CA2377299C - Mesalazine controlled release oral pharmaceutical compositions - Google Patents
Mesalazine controlled release oral pharmaceutical compositions Download PDFInfo
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- CA2377299C CA2377299C CA002377299A CA2377299A CA2377299C CA 2377299 C CA2377299 C CA 2377299C CA 002377299 A CA002377299 A CA 002377299A CA 2377299 A CA2377299 A CA 2377299A CA 2377299 C CA2377299 C CA 2377299C
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- active ingredient
- matrix
- weight
- lipophilic matrix
- lipophilic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/606—Salicylic acid; Derivatives thereof having amino groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
- A61K9/2846—Poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
Controlled-release oral pharmaceutical compositions containing as active ingredient 5-amino-salicylic acid, com-prising: a) an inner lipophilic matrix consisting of substances with melting point below 90 .degree.C in which the active ingredient is at least partly inglobated; b) an outer hydrophilic matrix in which the lipophilic matrix is dispersed; c) optionally other excipients.
Description
MESALAZINE CONTROLLED RELEASE ORAL PHARMACEUTICAL
COMPOSITIONS
The present invention relates to controlled release oral pharmaceutical compositions containing as active ingredient 5-amino salicylic acid, also named mesalazine.
BACKGROUND OF THE INVENTION
Mesalazine is used in the treatment of Chron's disease and ulcerative colitis thanks to its antiinflammatory activity on the intestinal mucuses. Controlled-release formulations of mesalazine are disclosed in WO 95/16451, EP
0 453 001, EP 0 377 477.
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.
COMPOSITIONS
The present invention relates to controlled release oral pharmaceutical compositions containing as active ingredient 5-amino salicylic acid, also named mesalazine.
BACKGROUND OF THE INVENTION
Mesalazine is used in the treatment of Chron's disease and ulcerative colitis thanks to its antiinflammatory activity on the intestinal mucuses. Controlled-release formulations of mesalazine are disclosed in WO 95/16451, EP
0 453 001, EP 0 377 477.
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 bv the enzymes of some biological compartment.
All the procedures listed above suffer, however, from drawbacks and imperfections.
Inert matrices, for example, generally entail 'tion-linear, but esponential, 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 US 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) , 531-533õ (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 mesalazine.
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 by the present invention, which also allows to prepare compositions characterized by a high content in active ingredient.
DISCLOSURE OF THE INVENTION
The invention provides controlled release oral pharmaceutical compositions containing 5-amino-salicylic acid as the active ingredient, comprising:
a) an inner lipophilic matrix consisting of substances with melting point below 90 C in which the active ingredient is at least partially inglobated;
b) an outer hydrophilic matrix in which the lipophilic matrix is dispersed;
c) optionally other excipients.
DETAILED DISCLOSURE OF THE INVENTION
The compositions of the invention can be obtained with a method comprising the following steps:
a) the active ingredient is first inglobated in a low melting 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 matrix granules containing the active ingredient particles.
b) the inert matrix granules are subsequently mixed together with one or more hydrophilic water-swellable excipients.
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 and/or hydrogenated fatty acids, salts, esters or amides thereof, fatty acids mono-, di- or triglycerids, waxes, ceramides, cholesterol derivatives or mixtures thereof having melting point within the range of 40 to 90 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 5 acid, thus remarkably increasing the hydrophilic matrix viscosity following penetration of the solvent front until contact with the lipophilic matrix granules dispersed inside.
The weight content of the active ingredient in the lipophilic matrix usually ranges from 5 to 95%.
The 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 pass 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 polymers or copolymers of acrylic or methacrylic acid, alkylvinyl polymers, hydroxyalkyl celluloses, carboxyalkyl celluloses, polysaccharides, dextrins, pectins, starches and derivatives, natural or synthetic gums, alginic acid.
The lipophilic matrix granules containing the active ingredient are mixed the with hydrophilic compounds cited above in a weight ratio typically ranging from 100:0.5 to 100:20 (lipophilic matrix: hydrophilic matrix). Part of mesalazine 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 matrix, hydrogel-forming compounds and, optionally, active ingredient non 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.
The tablets, capsules and/or minitablets obtainable according to the invention can optionally be subjected to known coating processes with a gastro-resistant film, consisting of for example polymers of methacrylic acids (Eudragit(R)) or cellulose derivatives, such as cellulose acetophthalate.
