Pharmaceutical Product Development: Intranasal Scopolamine (INSCOP) Metered Dose Spray

Motion sickness (MS) has been a problem associated with space flight, the modern military and commercial air and water transportation for many years. Clinical studies have shown that scopolamine is the most effective medication for the prevention of motion sickness (Dornhoffer et al, 2004); however, the two most common methods of administration (transdermal and oral) have performance limitations that compromise its utility. Intranasal administration offers a noninvasive treatment modality, and has been shown to counter many of the problems associated with oral and transdermal administration. With the elimination of the first pass effect by the liver, intranasal delivery achieves higher and more reliable bioavailability than an equivalent oral dose. This allows for the potential of enhanced efficacy at a reduced dose, thus minimizing the occurrence of untoward side effects. An Intranasal scopolamine (INSCOP) gel formulation was prepared and tested in four ground-based clinical trials under an active Investigational New Drug (IND) application with the Food and Drug Administration (FDA). Although there were early indicators that the intranasal gel formulation was effective, there were aspects of formulation viscosity and the delivery system that were less desirable. The INSCOP gel formulation has since been reformulated into an aqueous spray dosage form packaged in a precise, metered dose delivery system; thereby enhancing dose uniformity, increased user satisfaction and palatability, and a potentially more rapid onset of action. Recent reports of new therapeutic indications for scopolamine has prompted a wide spread interest in new scopolamine dosage forms. The novel dosage form and delivery system of INSCOP spray shows promise as an effective treatment for motion sickness targeted at the armed forces, spaceflight, and commercial sea, air, and space travel markets, as well as prospective psychotherapy for mental and emotional disorders

Preliminary Evaluation of Commercial Off the Shelf (COTS) Packing Materials for Flight Medication Dispenser (FMD) Technology Development

With the advent of longer duration space missions, pharmaceutical use in space has increased. During the first 33 space shuttle missions, crew members took more than 500 individual doses of 31 different medications . Anecdotal reports from crew members described medications as generally "well tolerated" and "effective". However, reported use of increased medication doses and discrepancies in ground vs. flight efficacy may result from reduced potency or altered bioavailability due to changes in chemical and/or physical parameters of pharmaceutical stability. Based on preliminary results from a ground-based irradiation and an inflight study on pharmaceutical stability, three susceptible medications, Amoxicillin/Clavulanate and Sulfamethoxazole/trimethoprim antibiotics tablets and promethazine (PMZ), an antihistamine were selected for testing using two types of Oliver-Tolas bags, TPC-1475(Clear) and TPF-0599B (Foil) for radiation Shielding effectiveness. The material composition of the bags included aluminum coated Mylar sheathing coated with multifunctional nanocomposities based on polyethylene with dispersed boron-rich nanophases. Two bags of each medication were irradiated for different time intervals with 14.6 rad/min to achieve 0.1 Gy, 1 Gy and 10 Gy of cumulative radiation dose. Active pharmaceutical content (API) in each medication was determined and results analyzed. No significant difference in API content was observed between control and irradiated samples for both antibiotic tablets suggesting both types of bags may offer protection against gamma radiation; results with PMZ were inconclusive. These preliminary results suggest that Oliver-Tolas TPL-1475 and TPF-0599B materials may possess characteristics suitable for protection against ionizing radiation and can be considered for designing and further testing of FMD technology

PillCam(TradeMark), a Noninvasive Endoscopic Device for the Measurement of Gastrointestinal Motility Changes

