Development of amphotericin B-double loaded liposomes using Design of Experiment (DoE)

---

N Basaran Mutlu Agardan and Nevin Çelebi

Gazi University, Turkey

: J Pharm Drug Deliv Res

Abstract

---

Systemic invasive fungal infections are the leading causes of mortality and morbidity among immunocompromised patients such as, cancer patients undergoing chemotherapy, AIDS patients and recipients of solid organ transplants. Amphotericin B (AmB), a polyene group antibiotic is a common choice for life-threatening systemic fungal infections and parasitic diseases due to its broad spectrum of activity. AmB is a BCS class IV drug with low solubility and low permeability properties. Although amphotericin B is a very potent agent, clinical use is limited due to its narrow therapeutic index and side effects. Cyclodextrins (CDs) are a group of pharmaceutical excipients containing a lipophilic central cavity and a hydrophilic outer surface. In aqueous solutions, they have the ability to form inclusion complexes with many drugs by taking up a drug molecule/some lipophilic moiety of the drug molecule into their central cavity. The inclusion complexes are very successful at increasing the solubility of low-soluble drugs. The main goal of a drug delivery system is to enhance the therapeutic index and reduce side effects of encapsulated drug. Liposomes are the macro/nano sized vesicular drug delivery systems with well-established advantages. The aim of this study was firstly, preparation and characterization of inclusion complexes of AmB with CDs. Secondly, formulation development of AmB double loaded liposomes by loading AmB-CD inclusion complex to the inner hydrophilic compartment, and hyrdrophobic AmB to the outer phospholipid membrane. For this purpose, solubility studies were carried out by using three CD derivatives (α-CD, HP-β-CD and sulfobutyl ether β-CD). α-CD was found to be the most enhancing derivative of AmB solubility. AmB- α-CD complexes were prepared and characterized by DSC, FTIR, X-ray diffraction measurements. Design of experiment (DoE) is planned to assist the formulation of AmB and AmB- α-CD double loaded liposomes in order to obtain more comprehensive and comparable results. Recent Publications 1. Pattni B S, Chupin V V and Torchilin V P (2015) New developments in liposomal drug delivery. Chemical Reviews 115(19):10938–10966. 2. Mutlu Ağardan N B, Değim Z, Yılmaz Ş, Altıntaş and Topal T (2015) The effectiveness of raloxifene-loaded liposomes and cochleates in breast cancer therapy. AAPS PharmSciTech 1–10. 3. Maestrelli F, González-Rodríguez M L, Rabasco A M, Ghelardini C and Mura P (2010) New “drug-in cyclodextrin-in” deformable liposomes” formulations to improve the therapeutic efficacy of local anaesthetics. International Journal of Pharmaceutics 395(1):222–231. 4. Malaekeh-Nikouei B and Davies N (2009) Double loading of cyclosporine A in liposomes using cyclodextrin complexes. PDA Journal of Pharmaceutical Science and Technology 63(2):139–148. 5. Nucci M and Perfect J R (2008) When primary antifungal therapy fails. Clinical Infectious Diseases 46(9):1426–1433

Biography

---

N Basaran Mutlu Agardan graduated from Gazi University Faculty of Pharmacy, and obtained there her PhD from the Department of Pharmaceutical Technology. She then gained a scholarship from the Scientific and Technological Research Council of Turkey and completed her Post-doctoral research studies at the Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston. Her area of research focuses on the smart drug delivery systems, liposomes, drug/gene delivery in cancer and oral absorption enhancement. bmutlu@gazi.edu.tr