FORMULATION TECHNOLOGY CAN ENABLE ORAL DELIVERY OF NEW GENERATION MEDICINES
animal model using 5-aminosalicylic acid as the colon-targeted compound71, and the original patent claims effective delivery of insulin and salmon calcitonin to the colon70. In a γ-scintigraphy study of the in vivo performance in human subjects of placebo tablets with the CODES coating technology, the radiolabel incorporated into the tablet cores was only released after the dosage form arrived in the colon and there was an induction period on arrival before the disintegration of the tablet was seen, probably associated with the time required for acid generation and dissolution of the acid-soluble amino methacrylate copolymer core tablet coating72. Beyond the functional demonstration with 5-aminosalicylic acid, additional applications of this technology to the delivery of small or large molecules have not been reported. PHLORAL
PHLORAL is a hybrid pH/microflora-activated technology developed by some of the investigators who had previously developed COLAL, where it seeks to improve the consistency and accuracy of delivery, as well as assure rapid release of contained drug. COLAL relies on the controlled swelling of the amylose/ethylcellulose coating which can be a slow process resulting in a sustained-release mechanism73 that is not well-suited to fast release in the colon which leads to better targeting of the whole colon. PHLORAL aims to resolve these aspects by virtue of a pH and/or microflora triggered system as a “fail safe” targeting mechanism74. It can be manufactured using conventional pharmaceutical manufacturing equipment and is being applied to several products currently in clinical trials, including an advanced stage trial of a product for the treatment of IBD74. PHLORAL uses methacrylic acid–methyl methacrylate copolymer (1:2), Eudragit S™, as its
continued
Mixed lipophilic/amphiphilic matrix granules with drug Hydrophilic matrix polymer with optional drug content
Polymer coating soluble at pH ≥7.0
Figure 3. MMX technology. Once at or beyond the terminal ileum, the pHdependent soluble film coat will dissolve and allow hydration of the hydrophilic polymer matrix. This may contain drug which will then release by a diffusion process. As fluid continues to penetrate the hydrating viscous hydrophilic polymer matrix it reaches the lipophilic/amphiphilic granules and allows release of drug from those, again by diffusion through the hydrated hydrophilic matrix. There are embodiments of this technology that just have lipophilic drug containing granules, rather than the mixed lipophilic/amphiphilic granules, and embodiments where the hydrophilic matrix in initially free of drug.
pH-dependent soluble polymer, which starts to dissolve at pH 7.0, and it employs amylose or amylopectin as the microfloradegraded polysaccharide. The mixed polymer/polysaccharide film around a dosage form is applied using fluid bed coating from a solution/dispersion prepared by mixing appropriate amounts of the amylose dispersion in an organic/aqueous solvent and the enteric polymer solution, to obtain a preferred polysaccharide:polymer ratio75. The optimum pHdependent polymer:amylose ratio was found to be 7:3, which shows excellent resistance to in vitro drug release at pH 1.2 and pH 6.8 (for up to 12 hours), but at pH 7.0 without enzymes or at pH 6.8 in the presence of α-amylase from Baccilus licheniformis, drug release is initiated at around 3 hours and is complete within 4–6 hours75. PHLORAL has been demonstrated as superior to purely pH-dependent polymer systems in a study in eight healthy human subjects76. Core tablets labelled with technetium-99m (99mTc, 4MBq) were coated with the PHORAL coating and dosed in a randomised crossover protocol to the subjects either fasted or fed (after a 392 kcal breakfast), or 30
european INDUSTRIAL PHARMACY December 2016
• Issue 31
minutes prior to the breakfast. Following normal meal times, lunch 4 hours post dose and dinner 9 hours post dose, the release of the radioactive label from the dosage form was measured in vivo by γ-scintigraphy. In all cases (irrespective of feeding status), the label was released at the target site, either at the ileocecal junction, the ascending colon, the transverse colon or at the splenic or hepatic flexures. No dosage forms released any of the label in the stomach or small intestine and no dosage form failed to release the label in vivo74. This clearly distinguishes this technology from the purely pHdependent technologies typically used in established colon-targeted therapies where, in a number of cases, dosage units failed to release at all77. MMX® technology
A combined delayed-release/ extended-release tablet technology for the delivery of therapeutic agents to the whole colon has been developed, clinically validated in IBD and commercialised (for the glucocorticoid budesonide and the anti-inflammatory mesalazine). The technology is described as a multimatrix structure, hence MMX78. Tablets consist of a dispersion of
13