PROCESS FOR PRODUCING AN ORALLY ADMINISTERED PHARMACEUTICAL COMPOSITION WITH COLONIC DELIVERY

Abstract

The present invention relates to a process for preparing an orally administered pharmaceutical composition with colonic delivery, comprising at least one core and a coating layer, making it possible to obtain a pharmaceutical composition which exhibits uniform and reproducible dissolution and therefore likewise uniform and reproducible release of the active ingredient with low coefficients of variation, said process being characterized in that it comprises the following steps: a) Spraying onto a neutral support an aqueous suspension comprising at least one anionic (meth)acrylate copolymer that is soluble at a pH greater than 5.5 and at least one active ingredient intended to be delivered in the colon; or a′) Spraying onto a neutral support an aqueous suspension comprising at least one anionic (meth)acrylate copolymer that is soluble at a pH greater than 5.5 then b′) Dusting at least one active ingredient intended to be delivered in the colon onto the microgranules obtained after step a′); c′) carrying out steps a′) and b′) alternately until the desired content of active ingredient has been obtained and d) Coating the microgranules obtained after step a) or c′) by spraying a composition comprising at least one anionic (meth)acrylate copolymer that is soluble at a pH greater than 6, an anionic (meth)acrylate copolymer that is soluble at a pH greater than 7 and an anionic (meth)acrylate copolymer that is insoluble in an aqueous medium.

Claims

1. A process for preparing an orally administered pharmaceutical composition with colonic delivery comprising at least one core and a coating layer, characterized in that it comprises the following steps: a) Spraying onto a neutral support an aqueous suspension comprising at least one anionic (meth)acrylate copolymer that is soluble at a pH greater than 5.5 and at least one active ingredient intended to be delivered in the colon; or a′) Spraying onto a neutral support an aqueous suspension comprising at least one anionic (meth)acrylate copolymer that is soluble at a pH greater than 5.5 then b′) Dusting at least one active ingredient intended to be delivered in the colon onto the microgranules obtained after step a′); c′) carrying out steps a′) and b′) alternately until the desired content of active ingredient has been obtained and d) Coating the microgranules obtained after step a) or c′) by spraying a composition comprising at least one anionic (meth)acrylate copolymer that is soluble at a pH greater than 6, an anionic (meth)acrylate copolymer that is soluble at a pH greater than 7 and an anionic (meth)acrylate copolymer that is insoluble in an aqueous medium.

2. The process according to claim 1, characterized in that said anionic (meth)acrylate copolymer that is soluble at a pH greater than 5.5 of step a) or a′) is a methacrylic acid-ethyl acrylate (1:1) copolymer.

3. The process according to claim 1 or 2, characterized in that among the copolymers of step d) said anionic (meth)acrylate copolymer that is soluble at a pH greater than 6 is a methacrylic acid-methyl methacrylate (1:1) copolymer.

4. The process according to any one of claims 1 to 3, characterized in that among the copolymers of step d) said anionic (meth)acrylate copolymer that is soluble at a pH greater than 7 is a methacrylic acid-methyl methacrylate (1:2) copolymer.

5. The process according to any one of claims 1 to 4, characterized in that among the copolymers of step d) said copolymer that is insoluble in an aqueous medium is an ethyl acrylate-methyl methacrylate-methacrylic acid ester with a quaternary ammonium group copolymer (1:2:0.2), advantageously an ethyl acrylate-methyl methacrylate-methacrylic acid ester with a trimethylammonioethyl methacrylate chloride group copolymer (1:2:0.2).

6. The process according to any one of claims 1 to 5, characterized in that the composition sprayed in step d) has a ratio anionic (meth)acrylate copolymer that is soluble at a pH greater than 6: anionic (meth)acrylate copolymer that is soluble at a pH greater than 7: anionic (meth)acrylate copolymer that is insoluble in an aqueous medium of 4:3:3.

7. The process according to any one of claims 1 to 6, characterized in that said active ingredient intended to be delivered in the colon is selected from sulfasalazine, 5-aminosalicylic acid (mesalazine), budesonide, rifamycin, acamprosate or linaclotide.

8. The process according to any one of claims 1 to 7, characterized in that the orally administered pharmaceutical composition with colonic delivery obtained at the end of the process is in the form of microgranules.

9. The process according to any one of claims 1 to 8, characterized in that the dusting of the active ingredient in step b′) is carried out by manual or mechanical dusting in at least one conventional turbine.

Description

FIGURES

[0050] FIG. 1: Describes the results of Example 3.

[0051] The following examples are intended to illustrate the present invention in a non-limiting manner.

EXAMPLES

Example 1: Preparation of a Pharmaceutical Composition According to the Invention by Dusting in a Conventional Turbine

[0052] Composition A described in Table 2 was prepared according to the following protocol:

[0053] 1) Assembling Mesalazine Microgranules: [0054] Introducing neutral supports in the turbine (Mass temperature; 15-35° C.); [0055] Spraying the binding suspension comprising Eudragit L30D and triethylcitrate; [0056] Dusting the active ingredient by manual or mechanical dusting; [0057] Drying; and [0058] Sieving on a vibrating sieve of the SODEVA type with grids from 500 to 1000 μm.

[0059] At the end of assembly, the microgranules have a D50 comprised between 500 and 700 μm and a D90 comprised between 700 and 950 μm.

