An Oral Long-Acting Doxycycline for Onchocerciasis Eradication: Process Improvement for Small Batch Manufacturing

An Oral Long Acting Doxycycline for Onchocerciasis Eradication Process Improvement for Small Batch Manufacturing Project Summary Patients with Onchocerciasis African River Blindness are currently treated with microfilaricidal therapies such as ivermectin To achieve Onchocerciasis eradication however will require addition of a macrofilaricidal to current mass drug administration campaigns Doxycycline which has been shown to reduce macrofilaria life expectancy and embryogenesis in phase II clinical trials is an emerging candidate The barrier to a mass drug administration strategy however is significant patient nonadherence that limits effectiveness and increases cost Development of once weekly long acting oral regimens would substantially improve the efficacy of Onchocerciasis eradication campaigns No existing oral delivery system can achieve therapeutic serum levels for small molecules therapeutics beyond hours We have developed prototype oral capsules based on Lyndraandapos s Gastric Residence technology that can achieve a week or beyond of sustained therapeutic doxycycline levels in a pig model The goal of this grant is to achieve a reproducible scalable manufacturing capability that will lead to GMP production of clinical specimens for a phase human pharmacokinetic PK study of a novel long acting oral formulation of doxycycline This capability is critical before performing toxicology studies and filing an IND Process optimization will focus on the following aims Aim Small scale hot melt extrusion of the gastric residence polymer matrix Uniformity of drug compounding is critical to dosage form performance doxycycline release rate mechanical strength and to meeting regulatory requirements Our efforts will focus on optimizing methods of efficient and homogeneous compounding of doxycycline into Lyndraandapos s polymeric matrix using a scalable hot melt extrusion approach Aim Reproducible and scalable assembly of the multicomponent gastric residence dosage forms A work plan for sequential linear assembly compatible with GMP production has been developed and custom built tooling will be engineered and optimized Aim Quality control assays to evaluate the small batch manufacturing capability Analytical chemical mechanical and geometric validated quality control assays will be developed to provide bridging capability for future improvements The successful completion of the Phase I aims would lead to a Phase II SBIR for GMP production of clinical specimens for a phase human PK study including assembly automation tooling to facilitate production scale up in line quality control techniques long term stability testing and IND enabling toxicology Global eradication of African River Blindness will require mass drug administration of a macrofilaricidal agent yet adherence to such a campaign will inevitably be low given the six weeks of daily therapy required for doxycycline Using Lyndraandapos s Gastric Residence technology we have developed prototype oral capsules that provide sustained therapeutic doxycycline levels for a full week enabling doxycycline to be administered times instead of times thereby boosting adherence This grant will facilitate manufacturing of these novel dosage forms for human clinical testing