Introduction: Bioavailability and effectiveness of drugs given by mouth are governed in part by gastrointestinal (GI) motility and function. Microgravity has been shown to decrease GI motility as indicated by a 3 fold increase in gastrointestinal transit time (GITT). The PillCam(TradeMark), an endoscopic camera embedded in a capsule, is a novel noninvasive and unobtrusive device that is used for the diagnosis of GI pathology. The purpose of this study is to evaluate the usefulness of PillCam(TradeMark) as an alternative to the Lactulose Breath Hydrogen Test (LBHT) for estimating GI motility. The sensitivity and applicability of this device for detection and estimation of the effect of promethazine, a deterrent, and caffeine, a prokinetic, on GI motility were also examined. Method: In this semi-randomized cross-over design study, six male and six female subjects were administered the following 4 treatments: PillCam(TradeMark) alone, PillCam(TradeMark)+Lactulose (10g), PillCam(TradeMark)+caffeine (200mg), and PillCam(TradeMark)+Promethazine (50mg). Results: GITT ranged between 1:24 and 7:52 hr:min. Lactulose did not alter GITT. A significant increase in GITT was noticed after administration of PMZ when compared to values from PillCam(TradeMark) treatment alone or PillCam(TradeMark)+Lactulose treatment. No difference in GITT after caffeine treatment was noticed. While there were no gender related differences in GITT after administration of PillCam(TradeMark) or with lactulose, a significant difference (p<.05) between genders was observed after promethazine administration with mean GITT higher in males (5:50 hr:min) than females (4:15 hr:min). Conclusion: The PillCam(TradeMark) capsule is applicable for the determination of GITT using time stamped GI images. It can be successfully used for the assessment of drug induced changes in GI motility and therefore, may be applicable for microgravity and analog environment studies on GI motility and function

Space Environment Effects on Stability of Medications Flown on Space Shuttles and the International Space Station (ISS)

The purpose is to assess physical and chemical degradation of select pharmaceutical formulations from the Shuttle and ISS medical kits. Eleven pharmaceuticals dispensed as different dosage forms were selected based on their physical / chemical characteristics and susceptibility to environmental factors such as, temperature, humidity and light sensitivity. When available, ground-controls of the study medications with matching brand and lot numbers were used for comparison. Samples retrieved from flight were stored along with their matching controls in a temperature and humidity controlled environmental chamber. Temperature, humidity, and radiation data from the Shuttle and ISS were retrieved from onboard HOBO U12 Temp/RH Data Loggers, and from passive dosimeters. Physical and chemical analyses of the pharmaceuticals were conducted using validated United States Pharmacopeia (USP) methods. Results indicated degradation of 6 of the 11 formulations returned from space flights. Four formulations, Amoxicillin / Clavulanate, promethazine, sulfamethoxazole / trimethoprim, and ciprofloxacin tablets depicted discoloration after flight. Chemical content analyses using High or Ultra Performance Liquid Chromatography (HPLC / UPLC) methods revealed that dosage forms of Amoxicillin / Clavulanate, promethazine, sulfamethoxazole / trimethoprim, lidocaine, ciprofloxacin and mupirocin contained less than 95% of manufacturer s labeled claim of active drug compound. Shuttle and ISS environments affect stability and shelf life of certain mediations flown on these missions. Data analysis is in progress to examine the effect of specific space flight environmental factors on pharmaceutical stability. The degradation profiles generated from ground studies in analog environments will be useful in establishing predictive shelf-life profiles for medications intended for use during long-term space exploration missions

Stability of Formulations Contained in the Pharmaceutical Payload Aboard Space Missions

Efficacious pharmaceuticals with adequate shelf life are essential for successful space medical operations in support of space exploration missions. Physical and environmental factors unique to space missions such as vibration, G forces and ionizing radiation may adversely affect stability of pharmaceuticals intended for standard care of astronauts aboard space missions. Stable pharmaceuticals, therefore, are of paramount importance for assuring health and wellness of astronauts in space. Preliminary examination of stability of formulations from Shuttle and International Space Station (ISS) medical kits revealed that some of these medications showed physical and chemical degradation after flight raising concern of reduced therapeutic effectiveness with these medications in space. A research payload experiment was conducted with a select set of formulations stowed aboard a shuttle flight and on ISS. The payload consisted of four identical pharmaceutical kits containing 31 medications in different dosage forms that were transported to the International Space Station (ISS) aboard the Space Shuttle, STS 121. One of the four kits was stored on the shuttle and the other three were stored on the ISS for return to Earth at six months intervals on a pre-designated Shuttle flight for each kit; the shuttle kit was returned to Earth on the same flight. Standard stability indicating physical and chemical parameters were measured for all pharmaceuticals returned from the shuttle and from the first ISS increment payload along with ground-based matching controls. Results were compared between shuttle, ISS and ground controls. Evaluation of data from the three paradigms indicates that some of the formulations exhibited significant degradation in space compared to respective ground controls; a few formulations were unstable both on the ground and in space. An increase in the number of pharmaceuticals from ISS failing USP standards was noticed compared to those from the shuttle flight. A comprehensive evaluation of results is in progress

