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EP-4057998-B1 - PROCESS FOR MANUFACTURING A PHARMACEUTICAL COMPOSITION FOR ORAL INTAKE AND DRUG RELEASE IN THE COLON

EP4057998B1EP 4057998 B1EP4057998 B1EP 4057998B1EP-4057998-B1

Inventors

  • HERRY, CATHERINE
  • ZHU, Yuqiu
  • CRIERE, BRUNO

Dates

Publication Date
20260513
Application Date
20201113

Claims (9)

  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

FIELD OF INVENTION 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 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. 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. 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, 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 in order to achieve therapeutic concentrations in the ileum and colon. For example, the European patent application EP 0 040 590 (Applicant Aktiebolaget Hässle) describes oral pharmaceutical preparations capable of releasing a drug, for example 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 an anionic acrylic polymer soluble at just 5.5, such as, for example, 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 creating the core by mixing the active ingredient with a filler material and then extruding/spheronizing it, or by depositing the active ingredient on the surface of a support particle, or by manufacturing a core containing only the active ingredient; then, the core is coated, and this coating application is preferably carried out using a fluidized bed apparatus. However, the compositions described in this document do not allow for homogeneous and reproducible coating, which leads to dissolution of the composition and a non-homogeneous release of the active ingredient in the intestinal tract. Indeed, the manufacture of microgranules by extrusion/spheronizing results in microgranules of heterogeneous size; Thus, during coating, these microgranules will 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. 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. 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 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, into the colon. This method involves a powdering technique of the active ingredient which makes it possible to guarantee a homogeneous and reproducible particle size and coating with low coefficients of variation, and therefore a release of the active ingredient that is also homogeneous and reproducible with low coefficients of variation. 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 at pH greater than 5.5 and at least one active ingredient intended to be delivered into the colon; Or a') Spraying onto a neutral support of an aqueous suspension comprising at least one soluble anionic (meth)acrylate copolymer at pH greater than 5.5 then b') Powdering of at least one active ingredient intended to be delivered into the colon onto the microgranules obtained after step a'); c') Performing steps a') and b') alternately until the desired active ingredient content is obtained And d) Coating of the microgranules obtained after step a) or c') by spraying with 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 DESCR