazide, glibenclamide;
  • cathartics, such as bisacodil, sodium picosulfate;
  • antiepileptics, such as valproate, carbamazepine, phenyloin, gabapentin;
  • antitumorals, such as flutamide, etoposide;
  • oral cavity disinfectants or antimicrobials, such as benzalkonium chloride, cetylpyridinium chloride or tibezonium iodide, and some amino derivatives such as benzydamine and chlorhexidine as well as the salts and derivatives thereof;
  • sodium fluoride.
  • The compositions of the invention can further contain conventional excipients, for example bioadhesive excipients such as chitosans, polyacrylamides, natural or synthetic gums, acrylic acid polymers.
  • The compositions of the invention can contain more than one active ingredient, each of them being optionally contained in the hydrophilic matrix or in the inert amphiphilic matrix, and are preferably in the form of tablets, capsules or minitablets.
  • In terms of dissolution characteristics, contact with water or aqueous fluids causes the immediate penetration of water inside the more superficial layer of the matrix which, thanks to the presence of the aqueous solvent, swells due to the distension of the polymeric chains of the hydrogels, giving rise to a high viscosity hydrated front which prevents the further penetration of the solvent itself linearly slowing down the dissolution process to a well determined point which can be located at about half the thickness, until the further penetration of water would cause the disintegration of the hydrophilic layer and therefore the release of the content which, consisting of inert matrix granules, however induces the diffusion mechanism typical of these structures and therefore further slows down the dissolution profile of the active ingredient.
  • 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.
  • 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 matrix. 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 xantan gum, 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 have 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: mg 15
    cetyl alcohol
    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: mg 5
    cetyl alcohol
    glycerol palmitostearate mg 5
    amphiphilic matrix component: mg 7
    soy lecithin
    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: mg 0.5
    cetyl alcohol
    glycerol palmitostearate mg 0.5
    amphiphilic matrix component: mg 0.3
    diethylene glycol monoethyl ether
    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.
    • Example A
  • 2.7 kg of budesonide, 3.0 kg of lecithin (amphiphilic matrix forming material) and 3.0 kg of stearic acid (lipophilic matrix forming material) are mixing after sieving till an homogeneous mixture is obtained; then add 39.0 kg of inert, functional excipients and 9.0 kg of low viscosity hydroxypropylcellulose (binder) and mix for 10 minutes before adding purified water and kneading to a suitable consistence. Then pass the granulate through a rotating granulator equipped with the suitable screen and transfer the granulate to the fluid bed drier to lower the residual moisture content under 3%.
  • After a new sieving on the dry, the granulate is added of 9.0 kg of hydroxypropylcellulose (hydrophilic matrix forming material) and the suitable amount of functional excipients (in particular, microcrystalline cellulose, lactose and silicon dioxide) and, after 15 minutes of mixing, magnesium stearate in a suitable quantity to act as lubricant is added.
  • After a final blending, tablets of around 300 mg of unitary weight are generated.
  • The core are then subjected to be coated with a suspension obtained introducing into a stainless steel container 5.8 kg of Eudragit™ (methacrylate copolymers), 0.6 kg of triethylcitrate and 3.0 kg of dyes and talc, using alcohol as solvent.
  • The mean dissolution percentage (as average of six or more tablets) obtained with this tablet formulation were around 10-20% at second hour sampling, in the range 25% to 65% at fourth hour and a dissolution greater than 80% was achieved at 8th hour sampling.
    • Example B
  • Component mg/tablet
    Tablet
    Budesonide 9.0
    Stearic Acid 10.0
    Lecithin 10.0
    Microcristalline cellulose 156.0
    Hydroxypropylcellulose 60.0
    Lactose monohydrate 50.0
    Silicon dioxide 2.0
    Magnesium stearate 3.0
    Coating materials
    Eudragit L100 14.0
    Eudragit S100 12.0
    Talc 7.9
    Titanium dioxiede 4.5
    Triethylcitrate 1.6
    Alcohol q.s.
  • According to the present invention, coated tablets individually weighing about 220 mg are obtained.
  • The above described dissolution test is performed on the tablets of Example B.
