PROCESS FOR THE MANUFACTURE OF A PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION AND COLONAL RELEASE

Description

FIELD OF INVENTION

[0001] The present invention relates to a method for preparing a pharmaceutical composition for oral administration and colonic delivery comprising at least a core and a coating layer. EARLIER ART

[0002] Mesalazine or 5-aminosalicylic acid is an anti-inflammatory drug commonly used to treat inflammatory bowel diseases such as ulcerative colitis or Crohn's disease.

[0003] Mesalazine acts locally in the colon. However, oral administration of mesalazine is problematic because this drug is almost completely absorbed in the small intestine and, consequently, only a small amount reaches the colon to ensure its therapeutic action.

[0004] In the past, to overcome this difficulty, mesalazine formulations with special coatings were developed, characterized by releasing the active ingredient only in the desired area and thus avoiding systemic side effects. These pharmaceutical compositions are delayed-release or slow-release formulations, suitable for preventing or delaying the absorption of mesalazine in the proximal tract to achieve therapeutic concentrations in the ileum and colon. For example, European patent application EP 0 040 590 (applicant Aktiebolaget Hässle) describes oral pharmaceutical preparations capable of releasing a drug, such as mesalazine, selectively in the colon at a pH above 5.5.This is achieved by coating a core containing the active ingredient with a mixture of a soluble anionic acrylic polymer at pH 5.5, such as Eudragit L, in quantities ranging from 10 to 85%, and a water-insoluble quaternary ammonium-substituted acrylic polymer, such as Eudragit RS or RL, in quantities ranging from 15 to 90%. These compositions are manufactured first by producing the core through mixing the active ingredient with a filler material followed by extrusion / spheronization, or by depositing the active ingredient onto the surface of a support particle, or by manufacturing a core containing only the active ingredient. The core is then coated, preferably using a fluidized bed applicator.However, the compositions described in this document do not allow for homogeneous and reproducible coating, resulting in dissolution of the composition and a non-homogeneous release of the active ingredient in the intestinal tract. Indeed, the manufacturing of microgranules by extrusion / spheronization leads to microgranules of heterogeneous size; thus, during coating, these microgranules receive a different amount of polymer depending on their size, forming a heterogeneous polymer layer. The impact of this polymer layer heterogeneity subsequently results in variability in dissolution between the coated microgranules.

[0005] Alternatives were then sought, aiming to act on the transit time from the mouth to the terminal ileum of the manufactured pharmaceutical composition or on the enzymatic activity of the colonic microbial flora.

[0006] Nevertheless, there is still a need for a manufacturing process for an orally administered, colonically released pharmaceutical composition that ensures that the release of the active ingredient of the resulting composition is homogeneous and targeted in the colon, and that is simple, reproducible and economical. SUMMARY OF THE INVENTION

[0007] Within the scope of the present invention, the inventors have discovered a method for preparing a pharmaceutical composition that allows for the specific and homogeneous release of an active ingredient, in particular mesalazine, in the colon. This method involves a powdering technique for the active ingredient that ensures homogeneous and reproducible particle size and coating with low coefficients of variation, and therefore a similarly homogeneous and reproducible release of the active ingredient with low coefficients of variation.

[0008] The present invention thus relates to a method for preparing a pharmaceutical composition for oral administration and colonic delivery comprising at least a core and a coating layer, characterized in that it comprises the following steps: a) Spraying onto a neutral support of an aqueous suspension comprising at least one soluble anionic (meth)acrylate copolymer with a pH greater than 5.5 and at least one active ingredient intended for delivery into the colon; or a') Spraying onto a neutral support of an aqueous suspension comprising at least one soluble anionic (meth)acrylate copolymer with a pH greater than 5.5 then b') Dusting of at least one active ingredient intended for delivery into the colon onto the microgranules obtained after step a'); c') carrying out steps a') and b') alternately until the desired active ingredient content is obtained and d) Coating the microgranules obtained after step a) or c') by spraying a composition comprising at least one anionic (meth)acrylate copolymer soluble at pH above 6, one anionic (meth)acrylate copolymer soluble at pH above 7 and one anionic (meth)acrylate copolymer insoluble in aqueous medium. DETAILED DESCRIPTION OF THE INVENTION Definitions

[0009] For the purposes of this invention, "colonic delivery" or "colonic liberation" means the selective release of an active ingredient at the level of the colon, also called the large intestine.

