Intranasal Drug Delivery Technology for Space Motion Sickness, 01-9303

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Principal Investigators
Joe McDonough
 Hong Dixon
Joe Niño

Inclusive Dates: 04/01/02 - Current

Background - One of the challenges in space exploration is to minimize neurovestibular adaptation problems associated with long duration space flight. Astronauts frequently experience space motion sickness and disorientation because of changes in gravitational orientation. Therefore, it is of utmost importance that more effective antimotion sickness remedies be developed that can be used safely with minimal side  effects. These remedies should also include improved drug delivery systems to minimize dose, thus limiting toxicities. The current remedy for space motion sickness is racemic promethazine (PMZ) hydrochloride (HCl) delivered intramuscularly. The procedure is painful and results in incapacitation of the astronaut for 12 - 24 hours after administration.

Approach - The primary goal of this internal research program is to produce a more effective, less invasive treatment for space motion sickness by developing a novel intranasal drug delivery system using enantiomers of the phenothiazines (such as PMZ), as model compounds. It is likely that one enantiomer will be more effective than the racemate, thereby reducing side effects. Nasal delivery is far less invasive than intramuscular injection.

The first step of this project was to isolate and purify the enantiomers of commercially available racemic phenothiazines (promethazine, ethopropazine, and trimeprazine). The second step was to test each enantiomer in vitro for its efficacy by analysis of its H1 receptor antagonism and its cellular toxicity. The next step of this project was to develop an effective nasal delivery system using microencapsulation technology. The most active enantiomer, as determined above, was to be further formulated using microencapsulation technology, which incorporates appropriate absorption enhancers that will facilitate nasal delivery. The formulations so developed were to be fabricated and tested in an animal model to determine: 1) if racemization occurs in vivo and 2) if the relative plasma loading of the nasal delivery system compares with an intramuscular (im) route of administration. The more active phenothiazine enantiomer is expected to give significantly higher plasma and tissue concentrations when administered nasally, compared to an im route. Additionally, comparative brain concentrations of the phenothiazine resulting from nasal administration are expected to be higher than the im route of administration because of the direct central nervous system access available from nasal administration.

Accomplishments - Enantiomers of promethazine, ethopropazine, and trimeprazine were prepared at multigram scale and characterized. Enantiomers of promethazine and ethopropazine possessed crystal morphology different from their parent racemates. A single chiral high-performance liquid chromatographic (HPLC) method was developed to enable analysis of the optical purity of the enantiomers of ethopropazine, trimeprazine, and promethazine. The ethopropazine, trimeprazine, and promethazine were found to be nontoxic at 1 x 10-5 molar and toxic at 1 x 10-4 molar. The (-) ethopropzine enantiomer reduced IL-6 production by 95 percent of the histamine-stimulated cell while the (+) ethopropazine produced a 63-percent reduction in IL-6 production. The (+) promethazine enantiomer reduced IL-6 production to 90 percent of the histamine-stimulated cell while the (-) enantiomer produced a 50-percent reduction in IL-6 production.

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