A Novel Mesalamine Loaded Hybrid Nanoparticle-in-Microparticle for Colon Targeting: In-vitro and In-vivo Investigations

Purpose

Pharmaceutical research continues to focus on developing novel approaches for the effective treatment of ulcerative colitis (UC). To develop a better system than simple nanoparticle-in-microparticle (NP-in-MP), time-dependent NP or MP, and pH-dependent NP or MP, this work sought to construct an enhanced colon-targeting system with a combination of hybrid formulations and dual coating approach consisting of time-dependent nanoparticles loaded in pH-dependent microparticles.

Method

The model drug used was mesalamine, and the polymers used were ethyl cellulose (EC) as time dependent polymer and a mixture of Eudragit L100 (EL100) and Eudragit S100 (ES100) as pH dependent polymer. The NP-in-MP were optimized, prepared and characterized to obtain targeted and sustained delivery of drug. The NP were coated with ethyl cellulose to obtain sustained delivery. Then NP were entrapped within eudragit MP using the double emulsion solvent evaporation process. NP-in-MP were evaluated for particle size, entrapment efficiency, surface morphology, in-vitro drug release and in-vivo evaluation.

Results

The particle size and entrapment efficiency of the selected formulation was 12.4 ± 3.1 µm and 85.36 ± 2.6%. The in vitro drug release profile verified that the selected formulation released (6.94 ± 1.23%) less than 10% of the drug in an acidic environment, followed by continuous drug release (93.9 ± 3.15%) in a colonic environment. The MPO level confirmed that the maximum recovery (i.e., decrease in MPO level) was observed for NP-in-MP (3.02 ± 0.33, ***P < 0.001) followed by NP (6.2 ± 0.51) compared with disease control. NP-in-MP substantially improved body weight, diarrhea score and rectal bleeding (***P < 0.001) which indicates mucosal healing and the mitigation of inflammation. The NP-in-MP significantly increased colon length (***P < 0.001) and reduced spleen weight (**P < 0.01) in comparison to disease control. NP-in-MP also showed improved histological results compared to those of the other treatment groups.

Conclusion

The current findings demonstrate the efficient development of NP-in-MP for enhancing the delivery of NP to the colonic region. The in-vitro data confirms that the NP-in-MP prevented burst release of NP and also targeted them to the colon along with sustained delivery of their payload. The in-vivo data confirms that the NP-in-MP are better in treating colitis than NP. Therefore, it was concluded that a hybrid NP-in-MP can be a potential alternative than other treatment carriers to treat inflammatory bowel disease and colorectal cancer.

Graphical Abstract