[0010] For the purposes of this invention, "homogeneous" release or dissolution refers to homogeneous dissolution among the microgranules of a pharmaceutical composition, in terms of dissolution time and the area of ​​the intestinal tract where they release the active ingredient they contain. Homogeneous dissolution aims to achieve the same release kinetics of the active ingredient in the body among the different microgranules. In the context of this invention, homogeneous dissolution aims to enable localized release of the active ingredient in the colon by the majority of the microgranules of the composition according to the invention. This allows, on the one hand, a greater concentration of the active ingredient in the therapeutic target area, namely the colon, and on the other hand, avoids the side effects associated with the release of the active ingredient in other regions of the intestinal tract and its absorption in the small intestine.

[0011] For the purposes of this invention, "specific" or "targeted" release or dissolution means that the release of the active ingredient is specific or targeted to the part of the intestine considered in relation to other regions of the intestinal tract.

[0012] For the purposes of this invention, "anionic copolymer" means a copolymer containing anionic groups.

[0013] For the purposes of this invention, "methacrylate copolymer" means a copolymer obtained by polymerizing methacrylate monomers such as acrylic acid, methacrylic acid, or their esters. The methacrylate copolymer may, in particular, be a polymer resulting from the polymerization of at least two of the following monomers: acrylic acid, methacrylic acid, ethyl acrylate, methyl methacrylate, and the methacrylic acid ester with a quaternary ammonium group.

[0014] For the purposes of this invention, "water-insoluble copolymer" means any copolymer that is insoluble in water or in a physiological solution.

[0015] For the purposes of this invention, "D50" means the diameter exhibited by 50% of the microgranule population considered.

[0016] For the purposes of this invention, "D90" means the diameter exhibited by 90% of the microgranule population considered. Method for preparing a pharmaceutical composition according to the invention

[0017] The present invention relates to a method for preparing a pharmaceutical composition for oral administration and colonic delivery comprising at least a core and a coating layer, characterized in that it comprises the following steps: a) Spraying onto a neutral support of an aqueous suspension comprising at least one soluble anionic (meth)acrylate copolymer with a pH greater than 5.5 and at least one active ingredient intended for delivery into the colon; or a') Spraying onto a neutral support of an aqueous suspension comprising at least one soluble anionic (meth)acrylate copolymer with a pH greater than 5.5 then b') Dusting of at least one active ingredient intended for delivery into the colon onto the microgranules obtained after step a'); c') carrying out steps a') and b') alternately until the desired active ingredient content is obtained and d) Coating the microgranules obtained after step a) or c') by spraying a composition comprising at least one anionic (meth)acrylate copolymer soluble at pH above 6, one anionic (meth)acrylate copolymer soluble at pH above 7 and one anionic (meth)acrylate copolymer insoluble in aqueous medium.

[0018] This process therefore allows the obtaining of a pharmaceutical composition for oral administration and colonic delivery comprising at least a core and a coating layer, said core comprising at least a neutral support, an active ingredient intended to be delivered in the colon and at least one anionic (meth)acrylate copolymer soluble at pH greater than 5.5, said coating layer comprising at least one anionic (meth)acrylate copolymer soluble at pH greater than 6, one anionic (meth)acrylate copolymer soluble at pH greater than 7 and one anionic (meth)acrylate copolymer insoluble in water.

[0019] According to a preferred embodiment, the pharmaceutical composition for oral administration and colonic delivery obtained at the end of the process according to the invention is in the form of microgranules.

[0020] According to a preferred embodiment, the anionic (meth)acrylate copolymer soluble at pH above 5.5 in step a) or a') is a methacrylic acid-ethyl acrylate (1:1) copolymer. Preferably, said methacrylic acid-ethyl acrylate (1:1) copolymer used is the commercially available compound Eudragit®< L30D. The choice of this copolymer as a binder is due to its suitability for the powder coating technique.

[0021] According to a preferred embodiment, among the copolymers of step d), said anionic (meth)acrylate copolymer soluble at pH greater than 6 is a methacrylic acid-methyl methacrylate (1:1) copolymer. Preferably, said methacrylic acid-methyl methacrylate (1:1) copolymer used is the commercially available compound Eudragit® < L100. This copolymer delays the release of the copolymer-coated compounds in the intestinal tract until they reach the jejunum.

[0022] According to a preferred embodiment, among the copolymers of step d), said anionic (meth)acrylate copolymer soluble at pH above 7 is a methacrylic acid-methyl methacrylate (1:2) copolymer. Preferably, said methacrylic acid-methyl methacrylate (1:2) copolymer used is the commercially available compound Eudragit®< S100. This copolymer delays the release of the copolymer-coated compounds into the intestinal tract until they reach the ileum and colon.

