In the conventionally used and thoroughly investigated emulsification method, stability of peptides and proteins is still a challenge. Emerging methods like solvent displacement, layer-by-layer polymer deposition, electrospraying and supercritical fluid technologies have the potential to improve stability of the protein and peptide. Nonetheless, these methods are still under development and they need critical evaluation to improve production efficiency before proceeding to in vivo efficacy studies. Improvement should be achieved by strengthening cooperation between academic research groups, pharmaceutical companies and regulatory authorities.
The
aim of this study was to develop a formulation with a sustained
intra-articular release of the anti-inflammatory drug tacrolimus.
Drug release kinetics from the prepared tacrolimus loaded monodisperse
biodegradable microspheres based on poly(d-l-lactide-PEG)-b-poly(l-lactide) multiblock copolymers were tunable
by changing polymer composition, particularly hydrophobic–hydrophilic
block ratio. The monospheres were 30 μm and released the drug,
depending on the formulation, in 7 to >42 days. The formulation
exhibiting
sustained release for 1 month was selected for further in vivo evaluation.
Rat knees were injected with three different doses of tacrolimus (10
wt %) loaded monospheres (2.5, 5.0, and 10 mg), contralateral control
knees with saline. Micro-CT and histology showed no negative changes
on cartilage, indicating good biocompatibility. Minor osteophyte formation
was seen in a dose dependent fashion, suggesting local drug release
and therapeutic action thereof. To investigate in vivo drug release,
tacrolimus monospheres were injected into horse joints, after which
multiple blood and synovial fluid samples were taken. Sustained intra-articular
release was seen during the entire four-week follow-up, with negligible
systemic drug concentrations (<1 ng/mL), confirming the feasibility
of local intra-articular drug delivery without provoking systemic
effects. Intra-articular injection of unloaded monospheres led to
a transient inflammatory reaction, measured by total synovial leucocyte
count (72 h). This reaction was significantly lower in joints injected
with tacrolimus loaded monospheres, showing not only the successful
local tacrolimus delivery but also local anti-inflammatory action.
This local anti-inflammatory potential without systemic side-effects
can be beneficial in the treatment of inflammatory joint diseases,
among which is osteoarthritis.
PurposeThe increasing prevalence and treatment costs of kidney diseases call for innovative therapeutic strategies that prevent disease progression at an early stage. We studied a novel method of subcapsular injection of monodisperse microspheres, to use as a local delivery system of drugs to the kidney.MethodsWe generated placebo- and rapamycin monodisperse microspheres to investigate subcapsular delivery of drugs. Using a rat model of acute kidney injury, subcapsular injection of placebo and rapamycin monodisperse microspheres (monospheres) was compared to subcutaneous injection, mimicking systemic administration.ResultsWe did not find any adverse effects related to the delivery method. Irrespective of the injection site, a similar low dose of rapamycin was present in the circulation. However, only local intrarenal delivery of rapamycin from monospheres led to decreased macrophage infiltration and a significantly lower amount of myofibroblasts in the kidney, where systemic administration did not. Local delivery of rapamycin did cause a transient increase in the deposition of collagen I, but not of collagen III.ConclusionsWe conclude that therapeutic effects can be increased when rapamycin is delivered subcapsularly by monospheres, which, combined with low systemic concentrations, may lead to an effective intrarenal delivery method.Electronic supplementary materialThe online version of this article (doi:10.1007/s11095-015-1700-8) contains supplementary material, which is available to authorized users.
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