CONTROLLED RELEASE AND TASTE MASKING ORAL PHARMACEUTICAL COMPOSITIONS

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.

Claims

1. A controlled release oral pharmaceutical composition in the form of a tablet consisting essentially of: (1) a tablet core consisting of a mixture of ingredients, said ingredients comprising: a) budesonide in an amount to treat intestinal inflammation; b) hydroxyalkyl cellulose; c) lactose; d) colloidal silica; and e) microcrystalline cellulose; and (2) a gastro-resistant film coating on said tablet core, said coating comprising at least one methacrylic acid polymer or methacrylic acid copolymer.

2. The controlled release oral pharmaceutical composition according to claim 1, wherein said mixture of ingredients in said tablet core further comprises a lubricant.

3. The controlled release oral pharmaceutical composition according to claim 1, wherein said mixture of ingredients in said tablet core further comprises a lipophilic compound.

4. The controlled release oral pharmaceutical composition according to claim 3, wherein said lipophilic compound is selected from the group consisting of palmitic, stearic, myristic, lauric, laurylic, or oleic acid or mixtures thereof, or salts or alcohols or mono-, di-, or triglycerides or ester derivatives thereof.

5. The controlled release oral pharmaceutical composition according to claim 4, wherein said lipophilic compound comprises stearic acid, or salt, alcohol or ester derivative thereof.

6. The controlled release oral pharmaceutical composition according to claim 5, wherein said lipophilic compound comprises the alcohol of stearic acid, or salt or ester derivative thereof.

7. The controlled release oral pharmaceutical composition according to claim 1, wherein said mixture of ingredients in said tablet core further comprises an alcohol of stearic acid, or salt or ester derivative thereof.

8. A controlled release oral pharmaceutical composition in the form of a tablet consisting essentially of: (1) a tablet core consisting of a mixture of ingredients, said ingredients comprising: a) 9 mg of budesonide; b) hydroxypropyl cellulose; c) lactose; d) colloidal silica; and e) microcrystalline cellulose; and (2) a gastro-resistant film coating on said tablet core, said coating comprising at least one methacrylic acid polymer or methacrylic acid copolymer.

9. The controlled release oral pharmaceutical composition according to claim 8, wherein said mixture of ingredients in said tablet core further comprises a lubricant.

10. The controlled release oral pharmaceutical composition according to claim 9, wherein said mixture of ingredients in said tablet core further comprises a lipophilic compound.

11. The controlled release oral pharmaceutical composition according to claim 10, wherein said lipophilic compound is selected from the group consisting of palmitic, stearic, myristic, lauric, laurylic, or oleic acid or mixtures thereof, or salts or alcohols or mono-, di-, or triglycerides or ester derivatives thereof.

12. The controlled release oral pharmaceutical composition according to claim 11, wherein said lipophilic compound comprises stearic acid, or salt, alcohol or ester derivative thereof.

13. The controlled release oral pharmaceutical composition according to claim 12, wherein said lipophilic compound comprises the alcohol of stearic acid, or salt or ester derivative thereof.

14. The controlled release oral pharmaceutical composition according to claim 8, wherein said mixture of ingredients in said tablet core further comprises an alcohol of stearic acid, or salt or ester derivative thereof.

15. The controlled release oral pharmaceutical composition according to claim 8, wherein said gastro-resistant film coating further comprises triethyl citrate, talc and titanium dioxide.

16. The controlled release oral pharmaceutical composition according to claim 13, wherein said gastro-resistant film coating further comprises triethyl citrate, talc and titanium dioxide.

17. A controlled release oral pharmaceutical composition in the form of a tablet consisting essentially of: (1) a tablet core consisting of a mixture of ingredients, said ingredients comprising: a) budesonide in an amount to treat intestinal inflammation; b) hydroxyalkyl cellulose; and c) stearic acid, or salt, alcohol or ester derivative thereof; and (2) a gastro-resistant film coating on said tablet core, said coating comprising at least one methacrylic acid polymer or methacrylic acid copolymer.

18. The controlled release oral pharmaceutical composition according to claim 17, wherein said mixture of ingredients in said tablet core further comprises microcrystalline cellulose, lactose, and colloidal silica.

19. A controlled release oral pharmaceutical composition in the form of a tablet consisting essentially of: (1) a tablet core consisting of a mixture of ingredients, said ingredients comprising: a) 9 mg of budesonide; b) hydroxypropyl cellulose; c) stearic acid, or salt, alcohol or ester derivative thereof; and (2) a gastro-resistant film coating on said tablet core, said coating comprising at least one methacrylic acid polymer or methacrylic acid copolymer.

20. The controlled release oral pharmaceutical composition according to claim 19, wherein said mixture of ingredients in said tablet core further comprises microcrystalline cellulose, lactose, and colloidal silica.

21. The controlled release oral pharmaceutical composition according to claim 19, wherein said gastro-resistant film coating further comprises triethyl citrate, talc and titanium dioxide.

22. A method for treating intestinal inflammatory disease comprising administering to a patient the controlled release oral pharmaceutical composition according to claim 1.

23. A method for treating intestinal inflammatory disease comprising administering to a patient the controlled release oral pharmaceutical composition according to claim 2.

24. A method for treating intestinal inflammatory disease comprising administering to a patient the controlled release oral pharmaceutical composition according to claim 6.

25. A method for treating intestinal inflammatory disease comprising administering to a patient the controlled release oral pharmaceutical composition according to claim 7.

26. A method for treating intestinal inflammatory disease comprising administering to a patient the controlled release oral pharmaceutical composition according to claim 8.

