(W1130-07-39) Investigating ISFIs with PLGA as Sustained Release Formulations for the Urinary Bladder

Purpose: The urinary bladder as site of application is difficult to address, regarding the formulation development. Formulations face a site of application with a difficult release medium, the urine. It is characterized by a wide pH range (4-8), lifestyle-depending concentrations of amino acids and salts, varying volumes and the voiding of the urine [1]. Current medications for neurogenic detrusor overactivity (NDO) have either high systemic side effects (orally administered) or are eliminated by voiding. In situ forming implants (ISFI) with the polymer Poly (L-lactic-co-glycolide acid) (PLGA) are an approach to achieve a sustained release of the active pharmaceutical ingredient (API)[2]. In addition, the system degrades over a certain amount of time without getting eliminated. The aim is to investigate ISFI as a carrier system for the API oxybutynin and test the drug release under in-vitro conditions.

Methods: For the preparation of the ISFI-solutions, oxybutynin base (1.5 %, 3.0 %, 7.5 % and 15 % (w/w)) was dissolved under continuous stirring in glycofurol (GF) for 24 h. Resomer RG 502 (30 % (w/w)) was added to the drug-solution and stirred for 24 h. Finally, the solution was ultrasonicated for 2 h. Drug release from the formulations was assessed using a shaking bath at a temperature of 37 °C. ISFI-solutions were injected into glass vials containing 20 mL artificial urine pH 6 as release medium. Samples of 0.4 mL were taken after 1 h, 2 h, 4 h, 8 h, 12 h, 24 h and after that daily for one week and analyzed by HPLC. The removed volume was replaced with new release medium. After the daily samples were collected, the complete release medium was replaced with fresh artificial urine to simulate one urination per day. The release medium collected daily was analyzed for lactic acid to give an insight in the PLGA degradation. High performance liquid chromatography (HPLC) analysis for oxybutynin base and lactic acid were performed on a Shimadzu, LC-2030C 3D Plus (Kyoto, Japan). A RP18 column (LiChrospher 100 RP 18-5 µ EC, 250 x 4.6 mm) was used. For drug and lactic acid detection, the photodiode array detector was set to 203 nm. The column temperature was set to 40 °C. Viscosity was measured by using a rotational viscometer MCR92 with a cone-plate measuring device.

Results: ISFI with respect to API released were compared regarding their initial release (24 h) and the final cumulative amount of API released (7 d). An increase in drug loading led to a comparably higher initial release and the cumulative amount of API was high for the formulation with 7.5 % oxybutynin content, compared to ISFI with 3 % drug load. Additionally ISFI-solutions with a lower drug loading were characterized by a higher viscosity, which could be connected to the faster formation of these implants. The degradation process of PLGA-containing implants is based on the autocatalysis of the polymer itself. A factor influencing the autocatalysis was the drug load of tested ISFI. The notable impact had the drug load on the degradation process, which could be seen comparing the ISFI with 1.5 % with the ISFI with 15 % oxybutynin base content.

Conclusion: ISFI for the use in the urinary bladder were investigated regarding the impact of drug load on the drug release and the degradation process of these implants. An increase of alkaline drug content contributed to an enhanced drug release and accelerated degradation process. This is the consequence of the formation of areas with an alkaline microclimate, due to the alkaline character of the drug inside the implant. Therefore, it can be concluded that, the use of ISFI in the urinary bladder is effective. Influence factors like the release medium may be investigated for a further reaching understanding of ISFI.

References: [1] R. Siener, „The Effect of Different Diets on Urine Composition and the Risk of Calcium Oxalate Crystallisation in Healthy Subjects“, European Urology, Bd. 42, Nr. 3, S. 289–296, Sep. 2002, doi: 10.1016/S0302-2838(02)00316-0.
[2] I. C. Young u. a., „Dose-Ranging Plasma and Genital Tissue Pharmacokinetics and Biodegradation of Ultra-Long-Acting Cabotegravir In Situ Forming Implant“, Pharmaceutics, Bd. 15, Nr. 5, S. 1487, Mai 2023, doi: 10.3390/pharmaceutics15051487.

Acknowledgements: This research was partially sponsored by Farco-Pharma GmbH. The company had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the abstract, or in the decision to publish the results. The other authors declare no conflict of interest.

API released for different ISFI in artificial urine at pH 6 for 7 days (A and B). Degradation of the PLGA in ISFIs, characterized by the measured lactic acid content in the release medium for different implants (C and D).

Viscosity of ISFI-solutions with different drug loads and compared with a solution without API.