In situ crosslinkable heparin‐containing poly(ethylene glycol) hydrogels for sustained anticoagulant release

Abstract

Low molecular weight heparin (LMWH) is widely used in anticoagulation therapies and for the prevention of thrombosis. LMWH is administered by subcutaneous injection usually once or twice per day. This frequent and invasive delivery modality leads to compliance issues for individuals on prolonged therapeutic courses, particularly pediatric patients. Here, we report a long-term delivery method for LMWH via subcutaneous injection of long-lasting hydrogels. LMWH is modified with reactive maleimide groups so that it can be crosslinked into continuous networks with four-arm thiolated polyethylene glycol (PEG-SH). Maleimide-modified LMWH (Mal-LMWH) retains bioactivity as indicated by prolonged coagulation time. Hydrogels comprising PEG-SH and Mal-LMWH degrade via hydrolysis, releasing bioactive LMWH by first-order kinetics with little initial burst release. Separately dissolved Mal-LMWH and PEG-SH solutions were co-injected subcutaneously in New Zealand White rabbits. The injected solutions successfully formed hydrogels in situ and released LMWH as measured via chromogenic assays on plasma samples, with accumulation of LMWH occurring at day two and rising to near-therapeutic dose equivalency by day 5. These results demonstrate the feasibility of using LMWH-containing, crosslinked hydrogels for sustained and controlled release of anticoagulants.

Poly(ethylene glycol) (PEG)-lactic acid nanocarrier-based degradable hydrogels for restoring the vaginal microenvironment

“…A maximum release of 23% of bound lactic acid in PBS and 47% in AB was observed (Figure 1A). Since the hydrolysis of esters in buffer is pseudo first-order, the kinetics of nanocarrier hydrolysis were determined by plotting the log of the percentage remaining PEG-LA nanocarriers against time (Figure 1B) [43, 44]. The data were fit using linear regression and the rate constant ( k ) and half-life (t 1/2 ) of nanocarrier hydrolysis was estimated from the slope.…”

Thiol–ene Click Hydrogels for Therapeutic Delivery

“…One approach to mitigating this issue is using a double-barrel syringe to control reactive precursor mixing and achieve rapid and consistent in situ polymerizations. 102-103 …”

Passive targeting and lung tolerability of enoxaparin microspheres for a sustained antithrombotic activity in rats

“…Õ , is the only available dosage form in the market, as the drug's physico-chemical properties hinder its absorption from the GIT and most other mucosal surfaces (Baldwin et al, 2012). Unfortunately, Clexane Õ suffers from short half-life (4.5 h) and general distribution of the drug to all body parts, resulting in the need for daily parenteral administration of large doses with increased risk of hemorrhage especially with long-term LMWH usage.…”