CPL SR microparticle formulation development (3-month release)
Microparticles were manufactured using CPLs novel CriticalMixTM process, composed of RG502 (commercially available biodegradable polymer) with a range of release altering excipients such as hyaluronic acid (HA), Poloxamer, PEG and sugars. Microparticles were loaded with 13%w/w bevacizumab and assessed for in vitro release. All formulations had a burst release of 80% within the 1st hour. By the 1-month time-point, bevacizumab release is in the range of 1-5 ng, before a second phase of bevacizumab release is initiated. The second phase of release is associated with the onset of polymer degradation, and the controlled release of bevacizumab from the microparticles. At 3-months, more than 100ng of bevacizumab is being release from the microparticles. Microparticles containing PEG achieved a consistent release of bevacizumab over 3-months (300-500ng from 1-3 months).
Lucentis (ranicizumab) has a Cmax of 0.79-2.90ng/mL and a Cmin of 0.07-0.49ng/mL in vivo. CPL microparticles are significantly above this threshold in vitro. Therefore, with a higher pay-load of bevacizumab, a lower concentration of microparticles could be administered into the eye, potentially achieving a similar or greater therapeutic effect.
Target Product Profile
Having approached key opinion leaders in ophthalmology and wet AMD, populations highlighted as most at risk of acquiring wet AMD included: adults in their late 70s, smokers (3x at risk than other population groups), the ageing population, CFH variant, and those with a genetic risk associated with the disease. There is a lot of research being invested into the treatment for dry and wet AMD, including stem cell research. A long-acting treatment was regarded as a preferred method of treatment for the elderly, particularly for those patients who would find it difficult to regularly attend hospital for treatment.
Pharmacoeconomic model
Applying the NICE model for ranibizumab, has limited value in establishing the cost effectiveness of slow release bevacizumab.
Key findings include:
• previous work for NICE has not included in QALYs the discomfort due to injections,
• inclusion of such discomfort would have minimal impact on QALYs,
• trial evidence suggests that fewer injections are associated with more adverse events.
• small differences in Quality of Life, favoring continuous over discontinuous treatment, were observed in the IVAN trial
• cost savings due to reduced injections were relatively small in the IVAN trial but this may be due to the monitoring required in trial conditions.
Conclusion
Critical Pharmaceuticals successfully encapsulated Avastin® in a biodegradable polymer (50:50 PLGA) using its supercritical Fluid technology, to form a 3-month sustained release microparticle.