The compositions of the invention can contain a high percentage of active ingredient compared with the total composition weight up to 95%, an advantageous characteristic in the case of mesalazine which requires rather high unitary doses.
In terms of dissolution characteristics, the compositions of the invention provide a release profile of the active ingredient more homogeneous than the traditional systems. In fact, the immediate penetration of water inside the superficial layer of the hydrophilic matrix and the consequent swelling due to the distension of the polymeric chains of the hydrogels, gives rise to a high viscosity hydrated front which prevents the further penetration of water, 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 lipophilic granules, however induces the diffusional mechanism typical of these structures and therefore further slows down the dissolution profile of the active ingredient.
The following examples illustrate the invention in greater detail.
Example 1 770 g of 5-aminosalicylic acid are added in a kneader with 20 g of carnauba wax and 50 g of stearic acid with heating until homogeneous dispersion, then extruded into small granules while cold.
The inert matrix granules are loaded into a mixer in which 30 g of Carbopol 971P 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 649 mg/tablet or 510 mg/tablet to obtain 500 and 400 mg dosages, respectively.
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 dissolution profile of these tablets shows the release of an active ingredient amount lower than 30% within the first hour of permanence in simulated enteric juice, an amount lower than 60% at the fourth hour and an amount lower than 90% at the eighth hour, thus proving that the double matrix effectively controls dissolution.
Example 2 1000 g of 5-aminosalicylic acid are added in a kneader with 10 g of carnauba wax and 20 g of stearic acid with heating until homogeneous dispersion, then extruded into small granules while cold or directly granulated in a high rate mixer.
The resulting granules are loaded into a mixer in which 80 g of hydroxypropyl methylcellulose and 12 g of sodium starch glycolate are sequentially added. After a first mixing step, 11 g of silica colloidal and 11 g of magnesium stearate are added. The final mixture is homogenized, then tabletted to a unitary weight of 1144 mg/tablet.
The resulting tablets are then film coated with polymethacrylates or cellulose acetophthalate and plasticizers to provide gastric resistance.
The dissolution profile of these tablets after a lag time of permanence in the stomach and partly in the intestine provides the release of no more than 30% within the first hour, no more than 55% within two hours, no more than 70% within four hours, no more than 90% within eight hours.
Example 3 850 g of 5-aminosalicylic acid are added in granulator/kneader with 9 g of beeswax and 22 g of palmitic acid with heating, until homogeneous dispersion; then worked to a granulate in a high shear granulating device. The resulting granules are then loaded into a mixer which is added in succession with 45.5 g of hydroxypropyl methylcellulose, 45.5 g of microcrystalline cellulose, 20 g of sodium starch glycolate, 22 g of colloidal silica and 22 g of magnesium stearate. After homogenization, the final mixture is tabletted to a unitary weight of 975 mg/tablet.
The resulting tablets are then film coated with polymethacrylates or acetophthalate of cellulose and plasticizers to provide gastric resistance.
The dissolution profile of these tablets after a lag time of permanence in the stomach and partly in the intestine provides the release of no more than 30% within the first hour, no more than 50% within two hours, no more than 70% within four hours, no more than 90% within eight hours.
All the procedures listed above suffer, however, from drawbacks and imperfections.
Inert matrices, for example, generally entail 'tion-linear, but esponential, 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 US 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) , 531-533õ (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 mesalazine.
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 by the present invention, which also allows to prepare compositions characterized by a high content in active ingredient.
DISCLOSURE OF THE INVENTION
The invention provides controlled release oral pharmaceutical compositions containing 5-amino-salicylic acid as the active ingredient, comprising:
a) an inner lipophilic matrix consisting of substances with melting point below 90 C in which the active ingredient is at least partially inglobated;
b) an outer hydrophilic matrix in which the lipophilic matrix is dispersed;
c) optionally other excipients.
DETAILED DISCLOSURE OF THE INVENTION
The compositions of the invention can be obtained with a method comprising the following steps:
a) the active ingredient is first inglobated in a low melting 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 matrix granules containing the active ingredient particles.
b) the inert matrix granules are subsequently mixed together with one or more hydrophilic water-swellable excipients.
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 and/or hydrogenated fatty acids, salts, esters or amides thereof, fatty acids mono-, di- or triglycerids, waxes, ceramides, cholesterol derivatives or mixtures thereof having melting point within the range of 40 to 90 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 5 acid, thus remarkably increasing the hydrophilic matrix viscosity following penetration of the solvent front until contact with the lipophilic matrix granules dispersed inside.
