ABSTRACT
This article describes the utilization of (methoxy)poly(ethylene glycol)-b-poly(1,3-trimethylene carbonate) ((m)PEG-PTMC) diblock and triblock copolymers for the formulation of in situ forming depot long-acting injectables by solvent exchange. The results shown in this manuscript demonstrate that it is possible to achieve long-term drug deliveries from suspension formulations prepared with these copolymers, with release durations up to several months in vitro. The utilization of copolymers with different PEG and PTMC molecular weights affords to modulate the release profile and duration. A pharmacokinetic study in rats with meloxicam confirmed the feasibility of achieving at least 28 days of sustained delivery by using this technology while showing good local tolerability in the subcutaneous environment. The characterization of the depots at the end of the in vivo study suggests that the rapid phase exchange upon administration and the surface erosion of the resulting depots are driving the delivery kinetics from suspension formulations. Due to the widely accepted utilization of meloxicam as an analgesic drug for animal care, the results shown in this article are of special interest for the development of veterinary products aiming at a very long-term sustained delivery of this therapeutic molecule.
ABSTRACT
This article presents BEPO®, an in situ forming depot (ISFD) technology mediated by a solvent-exchange mechanism. The matrix of the in situ formed drug delivery depot is composed of the combination of a diblock (DB) and a triblock (TB) polyethylene glycol-polyester copolymer. This combination offers a broad capability to tune the release of a wide variety of drugs to the desired pharmacokinetics. The work described in the present article demonstrates that the delivery rate and profile can be adjusted by changing the composition of either TB or DB or the relative ratio between them, among other parameters. It has been shown that the polymeric composition of the formulation has a substantial impact on the solvent exchange rate between the organic solvent and the surrounding aqueous medium which subsequently determines the internal structure of the resulting depot and the delivery of the therapeutic cargo. This has been demonstrated studying the in vitro release of two model molecules: bupivacaine and ivermectin. Formulations releasing these drugs have been administered to animal models to show the possibility of delivering therapeutics from weeks to months by using BEPO® technology.
Subject(s)
Absorbable Implants , Polyethylene Glycols , Animals , Drug Carriers , Drug Delivery Systems , Kinetics , Micelles , PolyestersABSTRACT
Doublecortin-like kinase 1 (DCLK1) is a serine/threonine kinase that belongs to the family of microtubule-associated proteins. Originally identified for its role in neurogenesis, DCLK1 has recently been shown to regulate biological processes outside of the CNS. DCLK1 is among the 15 most common putative driver genes for gastric cancers and is highly mutated across various other human cancers. However, our present understanding of how DCLK1 dysfunction leads to tumorigenesis is limited. Here, we provide evidence that DCLK1 kinase activity negatively regulates microtubule polymerization. We present the crystal structure of the DCLK1 kinase domain at 1.7 Å resolution, providing detailed insight into the ATP-binding site that will serve as a framework for future drug design. This structure also allowed for the mapping of cancer-causing mutations within the kinase domain, suggesting that a loss of kinase function may contribute to tumorigenesis.
