The present invention relates to controlled release oral pharmaceutical compositions containing as active ingredient 5-amino salicylic acid, also named mesalazine.
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 by the enzymes of some biological compartment.
All the procedures listed above suffer, however, from drawbacks and imperfections.
Inert matrices, for example, generally entail non-linear, but 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 xe2x80x9csite-releasexe2x80x9d, but they involve the problem of finding the suitable enzyme or reactive to degradation. Furthermore, they frequently release in situ metabolites that are not wholly toxicologically inert.
A number of formulations based on inert lipophilic matrices have been described: Drug Dev. Ind. Pharm. 13 (6), 1001-1022, (1987) discloses a process making use of varying amounts of colloidal silica as a porization element for a lipophilic inert matrix in which the active ingredient is incorporated.
The same notion of canalization of an inert matrix is described in U.S. Pat. No. 4,608,248 in which a small amount of a hydrophilic polymer is mixed with the substances forming an inert matrix, in a non sequential compenetration of different matrix materials.
EP 375,063 discloses a technique for the preparation of multiparticulate granules for the controlled-release of the active ingredient which comprises co-dissolution of polymers or suitable substances to form a inert matrix with the active ingredient and the subsequent deposition of said solution on an inert carrier which acts as the core of the device. Alternatively, the inert carrier is kneaded with the solution containing the inert polymer and the active ingredient, then the organic solvent used for the their dissolution is evaporated off to obtain a solid residue. The resulting structure is a xe2x80x9creservoirxe2x80x9d, i.e. is not macroscopically homogeneous along all the symmetry axis of the final form.
The same xe2x80x9creservoirxe2x80x9d structure is also described in Chem. Pharm. Bull. 46 (3), 531-533, (1998) which improves the application through an annealing technique of the inert polymer layer which is deposited on the surface of the pellets.
To the xe2x80x9creservoirxe2x80x9d 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 xe2x80x9creservoirxe2x80x9d 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.
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 90xc2x0 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.