ABSTRACT
Hydrophobic ion pairing (HIP) complexation was found to be an efficient approach in modulating the release and enhancing the stability and encapsulation of hydrophilic macromolecules such as proteins in hydrophobic nano/microcarriers. The present work strives to develop and optimize the preparation of the HIP complex of the antimicrobial enzyme lysozyme (LYZ) with the ion-pairing agent (IPA) sodium dodecyl sulphate (SDS) relying on the quality-by-design (QbD) approach. The quality target product profile (QTPP) includes the achievement of maximal lipophilicity in a reversible manner to enable the maintenance of biological activity. The related critical quality attributes (CQAs) were defined as complexation efficacy, complex stability, enzyme recovery and activity. Three risk assessment (RA) tools were used to identify and rank the critical process parameters (CPPs) and critical material attributes (CMAs). From this assessment, the pH of the medium, LYZ:SDS molar ratio and drying conditions were determined as high-risk factors that need to be investigated. To the best of our knowledge, for the first time, electrostatic titration was used as a smart approach to determine the optimum molar ratio at different pH values. Based on the predefined CQAs, pH 8 with an LYZ/SDS molar ratio of 1:8 was found to be the optimal condition for complexation efficiency and recovery (%) of a biologically active enzyme. A cost-effective drying process based on a ventilated oven was developed, which resulted in complex qualities comparable to those obtained by the commonly used freeze-drying method. In a nutshell, the optimum conditions for the preparation of the LYZ/SDS HIP complex were efficiently facilitated by the rational application of QbD principles and the utilization of efficient electrostatic titration and ventilated oven-drying methods.
ABSTRACT
Mucoadhesive buccal films have found increased popularity in pharmaceutical drug delivery due to the several advantages that they possess. The present study strives to develop and optimize chitosan-based mucoadhesive buccal films by relying on quality-by-design (QbD) principles. Previous knowledge and experience were employed to firstly identify the critical quality attributes (CQAs), followed by a thorough risk assessment, which led to the selection of seven critical material attributes and process parameters, namely, the polymer grade and concentration, the plasticizer type and concentration, the citric acid (CA) concentration, the amount of the casted solution, and the drying condition. Their effects on the breaking hardness and mucoadhesivity, selected as CQAs, were investigated in three steps by three designs of the experiment (DoE). The medium molecular weight of chitosan (CH) was the preferred choice in the optimized formulation, and its concentration was the most important factor affecting the CQAs, thickness, and moisture content of the films. It was found that 0.364 g/cm2 was the suitable amount of the casting solution, and its optimum drying conditions were presented in the form of a design space. Glycerol (Gly) was the best choice as a plasticizer, and a design space representing several combinations of CH and CA concentrations that produce films with the required quality was constructed at a fixed concentration of 35% Gly. A formula from this design space was selected and employed to load with two model drugs to test its drug-carrying properties for drugs with different physicochemical characteristics. Uniform drug distribution with an immediate release profile was achieved in both drugs, although one of the CQAs was outside of the specifications in the case of lidocaine-containing film. To summarize, the obtention of the optimum mucoadhesive buccal film based on CH was efficiently facilitated by the rational application of QbD principles and the DoE approach.
ABSTRACT
For many years, researchers have been making efforts to find a manufacturing technique, as well as a drug delivery system, that will allow for oral delivery of biopharmaceuticals to their target site of action without impairing their biological activity. Due to the positive in vivo outcomes of this formulation strategy, self-emulsifying drug delivery systems (SEDDSs) have been intensively studied in the last few years as a way of overcoming the different challenges associated with the oral delivery of macromolecules. The purpose of the present study was to examine the possibility of developing solid SEDDSs as potential carriers for the oral delivery of lysozyme (LYS) using the Quality by Design (QbD) concept. LYS was successfully ion paired with anionic surfactant, sodium dodecyl sulphate (SDS), and this complex was incorporated into a previously developed and optimized liquid SEDDS formulation comprising medium-chain triglycerides, polysorbate 80, and PEG 400. The final formulation of a liquid SEDDS carrying the LYS:SDS complex showed satisfactory in vitro characteristics as well as self-emulsifying properties (droplet size: 13.02 nm, PDI: 0.245, and zeta potential: -4.85 mV). The obtained nanoemulsions were robust to dilution in the different media and highly stable after 7 days, with a minor increase in droplet size (13.84 nm) and constant negative zeta potential (-0.49 mV). An optimized liquid SEDDS loaded with the LYS:SDS complex was further solidified into powders by adsorption onto a chosen solid carrier, followed by direct compression into self-emulsifying tablets. Solid SEDDS formulations also exhibited acceptable in vitro characteristics, while LYS preserved its therapeutic activity in all phases of the development process. On the basis of the results gathered, loading the hydrophobic ion pairs of therapeutic proteins and peptides to solid SEDDS may serve as a potential method for delivering biopharmaceuticals orally.
