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Abstract
This work aimed to achieve long-lasting delivery of radix ophiopogonis polysaccharide (ROP) by sucrose acetate isobutyrate (SAIB)-based in situ forming systems (ISFSs) alone or combined with mono-PEGylation of ROP. When the ‘90%SAIB/10% solvent’ system was used, the mean residence time (MRT) of ROP was prolonged by 4.3 5 ∼ 7.00 times and the initial release rate was reduced significantly. However, this system was only suitable for days-long sustained release of ROP in short-term therapy. As to the ‘SAIB/additives/solvent’ system containing mono-PEGylated ROP, the results indicated that SAIB/poly(d,l-lactide-co-glycolide) (PLGA)/N-methyl-2-pyrrolidone (NMP) was superior to SAIB/polylactic acid (PLA)/NMP and SAIB/PLA/ethanol in controlled release. Moreover, weeks- to months-long (16–60 d) smooth release of ROP could be achieved by varying the concentration (10–30%) and molecular weight (MW) of PLGA (10–50 kDa) or by employing a moderate MW of PEGylated ROP (∼20 or ∼30 kDa). With further increasing the conjugate MW to ∼40 kDa, the contribution of drug elimination to its plasma retention seemed to surpass that of the SAIB-based system, resulting in that the system no longer had an obvious influence on the in vivo behavior of the conjugate. Besides, the results of host response confirmed that with less solvent being used, the SAIB-based systems showed a higher biocompatibility than the PLGA-based systems, suggesting that they could be freely chosen in the prevention and/or cure of chronic diseases.
Highlights
Though macromolecule-based active agents, e.g. proteins, polypeptides, genes, and polysaccharides, are of great value in the treatment of a variety of diseases, unfavorable properties including low oral bioavailability, short plasma half-lives, and/or potential degradation in drug delivery, make their clinical applications quite challenging (Bao et al, 2016; Li et al, 2016; O’Neill et al, 2017; Wang & Burdick, 2017)
Sucrose acetate isobutyrate extended-release (SABER) systems for PEGylated-radix ophiopogonis polysaccharide (ROP) To investigate the feasibility of sucrose acetate isobutyrate (SAIB)-based in situ forming systems (ISFSs) in combination with PEGylated ROPs and release-modifying agents for long-lasting delivery of ROP, the SAIB/PLGA/NMP system with a series of PLGA molecular weight (MW) and 30 kDa PEG mono-PEGylated ROP (MP30k-R) were tested with the results shown in Figure 2(a) and Table 3
With the reasonable combination of SABER systems with PEGylated drugs having a MW around the glomerular filtration threshold, anticipant long-lasting and steady plasma exposure of drugs could be achieved without bringing the in vivo accumulation problem
Summary
Though macromolecule-based active agents, e.g. proteins, polypeptides, genes, and polysaccharides, are of great value in the treatment of a variety of diseases, unfavorable properties including low oral bioavailability, short plasma half-lives, and/or potential degradation in drug delivery, make their clinical applications quite challenging (Bao et al, 2016; Li et al, 2016; O’Neill et al, 2017; Wang & Burdick, 2017). Long-acting drug delivery systems are desired to improve patient compliance, reduce administration frequency, and minimize adverse effects. The main strategies used in long-acting delivery of hydrophilic macromolecular drugs are (i) using sustained-release delivery systems and (ii) chemical modification of parent drugs. Among sustained-release delivery systems, in situ forming systems (ISFSs) have become the focus of attention with the advantages of ease of administration, potential for local/sitespecific delivery, potential for improved drug stability, and simplified manufacturing (Wright & Burgess, 2012). Sucrose acetate isobutyrate extended-release (SABER) systems are composed of sucrose acetate isobutyrate (SAIB), and one or more pharmaceutically acceptable solvents (ethanol, N-methyl-2-pyrrolidone, dimethyl sulfoxide, benzyl alcohol, benzyl benzoate (BB), etc.) as well as other excipients. When SAIB is mixed with pharmaceutically acceptable solvents, the viscosity of the system can be dramatically reduced, making it possible to be injected through standard needles. When the system is injected, the diffusion of solvents out of the depot results in an increase in viscosity, decreasing the release rate of drugs trapped in depots and obtaining a Supplemental data for this article can be accessed here
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