Critical process parameters in manufacturing of liposomal formulations of amphotericin B

Rivnay, Benjamin; Wakim, Joseph; Avery, Ken; Petrochenko, Peter; Myung, Ja Hye; Kozak, Darby; Yoon, Seongkyu; Landrau, Nelson; Nivorozhkin, Alex

doi:10.1016/j.ijpharm.2019.04.052

Cited by 32 publications

(31 citation statements)

References 29 publications

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“…However, conventional liposomes (Figure 6C) revealed at least two lipid bilayers confirmed the multivesicular structure of the liposomes. The lyophilization of liposomes is one of the best ways to circumvent many of the stability problems associated with liquid liposome suspensions; thus, this is a frequently used technique to improve the stability of systems that are unstable in an aqueous environment, such as proteins and liposomes [19,27]. It has been reported that the liposomes containing drug molecules can be lyophilized and reconstituted with significant drug retention, which is measured as the percent of the encapsulated drug and without a significant change in the mean vesicle size.…”

Section: Discussionmentioning

confidence: 99%

“…Among these formulations, the liposomal formulation (AmBisome ® ) has significantly lower toxicity when compared to the other formulations, thus permitting larger doses to be administered; accordingly, AmBisome ® is more effective than the other formulations [18]. However, despite the advantages of the liposomal formulation, these preparations are not easily accessible because of the high cost of manufacturing and the preparation method used, which is rather complex for scaling-up [19]. Therefore, an alternate simple, scalable, and cost-effective liposomal preparation method is needed for rectifying these issues.…”

Section: Introductionmentioning

confidence: 99%

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Preparation, Characterization, and In Vivo Pharmacokinetic Study of the Supercritical Fluid-Processed Liposomal Amphotericin B

et al. 2019

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Here, we aimed to prepare and optimize liposomal amphotericin B (AmB) while using the supercritical fluid of carbon dioxide (SCF-CO2) method and investigate the characteristics and pharmacokinetics of the SCF-CO2-processed liposomal AmB. Liposomes containing phospholipids, ascorbic acid (vit C), and cholesterol were prepared by the SCF-CO2 method at an optimized pressure and temperature; conventional liposomes were also prepared using the thin film hydration method and then compared with the SCF-CO2-processed-liposomes. The optimized formulation was evaluated by in vitro hemolysis tests on rat erythrocytes and in vivo pharmacokinetics after intravenous administration to Sprague-Dawley rats and compared with a marketed AmB micellar formulation, Fungizone®, and a liposomal formulation, AmBisome®. The results of the characterization studies demonstrated that the SCF-CO2-processed-liposomes were spherical particles with an average particle size of 137 nm (after homogenization) and drug encapsulation efficiency (EE) was about 90%. After freeze-drying, mean particle size, EE, and zeta potential were not significantly changed. The stability study of the liposomes showed that liposomal AmB that was prepared by the SCF method was stable over time. In vivo pharmacokinetics revealed that the SCF-CO2-processed-liposomes were bioequivalent to AmBisome®; the hemolytic test depicted less hematotoxicity than Fungizone®. Therefore, this method could serve as a potential alternative for preparing liposomal AmB for industrial applications.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Preparation, Characterization, and In Vivo Pharmacokinetic Study of the Supercritical Fluid-Processed Liposomal Amphotericin B

et al. 2019

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“…Patent expiration protecting the original lipid-based AmB formulations in the market represented an opportunity for the introduction of less expensive generics. However, generic manufacturing of AmB lipid formulations requires careful control of processing conditions and appropriate bioequivalence testing, since changes in phospholipid composition, size and charge of liposomes, drug-lipid molar ratio as well as the manufacturing process can alter the formulation efficacy and toxicity [25,149,150]. Even liposomal formulations with the same chemical composition of AmBisome ® that reached national markets, such as Phosome ® , Lambin ® or Anfogen ® , may reveal distinct pharmacokinetics, drug release and safety profiles, suggesting that different manufacturing processes may alter the properties of the final product [149,[151][152][153].…”

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confidence: 99%

Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy

2020

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Amphotericin B (AmB), a broad-spectrum polyene antibiotic in the clinic for more than fifty years, remains the gold standard in the treatment of life-threatening invasive fungal infections and visceral leishmaniasis. Due to its poor water solubility and membrane permeability, AmB is conventionally formulated with deoxycholate as a micellar suspension for intravenous administration, but severe infusion-related side effects and nephrotoxicity hamper its therapeutic potential. Lipid-based formulations, such as liposomal AmB, have been developed which significantly reduce the toxic side effects of the drug. However, their high cost and the need for parenteral administration limit their widespread use. Therefore, delivery systems that can retain or even enhance antimicrobial efficacy while simultaneously reducing AmB adverse events are an active area of research. Among those, lipid systems have been extensively investigated due to the high affinity of AmB for binding lipids. The development of a safe and cost-effective oral formulation able to improve drug accessibility would be a major breakthrough, and several lipid systems for the oral delivery of AmB are currently under development. This review summarizes recent advances in lipid-based systems for targeted delivery of AmB focusing on non-parenteral nanoparticulate formulations mainly investigated over the last five years and highlighting those that are currently in clinical trials.

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“…In this manufacturing process, the amphotericin B and DSPG complex remains an essential element. [23] Since amphotericin B is water-insoluble, it is difficult to make a complex in an aqueous phase. Therefore, the solubility of amphotericin B was altered using the protonation of the amine group from amphotericin B. Acidified DSPG receives the proton from amphotericin B and forms a complex in aqueous phases.…”

Section: Discussionmentioning

confidence: 99%

Scalable solvent-free production of liposomes

Khadke

Roces

Donaghey

et al. 2020

Journal of Pharmacy and Pharmacology

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Objectives A major challenge faced with the manufacture of liposomes is the high volumes of organic solvents used during manufacturing. Therefore, we have implemented an organic solvent‐free production method for drug‐loaded liposomes and demonstrated its applicability with both aqueous core‐loaded and bilayer‐loaded drugs. Methods Liposomes were produced by high shear mixing dry powder lipids with an aqueous buffer, followed by down‐sizing using a Microfluidizer processor. Liposomes were purified via tangential flow filtration and characterised in terms of size, polydispersity index, zeta potential and drug loading. Key findings Doxorubicin‐loaded PEGylated liposomes can be manufactured using this solvent‐free method with particle sizes of 100–110 nm, low polydispersity index (PDI) (<0.2) and high drug loading (97–98%). If required, liposomes can be further down‐sized via microfluidic processing without impacting drug loading. Similar results were achieved with non‐PEGylated liposomes. With bilayer‐loaded amphotericin B liposomes, again liposomes can be prepared within a clinically appropriate size range (100–110 nm in size, low PDI) with high drug loading (98–100%). Conclusions We apply a simple and scalable solvent‐free method for the production of both aqueous core or bilayer drug‐loaded liposomes.

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Critical process parameters in manufacturing of liposomal formulations of amphotericin B

Cited by 32 publications

References 29 publications

Preparation, Characterization, and In Vivo Pharmacokinetic Study of the Supercritical Fluid-Processed Liposomal Amphotericin B

Preparation, Characterization, and In Vivo Pharmacokinetic Study of the Supercritical Fluid-Processed Liposomal Amphotericin B

Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy

Scalable solvent-free production of liposomes

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