Liposomal Formulations in Clinical Use: an Updated Review
Total Page：16
File Type：pdf, Size：1020Kb
pharmaceutics Review Liposomal Formulations in Clinical Use: An Updated Review Upendra Bulbake †, Sindhu Doppalapudi †, Nagavendra Kommineni and Wahid Khan * Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad 500037, India; [email protected] (U.B.); [email protected] (S.D.); [email protected] (N.K.) * Correspondence: [email protected] † These authors contributed equally to this work. Academic Editor: Murali Mohan Yallapu Received: 16 January 2017; Accepted: 23 March 2017; Published: 27 March 2017 Abstract: Liposomes are the first nano drug delivery systems that have been successfully translated into real-time clinical applications. These closed bilayer phospholipid vesicles have witnessed many technical advances in recent years since their first development in 1965. Delivery of therapeutics by liposomes alters their biodistribution profile, which further enhances the therapeutic index of various drugs. Extensive research is being carried out using these nano drug delivery systems in diverse areas including the delivery of anti-cancer, anti-fungal, anti-inflammatory drugs and therapeutic genes. The significant contribution of liposomes as drug delivery systems in the healthcare sector is known by many clinical products, e.g., Doxil®, Ambisome®, DepoDur™, etc. This review provides a detailed update on liposomal technologies e.g., DepoFoam™ Technology, Stealth technology, etc., the formulation aspects of clinically used products and ongoing clinical trials on liposomes. Keywords: liposomes; therapeutics; drug delivery; liposome technology; nanotechnology; clinical trials; marketed products 1. Introduction The concept of liposomal drug delivery system has revolutionised the pharmaceutical field. Alec Bangham, in 1961 [1], first described liposomes. Since then active research in the field of liposomes have been carried out and their applications are now well established in various areas, such as drug, biomolecules and gene delivery [2]. Liposomes are spherical vesicles characterised by a bilayer of lipids with an internal aqueous cavity. Liposome structural components are phospholipids or synthetic amphiphiles incorporated with sterols, such as cholesterol, to influence membrane permeability. Thin-film hydration is the most widely used preparation method for liposomes, in which lipid components with or without a drug are dissolved in an organic solvent. The solvent will be evaporated by rotary evaporation followed by rehydration of the film in an aqueous solvent. The other methods include reverse-phase evaporation, freeze-drying and ethanol injection [2]. Techniques like membrane extrusion, sonication, homogenization and/or freeze-thawing are being employed to control the size and size distribution. Liposomes can be formulated and processed to differ in size, composition, charge and lamellarity. Due to extensive developments in liposome technology, a number of liposome-based drug formulations are available for human use and many products are under different clinical trials. Encapsulation of drugs in liposomes (as shown in Figure1) enhanced the therapeutic indices of various agents, mainly through alterations in their pharmacokinetics and pharmacodynamics. Drugs with different solubility can be encapsulated in liposomes, hydrophobic drugs have affinity to the phospholipid bilayer and hydrophilic drugs are entrapped in the aqueous cavity. The first successful Pharmaceutics 2017, 9, 12; doi:10.3390/pharmaceutics9020012 www.mdpi.com/journal/pharmaceutics Pharmaceutics 2017, 9, 12 2 of 33 Pharmaceutics 2017, 9, 12 2 of 33 Pharmaceutics 2017, 9, 12 2 of 33 ® milestonemilestone in in liposome-based liposome-based productsproducts was the the introduction introduction of of Doxil Doxil® to tothe the U.S. U.S. market market in 1995 in 1995 for for milestone in liposome-based products was the introduction of Doxil® to the U.S. market in 1995 for thethe treatment treatment of of patients patients withwith ovarianovarian cancer cancer and and AIDS-related AIDS-related Kaposi’s Kaposi’s sarcoma sarcoma after after the the failure failure of of the treatment of patients with ovarian cancer and AIDS-related Kaposi’s sarcoma after the failure of priorprior systemic systemic chemotherapy chemotherapy oror intolerance to to su suchch therapy. therapy. Gabizon Gabizon and and Barenholz Barenholz commenced commenced the the prior systemic chemotherapy or intolerance to such therapy. Gabizon and Barenholz commenced the developmentdevelopment of of DoxilDoxil®® inin IsraelIsrael and the the USA USA [3]. [3]. It It was was th thee first first nano-sized nano-sized liposomal liposomal product product to to development of Doxil® in Israel and the USA [3]. It