Studies in Oxcarbazepine Modified Release Formulations Using Quality by Deisgn Approach

Abstract

Oxcarbazepine, an antiepileptic drug, is used in the treatment of partial and generalized tonicclonic seizures in children and adults. The maximum dose administered per day is 2400 mg and administered 2 to 3 times in divided doses. It is available in market as 150, 300 and 600 mg of immediate release (IR) and extended release (ER) tablets. Immediate release of high dose of oxcarbazepine leads to side effect such as dizziness, drowsiness, fatigue, nausea, vomiting, headache, sleeping trouble, acne, dry mouth or constipation which anticipate the modification of oxcarbazepine release from the formulation for better therapeutic efficacy and patient compliance. The available extended release formulation is tablet, unit solid dosage form. The objective of the presented investigation was to develop twice a day oral modified release multiparticulate drug delivery system of oxcarbazepine to overcome disadvantages associated with unit modified release solid dosage form. Required release profile was generated using pharmacokinetic parameters of oxcarbazepine and was used for comparison of developed formulations. Three different dosage forms, microspheres, pellets and modified release granules were prepared adopting systematic approaches i.e. Quality by Design (QbD). Microspheres were prepared by multiple emulsion solvent evaporation technique using chitosan and ethyl cellulose as release retarding polymers. Quality targeted product profile (QTPP) and critical quality attributes (CQAs) were identified. Critical material attributes (CMAs) and critical process parameters (CPPs) were identified by risk assessment. The selected factors were screened by employing Plackett and Burman screening design. The most critical factors (temperature and volume of water) were used for further optimization (32 full factorial design). All the batches showed small particle size and good % encapsulation efficiency. Different approaches were tried to decrease initial burst release. Pellets were prepared by extrusion spheronization technique using Avicel PH101 as filler, lactose monohydrate as pore forming agent and ethyl cellulose solution as binder. QTPP and CQAs were identified. Critical material attributes (CMAs) and critical process parameters (CPPs) were identified by initial risk assessment. Box Behnken design was used for optimization study. Pellets showed excellent flow properties and good spherisity. Modified release granules were prepared by melt and mix method using carnauba wax, glyceryl monostearate and bees wax. QTPP and CQAs were identified and CMAs and CPP were identified by initial risk assessment. 32 full factorial design was used for optimization. All the batches showed good % yield and drug content. The optimized formulations were subjected to SEM, XRD, dissolution in hydroalcoholic media, effect of pH and food (viscosity) on drug release, stability study and for prediction of i in vivo drug release. The type and the amount of excipients present in the different formulations have got an impact on drug dissolution. Based on the in vitro drug dissolution studies in different media, modified drug release is expected from the formulated products. The drug release from pellets was quite close to the expected drug release profile. Further pellets are easy to manufacture, scale up and cost effective. Thus pellets were considered as the best dosage form amongst the developed formulations.