ABSTRACT
The current method of choice for astronauts to treat space motion sickness is an intra-muscular injection of promethazine hydrochloride (PMZ HCl) which is invasive and causes considerable local irritation and discomfort at the site of injection. Intra-nasal delivery is considered a feasible alternative route for administration of medications to treat space motion sickness. The purpose of this research is to develop a PMZ HCl formulation that can be administered intra-nasally without irritation (i.e. leukocyte infiltration) in the nasal epithelium when dosed at PMZ HCl concentrations greater than the cytotoxic limit. The biocompatibility of PMZ HCl was tested in vitro and was shown to be cytotoxic at concentrations greater than 10(-5) molar regardless of pH. A controlled-release microencapsulated dosage formulation was developed using spinning disk atomization and release rates for the PMZ HCl microcapsules were determined in phosphate buffered saline. An animal study was conducted to determine the irritation response of rat nasal mucosa when dosed with encapsulated and non-encapsulated PMZ HCl.
Subject(s)
Administration, Intranasal , Capsules , Gels , Motion Sickness/prevention & control , Promethazine/administration & dosage , Animals , Cell Line , Cell Survival/drug effects , Drug Carriers , Humans , Lung , Nasal Mucosa/drug effects , Nasal Mucosa/pathology , Promethazine/toxicity , RatsABSTRACT
Use of microencapsulation technology in combination with absorption enhancers eliminated epithelium irritation and necrosis commonly associated with nasal delivery of cytotoxic therapeutic agents. Phenothiazines, such as ethopropazine (ETZ), promethazine, trimeprazine and propiomazine have been used for the treatment of allergenic conditions, motion sickness, nausea, Parkinson's disease, Prion disease and as a sedative for psychiatric disorders. The enantiomers of commercially available racemic phenothiazines were isolated and purified using classical diastereomeric salt techniques. The racemate and the enantiomers of ETZ were tested in vitro for their cellular toxicity using lung fibroblast cells. Each enantiomer was shown to be cytotoxic at concentrations greater than 10(-5) molar. The ETZ enantiomers were encapsulated using spinning disk atomization to prepare a nasal delivery dosage form that does not produce an irritation response. Release rates for the ETZ microcapsules were determined in vitro and an animal study was conducted to determine the irritation response of rat nasal mucosa when dosed with encapsulated vs. non-encapsulated ETZ.