was the first nano-sized liposomal product to obtainobtain regulatory regulatory approval. approval. Later, Later, NeXstar NeXstar Pharmaceuticals Pharmaceuticals USA USA also also developed developed a liposomal a liposomal product, obtain regulatory approval. Later, NeXstar Pharmaceuticals USA also developed a liposomal DaunoXomeproduct, DaunoXome®, for the delivery®, for the of delivery daunorubicin of daunorubicin (DNR), which (DNR was), which approved was approved by the U.S. by FDA the U.S. in 1996 product, DaunoXome®, for the delivery of daunorubicin (DNR), which was approved by the U.S. FDA in 1996 for the management of advanced HIV-associated Kaposi’s sarcoma. Subsequently, a few forFDA the managementin 1996 for the of management advanced HIV-associated of advanced HIV-as Kaposi’ssociated sarcoma. Kaposi’s Subsequently, sarcoma. Subsequently, a few more products a few more products have become available for the management of various cancers. These products® havemore become products available have forbecome the management available for of the various management cancers. Theseof various products cancers. includes These Depocyt products by includes Depocyt® by ®SkyPharma Inc., Myocet® by Elan® Pharmaceuticals, Mepact® by Takeda ® SkyPharmaincludes Depocyt Inc., Myocet® by SkyPharmaby Elan Pharmaceuticals, Inc., Myocet® Mepactby Elan byPharmaceuticals, Takeda Pharmaceutical Mepact® andby Takeda Marqibo Pharmaceutical and Marqibo® by Talon Therapeutics. Recently, a fluorouracil and leucovorin byPharmaceutical Talon Therapeutics. and Marqibo Recently,® aby fluorouracil Talon Therapeutics. and leucovorin Recently, combination a fluorouracil therapy-based and leucovorin product combination therapy-based product was approved for metastatic adenocarcinoma of the pancreas. wascombination approved fortherapy-based metastatic adenocarcinomaproduct was approved of the pancreas.for metastatic This adenocarcinoma product is marketed of the as pancreas. Onivyde ™ This product is marketed as Onivyde™ by Merrimack Pharmaceuticals, Inc. Although cancer was the byThis Merrimack product Pharmaceuticals,is marketed as Onivyde™ Inc. Although by Merrimack cancer Pharmaceuticals, was the most widely Inc. Although explored cancer area in was terms the of most widely explored area in terms of clinically approved products of liposomes, liposomal products clinicallymost widely approved explored products area in of terms liposomes, of clinically liposomal approved products products were of also liposomes, developed liposomal for other products diseases were also developed for other diseases (Figure 2). For fungal infections, the U.S. FDA approved (Figurewere2 also). For developed fungal infections, for other the diseases U.S. FDA (Figure approved 2). For Amphotec fungal infections,® and Ambisome the U.S.® FDAin 1996 approved and 1997, Amphotec® and Ambisome® in 1996 and 1997, respectively. Treatment of fungal infections has respectively.Amphotec® Treatment and Ambisome of fungal® in infections1996 and has1997, benefited respectively. since Treatment the development of fungal of infections these liposomal has benefited since the development of these liposomal formulations of Amphotericin B (AmB). Also, formulationsbenefited since of Amphotericinthe development B (AmB).of these Also,liposomal liposomes formulations have become of Amphotericin important B carrier(AmB). systemsAlso, liposomes have become important carrier systems in vaccine development and interest in liposomal liposomes have become important carrier systems in vaccine development and interest in liposomal invaccines vaccine have development markedly andincreased interest because in liposomal of the development vaccines have of products markedly Epaxal increased® and becauseInflexal® ofV. the vaccines have markedly increased® because of the® development of products Epaxal® and Inflexal® V. developmentBoth products of productsare developed Epaxal by andCrucell, Inflexal BernaV. Biotech Both products for vaccination are developed against byhepatitis Crucell, and Berna Both products are developed by Crucell, Berna Biotech for vaccination against hepatitis and Biotechinfluenza, for vaccinationrespectively. against hepatitis and influenza, respectively. influenza, respectively. Drugs with toxicity and efficacy Liposome Liposomal drug with reduced toxicity Drugs withproblems toxicity and efficacy Liposome Liposomaland/or drug enhanced with reduced efficacy toxicity problems and/or enhanced efficacy Figure 1. Schematic representation showing the advantages of formulating drugs in liposomes. FigureFigure 1. 1.Schematic Schematic representation representation showingshowing the advant advantagesages of of formulating formulating drugs drugs in in liposomes. liposomes. Doxil® ® Doxil Abelcet® ®