Aqueous Solubility Enhancement Approaches And Nanostructured Lipid Carriers Of Mycophenolate Mofetil Using Formulation By Design

Abstract

Solid organ transplantation has become standard critical therapy for end-stage organ failure. The major limitation of this therapy is graft rejection and to tackle this situation, patient is subjected to life-long immunosuppressive therapy. Adherence to this prescribed immunosuppressive regimen is crucial to maintain constant plasma concentration thus preventing severe life-threatening outcomes. Mycophenolate mofetil is an immunosuppressive agent used in most solid organ transplant regimens in combination with other agents. MMF falls under BCS Class Ⅱ and has solubility limitations, highlighting the need to increase the solubility of the drug which ultimately leads to improved dissolution rate. MMF is associated with severe gastrointestinal adverse effects which often results in discontinuation of therapy or dose splitting causing non-adherence to the regimen more probable leading to an increase in risks of graft rejections. With a half-life of 8- 16 hours, 95% of steady-state plasma concentration is observed after 48 hours leading to significant lag time between administration and therapeutic action. Sustained release formulation can provide better therapeutic alternative to reduce the fluctuations in drug concentration in plasma. With sustained release dosage forms, the steady-state concentrations can be reached more promptly than immediate release dosage forms and the next doses will help maintain the steady-state concentrations effortlessly. Sustained release dosage forms show release for prolonged period hence reducing the dose frequency of the drug. Of all the sustained release formulations, nanostructured lipid carriers (NLCs) are more preferred due to several advantages such as small particle size, large surface area and modifiable surface. Therefore, formulating NLCs of MMF with sustained release can help reduce the dosing frequency and release the drug for a long time. The aim of the current work was to enhance the aqueous solubility of the lipophilic MMF employing approaches such as hydrotropic solubilization technique and cyclodextrin inclusion complexation. Various hydrotropic agents were selected for hydrotropic solubilization and observed for solubility enhancement while binary complex of β cyclodextrin was also utilized for solubility enhancement of this drug. Sustained release NLCs of MMF was also prepared through high sheer homogenization and ultrasonication process. The developed formulation was found stable and tested for various critical quality attributes exhibiting satisfactory results. Application of Formulation by Design approach was successfully applied for Department of Pharmaceutical Sciences & Technology, MRSPTU ix implementation of Quality by Design principles. The present work may offer more suitable drug delivery system of immunosuppressant MMF providing an extended drug release and decrease the pill burden while improving patient’s quality of life.