(W1230-02-13) Studying Drug Release in Multilayered Polymer-Drug Formulations for Oral Delivery

Purpose: Polymers are versatile materials, as they provide relative ease of incorporating a wide range of functionalities when compared to other functional materials. This is the reason behind the widespread use of polymers in drug delivery. However, while there are many proof-of-concept studies on polymeric controlled release systems for oral delivery, few such systems have been commercialized. This is particularly because precise control of drug diffusion and stimuli-response is required for actual implementation inside the human body. Such control is missing in a large number of the reported systems, partly because of a lack of full theoretical understanding of drug diffusivity in polymers. This is even more challenging for multilayered systems where the detailed changes of the molecular conformations and layer structure in an in vivo setting are difficult to observe and interpret. Multilayered drug delivery formulations are formed by layers of polymeric media that may show different stimuli-response. Layers formed by two different polymers (or different polymer concentrations) with different drug diffusivity in the two layers can be employed. If the drug diffusivity and/or drug concentration is lesser in the outer layer, the drug release rate will be slow in the beginning followed by a rapid release once the drug is diffused out of inner layer. Barrier layers with almost no drug diffusion may also be incorporated to prevent drug diffusion in a particular direction. For instance, a gastric-resistant layer is used for many formulations that prevent drug release in highly acidic conditions of the stomach, which then dissolves in the basic environment of the intestine where drug release is desired.

Methods: Direct compression method is used to prepare formulations of Poly-methyl-methacrylate-co-methacrylic acid (PMA-MAA) and hydroxypropyl methyl cellulose (HPMC) with naproxen. Naproxen:PMA-MAA weight ratio of 1:1 (top and bottom layers) and 1:5 (middle layer) are used to develop a Formulation A15 that shows erosion in the top layer but only diffusion in the middle layer. Formulation B11 and B12 contain 1:1 naproxen:HPMC and 1:2 naproxen:HPMC, respectively, in the middle layer and 1:1 naproxen:PMA-MAA in the top layer. Formulations are prepared by filling die with powder mixture of drug, polymer and additive, which are mixed in the mortar pestle and directly compressed in the tablet punching machine. For this purpose, die is first filled with the powder mixture of bottom layer followed by the middle layer and the top layer. A small pre-compression force is applied after each layer and a final post-compression force is applied after all the layers have been formed. We ensure that the compression is large enough such that the layers are not detached during dissolution experiments. Drug release experiments are performed in USP 2 (paddle) apparatus in perfect sink conditions and the API concentration in the bowl is obtained using UV-Vis spectrophotometer. Experiments are complemented with a multiphysics model that accounts for the diffusion, erosion, and swelling effects. In the first set of simulations, we considered the erosion and swelling effects to be negligible and obtained the drug diffusion coefficients for single-layered formulations by fitting the COMSOL simulations of the multiphysics model with the experimental data. These diffusion coefficients are then used to predict the drug release from multi-layered formulations. In the second set of simulations, we include the erosion effect by considering a fixed depletion rate of layers that is obtained from the image analysis in drug release experiments. In the third set of simulations, we also include the swelling effect by considering the diffusion of both drug and water through the formulation layers. All simulations are conducted assuming perfect sink conditions.

Results: In general, the drug release rate from a layer depends on the amount of polymer in the layer. As expected, the drug release from Formulation A15 is in between the behavior of single layer 1:1 and 1:5 formulations of naproxen and PMA-MAA. For Formulation B11 and B12, the drug release rate is high in the beginning (up to 10 minutes) due to fast erosion of top and bottom layers. The drug release occurs through the middle layer at intermediate times and therefore slow. For the case of Formulation B11, there is a sudden jump in the drug release when the tablet becomes very thin and gets stretched due to the hydrodynamic forces induced by stirring. Multiphysics model was reliably able to fit drug release profiles in most of the cases, with few exceptions in cases where significant cross-contamination of layers is observed.

Conclusion: Our results indicate that multilayer formulations may provide better control over the drug release profile than the single-layer formulation because each layer may have different mechanism of drug release or provide different kinds of resistance. Moreover, since the swelling/erosion characteristics of a polymer depends on the environmental and flow conditions, they may be tailored to the desired stimuli-responsive release behavior.

Acknowledgements: This work is funded by Science and Engineering Research Board (SERB) grant CRG/2021/001260.

Drug release through multilayer formulations. Data for single-layer formulations are also added in a) for reference. Inset in a) shows a compressed formulation.