Drexel researchers have developed a controlled-release formulation of minocycline hydrochloride (MH), a potent neuro-protective and anti-inflammatory therapeutic for the treatment of spinal cord injury and reduction of its crippling effects.

Spinal cord injury (SCI) causes partial or complete loss of sensory, motor, and autonomic functions below the injury site. Following the initial trauma the lesion site expands significantly over time due to secondary injury cascades and leads to deleterious functional loss. Many mechanisms, including inflammation, contribute to secondary injury. However, most current treatment strategies only target one or a few elements in the injury cascades, and have been largely unsuccessful in clinical trials. MH is the only drug that can target all the major secondary injury mechanisms.  It was considered to be the highest scoring neuroprotective therapy for SCI in a recent systematic review of pre-clinical data (1). However, the doses of MH used in these animal studies (90-135 mg/kg/day for 1-5 days) are much higher than those used in a recent Phase II clinical trial (12-22.5 mg/kg/day for 7 days) and the standard human dose (3 mg/kg/day). Although the dosing regimen in the clinical trial was suggested to be safe, one patient displayed elevated liver enzymes, indicating hepatocellular toxicity. Even at this high dose level, MH concentration in the cerebrospinal fluid at steady state was only 2.3 µg/ml, which is far below the fully neuroprotective level of 35-75 µg/ml.  To achieve high concentrations of MH at the site of injury it could be applied locally; however, it was impossible until now because MH is unstable in aqueous solution and, as a small molecule with high water solubility, is not amenable for traditional controlled release systems.

To overcome these limitations, Drexel researchers have developed a biocompatible, biodegradable, and injectable hydrogel system capable of controlled release of MH. This hydrogel system can be injected into the intrathecal space between the dura and the injured spinal cord to avoid additional tissue damage. It can also be used in conjunction with spinal cord surgery, which is often performed to treat SCI. Drexel’s controlled release system features high drug entrapment efficiency (100% in hydrogel), high drug loading efficiency (about 45%), and stable long term release. The rate of the release can be controlled in the range from several days up to 71 days, or even longer, if desired. Additionally, this formulation preserves the biological activity of MH, which makes it suitable for a variety of clinical applications, including treating infection, inflammation, tumors, as well as cardiovascular, renal and neural protection.

A study in a clinically relevant rat model of cervical SCI has shown that compared to systemic injection of high doses of MH (90-135 mg/kg/day), local delivery of a small amount of MH (total dose of 1.3 mg/kg over 21 days) from Drexel’s hydrogel system resulted in significantly higher MH concentration in the local spinal cord tissue and was more effective in reducing tissue damage and improving functional recovery in treated animals.