HK1085669B - Mesalazine controlled release oral pharmaceutical compositions - Google Patents

Description

Mesalazine controlled release oral pharmaceutical composition

The application case is a divisional application, the parent application number is 00808889.6 (International application number is PCT/EP00/05321), the application date is 6 months and 8 days in 2000, and the invention is named as a mesalazine controlled-release oral pharmaceutical composition.

The present invention relates to controlled release oral pharmaceutical compositions containing 5-aminosalicylic acid (also known as mesalazine) as active ingredient.

Background

Mesalazine is used in the treatment of crohn's disease and ulcerative colitis due to its anti-inflammatory activity on the intestinal mucosa. Controlled release formulations of mesalazine are disclosed in WO95/16451, EP 0453001, EP 0377477.

Sustained, controlled, delayed or at least modified release dosage forms can be prepared according to different known processes:

1. the use of an inert matrix, wherein the main component of the matrix structure has a certain resistance to solvent penetration due to its poor affinity for aqueous liquids; such properties are known to be lipophilic.

2. The use of a hydrophilic matrix, wherein the main component of the matrix structure has a higher resistance to solvent advance, significantly increases the viscosity inside the hydrated layer due to the presence of strongly hydrophilic groups in its chains, mainly in the branches.

3. The use of a bioerodible matrix that is capable of being degraded by enzymes within some biological lumens.

However, all of the above operations are subject to drawbacks and imperfections.

Inert matrix: for example, it is common to impart a non-linear, but rather an exponential (esponential) release of the active ingredient.

Hydrophilic matrix: has a linear behavior until some fraction of the active ingredient has been released, after which they deviate significantly from the linear release.

Bioerodible matrix: are desirable to perform so-called "in situ release", but they involve the problem of finding suitable enzymes or are otherwise reactive towards degradation. Furthermore, they often release metabolites in situ (in situ), which are not completely toxicologically inert.

A large number of formulations based on inert lipophilic bases have been described: drug dev.ind.pharm 13(6), 1001-1022 (1987) disclose the use of varying amounts of colloidal silica as a microporous component of a lipophilic inert matrix into which an active ingredient is incorporated.

US 4,608,248 describes the same inert matrix tubing concept, wherein a small amount of hydrophilic polymer is mixed with each substance in a discontinuous co-infiltration (formation) of different matrix materials to form an inert matrix.

EP 375,063 discloses a process for the preparation of multiparticulate granules for controlled release of an active ingredient, which comprises co-dissolving a polymer or suitable material with the active ingredient to form an inert matrix, and subsequently depositing the solution on an inert carrier which acts as a drug core. Alternatively, the inert carrier is kneaded with a solution containing the inert polymer and the active ingredient, and then the organic solvent used for its dissolution is removed by evaporation to give a solid residue. The resulting structure is a "drug depot", i.e., not macroscopically uniform along all axes of symmetry of the final shape.

The same "drug library" structure is also described in chem. pharm. ball. 46(3), 531-533, which improves the utility by annealing a layer of inert polymer deposited on the surface of the pellets.

The product obtained according to the process described in WO 93/00889 also belongs to the "drug depot" structure, in which a process for the preparation of pellets in a hydrophilic matrix is disclosed, comprising:

-dissolving the active ingredient with a gastro-resistant hydrophilic polymer in an organic solvent;

-drying the suspension;

subsequent kneading and formulation of the pellets in a hydrophilic or lipophilic matrix, with no difference in effectiveness between the two types of application.

EP 0453001 discloses multiparticulates with a "depot" structure inserted in a hydrophilic matrix. The basic multiparticulates employ two coating films to reduce the release rate of the active ingredient, the purpose of the pH-dependent film being a protective effect on the stomach and the purpose of the pH-independent methacrylic film being to slow the penetration of aqueous fluids.

WO95/16451 discloses a composition formed solely of a hydrophilic matrix coated with a gastro-resistant film for controlling the dissolution rate of mesalazine.

