Sustained-release drug delivery systems

Abstract

The design and development of a sustained-release drug delivery system targeting the administration of active pharmaceutical ingredients (APIs) to the eye could overcome the limitations of topically administered eye drops. Understanding how to modify or design new materials with specific functional properties that promote the attachment and release of specific drugs over longer time periods, alongside understanding clinical needs, can lead to new strategic opportunities to improve treatment options. In this paper we discuss two approaches to the design or modification of materials to produce a sustained therapeutic effect. Firstly, we discuss how the synthesis of a peptide hydrogel from a naturally-derived antimicrobial material led to the design of a bandage contact lens which may be able to be used prophylactically to reduce post-surgery infection. Secondly, we discuss how silicone oil tamponade agents used to treat retinal detachments can have adjunctive behaviour to enhance the solubility of the anti-proliferative drug retinoic acid and produce a sustained release over several weeks. These studies are the result of close partnerships between clinical ophthalmologists, materials scientists, and chemists, and illustrate how these partnerships can lead to comprehensive understandings that have the potential to change patient outcomes.

Fig. 1. Poly-ε-lysine bandage contact lens.

A Schematic of the hydrogel structure with potential API binding sites; B Cast lens and demonstration of pinching flexibility; C Potential APIs that can be bound via carboxyl group.

Fig. 2. Reduction in Pseudomonas aeruginosa outgrowth from poly-ε-lysine hydrogels with pendent poly-ε-lysine (pɛK+), poly-ε-lysine hydrogels (pεK) and LB agar discs.

The hydrogels and LB agar discs were incubated overnight in Pseudomonas aeruginosa (PAO1, PA39016, and PA58017) at 10³, 10⁴, 10⁵, 10⁶, and 10⁷ CFU for 24 h, removed from buffer, and plated onto LB agar plates, incubated overnight at 37 °C. Scale bar = 6 mm [7].

Fig. 3. Antimicrobial activity of poly-ε-lysine hydrogels with pendent poly-ε-lysine (pɛK+), compared with poly-ε-lysine (pεK) hydrogels and commercial hydrogel CL against Pseudomonas aeruginosa isolates.

Viable Pseudomonas aeruginosa in PBS buffer (A, C) and associated with pεK+ hydrogel (B, D), compared with pεK hydrogel and commercial hydrogel CL. PεK+ hydrogel, pεK hydrogel, and commercial hydrogel CLs were inoculated with P aeruginosa (PAO1, PA39016, and PA58017) at 10³ (A, B) and 10⁶ (C, D) CFU for 24 h. Viable bacterial counts were determined as CFU. Values represent mean of four independent experiments, error bars represent the standard deviation. *P < 0.05 using two-way ANOVA and post hoc Tukey’s analysis [7].

Fig. 4. Toxicity of poly-ε-lysine hydrogels with pendent poly-ε-lysine (pɛK+), compared with poly-ε-lysine (pεK) hydrogels and commercial hydrogel CL against Acanthamoeba castellanii.

A Graph to show the percentage of dead trophozoites at 24 h; B Graph shows the percentage of dead trophozoites at 7 days to total live and dead trophozoites; C Graph to show the percentage of dead cysts at 24 h; D Graph shows the percentage of dead cysts at 7 days to total live and dead trophozoites; Chlorohexidine was the positive control. Experiments were performed in triplicate (n = 3), with three wells per experiment and five fields of view in each well. One-way ANOVA was performed with a post hoc Tukey’s analysis, and P < 0.05 was considered significant [10].

Fig. 5. Comparison of saturation concentration of atRA measured in silicone oil (SIO) via acetone extraction followed by UV–Vis (SIO1000 n = 4, SIO5000 n = 3) and radioactivity measurements (SIO1000 n = 4; SIO5000 n = 4).

Literature value taken from Araiz et al. [21] Error bars +1 standard deviation.

Fig. 6. Schematic representation of silicone oil-API modification strategies to increase solubility and release.

A API molecules co-dissolved within the silicone oil with graft co-polymers of methacrylated poly-dimethylsiloxane (PDMSMA) and methacrylated ethylene glycol (OEGMA) using RAFT polymerisation [18]; B Co-dissolved API conjugate between a short chain hydroxy-terminated poly-dimethylsiloxane and atRA via an esterification reaction.

Fig. 7. Graft copolymers with varying ratio, chain length and composition.

A Monomethacryloxypropyl poly(dimethylsiloxane) methacrylate and oligo(ethylene glycol)monomethyl ethermethacrylate used during this study; B Schematic representation of structural and compositional variation within the statistical graft copolymers (i) low incorporation of hydrophilic grafts or similar chain length to hydrophobic chains; (ii) variation of hydrophobic graft length; (iii) increased composition of hydrophilic chains, and (iv) increased hydrophobic graft chain length at higher ratios of hydrophilic chains [18].

Fig. 8. Studies of atRA release from silicone oil tamponades into aqueous media in the absence (open red triangles) and presence of statistical graft copolymer, using drug mixtures containing ³H-labelled atRA.

Effect of increasing dissolved graft copolymer from 5 v/v% (open blue circles) to 10 v/v% (open green squares) within the silicone oil at all-trans retinoic acid concentrations of (A) 20 μg/mL, and (B) 200 μg/mL [18].