  • The results are the following (indicated as average value):
  •
    after 2 hours at pH 1 resistant (<5%)
    after 1 hour at pH 6.4 resistant (<5%)
    after 2 hours at pH 7.2 15%
    after 4 hours at pH 7.2 37%
    after 8 hours at pH 7.2 91%
    • Example C
  • Budesonide (3.0 kg) is mixed with soybean Lecithin (5.0 kg) till an homogeneous mixture is obtained. Then carnauba wax (2.0 kg) and stearic acid (2.0 kg) sieved through a fine screen are added. After mixing, the powders are added with other functional excipients and kneaded with a binder solution obtained by dissolving medium viscosity polyvinylpirrolidone in water. After drying in a fluid bed and milling throughout a suitable screen, hydroxypropylmethylcellulose (35.0 kg) and other excipients, including magnesium stearate as lubricant, in a suitable quantity are added and the mixture is blended till an homogeneous powder dispersion is obtained.
  • The powder mixture is subjected to compression in a rotating tabletting machine and the tablets so obtained are coated in a pan coat with a gastroresistant composition containing Eudragit™, plasticizers, dyes and pigments.
  • According to the present example, coated tablets individually weighing around 105 mg are obtained.
  • The results of the above described dissolution test are the following (indicated as average value of at least six tablets):
  •
    after 2 hours at pH 1 resistant (<5%)
    after 1 hour at pH 6.4 resistant (<5%)
    after 2 hours at pH 7.2  9%
    after 4 hours at pH 7.2 28%
    after 8 hours at pH 7.2 86%
    • Example D
  • 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 [deg.] 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™ are added. 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.
  • Tablets are then subjected to coating using a suspension n containing polyacrylate and poly methacrilate copolymers in addition to other dyes, plasticizers and colouring agents in solvent (ethylic alcohol).
  • The results of the dissolution test performed on these coated tablets are the following (indicated as average value of at least six tablets):
  •
    after 2 hours at pH 1 resistant (<5%)
    after 1 hour at pH 6.4 resistant (<5%)
    after 2 hours at pH 7.2 11%
    after 4 hours at pH 7.2 32%
    after 8 hours at pH 7.2 76%

Claims (32)

1. (canceled)
2. (canceled)
3. A controlled release oral pharmaceutical composition consisting essentially of:
(1) a tableted core consisting of a dispersion of ingredients, said ingredients comprising:
a) budesonide in an amount to treat intestinal inflammation;
b) magnesium stearate, stearic acid, or a mixture thereof;
c) hydroxyalkyl cellulose; and
d) optionally starch or a starch derivative; and
(2) a coating on said tableted core, said coating consisting essentially of a gastro-resistant film.
4. The controlled release oral pharmaceutical composition according to claim 3, wherein said ingredients further comprise lactose.
5. The controlled release oral pharmaceutical composition according to claim 3, wherein said ingredients comprise magnesium stearate.
6. The controlled release oral pharmaceutical composition according to claim 3, wherein said hydroxyalkyl cellulose is hydroxypropyl methylcellulose.
7. The controlled release oral pharmaceutical composition according to claim 3, wherein said ingredients comprise starch.
8. The controlled release oral pharmaceutical composition according to claim 7, wherein said ingredients comprise magnesium stearate.
9. The controlled release oral pharmaceutical composition according to claim 8, wherein said ingredients further comprise lactose.
10. The controlled release oral pharmaceutical composition according to claim 7, wherein said hydroxyalkyl cellulose is hydroxypropyl methylcellulose.
11. The controlled release oral pharmaceutical composition according to claim 3, wherein said ingredients comprise a starch derivative and magnesium stearate.
12. The controlled release oral pharmaceutical composition according to claim 11, wherein said hydroxyalkyl cellulose is hydroxypropyl methylcellulose.
13. The controlled release oral pharmaceutical composition according to claim 3, wherein said ingredients comprise a starch derivative and magnesium stearate and further comprise lactose, lecithin, and microcrystalline cellulose.
14. The controlled release oral pharmaceutical composition according to claim 13, wherein said hydroxyalkyl cellulose is hydroxypropyl methylcellulose.
15. The controlled release oral pharmaceutical composition according to claim 3, wherein said gastro-resistant film comprises methacrylic acid polymer.
16. The controlled release oral pharmaceutical composition according to claim 4, wherein said gastro-resistant film comprises methacrylic acid polymer.
17. The controlled release oral pharmaceutical composition according to claim 5, wherein said gastro-resistant film comprises methacrylic acid polymer.
18. The controlled release oral pharmaceutical composition according to claim 6, wherein said gastro-resistant film comprises methacrylic acid polymer.
19. The controlled release oral pharmaceutical composition according to claim 7, wherein said gastro-resistant film comprises methacrylic acid polymer.
20. The controlled release oral pharmaceutical composition according to claim 8, wherein said gastro-resistant film comprises methacrylic acid polymer.