[0023] According to a preferred embodiment, among the copolymers of step d), said aqueous-insoluble copolymer is an ethyl acrylate-methyl methacrylate-methacrylic acid ester copolymer with a quaternary ammonium group (1:2:0.2), advantageously an ethyl acrylate-methyl methacrylate-methacrylic acid ester copolymer with a trimethylammonioethyl methacrylate chloride group (1:2:0.2). Preferably, said ethyl acrylate-methyl methacrylate-methacrylic acid ester copolymer with a quaternary ammonium group used is the commercially available compound Eudragit® RL100. This copolymer allows for the controlled release of the compounds coated with this copolymer over time.

[0024] According to a preferred embodiment, the composition sprayed in step d) has a ratio of 4:3:3 of anionic (meth)acrylate copolymer soluble at pH above 6: anionic (meth)acrylate copolymer soluble at pH above 7: anionic (meth)acrylate copolymer insoluble in aqueous media. The mixture of the three coating copolymers results in a pH-dependent release of the pharmaceutical composition because these three polymers dissolve at different pH levels. This mixture of the three polymers thus allows for the formation of coating irregularities as the pharmaceutical composition moves through the intestinal tract and the release of the product at the desired location, i.e., in the colon.

[0025] In the context of the present invention, the three coating polymers are applied in a single layer. This differs from prior art coatings in which each polymer forms a separate layer. Thus, the pharmaceutical composition prepared according to the process of the invention may comprise one or more coating layers, each layer comprising a mixture of the three polymers mentioned above.

[0026] Advantageously, the pharmaceutical composition prepared according to the process of the invention comprises a single coating layer.

[0027] Preparing a pharmaceutical composition with a coating that includes all polymers in a single layer, and advantageously a single-layer coating, offers significant time savings and therefore cost advantages. Furthermore, single-layer coating allows for better adjustment of the coating density, particularly in the event of technical problems during preparation (compressed air issues, nozzle clogging, or other problems). Indeed, with multi-layer coatings, where each layer contains a different polymer, adjustments to the coating, especially the initial coating layers, are not possible. This is problematic, particularly if a technical issue arises during the application of the first layers. Technical problems are only detected at the end of the process, once all layers have been applied, making it impossible to readjust the coating density of the initial layers.

[0028] According to a preferred embodiment, the powdering of the active ingredient in step b') is carried out by manual or mechanical powdering in at least one conventional flat-bottomed turbine. This manual or mechanical powdering process advantageously obtains and guarantees the cores of the pharmaceutical composition in the form of microgranules with a tight particle size distribution.

[0029] This compact particle size distribution allows for a homogeneous and reproducible coating around the microgranules. Because the microgranules are all the same size thanks to manual or mechanical powdering, they receive the same amount of polymer, forming a layer of uniform thickness on all of them. During administration of the pharmaceutical composition, this results in low coefficients of variation during granule dissolution in the body, meaning homogeneous dissolution of the coated microgranules.

[0030] Advantageously and without limitation, the active ingredient intended to be delivered into the colon may be an anti-infective, for example an antibiotic, an anti-inflammatory agent, an antihistamine, an anticholinergic, an antiviral, an antimitotic, peptides, proteins, genes, antisense oligonucleotides, diagnostic agents and / or immunosuppressive agents or bacteria.

[0031] Advantageously, the active ingredient intended to be delivered into the colon can be water-soluble or fat-soluble.

[0032] Among the active ingredients intended for delivery to the colon that are particularly advantageous are anti-inflammatory agents, antitumor agents, antisense oligonucleotides, and enzymes capable of inactivating antibiotics in the colon, including β-lactamases or enzymes capable of inactivating macrolides and related drugs such as erythromycin esterase.

[0033] More advantageously, the active ingredient intended to be delivered into the colon is an anti-inflammatory agent.

[0034] Preferably, the active ingredient intended for delivery into the colon is chosen from salicylazolesulfapyridine or sulfasalazine (Salazopyrine), 5-aminosalicylic acid (mesalazine), budesonide, rifamycin, acamprosate or linaclotide. FIGURES

[0035] FIG. 1 : It describes the results of example 3.

[0036] 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 powdering in a conventional turbine

[0037] Composition A described in Table 2 was prepared according to the following protocol: 1) Assembly of Mesalazine microgranules: Introduction of neutral supports into the turbine (Bulk temperature; 15 - 35°C); Spraying of the binding suspension comprising Eudragit L30D and triethylcitrate; Powdering of the active ingredient by manual or mechanical powdering; Drying; and Sieving on a SODEVA type vibrating sieve with 500 to 1000 µm grids.

[0038] At the end of the assembly, the microgranules have a D50 between 500 and 700 µm and a D90 between 700 and 950 µm. 2) Coating

[0039] Following the assembly stage, the microgranules are coated by spraying the coating suspension onto the active microgranules.

