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[Display omitted] For many biopharmaceuticals, subcutaneous (sc) administration is the only viable route. However, there is no in vitro method available accurately predicting the absorption profiles of subcutaneously injected pharmaceuticals. In this work, we show that a recently developed microfluidics method for interaction studies (MIS) has the potential to be useful in this respect. The method utilises the responsiveness of polyelectrolyte microgel networks to oppositely charged molecules as a means to monitor the interaction between peptides and hyaluronic acid (HA), a major constituent of the subcutaneous extracellular matrix. We use the method to determine parameters describing the strength of interaction between peptide and HA as well as the peptide's aggregation tendency and transport properties in HA networks. The results from MIS studies of the peptide drugs exenatide, pramlintide, vancomycin, polymyxin B, lanreotide, MEDI7219 and AZD2820 are compared with results from measurements with the commercially available SCISSOR system and in vivo absorption and bioavailability data from the literature. We show that both MIS and SCISSOR reveal differences in the peptides' diffusivity and tendency to aggregate in the presence of HA. We show that MIS is particularly good at discriminating between peptides forming aggregates stabilised by non-electrostatic forces in the presence of HA, and peptides forming complexes stabilised by electrostatic interactions with HA. The method provides two parameters that can be used to quantify the peptides' aggregation tendency, the one describing the peptide packing density in complexes with HA and the other the apparent diffusivity upon release in a medium of physiological ionic strength and pH. The order of the peptides when ranked by increasing binding strength at pH 7.4 determined with MIS is shown to be in agreement with the order when ranked by the apparent 1st order absorption rate constant (k a) after sc administration in humans: lanreotide (Autogel) < exenatide (IRF) < AZD2820 < pramlintide < lanreotide (IRF) (IRF: Immediate release formulation). A correlation is found between the 1st order release rate constant determined with SCISSOR and k a for lanreotide (Autogel), exenatide and AZD2820. A mechanism relating the magnitude of k a to the peptides' charge is proposed. [ABSTRACT FROM AUTHOR]

[Display omitted] Drug-eluting beads made of responsive polyelectrolyte networks are used in the treatment of liver cancer. Aggregates of loaded drugs in complex with the networks dissolve upon release, causing swelling of the network. According to a recent mechanism the release and swelling rates are controlled by the mass transport of drug through a depletion layer created in the microgel. We hypothesise that the mechanism, in which the stability of the drug aggregates and the swelling properties of the network play crucial roles, offers means to control the release profile also for other drugs. To test this, we investigated the loading and release properties of amitriptyline, chlorpromazine and doxepin in polyacrylate, hyaluronate and DCbead™ microgels in a microfluidic setup. Loaded drugs could be released to a medium with physiological ionic strength and pH. The binding strength increased with decreasing critical micelle concentration of the drugs and increasing linear charge density of network chains. Microgels displayed drug-rich core/swollen shell coexistence, and swelled during release at a rate in agreement with the depletion layer mechanism, indicating its generality. The results demonstrate the potential of microgels as vehicles for amphiphilic drugs and the usefulness of the microfluidics method for in vitro studies of such systems. [ABSTRACT FROM AUTHOR]

[Display omitted] Subcutaneous injection is one of the most common approaches for administering biopharmaceuticals unsuitable for oral delivery. However, there is a lack of methods to predict the behavior of biopharmaceuticals within the extracellular matrix of the subcutaneous tissue. In this work, we present a novel miniaturized microfluidic-based in vitro method able to investigate interactions between drug molecules and the polymers of the subcutaneous extracellular matrix. To validate the method, microgels consisting of, respectively, covalently cross-linked hyaluronic acid, polyacrylic acid, and commercially available DC Bead™, were exposed to three model substances: cytochrome C , protamine sulfate and amitriptyline hydrochloride. These components were chosen to include systems with widely different physiochemical properties (charge, size, self-assembly, etc.) The experimental results were compared with theoretical predictions from a gel model developed earlier. The results show that the method is suitable as a rapid screening method for automated, large-scale, probing of interactions between biopolymers and drug molecules, with small consumption of material. [ABSTRACT FROM AUTHOR]