Muhammad Asad,Akhtar Rasul ,Ghulam Abbas,Muhammad Ajmal Shah,Imran Nazir
Abstract
Biopharmaceutical classification systems (BCS) class III drugs belongs to a group of drugs with high solubility in gastrointestinal (GI) fluids and low membrane permeability result in significantly low bioavailability. Self-emulsifying drug delivery systems (SEDDS) considered a suitable candidate to enhance the bioavailability of poorly soluble drugs by improving their membrane permeability, however, incorporating hydrophilic drugs in to these carriers remained a great challenge. The aim of this study was to develop hydrophobic ion pairs (HIPs) of a model BCS class-III drug tobramycin (TOB) in order to incorporate into SEDDS and improve its bioavailability. HIPs of TOB were formulated using anionic surfactants sodium docusate (DOC) and sodium dodecanoate (DOD). The efficiency of HIPs was estimated by measuring the concentration of formed complexes in water, zeta potential determination and log P value evaluation. Solubility studies of HIPs of TOB with DOC were accomplished to screen the suitable excipients for SEDDS development. Consequently, HIPs of TOB with DOC were loaded into SEDDS and assessed the log DSEDDS/release medium and dissociation of these complexes at different intestinal pH over time. Moreover, cytotoxic potential of HIPs of TOB and HIPs loaded SEDDS formulations was evaluated.
Introduction
Pursuant to biopharmaceutical classification system (BCS), the rate and extent of drug absorption mainly depend on their solubility and permeability through the biological membranes [1]. During recent decades, BCS class-III drugs in particular therapeutic peptides and proteins are focus of interest due to their high therapeutic potential [2, 3]. BCS class-III drugs are hydrophilic compounds and highly soluble in gastrointestinal (GI) fluids but exhibit low permeability across the epithelial cells [4]. Hence, enormous BCS class-III drugs still has to be administered through a parenteral route and often requires the assistance of trained specialists. Therefore, the pharmaceutical industry is mainly focused on the development of oral delivery systems for BCS class III drugs to improve the patient compliance.
Material and methods
2.1. Materials
Tobramycin (TOB) was a gift sample from Welmark Pharmaceuticals (Hattar, Pakistan). Docusate sodium (DOC), sodium dodecanoate (DOD), Propylene glycol and acetonitril were obtained from Sigma-Aldrich (Darmstadt, Germany). Peceol (glycerol monooleate, HLB = 3), Cremophor RH (castor oil, hydrogenated, ethoxylated) and Maisine 35–1 (glycerol monolinoleate, HLB = 1) were a gift from Gattefossé (Lyon France).
2.2. Methods
2.2.1. HPLC analysis.
The concentration of TOB was quantified by HPLC using a previously described method [19, 20]. Samples were analyzed by using a reverse phase C-18100 mm× 4.6 mm, 5 μm column as stationary phase. Acetonitrile 50% (v/v) and water 50% (v/v) used as a mobile phase. The flow rate of 1mL/min was used. Sample of 20 μL was injected and concentration of TOB was evaluated at a wavelength of 230 nm.
Results
3.1. Preparation of HIPs
Precipitation efficiency could not reach the 100% probably because intra-molecular hydrogen bonding can occur, therefore, the interaction between drug and surfactant can be reduced. As according to theory, the maximum complexation should occur at equimolar ratio of cationic and anionic charges. Therefore, the highest precipitation efficiency of HIPs of TOB should be registered at molar ratio 1:5, because TOB exhibit five positive charges due to the presence of–NH3+ and surfactants in solution exhibit one negative charge as illustrated in Fig 1. The ion pair formation is primarily based on columbic force which is directly proportional to the magnitudes of the charges [25].
Discussion
3.2. Lipophilicity (Log P) determination
The diffusion of drugs across the absorption membrane of GI tract is based on the capability of the drugs to cross phospholipidic bilayer of epithelial membranes. According to this, compounds with hydrophobic properties should permeate easier across the biological membranes than molecules with hydrophilic character [30]. Enhancing the lipophilic behavior of hydrophilic ionizable drugs via HIP has efficiently increased their ability to permeate across the epithelial membranes [10]. Miller et al. reported that the permeation of phenformin was improved 4.9-fold across the Caco-2 cell monolayers by enhancing its lipophilic character using 1-hydroxy-2-naphtoic acid as counter ion [31].
Conclusion
Within the present study, we utilized the concept of HIP to improve the lipophilicity of a model BCS class III drug TOB followed by its incorporation into lipid based nanocarrier systems. Lipophilicity of TOB was increased utilizing various counterions. Lipid based delivery systems in particular SEDDS have synergistic effect as HIPs is likely stable in these oily droplets due to their lower dielectric constant compared to intestinal fluids and permeate more rapidly across the lipophilic membranes.
Citation: Asad M, Rasul A, Abbas G, Shah MA, Nazir I (2023) Self-emulsifying drug delivery systems: A versatile approach to enhance the oral delivery of BCS class III drug via hydrophobic ion pairing. PLoS ONE 18(6): e0286668. https://doi.org/10.1371/journal.pone.0286668
Editor: Kaisar Raza, Central University of Rajasthan, INDIA
Received: January 11, 2023; Accepted: May 20, 2023; Published: June 9, 2023
Copyright: © 2023 Asad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