21. The controlled release oral pharmaceutical composition according to claim 9, wherein said gastro-resistant film comprises methacrylic acid polymer.
22. The controlled release oral pharmaceutical composition according to claim 10, wherein said gastro-resistant film comprises methacrylic acid polymer.
23. The controlled release oral pharmaceutical composition according to claim 11, wherein said gastro-resistant film comprises methacrylic acid polymer.
24. The controlled release oral pharmaceutical composition according to claim 12, wherein said gastro-resistant film comprises methacrylic acid polymer.
25. The controlled release oral pharmaceutical composition according to claim 13, wherein said gastro-resistant film comprises methacrylic acid polymer.
26. The controlled release oral pharmaceutical composition according to claim 14, wherein said gastro-resistant film comprises methacrylic acid polymer.
27. A method for treating intestinal inflammatory disease in a patient, comprising administering to the patient the controlled release oral pharmaceutical composition according to claim 3.
28. A method for treating intestinal inflammatory disease in a patient, comprising administering to the patient the controlled release oral pharmaceutical composition according to claim 4.
29. A method for treating intestinal inflammatory disease in a patient, comprising administering to the patient the controlled release oral pharmaceutical composition according to claim 5.
30. A method for treating intestinal inflammatory disease in a patient, comprising administering to the patient the controlled release oral pharmaceutical composition according to claim 7.
31. A method for treating intestinal inflammatory disease in a patient, comprising administering to the patient the controlled release oral pharmaceutical composition according to claim 11.
32. A method for treating intestinal inflammatory disease in a patient, comprising administering to the patient the controlled release oral pharmaceutical composition according to claim 15.
US16/139,672 1999-06-14 2018-09-24 Controlled release and taste masking oral pharmaceutical compositions Abandoned US20190022112A1 (en)

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US16/139,672 US20190022112A1 (en) 1999-06-14 2018-09-24 Controlled release and taste masking oral pharmaceutical compositions
US16/234,951 US20190134061A1 (en) 1999-06-14 2018-12-28 Controlled release and taste masking oral pharmaceutical compositions

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IT1999MI001317A ITMI991317A1 (en) 1999-06-14 1999-06-14 THERAPEUTIC SYSTEMS WITH MODIFIED RELEASE FOR ORAL PHARMACEUTICAL FORM
ITMI99A001317 1999-06-14
IT2000MI000422A IT1317871B1 (en) 2000-03-03 2000-03-03 Controlled release and taste masking oral compositions comprising active ingredient incorporated in a matrix structure
ITMI2000A000422 2000-03-03
PCT/EP2000/005356 WO2000076478A1 (en) 1999-06-14 2000-06-09 Controlled release and taste masking oral pharmaceutical compositions
US953201A 2001-12-12 2001-12-12
US12/210,969 US8029823B2 (en) 1999-06-14 2008-09-15 Controlled release and taste masking oral pharmaceutical composition
US13/249,839 US20120021053A1 (en) 1999-06-14 2011-09-30 Controlled release and taste-masking oral pharmaceutical composition
US13/462,409 US8293273B2 (en) 1999-06-14 2012-05-02 Controlled release and taste masking oral pharmaceutical composition
US13/617,138 US8784888B2 (en) 1999-06-14 2012-09-14 Controlled release and taste masking oral pharmaceutical composition
US14/308,305 US9532954B2 (en) 1999-06-14 2014-06-18 Controlled release and taste masking oral pharmaceutical compositions
US15/369,296 US10064878B2 (en) 1999-06-14 2016-12-05 Controlled release and taste masking oral pharmaceutical compositions
US15/646,330 US10143698B2 (en) 1999-06-14 2017-07-11 Controlled release and taste masking oral pharmaceutical compositions
US16/139,672 US20190022112A1 (en) 1999-06-14 2018-09-24 Controlled release and taste masking oral pharmaceutical compositions

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US11/268,500 Expired - Lifetime US7410651B2 (en) 1999-06-14 2005-11-08 Controlled release and taste masking oral pharmaceutical composition
US11/378,378 Expired - Lifetime US7410652B2 (en) 1999-06-14 2006-03-20 Controlled release and taste masking oral pharmaceutical composition