27. A method for treating intestinal inflammatory disease comprising administering to a patient the controlled release oral pharmaceutical composition according to claim 9.

28. A method for treating intestinal inflammatory disease comprising administering to a patient the controlled release oral pharmaceutical composition according to claim 13.

29. A method for treating intestinal inflammatory disease comprising administering to a patient the controlled release oral pharmaceutical composition according to claim 17.

30. A method for treating intestinal inflammatory disease comprising administering to a patient the controlled release oral pharmaceutical composition according to claim 19.

Description

DETAILED DISCLOSURE OF THE INVENTION

[0038] The compositions of the invention can be prepared by a method comprising the following steps:

[0039] 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.

[0040] 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.

[0041] 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 tableting. 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.

[0042] 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).

[0043] 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.

[0044] 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.

[0045] 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.

[0046] Alternatively, the order of formation of the inert and amphiphilic matrices can be reversed, incorporating the inert matrix inside the amphiphilic compounds.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] In case of taste-masking formulations, the use of polyalcohols such as xylitol, maltitol and mannitol as hydrophilic compounds can also be advantageous.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] Active ingredients which can conveniently be formulated according to the invention comprise: [0055] analgesics, such as acetaminophen, phenacetin, sodium salicylate; antitussives, such as dextromethorphan, codeine phosphate; [0056] bronchodilators, such as albuterol, procaterol; [0057] antipsychotics, such as haloperidol, chlorpromazine; [0058] antihypertensives and coronary-dilators, such as isosorbide mono- and dinitrate, captopril; [0059] selective 2 antagonists such as salbutamol, terbutaline, ephedrine, orciprenaline sulfate; [0060] calcium antagonists, such as nifedipine, nicardipine, diltiazem, verapamil; [0061] antiparkinson drugs, such as pergolide, carpidopa, levodopa; [0062] 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; [0063] antidiarrheals and intestinal antiinflammatories, such as loperamide, 5-aminosalicylic, olsalazine, sulfasalazine, budenoside; [0064] spasmolytics such as octylonium bromide; [0065] anxiolytics, such as chlordiazepoxide, oxazepam, medazepam, alprazolam, donazepam, lorazepan; [0066] oral antidiabetics, such as glipizide, metformin, phenformin, gilclazide, glibenclamide; [0067] cathartics, such as bisacodil, sodium picosulfate; [0068] antiepileptics, such as valproate, carbamazepine, phenyloin, gabapentin; [0069] antitumorals, such as flutamide, etoposide; [0070] 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; [0071] sodium fluoride.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] The following Examples illustrate the invention in greater detail.

Example 1

[0078] 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 tableted 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.

[0079] 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

[0080] 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.

[0081] 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.

[0082] 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 tableted to unitary weight of 250 mg/tablet.

Example 3

[0083] 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.

[0084] The final mixture is tableted to unitary weight of 1170 mg/tablet equivalent to 850 mg of active ingredient.

[0085] 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

[0086] 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.

[0087] 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.

[0088] The final mixture is tableted to unitary weight of 200 mg/tablet equivalent to 120 mg of active ingredient.

[0089] 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

[0090] 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 tableted to unitary weight of 1000 mg/tablet equivalent to 900 mg of active ingredient.

Example 6

[0091] 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.

[0092] 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.

[0093] The final mixture is tableted to unitary weight of 400 (200) mg/tablet equivalent to 50 (25) mg of carbidopa and 200 (100) mg di levodopa.

Example 7

[0094] 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.

[0095] 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.

[0096] 425 g of the resulting granulate are added with 60 g of hydroxypropyl methylcellulose, 5 g of policarbophil and 10 g of magnesium stearate.

[0097] The final mixture is tableted to unitary weight of 500 mg/tablet equivalent to 200 mg of active ingredient.

[0098] 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

[0099] 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.

[0100] The final mixture is tableted to unitary weight of 720 mg/tablet equivalent to 500 mg of active ingredient.

[0101] 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

[0102] 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 tableted to unitary weight of about 500 mg, having hardness suitable for being dissolved in the mouth and a pleasant taste.

Example 10

[0103] 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

[0104] Operating as described in example 9, but with the following components:

TABLE-US-00001 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

[0105] 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

[0106] Operating as described in example 9, but with the following components:

TABLE-US-00002 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 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

[0107] 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

[0108] Operating as described in example 9, but with the following components:

TABLE-US-00003 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 mg 0.3 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

[0109] 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

[0110] 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 tableted to about 500 mg tablets, having hardness suitable for being dissolved in the mouth and pleasant taste.

Example A

[0111] 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%.

[0112] 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.

[0113] After a final blending, tablets of around 300 mg of unitary weight are generated.

[0114] 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.

[0115] 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.sup.th hour sampling.

Example B

[0116]

TABLE-US-00004 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.

[0117] According to the present invention, coated tablets individually weighing about 220 mg are obtained.

[0118] The above described dissolution test is performed on the tablets of Example B.

[0119] The results are the following (indicated as average value):

TABLE-US-00005 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

[0120] 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.

[0121] The powder mixture is subjected to compression in a rotating tableting machine and the tablets so obtained are coated in a pan coat with a gastroresistant composition containing Eudragit, plasticizers, dyes and pigments.

[0122] According to the present example, coated tablets individually weighing around 105 mg are obtained.

[0123] The results of the above described dissolution test are the following (indicated as average value of at least six tablets):

TABLE-US-00006 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

[0124] 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 tableted to unitary weight of 250 mg/tablet.

[0125] 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).

[0126] The results of the dissolution test performed on these coated tablets are the following (indicated as average value of at least six tablets):

TABLE-US-00007 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%