Igor Legen

A Novel Beads-Based Dissolution Method for the In Vitro Evaluation of Extended Release HPMC Matrix Tablets and the Correlation with the In Vivo Data

The aim of this work was to establish alternative in vitro dissolution method with good discrimination and in vivo predictability for the evaluation of HPMC extended release matrix tablets. For this purpose, two different HPMC matrix tablet formulations were first evaluated by a range of conventional dissolution testing methods using apparatus 1, apparatus 2, and apparatus 3 according to US Pharmacopoeia. Obtained results showed low discrimination between the tested samples. Afterward, a novel dissolution testing method which combines plastic beads and apparatus 3 was developed with the aim to better mimic the mechanical forces that occur in vivo. Results showed that sufficiently large mechanical stress with high dips per minute program setting (apparatus 3) was needed to obtain in vitro discriminative results, which are in accordance with the in vivo data. The in vivo relevance of the method was confirmed with the establishment of the level A in vitro–in vivo correlation.

Determining the Polymer Threshold Amount for Achieving Robust Drug Release from HPMC and HPC Matrix Tablets Containing a High-Dose BCS Class I Model Drug: In Vitro and In Vivo Studies

It is challenging to achieve mechanically robust drug-release profiles from hydrophilic matrices containing a high dose of a drug with good solubility. However, a mechanically robust drug release over prolonged period of time can be achieved, especially if the viscosity and amount of the polymer is sufficiently high, above the “threshold values.” The goal of this research was to determine the hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC) polymer threshold amount that would enable robust drug release from matrix tablets containing a high dose of levetiracetam as a class I model drug according to the Biopharmaceutical Classification System (BCS). For this purpose, formulations containing HPC or HPMC of similar viscosity range, but in different amounts, were prepared. Based on the dissolution results, two final formulations were selected for additional in vitro and in vivo evaluation to confirm the robustness and to show bioequivalence. Tablets were exposed to various stress conditions in vitro with the use of different mechanically stress-inducing dissolution methods. The in vitro results were compared with in vivo results obtained from fasted and fed bioequivalence studies. Under both conditions, the formulations were bioequivalent and food had a negligible influence on the pharmacokinetic parameters Cmax and area under the curve (AUC). It was concluded that the drug release from both selected formulations is mechanically robust and that HPC and HPMC polymers with intrinsic viscosities above 9 dL/g and in quantities above 30% enable good mechanical resistance, which ensures bioequivalence. In addition, HPC matrices were found to be more mechanically robust compared to HPMC.

A Novel Intestine Model Apparatus for Drug Dissolution Capable of Simulating the Peristaltic Action

A novel dissolution apparatus has been proposed as an alternative apparatus for dissolution testing. In this study, we evaluated the performance of the new intestine model for simulating the peristaltic action (IMSPA), generating the movement that closely mimics peristaltic contractions of the small intestine. Two polyethylene oxide matrix tablet formulations, containing a model drug belonging to class III of the Biopharmaceutics Classification System, were tested. Dissolution was also performed in the USP2 apparatus. The release profiles were further compared to the in vivo data to evaluate the in vivo relevance of the new apparatus. The results demonstrated that the novel apparatus showed good discriminatory power between different polyethylene oxide formulations. Moreover, a better relation to the in vivo data was established by the IMSPA as compared to the USP2 apparatus. In conclusion, the model parameters were efficiently controlled to ensure the dissolution conditions crucial for evaluating the in vivo release performance of the tested formulations.

Neuro-fuzzy models as an IVIVR tool and their applicability in generic drug development.

The usefulness of neuro-fuzzy (NF) models as an alternative in vitro-in vivo relationship (IVIVR) tool and as a support to quality by design (QbD) in generic drug development is presented. For drugs with complicated pharmacokinetics, immediate release drugs or nasal sprays, suggested level A correlations are not capable to satisfactorily describe the IVIVR. NF systems were recognized as a reasonable method in comparison to the published approaches for development of IVIVR. Consequently, NF models were built to predict 144 pharmacokinetic (PK) parameter ratios required for demonstration of bioequivalence (BE) for 88 pivotal BE studies. Input parameters of models included dissolution data and their combinations in different media, presence of food, formulation strength, technology type, particle size, and spray pattern for nasal sprays. Ratios of PK parameters Cmax or AUC were used as output variables. The prediction performance of models resulted in the following values: 79% of models have acceptable external prediction error (PE) below 10%, 13% of models have inconclusive PE between 10 and 20%, and remaining 8% of models show inadequate PE above 20%. Average internal predictability (LE) is 0.3%, and average external predictability of all models results in 7.7%. In average, models have acceptable internal and external predictabilities with PE lower than 10% and are therefore useful for IVIVR needs during formulation development, as a support to QbD and for the prediction of BE study outcome.

Determining The Pressure-Generating Capacity of The Classical and Alternative In Vitro Dissolution Methods Using a Wireless Motility Capsule

PurposeIn vitro dissolution tests are an important tool for prediction of in vivo behavior of pharmaceutical dosage forms. One of the main reasons behind poor in vitro-in vivo correlation is the lack of knowledge about the true in vivo conditions and the failure to replicate them adequately in vitro. The objective of this study was to investigate the conditions during the dissolution testing in terms of their capability to generate the biorelevant pressure values that orally administered dosage forms are exposed to in vivo.MethodsUsing the SmartPill®, three classical dissolution systems (USP 1–3) were subjected to the pressure measurements. With USP 3, the addition of plastic beads was also examined. Additionally, two novel in vitro dissolution models capable of simulating the peristaltic action were also investigated, namely, the advanced gastric simulator (AGS) and the intestine model for simulating the peristaltic action (IMSPA).ResultsThe USP 1 and USP 2 systems showed no significant pressure readings, while the USP 3 (and especially its combination with plastic beads) showed measurable pressure peaks but still below the reported in vivo values. The AGS and the IMSPA, on the other hand, offered precise and repeatable controlled contractions of a silicone container resulting in the maximum pressure values very close to the reported in vivo measurements by the SmartPill® device.ConclusionsThe results therefore support the in vivo relevance of the newly developed AGS and IMSPA models and present their potential for further optimization of dissolution testing methods.