In the preparation of sustained, controlled release dosage forms of drugs that are normally active against gastrointestinal tract, it is important to ensure controlled release from the first stage after administration, when the inert matrix has a maximum release rate over logarithmic phase, i.e. a higher deviation from linear release.

The present invention has achieved the stated object and makes it possible to prepare compositions which are characterized by a high content of active ingredient.

Disclosure of the invention

The present invention provides a controlled release oral pharmaceutical composition containing 5-aminosalicylic acid as an active ingredient comprising:

a) an inner lipophilic matrix consisting of a substance having a melting point below 90 ℃, wherein at least part of the active ingredient is entrapped (inglobate);

b) an outer hydrophilic matrix in which the lipophilic matrix is dispersed;

c) optionally other excipients.

Detailed description of the invention

The compositions of the invention can be obtained by a process comprising the following steps:

a) the active ingredient is first incorporated into a low melting excipient or mixture of excipients, while heating to soften and/or melt the excipient itself, thereby incorporating the active ingredient by simple dispersion.

After cooling at room temperature, the inert matrix is shaped and its volume can be reduced, resulting in matrix granules containing active ingredient particles.

b) The inert matrix particles are then mixed together with one or more hydrophilic water-swellable excipients.

In this way, when the tablet comes into contact with biological fluids, a high viscosity swelling layer is formed, which coordinates the solvent molecules and acts as a barrier to the penetration of the aqueous fluid itself inside the new structure. The barrier antagonizes the initial "burst effect" caused by the dissolution of the drug contained within the inert matrix, which also occurs within the hydrophilic matrix.

The lipophilic matrix consists of a material selected from the group consisting of: unsaturated and/or hydrogenated fatty acids, salts, esters or amides thereof, fatty acid mono-, di-or triglycerides, waxes, ceramides, cholesterol derivatives or mixtures thereof, having a melting point in the range of 40 to 90 ℃.

If desired, the fatty acid calcium salt may be incorporated into the lipophilic matrix and subsequently dispersed in the hydrophilic matrix made of alginic acid, thus significantly increasing the viscosity of the hydrophilic matrix after the previous solvent infiltration until contact with the lipophilic matrix particles dispersed therein.

The content by weight of active ingredient in the lipophilic matrix is generally between 5 and 95%.

The inert lipophilic matrix may be reduced to granules by extrusion and/or granulation processes or any other known process that preserves the uniform dispersibility and matrix structure of the starting mixture.

The hydrophilic matrix consists of an excipient known as a hydrogel, that is to say a substance which undergoes a so-called "molecular relaxation" from the dry state to the hydrated state, that is to say a significant increase in mass and weight following the concerted action of the polar groups present in the polymeric chains of the excipient itself with a large number of water molecules.

Examples of hydrogels which can be used according to the invention are compounds selected from the following: polymers or copolymers of acrylic or methacrylic acid, alkyl vinyl polymers, hydroxyalkyl celluloses, carboxyalkyl celluloses, polysaccharides, dextrins, pectins, starches and derivatives, natural or synthetic gums, alginic acid.

Lipophilic matrix particles containing the active ingredient are mixed with the above hydrophilic compound, usually in a weight ratio of 100: 0.5 to 100: 20 (lipophilic matrix: hydrophilic matrix). A portion of mesalazine may optionally be mixed with hydrophilic substances, resulting in compositions, preferably tablets, capsules and/or mini-tablets, in which the active ingredient is dispersed both in a lipophilic matrix and in a hydrophilic matrix.

The mixture of lipophilic matrix, hydrogel-forming compound and optionally active ingredient not entrapped in the lipophilic matrix is compressed to give a macroscopically homogeneous overall structure, i.e. a matrix containing a dispersion of lipophilic particles in a hydrophilic matrix.