Stability of Dosage Forms in the Pharmaceutical Payload Aboard Space Missions

Efficacious pharmaceuticals with adequate shelf lives are essential for successful space medical operations. Stability of pharmaceuticals, therefore, is of paramount importance for assuring the health and wellness of astronauts on future space exploration missions. Unique physical and environmental factors of space missions may contribute to the instability of pharmaceuticals, e.g., radiation, humidity and temperature variations. Degradation of pharmaceutical formulations can result in inadequate efficacy and/or untoward toxic effects, which could compromise astronaut safety and health. Methods: Four identical pharmaceutical payload kits containing 31 medications in different dosage forms (liquid, tablet, capsule, ointment and suppository) were transported to the International Space Station aboard the Space Shuttle (STS-121). One of the 4 kits was stored on the Shuttle and the other 3 were stored on the International Space Station (ISS) for return to Earth at 6-month interval aboard a pre-designated Shuttle flight for each kit. The kit stored on the Shuttle was returned to Earth aboard STS-121 and 2 kits from ISS were returned on STS 117 and STS-122. Results: Analysis of standard physical and chemical parameters of degradation was completed for pharmaceuticals returned by STS-121 after14 days, STS - 117 after11 months and STS 122 after 19 months storage aboard ISS. Analysis of all flight samples along with ground-based matching controls was completed and results were compiled. Conclusion: Evaluation of results from the shuttle (1) and ISS increments (2) indicate that the number of formulations degraded in space increased with duration of storage in space and was higher in space compared to their ground-based counterparts. Rate of degradation for some of the formulations tested was faster in space than on Earth. Additionally, some of the formulations included in the medical kits were unstable, more so in space than on the ground. These results indicate that the space flight environment may adversely affect the shelf life of pharmaceuticals aboard space missions

Evaluation of Physical and Chemical Changes in Pharmaceuticals Flown on Space Missions

Efficacy and safety of medications used for the treatment of astronauts in space may be compromised by altered stability in space. We compared physical and chemical changes with time in 35 formulations contained in identical pharmaceutical kits stowed on the International Space Station (ISS) and on Earth. Active pharmaceutical content (API) was determined by ultra- and high-performance liquid chromatography after returning to Earth. After stowage for 28 months in space, six medications aboard the ISS and two of matching ground controls exhibited changes in physical variables; nine medications from the ISS and 17 from the ground met the United States Pharmacopeia (USP) acceptance criteria for API content after 28 months of storage. A higher percentage of medications from each flight kit had lower API content than the respective ground controls. The number of medications failing API requirement increased as a function of time in space, independent of expiration date. The rate of degradation was faster in space than on the ground for many of the medications, and most solid dosage forms met USP standard for dissolution after storage in space. Cumulative radiation dose was higher and increased with time in space, whereas temperature and humidity remained similar to those on the ground. Exposure to the chronic low dose of ionizing radiation aboard the spacecraft as well as repackaging of solid dosage forms in flight-specific dispensers may adversely affect stability of pharmaceuticals. Characterization of degradation profiles of unstable formulations and identification of chemical attributes of stability in space analog environments on Earth will facilitate development of space-hardy medications