Development of a self-nanoemulsifying drug delivery system for oral delivery of beta-lactamase

The objective of the study was to develop a self-nanoemulsifying drug delivery system (SNEDDS) to deliver protein drugs orally. beta-lactamase (BLM), a hydrophilic protein of 29K Dalton, was loaded into a lipophilic SNEDDS (consist of an oil, a surfactant and a co-surfactant) by preparing a solid dispersion of BLM using a phospholipid and then load this dispersion into SNEDDS. A 2^3 full factorial with 4 center/pure error points experimentaldesign was adopted to develop SNEDDS prototypes with different excipients. Thirty three SNEDDS protoypes obtained were evaluated for loading of BLM-phospholipid solid dispersion into it. Out of those 33, sixteen successful BLM-loaded SNEDDS were obtained. The loading capacity was in the range of 1927.8 +/- 1.5 to 2066.4 +/- 1.3 mU BLM/1g of SNEDDS. The efficacy of these 16 BLM-loaded SNEDDS to deliver BLM was studied with MDCK cell monolayers in-vitro. BLM-loaded SNEDDS formula (NE-12-7) of 49.89% Lauroglycol FCC, 33.21% Cremophor EL, 16.59% Transcutol HP, 0.248% hydrogenated phosphatidyl choline (soy) and 0.062% BLM resulted in maximum in-vitro transport rate and then was further studied in oral pharmacokinetic studies in rats. The BLM-loaded SNEDDS (NE-12-7) exhibited good stability and upon dilution with aqueous media resulted in nanoemulsion with droplet size less than 50 nm. The permeability of BLM in the SNEDDS was 40-fold higher than that by the solution form across MDCK monolayer. In-vivo PK data after oral administration demonstrated that the SNEDDS significantly (P<0.01) enhanced the bioavailability (2.5 folds), Cmax (2.7 folds) and Mean Resident Time (MRT, 1.3 folds) compared to the free solution. The relative oral bioavailability of BLM when delivered by SNEDDS and by free solution was 6.3 +/- 0.5% and 2.4 +/- 1.0%, respectively. The C max was 1.90 +/- 0.09 mU/ml and MRT was 12.12 +/- 4.97 hours for the SNEDDS. Thus, SNEDDS could significantly increase the transport of BLM across cell monolayer in-vitro, and enhance the oral absorption in rats. SNEDDS system may be a potential system for oral delivery of protein drugs.