The tablets, capsules and/or mini-tablets obtainable according to the invention may optionally be subjected to known coating processes with gastro-resistant films, for example made of methacrylic acid polymersOr cellulose derivatives, e.g. cellulose acetylphthalateAnd (3) acid ester composition.

The compositions of the invention may contain up to 95% of active ingredient, relative to the weight of the total composition, which is advantageous for mesalazine, since the latter requires a rather high unit dose.

The compositions of the present invention provide more uniform release of the active ingredient than conventional systems in terms of dissolution profile. In fact, the immediate penetration of water inside the surface layer of the hydrophilic matrix and the subsequent swelling due to the swelling of the hydrogel polymeric chains, causes an increase in the viscosity of the previous hydration, which prevents the further penetration of water, linearly slowing down the dissolution process to a given point, which may be located at about half the thickness, until the further penetration of water will lead to the disintegration of the hydrophilic layer and the release of the content, whereas the content consisting of lipophilic particles induces these structurally characteristic diffusion mechanisms, thus further slowing down the dissolution of the active ingredient.

The following examples illustrate the invention in more detail.

Example 1

770g of 5-aminosalicylic acid, 20g of carnauba wax and 50g of stearic acid are added in a kneader, heated until uniformly dispersed, then extruded into small granules and cooled.

The inert matrix granules are charged into a mixer to which 30g of Carbopol are added in sequenceAnd 65g of hydroxypropylmethylcellulose.

After the first mixing step to disperse the powder homogeneously, 60g microcrystalline cellulose and 5g magnesium stearate are added. After mixing, the final blend was compressed into a single weight of 649 mg/tablet or 510 mg/tablet, resulting in 500 and 400mg doses, respectively.

The resulting tablets are film coated with cellulose acetyl phthalate or polymethacrylate and a plasticizer to provide gastric tolerance and prevent premature release of the product in the stomach.

Dissolution of these tablets showed that the release of active ingredient in simulated intestinal fluid was less than 30% in the first hour, less than 60% in the fourth hour, and less than 90% in the eighth hour, thus confirming that the dual matrix is effective in controlling dissolution.

Example 2

1000g of 5-aminosalicylic acid, 10g of carnauba wax and 20g of stearic acid are added in a kneader, heated until uniform dispersion, then extruded into small granules, cooled or directly granulated in a high-speed mixer.

The resulting granules were charged into a mixer, to which 80g of hydroxypropylmethylcellulose and 12g of sodium starch glycolate were added in this order. After the first mixing step, 11g of colloidal silicon dioxide and 11g of magnesium stearate are added. The final mixture was homogenized and then compressed into a single weight of 1144 mg/tablet.

The resulting tablets are then film coated with polymethacrylate or cellulose acetyl phthalate and a plasticizer to provide gastric tolerance.

The dissolution of these tablets in the stomach and partly in the intestine after a certain time period provides the following release: not more than 30% in the first hour, not more than 55% in the second hour, not more than 70% in the fourth hour, and not more than 90% in the eighth hour.

Example 3

850g of 5-aminosalicylic acid, 9g of beeswax and 22g of palmitic acid are added into a granulating/kneading machine and heated until uniformly dispersed; and then processed into granules in a high shear granulation apparatus. The resulting granules were then charged to a mixer and 45.5g of hydroxypropyl methylcellulose, 45.5g of microcrystalline cellulose, 20g of sodium starch glycolate, 22g of colloidal silicon dioxide and 22g of magnesium stearate were added in succession. After homogenization, the final mixture was compressed into a single weight of 975 mg/tablet.

The resulting tablets are then film coated with polymethacrylate or cellulose acetyl phthalate and a plasticizer to provide gastric tolerance.

The dissolution of these tablets in the stomach and partly in the intestine after a certain time period provides the following release: not more than 30% in the first hour, not more than 50% in the second hour, not more than 70% in the fourth hour, and not more than 90% in the eighth hour.