The weight content of the active ingredient in the lipophilic matrix usually ranges from 5 to 95%.
The 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 pass 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 polymers or copolymers of acrylic or methacrylic acid, alkylvinyl polymers, hydroxyalkyl celluloses, carboxyalkyl celluloses, polysaccharides, dextrins, pectins, starches and derivatives, natural or synthetic gums, alginic acid.
The lipophilic matrix granules containing the active ingredient are mixed the with hydrophilic compounds cited above in a weight ratio typically ranging from 100:0.5 to 100:20 (lipophilic matrix: hydrophilic matrix). Part of mesalazine 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 matrix, hydrogel-forming compounds and, optionally, active ingredient non 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.
The tablets, capsules and/or minitablets obtainable according to the invention can optionally be subjected to known coating processes with a gastro-resistant film, consisting of for example polymers of methacrylic acids (Eudragit(R)) or cellulose derivatives, such as cellulose acetophthalate.
The compositions of the invention can contain a high percentage of active ingredient compared with the total composition weight up to 95%, an advantageous characteristic in the case of mesalazine which requires rather high unitary doses.
In terms of dissolution characteristics, the compositions of the invention provide a release profile of the active ingredient more homogeneous than the traditional systems. In fact, the immediate penetration of water inside the superficial layer of the hydrophilic matrix and the consequent swelling due to the distension of the polymeric chains of the hydrogels, gives rise to a high viscosity hydrated front which prevents the further penetration of water, 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 lipophilic granules, however induces the diffusional mechanism typical of these structures and therefore further slows down the dissolution profile of the active ingredient.
The following examples illustrate the invention in greater detail.
Example 1 770 g of 5-aminosalicylic acid are added in a kneader with 20 g of carnauba wax and 50 g of stearic acid with heating until homogeneous dispersion, then extruded into small granules while cold.
The inert matrix granules are loaded into a mixer in which 30 g of Carbopol 971P 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 649 mg/tablet or 510 mg/tablet to obtain 500 and 400 mg dosages, respectively.
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 dissolution profile of these tablets shows the release of an active ingredient amount lower than 30% within the first hour of permanence in simulated enteric juice, an amount lower than 60% at the fourth hour and an amount lower than 90% at the eighth hour, thus proving that the double matrix effectively controls dissolution.
Example 2 1000 g of 5-aminosalicylic acid are added in a kneader with 10 g of carnauba wax and 20 g of stearic acid with heating until homogeneous dispersion, then extruded into small granules while cold or directly granulated in a high rate mixer.
The resulting granules are loaded into a mixer in which 80 g of hydroxypropyl methylcellulose and 12 g of sodium starch glycolate are sequentially added. After a first mixing step, 11 g of silica colloidal and 11 g of magnesium stearate are added. The final mixture is homogenized, then tabletted to a unitary weight of 1144 mg/tablet.
The resulting tablets are then film coated with polymethacrylates or cellulose acetophthalate and plasticizers to provide gastric resistance.
The dissolution profile of these tablets after a lag time of permanence in the stomach and partly in the intestine provides the release of no more than 30% within the first hour, no more than 55% within two hours, no more than 70% within four hours, no more than 90% within eight hours.
Example 3 850 g of 5-aminosalicylic acid are added in granulator/kneader with 9 g of beeswax and 22 g of palmitic acid with heating, until homogeneous dispersion; then worked to a granulate in a high shear granulating device. The resulting granules are then loaded into a mixer which is added in succession with 45.5 g of hydroxypropyl methylcellulose, 45.5 g of microcrystalline cellulose, 20 g of sodium starch glycolate, 22 g of colloidal silica and 22 g of magnesium stearate. After homogenization, the final mixture is tabletted to a unitary weight of 975 mg/tablet.
The resulting tablets are then film coated with polymethacrylates or acetophthalate of cellulose and plasticizers to provide gastric resistance.
The dissolution profile of these tablets after a lag time of permanence in the stomach and partly in the intestine provides the release of no more than 30% within the first hour, no more than 50% within two hours, no more than 70% within four hours, no more than 90% within eight hours.
Example 4 1100 g of 5-aminosalicylic acid are added in granulator/kneader with 10 g of wax carnauba and 20 g of stearic acid.