US12/210,969 Ceased US8029823B2 (en) 1999-06-14 2008-09-15 Controlled release and taste masking oral pharmaceutical composition
US13/249,839 Abandoned US20120021053A1 (en) 1999-06-14 2011-09-30 Controlled release and taste-masking oral pharmaceutical composition
US13/462,409 Expired - Lifetime US8293273B2 (en) 1999-06-14 2012-05-02 Controlled release and taste masking oral pharmaceutical composition
US13/462,430 Abandoned US20120220559A1 (en) 1999-06-14 2012-05-02 Controlled Release and Taste Masking Oral Pharmaceutical Composition
US13/477,592 Expired - Fee Related USRE43799E1 (en) 1999-06-14 2012-05-22 Controlled release and taste masking oral pharmaceutical composition
US13/597,867 Abandoned US20120321710A1 (en) 1999-06-14 2012-08-29 Controlled Release and Taste Masking Oral Pharmaceutical Composition
US13/617,138 Expired - Fee Related US8784888B2 (en) 1999-06-14 2012-09-14 Controlled release and taste masking oral pharmaceutical composition
US13/660,308 Abandoned US20130053360A1 (en) 1999-06-14 2012-10-25 Controlled release and taste masking oral pharmaceutical composition
US14/308,305 Expired - Fee Related US9532954B2 (en) 1999-06-14 2014-06-18 Controlled release and taste masking oral pharmaceutical compositions
US14/308,279 Expired - Fee Related US9320716B2 (en) 1999-06-14 2014-06-18 Controlled release and taste masking oral pharmaceutical compositions
US14/514,967 Abandoned US20150056279A1 (en) 1999-06-14 2014-10-15 Controlled Release and Taste Masking Oral Pharmaceutical Compositions
US15/369,296 Expired - Fee Related US10064878B2 (en) 1999-06-14 2016-12-05 Controlled release and taste masking oral pharmaceutical compositions
US15/646,330 Expired - Fee Related US10143698B2 (en) 1999-06-14 2017-07-11 Controlled release and taste masking oral pharmaceutical compositions
US15/646,538 Expired - Fee Related US10105374B2 (en) 1999-06-14 2017-07-11 Controlled release and taste masking oral pharmaceutical compositions
US16/132,718 Abandoned US20190015428A1 (en) 1999-06-14 2018-09-17 Controlled release and taste masking oral pharmaceutical compositions
US16/139,672 Abandoned US20190022112A1 (en) 1999-06-14 2018-09-24 Controlled release and taste masking oral pharmaceutical compositions
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US11/378,378 Expired - Lifetime US7410652B2 (en) 1999-06-14 2006-03-20 Controlled release and taste masking oral pharmaceutical composition
US12/210,969 Ceased US8029823B2 (en) 1999-06-14 2008-09-15 Controlled release and taste masking oral pharmaceutical composition
US13/249,839 Abandoned US20120021053A1 (en) 1999-06-14 2011-09-30 Controlled release and taste-masking oral pharmaceutical composition
US13/462,409 Expired - Lifetime US8293273B2 (en) 1999-06-14 2012-05-02 Controlled release and taste masking oral pharmaceutical composition
US13/462,430 Abandoned US20120220559A1 (en) 1999-06-14 2012-05-02 Controlled Release and Taste Masking Oral Pharmaceutical Composition
US13/477,592 Expired - Fee Related USRE43799E1 (en) 1999-06-14 2012-05-22 Controlled release and taste masking oral pharmaceutical composition
US13/597,867 Abandoned US20120321710A1 (en) 1999-06-14 2012-08-29 Controlled Release and Taste Masking Oral Pharmaceutical Composition
US13/617,138 Expired - Fee Related US8784888B2 (en) 1999-06-14 2012-09-14 Controlled release and taste masking oral pharmaceutical composition
US13/660,308 Abandoned US20130053360A1 (en) 1999-06-14 2012-10-25 Controlled release and taste masking oral pharmaceutical composition
US14/308,305 Expired - Fee Related US9532954B2 (en) 1999-06-14 2014-06-18 Controlled release and taste masking oral pharmaceutical compositions
US14/308,279 Expired - Fee Related US9320716B2 (en) 1999-06-14 2014-06-18 Controlled release and taste masking oral pharmaceutical compositions
US14/514,967 Abandoned US20150056279A1 (en) 1999-06-14 2014-10-15 Controlled Release and Taste Masking Oral Pharmaceutical Compositions
US15/369,296 Expired - Fee Related US10064878B2 (en) 1999-06-14 2016-12-05 Controlled release and taste masking oral pharmaceutical compositions
US15/646,330 Expired - Fee Related US10143698B2 (en) 1999-06-14 2017-07-11 Controlled release and taste masking oral pharmaceutical compositions
US15/646,538 Expired - Fee Related US10105374B2 (en) 1999-06-14 2017-07-11 Controlled release and taste masking oral pharmaceutical compositions
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