Example 4

1100g of 5-aminosalicylic acid, 10g of carnauba wax and 20g of stearic acid were added in a granulator/kneader.

The homogenization/granulator was charged with 10g of polyacrylamide, 39.5g of microcrystalline cellulose and 22g of colloidal silicon dioxide, respectively, to obtain a homogeneous solid mixture which was placed in a mixer in which the active ingredient had been granulated and homogenized. 49.5g of hydroxypropylmethylcellulose was thoroughly mixed with 12g of sodium alginate, and then 5g of calcium carbonate, 34.5g of microcrystalline cellulose and 11g of magnesium stearate were added. The mixture was homogenized and then compressed to a final single weight of 1194 mg/tablet. The resulting tablets are then film coated with polymethacrylate or cellulose acetyl phthalate and a plasticizer to provide gastric tolerance.

The dissolution of these tablets in the stomach and partly in the intestine after a certain time period provides the following release: not more than 35% in the first hour, not more than 50% in the second hour, not more than 70% in the fourth hour, and not more than 90% in the eighth hour.

Example 5

1200g of 5-aminosalicylic acid, 10g of carnauba wax and 20g of stearic acid are added in a mixer, heated until uniformly dispersed, and then cold extruded into small granules or directly granulated in a high speed mixer.

The resulting granules were charged to a mixer and then 70g of hydroxypropylmethylcellulose and 20g of sodium starch glycolate were added in this order.

After the first mixing step, 80g of sodium carbonate and 5g of magnesium stearate are added. The final mixture was homogenized and then compressed into a single weight of 1375 mg/tablet.

The resulting tablets are then film coated with polymethacrylate or cellulose acetyl phthalate and a plasticizer to provide gastric tolerance.

The dissolution of these tablets in the stomach and partly in the intestine after a certain time period provides the following release: not more than 30% in the first hour, not more than 50% in the second hour, not more than 70% in the fourth hour, and not more than 90% in the eighth hour.

Claims (9)

1. A controlled release oral pharmaceutical composition containing 5-aminosalicylic acid as active ingredient comprising:

a) an internal lipophilic matrix consisting of substances with a melting point below 90 ℃, wherein the active ingredient is at least partially encapsulated, wherein the lipophilic matrix consists of a compound selected from the group consisting of: unsaturated and/or hydrogenated fatty acids, salts, esters or amides thereof, waxes, ceramides;

b) an external hydrophilic matrix in which the lipophilic matrix is dispersed, the hydrophilic matrix consisting of a compound selected from the group consisting of: polymers of acrylic or methacrylic acid, alkyl vinyl polymers, hydroxyalkyl celluloses, carboxyalkyl celluloses, polysaccharides, dextrins, pectins, alginic acid, natural or synthetic gums;

wherein the weight ratio of lipophilic to hydrophilic matrix is from 100: 0.05 to 100: 20, and wherein the composition releases up to 90% of the active agent within 8 hours of immersion in simulated intestinal fluid.

2. The composition of claim 1, wherein the lipophilic matrix has a melting point of 40 ℃ to 90 ℃.

3. The composition of claim 1, wherein the active ingredient is present in the lipophilic matrix in an amount of 5-95% by weight.

4. The composition of claim 1, wherein the hydrophilic matrix is a hydrogel-forming compound.

5. The composition of any one of claims 1-4, further comprising a gastro-resistant outer coating.

6. The composition according to claim 1, further comprising a gastro-resistant outer coating, wherein the weight content of the active ingredient in the lipophilic matrix is 5-95% and the weight ratio of lipophilic matrix to hydrophilic matrix is between 100: 0.05 and 100: 20.

7. The composition of claim 1, wherein the polymer of acrylic acid or methacrylic acid is a copolymer.

8. The composition of claim 1, wherein said polysaccharide is starch.

9. The composition of claim 1 wherein said fatty acid ester is a fatty acid mono-, di-or triglyceride.