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 12-24 hours. We have developed prototype oral capsules based on Lyndra'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 1 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 1: 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 Lyndra's polymeric matrix using a scalable hot-melt extrusion approach. Aim 2: 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 3: 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 1 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.
Public Health Relevance Statement: 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 Lyndra'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 6 times instead of 42 times, thereby boosting adherence. This grant will facilitate manufacturing of these novel dosage forms for human clinical testing.
Project Terms: Adherence; Adopted; African; Automation; base; Biological Assay; bisphosphonate; capsule; Chemicals; Clinical; Complex; cost; Custom; Deglutition; Development; Dosage Forms; Dose; Doxycycline; Drug Compounding; Drug Kinetics; Effectiveness; Embryonic Development; Encapsulated; Engineering; Esophageal; Esophagus; Family suidae; Formulation; Future; Gelatin; Goals; Grant; Hour; Human; Hydration status; improved; Injectable; Ivermectin; Lead; Life Expectancy; Lower Gastrointestinal Tract; manufacturing process; Mechanics; Medical; meetings; melting; Methods; Modeling; novel; Ocular Onchocerciasis; Onchocerciasis; Oral; Osteoporosis; Patient Noncompliance; Patients; Performance; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Polymers; Population; Process; process optimization; Production; prototype; Pyloric sphincter structure; Quality Control; Regimen; research clinical testing; residence; scale up; Serum; Site; Small Business Innovation Research Grant; small molecule therapeutics; Specimen; Sphincter; stability testing; Stomach; System; Techniques; Technology; Temperature; Therapeutic; Time; tool; Toxicology; Training; Work
