Variables for the design of an in vitro release test of Liposomal Drug Products (LDP): an example

PEROSIO, PAULA; CASADO, CRISTIAN; CÓRDOBA, LUCIA; MASSÓ, ROCIO; QUINZIO, EUGENIA; HERRERO, M. JIMENA; RIZZI, CAROLINA; BIANCO, ISMAEL D.; DABBENE, VIVIANA G.

Rosario

Congreso; 7ma Reunión Internacional de Ciencias Farmacéuticas (RICiFa); 2023

RICiFa

Encapsulation of drugs into liposomes can lead to the enhancement oftherapeutic efficacy of drugs, reduction of their toxicity andprolongation of their therapeutic effect. The unique ability ofliposomes to entrap drugs both in the aqueous and the lipid phasemake such delivery systems attractive for hydrophilic and hydrophobicdrugs.Critical quality attributes (CQAs) of the LDP are physical orchemical properties that can affect the product’s pharmacokinetic, pharmacodynamic and biological performance.Based on the mechanism of pharmacokinetics and the properties ofLDPs, CQAs typically include particle size and size distribution,drug loading efficiency and in vitro drug release rate (IDR),among others.Establishing appropriate IDR testing methods of LDP for assuringquality and performance requires the determination of factorsaffecting in vitro drug release. The aim of the present study was to investigate the effect ofdifferent test conditions (pH, Dissolution medium (DM) composition,salt concentration, temperature) of IDR, by using a dialysismembrane, on an Acid Hidrophilic Drug (AHD) encapsulated in a LDP.LDP samples (0.5 mL) were introduced into dialysis bags (10 mm avg.flat width, 12,4 KDa) and inmersed in 35 mL of DM, stirred at 125 rpmin an incubator set at different temperatures. Samples (0.5 mL) werecollected at predetermined time intervals (4, 24, 48 and 72 h) andAHD was quantified by reverse-phase high pressure chromatography(RP-HPLC). The volume of the DM was kept constant by adding fresh DM.The conditions were selected based on the recommendations of DraftGuidance on Doxorubicin Hydrochloride LDP, Food and DrugAdministration, May, 2022.DMs containing phosphate buffered saline (PBS), ammonium chloride(AmCl), NaCl, propylene glycol (PG) and methanol (MeOH) and differentincubation temperatures were studied in order to establish the bestconditions to obtain a suitable release profile.Under the conditions studied it was demonstrated that the releaserates of the AHD from the LDP satisfied the sink conditions and theAHD was stable up to 168 h.The pH of the DM was critical for the IDR of an AHD from a LDP with35-65 % IDR at pH 5.5, > 80 % IDR at pH 6.5 and > 85 % IDR atpH 7.5, after 24 h, at 38 °C. Practically no release of AHD from LDP was observed in the absence ofAmCl in the DM. Stressing the importance of the saline compositionof the DM in the IDR, the addition of NaCl led to a decrease to 10 %IDR at 24 h. The addition of PG led to a 25 % decrease in the IDR buta combination of PG with MeOH led to a 25 % increase in the IDR. Increasing the incubation temperature to 43 °C led to > 75 %release at 24 h and to > 90 % at 47 ºCAltogether, the results shown herein indicate that salt and solventcomposition of DM and its pH and incubation temperature are criticalparameters that could be modified in order to develop highlydiscriminatory IDR assays for quality control of LDP containing AHD.p { margin-bottom: 0.1in; direction: ltr; color: #000000; line-height: 115%; text-align: left; orphans: 2; widows: 2 }p.western { font-family: "Calibri", serif; font-size: 11pt; so-language: es-AR }p.cjk { font-family: "Calibri"; font-size: 11pt; so-language: es-AR }p.ctl { font-family: "Calibri"; font-size: 11pt; so-language: hi-IN }a:link { color: #0563c1 }