(T1230-03-15) Formulation and Evaluation of Solid Self-Micro Emulsifying Drug Delivery System (S-SMEDDS) of Celecoxib

Purpose: Celecoxib (CXB), being a BCS class II drug [low water solubility (3–7 mg/ml)], exhibits a considerable degree of absorption variability following oral administration⁽¹⁾. It undergoes pre-systemic metabolism, and peak plasma concentration is attained in 3 hours after the oral dose⁽²⁾. Also, it is being scrutinized by the USFDA due to its increased risk of cardiovascular and gastrointestinal complications, highlighting the urgent need for a formulation with a lower dose and enhanced bioavailability ⁽¹⁾. Therefore, to achieve quicker onset of action and reduce absorption variability and dose, it was decided to explore the SMEDDS formulation as it improves water solubility and dissolution rate. However, commercially available liquid SMEDDS (L-SMEDDS) formulations can be inconvenient for patients to carry and administer, whereas solid dosage form of capsules provides a more convenient solution. Hence Solid-SMEDDS (S-SMEDDS) (SMEDDS adsorbed and filled into capsules) of CXB with higher drug loading was chosen as the final dosage form as it has advantages over L-SMEDDS in terms of stability, liquid handling, transportation, and storage.

Methods: The work was divided into following parts: Part A: Preformulation study: Solubility study was conducted to select excipients that had the maximum ability to solubilize CXB. Solubility was performed by adding 10 mg of API to 1g of oil, surfactant, and co-surfactant, respectively, until saturation was observed. Further samples were loaded on an orbital shaker bath for 24 hours, followed by centrifugation and analysis of the pellet using UV-vis spectrophotometry at 253 λ_max to quantify the amount of API solubilized. Part B: Formulation Development: 1. SMEDDS Optimization: To achieve a clear SMEDDS formulation, optimization of the oil, surfactant, and co-surfactant ratios was carried out. CXB SMEDDS was prepared by adding CXB to mixture of oil, surfactant, and co-surfactant and further vortexing and heating till a clear SMEDDS was formed. 2. SMEDDS precipitation inhibitor optimization: Different precipitation inhibitors were evaluated in the SMEDDS formulation, as SMEDDS should remain robust on dilution. Hypremellose 4000 cps, Kollidon 30, Kollidon 12PF, Hypremellose 5 cps, and Hypremellose acetyl succinate were evaluated as precipitation inhibitors based on dilution tests. A dilution test was performed by diluting SMEDDS to 10, 100, and 1000 times with distilled water and 0.01N HCL (pH 2.0). 3. S-SMEDDS Preparation: Optimized batch of L-SMEDDS was converted to S- SMEDDS by adsorption technique using different adsorbents. Adsorbents like, Zeopharm^® 600, Aeroperl® 300 Pharma and synthetic amorphous silica were assessed for conversion of L-SMEDDS into free-flowing powder. This was later filled in capsule. Part C: Evaluation of L-SMEDDS and S-SMEDDS: The L-SMEDDS & S-SMEDDS were evaluated for globule size (on dilution using Malvern ZS90 Zetasizer), assay (by extracting the drug in methanol and analysis using UV-vis spectrophotometry at 253 λ_max) and in-vitro dissolution test (USP type II, 50 rpm, 900 mL of pH 2.0 with 0.2%w/v SLS).

Results: Part A: Solubility study and emulsification study: Maximum solubility of CXB was observed in Kollisolv^® PEG 400 (515 mg/g) followed by Acconon MC8-2 EP/NF (419 mg/g) and ABISOL™ IV (180 mg/g). Part B: Formulation and Development: The optimized SMEDDS formulation was chosen based on the clarity of liquid SMEDDS and its robustness to dilution. The optimized batch could load a high concentration of CXB up to 15% w/v, compared to 2.5% w/v of commercially available SMEEDS. Further Hypromellose 5 cps and Hypremellose acetyl succinate were added at 0.5% w/v concentration as precipitation inhibitors, as no precipitation was observed for around four hours on 10, 100, and 1000 times dilutions with water and 0.01N HCL (pH 2.0). AEROPERL^® 300 was chosen as an adsorbent to convert liquid SMEDDS to S-SMEDDS as it displayed a superior angle of repose of 27.5 ° (Excellent flow). A further 659 mg of blend was filled in a 00-el size capsule. Part C: Evaluation of liquid SMEDDS and S-SMEDDS: On dilution, the average globule size of the L-SMEDDS was found to be 185 nm, while that of the S-SMEDDS was 231nm. The assay values of the L-SMEDDS and S-SMEDDS were determined to be 100.5% and 102.5%, respectively. The in vitro dissolution test at the end of one hour in pH 2.0+0.2% SLS displayed ~3 fold increase in dissolution of L-SMEDDS (95%) and S-SMEDDS (81%) as compared to marketed IR formulation (30%) of CXB.

Conclusion: The present work clearly demonstrates the formulation of a robust S-SMEDDS formulation with a higher drug loading capacity than the commercially available formulation. Optimization of the oil, surfactant, and co-surfactant components, along with precipitation inhibitors, is critical for the high loading of CXB in the SMEDDS system. The current S-SMEDDS present a promising avenue for celecoxib delivery with enhanced dissolution compared to the marketed IR formulation and improved patient compliance with respect to L-SMEDDS.

References: 1. Mate, S., Kapoor, R., Talwar, M., Jain, G. K., & Centre, W. R. (2009, June 25). WO2010150144A2 - Low dose pharmaceutical compositions of celecoxib - Google Patents. https://patents.google.com/patent/WO2010150144A2/
2. Quan, G., Niu, B., Singh, V., Zhou, Y., Wu, C. Y., Pan, X., & Wu, C. (2017, December). Supersaturable solid self-microemulsifying drug delivery system: precipitation inhibition and bioavailability enhancement. International Journal of Nanomedicine, Volume 12, 8801–8811. https://doi.org/10.2147/ijn.s149717

Acknowledgements: The author would like to thank ABITEC Corporation, Evonik India Pvt. Ltd., BASF India Ltd., Nikkol group and IFF pharma solutions for providing excipient support and Aarti drugs Ltd. for providing Celecoxib API for this study.