Design, Development and Evaluation of Controlled-Release Formulation of Freely Water-Soluble Drugs

Abstract

Controlled release (CR) oral drug delivery systems are most effective for maintaining optimal concentration of drugs with narrow therapeutic range and short elimination halflife. In CR products, plasma drug levels are achieved by immediate release of initial dose followed by maintenance dose for a predetermined time. Cellulosic polymers such as hydroxypropyl methylcellulose (HPMC) and ethylcellulose are widely used hydrophilic polymers for oral controlled drug delivery system. Their gel forming property, nontoxicity ease of compression, greater drug loading tendency, pH independent solubility and flexibility to obtain desirable drug release profile. Drug release from these systems is the consequence of controlled matrix hydration, followed by gel formation, change of textural/rheological behavior, matrix erosion, and/or drug dissolution and diffusion. Drugs from BCS classification I and III class were selected to demonstrate the matrix formulation to achieve controlled release dosage form with different combinations of polymer. Lacosamide is classified as BCS class I and indicated as monotherapy in the treatment of partial-onset seizures with or without secondary generalization in adults, adolescents and children from 2 years of age with epilepsy. The drug is first approved by US FDA on Oct 28, 2008 with patent and exclusivity valid till 2023 and 2024. VIMPAT® in available in immediate dosage form ranging from 50mg,100mg, 150mg and 200mg as film coated tablet twice a day. Lacosamide is rapidly and completely absorbed by the body following first order kinetics. Tmax usually occurs between 1 and 4 h after administration and food does not affect the rate or extent of absorption. Lacosamide has an elimination half-life of about 13 h, making it an ideal candidate for twice daily dosing with an immediate release formulation. Controlled release formulations may therefore contribute to improved outcomes for epilepsy patients by providing better seizure control, whilst reducing the potential for adverse events. A once daily lacosamide CR tablet has been developed to provide more convenient dosing, potentially leading to improved patient compliance and a superior safety/ efficacy. Overactive bladder syndrome is a broadly occurring urological disorder with a distressing impact on the quality of life. Mirabegron is the first approved β3 -adrenoreceptor agonist, used as mono or in combination therapies for overactive bladder syndrome. The modifiedrelease tablet dosage form of mirabegron appear to be a proficient and suitable replacement for antimuscarinics and revealed the tremendous potential to overcome the adverse effects of conventional antimuscarinic drugs. To minimize the adverse effect and patience compliance drug need to be released slowly and controlled manner. Suitable formulation technology and polymer to be selected to achieve controlled release formulation. The aim of this study was to develop a sustained release hydrophilic matrix tablet of Lacosamide and Mirabegron. The study also evaluates the effect of formulation variables such as polymer concertation and viscosity grades of HPMC, combination with another rate controlling polymer on drug release. Thirty different formulations F1-F30 of lacosamide and F31-F60 of mirabegron of each model drug were prepared by wet granulation. The results of the physical parameters and assay were found to be within the acceptable range. Rate of drug release was indirectly proportional to concentration of polymer. The drug release rate from tablets containing HPMC was effectively controlled by higher viscosity grades and combination of polymer. For lacosamide matrix tablet polymer combination of hydroxyproplymethyl cellulose (HPMC) K100M and ethylcellulose shown highest degree of swelling and lowest erosion with r2 = 0.9714 for Higuchi equation. The f2 test were performed and found to be most similar to marketed product formulation. Similarly, Mirabegron formulation containing HPMC K100M and ethylcellulose (formulation F53) showed highest similarity with marketed formulation along with swelling behavior with r2 = 0.9921 for Higuchi model.