(M1530-07-40) Investigation of Nasal Delivery System of a Prokinetic for the Treatment of Gastroparesis and Other Motility Related Disorders

Purpose: Gastroparesis is defined as a chronic symptomatic disorder of the stomach characterized by delayed emptying in the absence of mechanical obstruction, typically treated using oral or IV prokinetics. The present work aims at delivery of prokinetic drug Metoclopromide through nasal route for rapid delivery of drug and to study its effect on the stomach muscle cells through nasal route.

Methods: The preformulation studies for nasal delivery of the investigated Active pharmaceutical Ingredient -Metoclopromide was carried out. FTIR studies and spectrophotometric studies (UV Vis and HPLC) to determine the identity and assay. Three different nasal spray formulations (Table 1) were prepared with different buffered solutions ranging from pH 3 – 6. Spray angle and spray pattern was studied by spray discharge studies measuring ovality index and Schlierin photography. Delivery of the formulation to the nasal tissue was compared using the standard spray nozzle and a modified spray nozzle (discharge tube ~ 4 cm). Microbial stability of the formulation was determined by performing the microbial challenge test using FTM (Fluid Thioglycolate medium) and Soyabean-Caesin Digest (SCD) media inoculated with Staphylococcus aureus and Candida albicans for 14 days at 37ᴼC. Drug permeation studies in sheep nasal tissue was carried out using Keshary–Chien diffusion cell. Toxicity and irritancy studies was carried out by HET-CAM assay. Mechanical activity of the gastric smooth muscle against developed formulation and marketed formulation was measured by Kymograph.

Results: The API identity and purity was confirmed by FTIR analysis and melting point study. The formulation with pH 5.8 was selected for further analysis as it was compatible with the pH of nasal mucosa. The developed formulation and marketed formulation of metoclopramide was found to be sensitive to light.  The addition of 0.01 % of Benzalkonium chloride was necessary to limit the microbiological growth in both FTM and SCD media (Table 2). Formulation was added to mechanical spray bottles and Spray volume was found to be 100µl/actuation. Spray pattern determined by Ovality index using erythrocin dye was found to be 1.07 ± 0.03 and average spray angle was determined by Schlierin imaging to be 30.8 ± 3.1° degree (Fig 1). The modified spray bottle showed higher penetration to the inferior conchae tissue compared to regular spray assessed using crystal violet stain recovery technique (t=Table 3).  The formulation showed exhibited an irritancy score of 2 in the HET CAM assay. Nearly 50 % of the drug permeated through the sheep nasal epithelial tissue in 1h (Fig 2). The gastric mechanical activity of the formulation was found to be similar to the marketed formulation in kymograph study (Fig 3).

Conclusion: Spray formulations are challenging in terms of mechanical , physical and pharmacological stand points. The variables to be monitored are spray angle, spray droplet size, spray velocity and formulation physico-chemical stability and end point delivery. We were able to achieve a desired formulation in terms of pharmaceutical characteristics and some degree of success in terms of site-specific delivery.  The microbial and irritancy assays showed that our formulation was suitable for animal experiments. Drug diffusion showed nearly 50 % permeation across the nasal epithelium which could be enhanced using penetration enhancers and other additives.  Some of the future scope of the work include delivery and pharmacokinetic study in animal models, histocompatibility studies and electrokinetic measurements across the gastric tissue.

Acknowledgments: Acknowledge the support extended by Dr. Gopal Krishna, Dr. Md Azamthulla and Dr. Sharon of MSRUAS in scheleirin photography, DRC studies and Microbiological experiments respectively.

Fig 1. Spray pattern and spray angle measured by ovality test and Schlierin photography



Fig 2. Drug diffusion of Metoclopramide formulation across sheep nasal epithelial tissue



Fig 3. Dose Response Curve of gastric contraction compared across developed formulation and marketed formulation