Remington Pharma Products

[Kenneth Larson]

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Abstract: Controlled release delivery is available for many routes of administration and offers many advantages (as microparticles and nanoparticles) over immediate release delivery. These advantages include reduced dosing frequency, better therapeutic control, fewer side effects, and, consequently, these dosage forms are well accepted by patients. Advances in polymer material science, particle engineering design, manufacture, and nanotechnology have led the way to the introduction of several marketed controlled release products and several more are in pre-clinical and clinical development. Keywords: polymers; copolymers; biomaterials; biodegradable; microparticle; nanoparticle; pharmaceutical dosage forms; particle engineering design; manufacture

Mansour, Heidi M., MinJi Sohn, Abeer Al-Ghananeem, and Patrick P. DeLuca. 2010. "Materials for Pharmaceutical Dosage Forms: Molecular Pharmaceutics and Controlled Release Drug Delivery Aspects" International Journal of Molecular Sciences 11, no. 9: 3298-3322.

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Pharmaceuticals selected for exploration space missions must remain stable and effective throughout mission timeframes. Although there have been six spaceflight drug stability studies, there has not been a comprehensive analytical analysis of these data. We sought to use these studies to quantify the rate of spaceflight drug degradation and the time-dependent probability of drug failure resulting from the loss of active pharmaceutical ingredient (API). Additionally, existing spaceflight drug stability studies were reviewed to identify research gaps to be addressed prior to exploration missions. Data were extracted from the six spaceflight studies to quantify API loss for 36 drug products with long-duration exposure to spaceflight. Medications stored for up to 2.4 years in low Earth orbit (LEO) exhibit a small increase in the rate of API loss with a corresponding increase in risk of product failure. Overall, the potency for all spaceflight-exposed medications remains within 10% of terrestrial lot-matched control with a 1.5 increase in degradation rate. All existing studies of spaceflight drug stability have focused primarily on repackaged solid oral medications, which is important because non-protective repackaging is a well-established factor contributing to loss of drug potency. The factor most detrimental to drug stability appears to be nonprotective drug repackaging, based on premature failure of drug products in the terrestrial control group. The result of this study supports a critical need to evaluate the effects of current repackaging processes on drug shelf life, and to develop and validate suitable protective repackaging strategies that help assure the stability of medications throughout the full duration of exploration space missions.

Drug products undergo degradation over time. Drug degradation is a chemical reaction that typically progresses at a consistent rate under a consistent set of storage conditions, assuming co-reactants are available in excess4,5,6,7. Many active pharmaceutical ingredients (APIs) are susceptible to degradation when exposed to atmospheric factors (e.g., oxygen or humidity), non-ionizing radiation (e.g., ultraviolet light) or ionizing radiation (e.g., gamma and alpha radiation). Degradation of finished drug products can be complex and, in addition to environmental factors, may also involve interactions of the API with excipients, which are pharmacologically inactive but not chemically inert. Chemical degradation in a drug product can result in both the loss of the API (i.e., loss of potency) and/or accumulation of impurities5. Degradation can also result in physical changes, which for solid oral drugs may include changes in moisture content, color, and hardness, and for nonsolid medications, phase separation, and other changes depending on the formulation. As a step toward characterizing the relative effect(s) of spaceflight on drug stability, we focus on the loss of potency associated with long-term spaceflight. Degradation impurities are also an important source of uncertainty that requires investigation in future studies, however available spaceflight studies do not permit relative quantitation of impurities in spaceflight and terrestrial medications. The Shelf Life Extension Program (SLEP) reported that of the 59 drug products with initial extension failures, 35 products failed based on potency (assay) criteria, compared to only seven that failed based on impurity or degradant content8. For this reason, quantitative evaluation of drug potency based on stability-indicating methods is a reasonable step towards characterizing spaceflight stability of medications.

NASA has previously supported six investigations into the stability of drugs after prolonged storage in LEO on board the International Space Station (ISS)9,10,11,12,13,14. With the exception of the study by Du et al.14, all these studies (5/6) have been opportunistic designs that take advantage of sui generis medications returned from orbit after varying periods of spaceflight. None of the studies include controls for comparative evaluation of LEO spaceflight drug stability. In contrast, Du et al. conducted a longitudinal drug stability study where spaceflight drugs were matched to corresponding terrestrial controls from the same manufacturing lot across four time points14. Despite the advantages of this study design, the Du et al.14 study is limited because it provides only a qualitative analysis of stability for an arbitrarily selected subset of the tested drugs rather than a quantitative assessment of overall drug stability and time-dependent failure. Consequently, uncertainty persists about the effect of spaceflight on medication stability. In this paper, we reanalyze the primary data from six previous spaceflight drug stability studies to quantify and better understand the effect of spaceflight exposure on drug potency. The goal of this work is to identify and address critical research gaps and uncertainties by implementing an experimental pharmaceutical testing strategy based on well-designed stability and stress studies.

Six primary English-language research studies were identified that reported spaceflight drug stability data. Of these studies, only two have published results. Among these studies, Du et al.14 performed the only study with lot-matched controls, while the five other studies used opportunistic spaceflight samples and manufacturer-matched drugs from different manufacturing lots as comparators (see Table 3). Among these studies, only one is published12. The four remaining investigations are non-peer reviewed NASA reports9,10,11 of which one study reanalyzed three medications that were the same samples initially tested and reported by Du et al. approximately three years earlier13. All available spaceflight drug stability studies are limited to LEO missions, which has significantly lower levels of ionizing radiation than are anticipated for exploration missions to the moon and beyond.

Quantitative analysis of the drug API content reported by Du et al.14 provides substantially more insight into the effect of spaceflight on drug stability than the original qualitative evaluation. Across all drugs at the 13-day time point, the difference in API content between spaceflight samples is within 5% of control content for most drugs (34 of 36) (Fig. 1). At 880 days of spaceflight storage, 39% of flight-exposed drugs (14 of 36) remain within 5% of control potency, and no drug has a loss of API exceeding 10% of control amounts. (To be clear, this is control level a range of 10%, not a multiplicative percentage.) Taken together, this supports a conclusion that the effect of spaceflight exposure on drug stability is relatively small overall (Supplementary Table 2).

Estimates of chemical degradation rates are crucial to enabling a mechanistic understanding of how API degradation is influenced by environmental conditions and to provide predictive insight for estimating drug strength over time. The FDA and the European Medicines Agency (EMA) accept that drug degradation rates are typically represented by linear kinetics; most commonly first-order reaction rates18. Regression models can test the null hypothesis of equality of slope or intercept relative to a control sample. However, the very low standard deviation for each drug (Supplementary Table 1) raises an uncertainty regarding the independence of replicates that justifies treating each mean value as a single independent observation. For each drug in this study, rates of degradation are visualized as a series of scatter plots upon which fitted first-order curves for control and flight samples are superimposed (Fig. 3). From these plots, it can be observed that for many of the APIs, the control and spaceflight degradation curves are close to parallel with the two curves primarily offset by variability in the location of the y-intercept (i.e., the API strength at time zero). These plots illustrate that, for most of the tested drugs, spaceflight contributes minimally to the degradation, as summarized numerically in Supplementary Table 3, which also provides extrapolated estimates of API half-life under control and flight conditions, as well as an estimation of API remaining at three years.

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