10 g of polyacrylamide, 39.5 of microcrystalline cellulose and 22 g of colloidal silica are separately loaded into the homogenizer/granulator to obtain a homogeneous solid mixture, which is placed in the mixer where the active ingredient has been granulated and homogenized. 49.5 g of hydroxypropyl methylcellulose and 12 g of sodium alginate are thoroughly mixed, then added with 5 g of calcium carbonate, 34.5 g of microcrystalline cellulose and 11 g of magnesium stearate. The mixture is homogenized, then tabletted to a final unitary weight of 1194 mg/tablet. The resulting tablets are then film-coated with polymethacrylates or cellulose acetophthalate and plasticizers to provide gastric resistance.
The dissolution profile of these tablets after a lag time of permanence in the stomach and partly in the intestine provides the release of no more than 35% within the first hour, no more than 50% within two hours, no more than 70% within four hours, no more than 90% within eight hours.
Example 5 1200 g of 5-aminosalicylic acid are added in mixer with 10 g of carnauba wax and 20 g of stearic acid, with heating until homogeneous dispersion, then cold extruded into small granules or directly granulated in the high rate mixer.
The resulting granules are loaded into a mixer, then 70 g of hydroxypropyl methylcellulose and 20 g of sodium starch glycolate are sequentially added.
After a first mixing step, 80 g of sodium carbonate and 5 g of magnesium stearate are added. The final mixture is homogenized, then tabletted to unitary weight of 1375 mg/tablet.
The resulting tablets are then film-coated with polymethacrylates or cellulose acetophthalate and plasticizers to provide gastric resistance.
5 The dissolution profile of these tablets after a lag time of permanence in the stomach and partly in the intestine provides the release of no more than 30% within the first hour, no more than 50% within two hours, no more than 70% within four hours, no more than 90% within eight 10 hours.
The dissolution profile of these tablets after a lag time of permanence in the stomach and partly in the intestine provides the release of no more than 35% within the first hour, no more than 50% within two hours, no more than 70% within four hours, no more than 90% within eight hours.
Example 5 1200 g of 5-aminosalicylic acid are added in mixer with 10 g of carnauba wax and 20 g of stearic acid, with heating until homogeneous dispersion, then cold extruded into small granules or directly granulated in the high rate mixer.
The resulting granules are loaded into a mixer, then 70 g of hydroxypropyl methylcellulose and 20 g of sodium starch glycolate are sequentially added.
After a first mixing step, 80 g of sodium carbonate and 5 g of magnesium stearate are added. The final mixture is homogenized, then tabletted to unitary weight of 1375 mg/tablet.
The resulting tablets are then film-coated with polymethacrylates or cellulose acetophthalate and plasticizers to provide gastric resistance.
5 The dissolution profile of these tablets after a lag time of permanence in the stomach and partly in the intestine provides the release of no more than 30% within the first hour, no more than 50% within two hours, no more than 70% within four hours, no more than 90% within eight 10 hours.
Claims (24)
1. Controlled-release oral pharmaceutical compositions containing as active ingredient 5-amino-salicylic acid, comprising:
a) an inner lipophilic matrix consisting of substances with melting point below 90°C in which the active ingredient is at least partly inglobated;
b) an outer hydrophilic matrix in which the lipophilic matrix is dispersed;
c) optionally other excipients.
a) an inner lipophilic matrix consisting of substances with melting point below 90°C in which the active ingredient is at least partly inglobated;
b) an outer hydrophilic matrix in which the lipophilic matrix is dispersed;
c) optionally other excipients.
2. Compositions as claimed in claim 1, wherein the lipophilic matrix consists of compounds selected from unsaturated and/or hydrogenated fatty acids, salts, esters or amides thereof, fatty acid mono-, di- or triglycerids, waxes, ceramides, and cholesterol derivatives.
3. Compositions as claimed in claim 1 or 2, wherein 5-aminosalicylic acid is inglobated in the molten lipophilic matrix by kneading, extrusion and/or granulation.
4. Compositions as claimed in any one of claims 1 to 3, wherein the hydrophilic matrix consists of hydrogel-forming compounds.
5. Compositions as claimed in claim 4 wherein the hydrophilic matrix consists of compounds selected from polymers or copolymers of acrylic or methacrylic acid, alkylvinyl polymers, hydroxyalkyl celluloses, carboxyalkyl celluloses, polysaccharides, dextrins, pectins, starches and derivatives, alginic acid, and natural or synthetic gums.
