CONTROLLED-RELEASE PHARMACEUTICAL FORMULATIONS FOR TREATMENT OF INTESTINAL INFECTIONS

Abstract

Disclosed are solid oral controlled-release pharmaceutical compositions of antibiotics/ antibacterials comprising a core consisting of a complex monolithic matrix comprising at least one low/medium viscosity hydroxypropyl methylcellulose, at least one medium/high viscosity hydroxypropyl methylcellulose, one or more methacrylic polymers or copolymers and/or cellulose acetate phthalate and/or hydroxypropyl methylcellulose acetate succinate or shellac, and an outer coating of said core consisting of a layer comprising ethylcellulose, or of a gastroresistant layer or of a layer comprising ethylcellulose coated in turn with gastroresistant polymers. The compositions of the invention enable the frequency of administration to be reduced, and the release of the medicament in particular sites of the gastrointestinal tract to be controlled.

Claims

1. A controlled-release solid oral pharmaceutical composition comprising an antibacterial/antibiotic for the treatment of intestinal infections in a core and an outer coating of said core, wherein : a) the core comprises: (i) a monolithic matrix containing the antibacterial/antibiotic, at least one hydroxypropyl methylcellulose having a viscosity ranging between 3 and 5000 mPa.s 2% in H2O at 20° C., at least one hydroxypropyl methylcellulose having a viscosity ranging between 13500 and 280000 mPa.s 2% in H2O at 20° C., at least one or two methacrylic polymers/copolymers and/or shellac, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, or (ii) a monolithic matrix as defined above adjacent to an immediate-release layer comprising the same antibacterial/antibiotic as contained in the monolithic matrix; b) the outer coating comprises a layer comprising ethylcellulose or a gastroresistant layer or a layer comprising ethylcellulose which in turn is coated with gastroresistant polymers.

2. The composition as claimed in claim 1, wherein the core comprises a monolithic matrix as defined in claim 1, point (i).

3. The composition as claimed in claim 1, wherein the core comprises a monolithic matrix as defined in claim 1, wherein said monolithic matrix is adjacent to an immediate-release layer, and wherein said monolithic matrix and said immediate-release layer comprise the antibacterial agent .

4. The composition as claimed in claim 1, wherein the coating comprises a layer comprising ethylcellulose.

5. The composition as claimed in claim 1, wherein the coating comprises a layer comprising ethylcellulose coated with gastroresistant polymers.

6. The composition as claimed in claim 1, wherein the coating comporises a gastroresistant layer.

7. The composition as claimed in claim 1, wherein the methacrylic acid polymer or copolymer is selected from the group consisting of pH-independent methacrylic ester copolymers, pH-independent ammonium alkyl methacrylate copolymers; amino alkyl methacrylate copolymers soluble at pH equal or less than 5.0, methacrylic acid copolymers soluble at pH equal or above 5.5, methacrylic acid copolymers soluble at pH 6.0-7.0 and pH-dependent methacrylic acid copolymers soluble at pH equal or above 7.0.

8. The composition as claimed in claim 1, wherein the monolithic matrix comprises shellac.

9. The composition as claimed in claim 1, wherein the gastroresistant coating comprises pH-dependent methacrylic acid copolymers soluble at pH equal or above 5.5; pH-dependent methacrylic acid copolymers soluble at pH 6.0-7.0; pH-dependent methacrylic acid copolymers soluble at pH equal or above 7.0; shellac; cellulose acetate phthalate; cellulose succinate.

10. The composition as claimed in claim 1, wherein the hydroxypropyl methylcellulose having a viscosity ranging between 3 and 5000 mPa.s 2% in H2O at 20° C. constitutes 1 to 20% of the weight of the core, the hydroxypropyl methylcellulose having a viscosity ranging between 13500 and 280,000 mPa.s 2% in H2O at 20° C. constitutes 1 to 20% of the weight of the matrix, and the methacrylic polymer/copolymer constitutes 0.1 to 2% of the weight of the core.

11. The composition as claimed in claim 1, wherein ethylcellulose is present in an amount of 1 to 20% of the weight of the core.

12. The composition as claimed in claim 1, wherein the antibacterial/antibiotic for the treatment of intestinal infections is selected from the group consisting of rifaximin, rifampicin, rifamycin SV and salts thereof, oral beta lactam antibiotics, macrolides, quinolones and metronidazole.

Description

BRIEF DESCRIPTION OF FIGURES

[0138] FIG. 1 a-d: dissolution profiles of the formulations according to WO 2015/087258.

[0139] FIG. 2 a-d: dissolution profiles of the formulations comprising pH-dependent Eudragit in the matrix containing HPMC.

[0140] FIG. 3 a-d: dissolution profiles of the formulations comprising shellac in the matrix containing HPMC.

[0141] FIG. 4 a-d: dissolution profiles of the formulations comprising cellulose acetate phthalate in the matrix containing HPMC.

[0142] FIG. 5 a-d: dissolution profiles of the formulations comprising pH-independent Eudragit in the matrix containing HPMC.

RESULTS

[0143] The results demonstrate that the addition of polymethacrylates, shellac or cellulose acetate phthalate to the matrix containing the two HPMCs with different viscosities gives rise to very similar dissolution profiles (%RSD ≤ 3% for each control point) and independence from the pH of the dissolution bath (pH 1.2, 5.5, 7.2), which are not possessed by the menthol formulations of the prior art without the complex matrix. Very similar results were obtained with the formulations of Examples 1-29.