AbstractpH-responsive biopolymers are employed in a plethora of biomedical and pharmaceutical applications, including the scope of designing enteric delivery systems to delay the drug release until reaching to the proximal and distal small intestines as the targeted sites (pH ~ 6.2 to 7.8) to induce systemic or localized therapeutic effects. However, there are shortage of GRAS (generally recognized as safe) pH-responsive polymers derived from sustainable resources with comparable features to the semi/synthetic counterparts in terms of performance, simplicity of processing, ease of modelling, and attaining reproducibility throughout the scale of production. In this insight, numbers of candidate polyacids biopolymers with pH-responsive properties were addressed thoroughly in the literature, however with limited exploration in designing enteric drug delivery systems (DDS) for pH-responsive drug delivery, including Jujuba/e (JUB), gum karaya (OGK), acemannan (ACN), arabinoxylan (AX), citrus pectin, casein protein (CAS), soya protein isolate (SPI), zein protein (ZN), whey protein isolate (WPI), and egg white protein (EGW).
This research aimed to investigate novel, green, GRAS pH-responsive polyacids for controlled drug release applications as gastro-resistance solid dosage forms, classified as polysaccharides and proteins-based polyacids that contain ionizable acidic functional moieties (i.e., -COOH), with estimated acid dissociation constant (pKa) and isoelectric point (IP) values between 2.5 to 5.8, demonstrating the lowest possible ionization and solubility upon the exposure to gastric simulated conditions (pH 1.2) and oppositely attaining maximum ionization (plateau) when exposed to the intestinal simulated conditions (pH 6.8 – pH 7.4). To propose simple approaches to conduct processing and purification of the investigated biomaterial. To perform physicochemical characterization and pH-responsive tests (pHRT) of the processed grades. To apply these bio-grades in the design of pH-responsive gastro-resistance scaffolds, including film-coated tablets, compaction-coated tablets, and compressed-matrix, thence evaluating their enteric performance and pH-sensitivity in modulating drug release (prednisolone) upon conducting in-vitro dissolution studies using USP-II dissolution apparatus, exposed to compendial simulated GI media.
The selection of candidate biopolymers was performed using novel analytical techniques including zeta potential analyser coupled with MPT-2 auto-titrator to scan polymer ionization profile vs pH shift in order to investigate ionization parameters including the primary pKa1, the presence of secondary pKa2, the slope of regression, and IP values. The second technique involved evaluating and comparing the solubility of the polymerised chains of carbons constituting their structure, upon the exposure to distinctive pH (1.2 vs 7.4), via measuring the elemental carbon using the inductively coupled plasma optical emission spectroscopy (ICP-OES) with 1930 Å and 2478 Å wavelengths to trace the elemental carbon corresponding to polymer ionization and solubility status. Furthermore, novel applications of conventional methods including phenol sulfuric acid assay (PSA) and Bradford assay (BSA) were exploited to investigate the pH-responsive behaviour based on detecting monosaccharides (at 490 nm) and amino acids (at 595 nm) corresponding to the solubility status of the polymers in simulated media. From the outcomes of screening phase, casein protein (CAS), jujuba/e polysaccharide (JUB), and gum Karaya polysaccharide (OGK) were prioritized for in-depth investigation in this research involved: raw biomaterial processing (CAS protein was processed following three pathways for re-polymerization, JUB was purified via the differential solubility to isolate polyacids polysaccharides, and OGK was processed using SN2 reaction conditions to obtain deacetylated DGK form), physicochemical characterization (including FT-IR, TGA, XRD, NMR, and content assay), pH-responsive tests (including zetasizer, ICP-O/AES, PSA, and BSA), and applying the pH-responsive grades in the design of enteric tablets.
CAS (pKa1 = 5.05 ± 0.16 and IP = 4.62 ± 0.11), JUB (pKa1= 3.43 ± 0.27), and OGK (pKa1 = 3.83 ± 0.45) were processed and purified successfully. The emergence of carbonyl carbon transitions (C=O) in FT-IR and NMR spectrums indicted the presence of acidic functional moieties (i.e., aspartic acids and glutamic acids in CAS, and uronic acids in JUB and DGK). The pH-responsive tests (pHRT) demonstrated the high acid resistance of these grades upon the exposure to gastric simulated media, and oppositely high buffer sensitivity when exposed to intestinal simulated media. The pKa and IP values of the processed CAS, JUB, and DGK were within the targeted range (2.5 to 5.8) indicating their suitability of use for enteric formulations purposes. CAS, JUB, and DGK selected processed/purified grades were successfully applied to design enteric solid dosage forms. These grades exhibited high compressibility due to their hydrophilic nature. Also, they have demonstrated compatibility with citrate esters, polyalcohols, glycol derivatives, and triglyceride as plasticizers producing uniform film with apparent elasticity and resilience. Dissolution tests outcomes for the successful film coated tablets, formulated based on CAS, JUB, and DGK processed grades, have illustrated the diffusion of less than 15 % of prednisolone upon the exposure to gastric simulated media (pH 1.2) for 2 h, 50 rpm, and 37°C, while releasing above 80% in less than ~ 40 min when exposed to intestinal simulated media (pH 6.8 – 7.4). Similar results were observed with compaction coated tablets and compressed matrix when expose to pH 1.2 (low drug diffusion
In conclusion, this research has presented simple analytical techniques to preliminary screen the pH-responsive behaviour of novel polymers (zeta potential measurements, ICP-O/AES, BSA, and PSA). The processed grades of CAS, JUB, DGK were deemed as novel, green, GRAS pH-responsive biopolymers suited for designing coated scaffolds, complying with the USP requirements for enteric formulations targeting the proximal and distal small intestinal sites for drug delivery.
|Date of Award||27 Mar 2023|
|Supervisor||Kofi Asare-Addo (Main Supervisor) & Barbara Conway (Co-Supervisor)|