6. Compositions as claimed in any one of claims 1 to 5 comprising a gastro-resistant outer coating.
7. Compositions as claimed in claim 6, wherein the gastro-resistant coating consists of methacrylic acid polymers or cellulose derivatives.
8. Compositions as claimed in any one of claims 1 to 7 in the form of tablets, capsules, or minitablets, wherein the active ingredient is completely contained inside the lipophilic matrix.
9. Compositions as claimed in any one of claims 1 to 7, in the form of tablets, capsules, or minitablets, wherein the active ingredient is dispersed both in the hydrophilic matrix and the lipophilic matrix.
10. Compositions as claimed in any one of claims 1 to 9, wherein the percentage of the active ingredient on the total composition weight ranges from 80 to 95%.
11. A process for the preparation of the compositions as defined in any one of claims 1 to 10, which comprises:
a) melt granulation of at least one portion of the active ingredient with the lipophilic excipients with melting point lower than 90°C;
b) mixing the granules from step a) with the hydrophilic excipients and subsequent tabletting or compression.
a) melt granulation of at least one portion of the active ingredient with the lipophilic excipients with melting point lower than 90°C;
b) mixing the granules from step a) with the hydrophilic excipients and subsequent tabletting or compression.
12. A controlled-release oral pharmaceutical composition containing as active ingredient 5-amino-salicylic acid, comprising:
a) an inner lipophilic matrix consisting of substances with melting point below 90°C in which the active ingredient is at least partly dispersed;
b) an outer hydrophilic matrix in which the lipophilic matrix and the active ingredient is dispersed;
wherein the composition releases up to 90% of the active agent within 8 hours of immersion in simulated enteric juice.
a) an inner lipophilic matrix consisting of substances with melting point below 90°C in which the active ingredient is at least partly dispersed;
b) an outer hydrophilic matrix in which the lipophilic matrix and the active ingredient is dispersed;
wherein the composition releases up to 90% of the active agent within 8 hours of immersion in simulated enteric juice.
13. A controlled-release oral pharmaceutical composition containing as active ingredient 5-amino-salicylic acid, comprising:
a) an inner lipophilic matrix consisting of substances with melting point below 90°C in which the active ingredient is at least partly dispersed;
b) an outer hydrophilic matrix in which the lipophilic matrix and the active ingredient is dispersed;
wherein the composition releases no more than 30% within the first hour of immersion in simulated enteric juice.
a) an inner lipophilic matrix consisting of substances with melting point below 90°C in which the active ingredient is at least partly dispersed;
b) an outer hydrophilic matrix in which the lipophilic matrix and the active ingredient is dispersed;
wherein the composition releases no more than 30% within the first hour of immersion in simulated enteric juice.
14. A composition according to claim 12 or 13 wherein the melting point of the lipophilic matrix is between 40°C and 90°C.
15. A composition according to claim 12 or 13 wherein the weight content of the active ingredient in the lipophilic matrix is between 5 to 95%.
16. A composition according to claim 12 or 13 wherein the weight ratio of lipophilic matrix to hydrophilic matrix is between 100:0.5 to 100:20.
17. A composition according to claim 12 or 13 wherein the hydrophilic matrix is a hydrogel-forming compound.
18. A composition according to claim 12 or 13, wherein the lipophilic matrix consists of compounds selected from unsaturated and/or hydrogenated fatty acids, salts, esters or amides thereof, fatty acid mono-, di- or triglycerids, waxes, ceramides, and cholesterol derivatives.
19. A composition according to claim 17 wherein the hydrogel-forming compound is selected from polymers or copolymers of acrylic or methacrylic acid, alkylvinyl polymers, hydroxyalkyl celluloses, carboxyalkyl celluloses, polysaccharides, dextrins, pectins, starches and derivatives, alginic acid, and natural or synthetic gums.
