Purpose To develop a biorelevant in vitro dissolution method for predicting in vivo performance of drug suspensions after intra-articular administration. Methods Side-Bi-Side diffusion cells (Permegear Inc., USA) with controlled stirring rate (450 rpm) in both compartments, with a constant flow of the medium in the receptor compartment (mimicking blood circulation) or with a constant flow of the medium from the donor (drug) compartment to the receptor compartment (open mode; mimicking tran-synovial flow) were used for the dissolution tests at room temperature. A glass fiber (GF/F) filter was used as the membrane between the donor and receptor compartment, with cellulose acetate and PTFE filters tested as well. The volume of medium in each compartment was 3.5 ml. Triamcinolone Acetate suspension (Adcortyl, 10 mg/ml) with medium [PBS + Tween 80 (1%)] was placed in the donor compartment and medium [PBS + Tween 80 (1%)] or organic solvent (methanol, 1-octanol) or a bi-phasic setup [PBS + Tween 80 (1%) with 1-octanol) was placed in the receptor compartment. Samples were taken from both compartments measuring drug dissolved (donor compartment) and drug diffused through the membrane (receptor compartment). For the experiments mimicking blood flow, the initial volume of medium in each compartment was 1.5 ml. Triamcinolone Acetate suspension with medium [PBS + Tween 80 (1%)] was placed in the donor compartment and medium [PBS + Tween 80 (1%)] was placed in the receptor compartment with constant medium flow through (0.2 mL/min) the receptor compartment. Samples were collected from the receptor compartment. For the experiments mimicking the tran-synovial flow, the medium (PBS + Tween 80 (1%) or biorelevant synovial fluid- developed based on physiological relevant values for human synovial fluid containing hyaluronic acid, albumin (BSA), γ-globulin and phosphatidylcholine) was flowing from the donor compartment to the receptor compartment at a constant rate of 0.1 mL/min or 0.2 mL/min through the membrane. Triamcinolone Acetate suspension was placed in the donor compartment and samples were collected from the receptor compartment. Samples were analysed with HPLC-UV directly or after protein precipitation for the biorelevant synovial fluid samples (addition of 0.5 ml of a 1.2 M trichloroacetic acid solution to 1 ml of sample; vortex and centrifugation at 12.400 g for 10 min; supernatant filtered through 0.45 μm regenerated cellulose filters and injected). All experiments were performed in triplicate for a period up to 24h. Results Drug dissolution (donor compartment) was higher than drug diffusion (receptor compartment). The % of drug dissolved in the donor compartment reached a 2% dissolved for all setups tested, while the % drug diffused was less than 0.5% with the use of GF/F and cellulose acetate filters, whereas a negligible % diffusion was observed with the use of the PTFE filter. With the use of the GF/F filter as the membrane the % drug dissolved (up to 2.6 %) and diffused (up to 0.3%) was similar for the experiments performed with 1-octanol and with the bi-phasic system in the receptor compartment whereas a higher drug dissolution (up to 11%) and drug diffusion (up to 13%) was observed when methanol was used as the medium in the receptor compartment. When the blood flow was simulated with the constant medium flow in the receptor compartment the % of drug diffused was 2.6% after 8h. The consideration of the tran-synovial flow led to a 100% drug diffusion after 10h on a first order rate when PBS + Tween 80 (1%) was used as the dissolution medium at a 0.2 mL/min constant flow rate. The use of a higher amount of drug injected in the donor compartment at a 0.2 mL/min constant flow rate and at 0.1 mL/min constant flow rate led to a 61% and 24% diffused after 12h. When the biorelevant synovial fluid was used as the dissolution medium a 5.5 % drug diffuse was measured after 12h. Conclusion The results from this study provide an understanding of the effect of media and hydrodynamics set on a biorelevant basis on the dissolution and diffusion of drugs after intra-articular administration. The Side-Bi-Side diffusion cells, with the use of a biorelevant synovial fluid mimicking tran-synovial fluid ultimately could be used for the prediction of in vivo drug performance after this type of administration.
|Publication status||Published - 2015|
|Event||AAPS Annual Meeting, 2015 - Orlando, USA United States|
Duration: 25 Oct 2015 → 29 Oct 2015
|Conference||AAPS Annual Meeting, 2015|
|Country||USA United States|
|Period||25/10/15 → 29/10/15|