[0040] Composition of the coating suspension for a 10% weight gain in polymer for spraying on 1000.0 g of active Mesalazine grains: Eudragit S100: 30.0g Eudragit RL100: 30.0g Eudragit L100: 40.0g TEC (triethylcitrate): 15.0g Talc: 40.0g Ethanol: 1395.0g

[0041] The coating suspension is prepared according to the following protocol: Weigh the ethanol into a container of suitable capacity and stir it with a propeller-equipped mixer (type IKA). Stir in the Eudragit® < S100 and wait for complete dissolution. Stir in the Eudragit® < L100 and wait for complete dissolution. Stir in the Eudragit® < RL100 and wait for complete dissolution. Add the triethyl citrate while stirring and maintain stirring for 1 hour. Stir in the talc and wait 30 minutes before starting the spraying. Spray the coating suspension onto the microgranules, maintaining agitation throughout the spraying process, as described below.

[0042] The coating is carried out in a Glatt GPCG1 type fluidized air bed in Wurster mode equipped with a Schlick gun (1.2mm nozzle).

[0043] Coating parameters: Table 1 Settings Order Air inlet temperature 30-35°C Product temperature 25-35°C Airflow 40-60 m3 / h Spray flow rate suspension 3-10 g / min Nebulizing air 1-2 bar

[0044] After coating, the microgranules are sieved through a suitably sized grid.

[0045] At the end of the coating process, the microgranules have a D50 between 600 and 800 µm and a D90 between 800 and 950 µm. Table 2 Composition A according to the invention 1000mg sachets 2000mg sachets Active pharmaceutical ingredient Mesalazine 1000 mg 2000 mg Neutral supports Neutral SP 400-500 µm 594.4 mg 1188.8 mg soluble anionic (meth)acrylate copolymer at pH greater than 5.5 Eudragit®< L30D 74.9 mg 149.7 mg Soluble anionic (meth)acrylate copolymer at pH greater than 6 Eudragit ®< L100 67.1 mg 134.1 mg Soluble anionic (meth)acrylate copolymer at pH greater than 7 Eudragit ®< S100 50.3 mg 100.6 mg Water-insoluble anionic (meth)acrylate copolymer Eudragit ®< RL100 50.3 mg 100.6 mg 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 conventional turbine powder coating

[0046] Comparative compositions B and C described in Tables 3 and 4 were prepared following the same protocol as that described in Example 1. Table 3 Comparative Composition B Heart Mesalazine 52,8 % Neutral SP 400-500 µm 31,4 % Eudragit®< L30D 4,0 % Triethyl citrate 0,4 % Coating 1 Eudragit®< E100 2,7 % Triethyl citrate 0.3 % Talc 1.3 % Coating 2 Eudragit ®< S100 4,6 % Triethyl citrate 0.7% Talc 1.8% 100,0 % Table 4 Comparative Composition C Heart Mesalazine 51,6 % Neutral SP 400-500 µm 30,7 % Eudragit®< L30D 3,9 % Triethyl citrate 0,4 % Coating Eudragit ®< S100 8,7 % Triethyl citrate 1,3 % Talc 3,4 % TOTAL 100,0 % Example 3: Study of the dissolution profile of compositions A, B and C

[0047] Protocol: The apparatus used is a USP II type dissolutest (paddle agitator). The equivalent of 1 g of the active ingredient in microgranule form is introduced into a vessel containing 750 mL of 0.1 N HCl, which is agitated for 2 hours at 50 rpm. A 10 mL sample is taken after 2 hours. The granules are collected and introduced into a vessel containing 950 mL of a pH 6.8 buffer solution (composed of 6.805 g of KH₂PO₄ and 22.4 mL of NaOH per 1 L), which is agitated for 1 hour at 50 rpm. A 10 mL sample is taken after 1 hour. 50 mL of 0.36 N NaOH solution is added to the vessel. The agitator is activated at 50 rpm. Samples of 5 mL are taken after 30, 45, 60, 90 and 120 min.

[0048] The samples are then analyzed by liquid chromatography and the amount of active ingredient released is determined by UV detection.

[0049] Results: The results are presented in the figure 1 , which illustrates the percentages of dissolution of compositions A, B and C as a function of time.

[0050] Conclusion: The dissolution profile of composition A is: <10% after 2h in 0.1N HCl and 1h at pH 6.8, then >80% after 2h at pH 7.8.

[0051] The inventors have thus demonstrated that the process according to the invention makes it possible to obtain a pharmaceutical composition exhibiting a homogeneous and reproducible dissolution and therefore a release of the active ingredient that is also homogeneous and reproducible with low coefficients of variation.

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.