20. A composition according to any one of claims 12 to 19 further comprising a gastro-resistant outer coating.
21. A controlled-release oral pharmaceutical composition containing as active ingredient 5-amino-salicylic acid, comprising:
an inner lipophilic matrix consisting of substances with melting point below 90°C selected from unsaturated and/or hydrogenated fatty acids, salts, esters or amides thereof, fatty acid mono-, di- or triglycerids, waxes, ceramides, and cholesterol derivatives in which the active ingredient is at least partly dispersed;
an outer hydrophilic matrix selected from polymers or copolymers of acrylic or methacrylic acid, alkylvinyl polymers, hydroxyalkyl celluloses, carboxyalkyl celluloses, polysaccharides, dextrins, pectins, starches and derivatives, alginic acid, and natural or synthetic gums in which the lipophilic matrix and the active ingredient is dispersed; and a gastro-resistant outer coating;
wherein the weight content of the active ingredient in the lipophilic matrix is between 5 to 95%, the weight ratio of lipophilic matrix to hydrophilic matrix is between 100:0.5 to 100:20, and the composition releases up to 90% of the active agent within 8 hours of immersion in simulated enteric juice.
an inner lipophilic matrix consisting of substances with melting point below 90°C selected from unsaturated and/or hydrogenated fatty acids, salts, esters or amides thereof, fatty acid mono-, di- or triglycerids, waxes, ceramides, and cholesterol derivatives in which the active ingredient is at least partly dispersed;
an outer hydrophilic matrix selected from polymers or copolymers of acrylic or methacrylic acid, alkylvinyl polymers, hydroxyalkyl celluloses, carboxyalkyl celluloses, polysaccharides, dextrins, pectins, starches and derivatives, alginic acid, and natural or synthetic gums in which the lipophilic matrix and the active ingredient is dispersed; and a gastro-resistant outer coating;
wherein the weight content of the active ingredient in the lipophilic matrix is between 5 to 95%, the weight ratio of lipophilic matrix to hydrophilic matrix is between 100:0.5 to 100:20, and the composition releases up to 90% of the active agent within 8 hours of immersion in simulated enteric juice.
22. A controlled-release oral pharmaceutical composition containing as active ingredient 5-amino-salicylic acid, comprising:
an inner lipophilic matrix consisting of substances with melting point below 90°C selected from unsaturated and/or hydrogenated fatty acids, salts, esters or amides thereof, fatty acid mono-, di- or triglycerids, waxes, ceramides, and cholesterol derivatives in which the active ingredient is at least partly dispersed;
an outer hydrophilic matrix selected from polymers or copolymers of acrylic or methacrylic acid, alkylvinyl polymers, hydroxyalkyl celluloses, carboxyalkyl celluloses, polysaccharides, dextrins, pectins, starches and derivatives, alginic acid, and natural or synthetic gums in which the lipophilic matrix and the active ingredient is dispersed; and a gastro-resistant outer coating;
wherein the weight content of the active ingredient in the lipophilic matrix is between 5 to 95%, the weight ratio of lipophilic matrix to hydrophilic matrix is between 100:0.5 to 100:20, and the composition releases no more than 30%
within the first hour of immersion in simulated enteric juice.
an inner lipophilic matrix consisting of substances with melting point below 90°C selected from unsaturated and/or hydrogenated fatty acids, salts, esters or amides thereof, fatty acid mono-, di- or triglycerids, waxes, ceramides, and cholesterol derivatives in which the active ingredient is at least partly dispersed;
an outer hydrophilic matrix selected from polymers or copolymers of acrylic or methacrylic acid, alkylvinyl polymers, hydroxyalkyl celluloses, carboxyalkyl celluloses, polysaccharides, dextrins, pectins, starches and derivatives, alginic acid, and natural or synthetic gums in which the lipophilic matrix and the active ingredient is dispersed; and a gastro-resistant outer coating;
wherein the weight content of the active ingredient in the lipophilic matrix is between 5 to 95%, the weight ratio of lipophilic matrix to hydrophilic matrix is between 100:0.5 to 100:20, and the composition releases no more than 30%
within the first hour of immersion in simulated enteric juice.
23. A controlled-release oral pharmaceutical composition according to claim 12 or 13 containing 77% by weight of 5-aminosalicylic acid, 2% by weight of carnauba wax, 5% by weight of stearic acid, 3% by weight of Carbopol 971 P, 6.5% by weight of hydroxypropyl methylcellulose, 6% by weight of microcrystalline cellulose and 0.5% by weight of magnesium stearate.