[0060] 2) Coating

[0061] Following the assembly step, the microgranules are coated by spraying the coating suspension on the active microgranules.

[0062] Composition of the coating suspension for a weight gain of 10% in polymer for a spray on 1000.0 g of active grains of Mesalazine: [0063] Eudragit 5100: 30.0 g [0064] Eudragit RL100: 30.0 g [0065] Eudragit L100: 40.0 g [0066] TEC (triethylcitrate): 15.0 g [0067] Talc: 40.0 g [0068] Ethanol: 1395.0 g

[0069] The coating suspension is prepared according to the following protocol: [0070] Weigh the Ethanol in a container of adapted capacity and stir it with a stirrer (IKA type) equipped with a propeller. [0071] Incorporate Eudragit® 5100 with stirring and wait for complete dissolution. [0072] Incorporate Eudragit® L100 with stirring and wait for complete dissolution. [0073] Incorporate Eudragit® RL100 with stirring and wait for complete dissolution. [0074] Add the Triethyl Citrate with stirring and maintain stirring for 1 hour. [0075] Incorporate the Talc while stirring and wait 30 minutes before starting the spraying. [0076] Spray the coating suspension onto the microgranules while maintaining agitation throughout the spraying, as described below.

[0077] The coating is carried out in a Glatt GPCG1 type fluidized air bed in Wurster mode equipped with a Schlick gun (1.2 mm nozzle).

[0078] Coating Parameters:

TABLE-US-00001 TABLE 1 Parameters Setpoint Air inlet temperature 30-35° C. Product temperature 25-35° C. Air flow rate 40-60 m.sup.3/h Suspension spray flow rate 3-10 g/min Nebulization air 1-2 bar

[0079] At the end of the coating, the microgranules are sieved on a grid of adapted size.

[0080] At the end of the coating, the microgranules have a D50 comprised between 600 and 800 μm and a D90 comprised between 800 and 950 μm.

TABLE-US-00002 TABLE 2 Composition A according Sachets of Sachets of to the invention 1000 mg 2000 mg Active pharmaceutical Mesalazine 1000 mg 2000 mg ingredient Neutral supports Neutral SP 594.4 mg 1188.8 mg 400-500 μm Anionic (meth)acrylate Eudragit ® 74.9 mg 149.7 mg copolymer that L30D is soluble at a pH greater than 5.5 Anionic (meth)acrylate Eudragit ® 67.1 mg 134.1 mg copolymer that L100 is soluble at a pH greater than 6 Anionic (meth)acrylate Eudragit ® 50.3 mg 100.6 mg copolymer that S100 is soluble at a pH greater than 7 Water-insoluble anionic Eudragit ® 50.3 mg 100.6 mg (meth)acrylate copolymer RL100 Plasticizer Triethyl Citrate 25.2 mg 50.3 mg Lubricant Talc 67.1 mg 134.1 mg Total 1936.6 mg 3873.2 mg

Comparative Example 2: Preparation of Comparative Compositions B and C by Dusting in a Conventional Turbine

[0081] Comparative compositions B and C described in Tables 3 and 4 were prepared according to the same protocol as that described in example 1.

TABLE-US-00003 TABLE 3 Comparative composition B Core Mesalazine 52.8% Neutral SP 400-500 μm 31.4% Eudragit ® L30D 4.0% Triethylcitrate 0.4% Coating 1 Eudragit ® E100 2.7% Triethylcitrate 0.3% Talc 1.3% Coating 2 Eudragit ® S100 4.6% Triethylcitrate 0.7% Talc 1.8% 100.0%

TABLE-US-00004 TABLE 4 Comparative composition C Core Mesalazine 51.6% Neutral SP 400-500 μm 30.7% Eudragit ® L30D 3.9% Triethylcitrate 0.4% Coating Eudragit ® S100 8.7% Triethylcitrate 1.3% Talc 3.4% TOTAL 100.0%

Example 3: Study of the Dissolution Profile of Compositions A, B and C

[0082] Protocol: the apparatus used is a USP II type dissolutest (stirring with blades). The equivalent of 1 g of active ingredient in the form of microgranules is introduced into a vessel containing 750 mL of 0.1N HCl, stirred for 2 hours at a speed of 50 rpm. A sample of 10 mL is taken after 2 hours. The grains are recovered and introduced into a vessel containing 950 mL of a buffer medium of pH 6.8 (composed of 6.805 g of KH.sub.2PO.sub.4 and 22.4 mL of NaOH per 1 L) stirred for 1 hour at a speed of 50 rpm. A sample of 10 mL is taken after 1 hour. 50 mL of a 0.36N NaOH solution are added to the vessel. Agitation is activated at 50 rpm. 5 mL samples are taken after 30, 45, 60, 90 and 120 min.

[0083] The samples are then analyzed by liquid chromatography and the amount of active ingredient released is determined by UV detection.

[0084] Results: the results are presented in FIG. 1, which illustrates the percentages of dissolution of compositions A, B and C as a function of time.

[0085] Conclusion: the dissolution profile of composition A is: <10% after 2 hours in 0.1N HCl and 1 hour at pH6.8, then >80% after 2 hours in pH7.8.

[0086] The inventors have thus demonstrated that the process according to the invention allows to obtain a pharmaceutical composition having a uniform and reproducible dissolution and therefore likewise uniform and reproducible release of the active ingredient with low coefficients of variation.