24. A controlled-release oral pharmaceutical composition according to claim 12 or 13 containing 87.41% by weight of 5-aminosalicylic acid, 0.87% by weight of carnauba wax, 1.74% by weight of stearic acid, 7% by weight of hydroxypropyl methylcellulose, 1.05% by weight of sodium starch glycolate, 0.96% by weight of silica colloidal and 0.96% by weight of magnesium stearate.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT1999MI001316A ITMI991316A1 (en) | 1999-06-14 | 1999-06-14 | ORAL PHARMACEUTICAL COMPOSITIONS WITH MODIFIED RELEASE OF MESALAZINE |
| ITMI99A001316 | 1999-06-14 | ||
| PCT/EP2000/005321 WO2000076481A1 (en) | 1999-06-14 | 2000-06-08 | Mesalazine controlled release oral pharmaceutical compositions |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2377299A1 CA2377299A1 (en) | 2000-12-21 |
| CA2377299C true CA2377299C (en) | 2009-05-12 |
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|---|---|---|---|
| CA002377299A Expired - Lifetime CA2377299C (en) | 1999-06-14 | 2000-06-08 | Mesalazine controlled release oral pharmaceutical compositions |
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|---|---|
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| EP (2) | EP1198226B1 (en) |
| JP (2) | JP4727875B2 (en) |
| CN (2) | CN1217665C (en) |
| AT (2) | ATE235234T1 (en) |
| AU (1) | AU5077200A (en) |
| CA (1) | CA2377299C (en) |
| DE (2) | DE60027608T2 (en) |
| DK (2) | DK1198226T3 (en) |
| ES (2) | ES2262749T3 (en) |
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| IT (1) | ITMI991316A1 (en) |
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| NO (1) | NO329402B1 (en) |
| PT (2) | PT1287822E (en) |
| RU (1) | RU2245148C2 (en) |
| TR (1) | TR200200561T2 (en) |
| WO (1) | WO2000076481A1 (en) |
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1999
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-
2000
- 2000-06-08 JP JP2001502815A patent/JP4727875B2/en not_active Expired - Lifetime
- 2000-06-08 MX MXPA01012888A patent/MXPA01012888A/en unknown
- 2000-06-08 DE DE60027608T patent/DE60027608T2/en not_active Expired - Lifetime
- 2000-06-08 CN CN008088896A patent/CN1217665C/en not_active Expired - Lifetime
- 2000-06-08 AT AT00935194T patent/ATE235234T1/en active
- 2000-06-08 TR TR2002/00561T patent/TR200200561T2/en unknown
- 2000-06-08 ES ES02026576T patent/ES2262749T3/en not_active Expired - Lifetime
- 2000-06-08 ES ES00935194T patent/ES2194732T3/en not_active Expired - Lifetime
- 2000-06-08 DE DE60001835T patent/DE60001835T2/en not_active Expired - Lifetime
- 2000-06-08 DK DK00935194T patent/DK1198226T3/en active
- 2000-06-08 PT PT02026576T patent/PT1287822E/en unknown
- 2000-06-08 CA CA002377299A patent/CA2377299C/en not_active Expired - Lifetime
- 2000-06-08 AU AU50772/00A patent/AU5077200A/en not_active Abandoned
- 2000-06-08 RU RU2002100365/15A patent/RU2245148C2/en active
- 2000-06-08 DK DK02026576T patent/DK1287822T3/en active
- 2000-06-08 WO PCT/EP2000/005321 patent/WO2000076481A1/en active Search and Examination
- 2000-06-08 PT PT00935194T patent/PT1198226E/en unknown
- 2000-06-08 EP EP00935194A patent/EP1198226B1/en not_active Expired - Lifetime
- 2000-06-08 US US10/009,491 patent/US6773720B1/en not_active Expired - Lifetime
- 2000-06-08 AT AT02026576T patent/ATE324104T1/en active
- 2000-06-08 EP EP02026576A patent/EP1287822B1/en not_active Expired - Lifetime
- 2000-06-08 CN CNB2005100833798A patent/CN100448448C/en not_active Expired - Lifetime
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2001
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2002
- 2002-10-30 HK HK02107880.6A patent/HK1046247B/en unknown
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2006
- 2006-05-18 HK HK06105756.7A patent/HK1085669A1/en unknown
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2009
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| Publication | Publication Date | Title |
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| CA2377299C (en) | Mesalazine controlled release oral pharmaceutical compositions | |
| US10143698B2 (en) | Controlled release and taste masking oral pharmaceutical compositions |
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