Glutathione enzyme and selenoprotein polymorphisms associate with mercury biomarker levels in Michigan dental professionals

Mercury is a potent toxicant of concern to both the general public and occupationally exposed workers (e.g., dentists). Recent studies suggest that several genes mediating the toxicokinetics of mercury are polymorphic in humans and may influence inter-individual variability in mercury accumulation. This work hypothesizes that polymorphisms in key glutathione synthesizing enzyme, glutathione s-transferase, and selenoprotein genes underlie inter-individual differences in mercury body burden as assessed by analytical mercury measurement in urine and hair, biomarkers of elemental mercury and methylmercury, respectively. Urine and hair samples were collected from a population of dental professionals (n = 515), and total mercury content was measured. Average urine (1.06 ± 1.24 ug/L) and hair mercury levels (0.49 ± 0.63 ug/g) were similar to national U.S. population averages. Taqman assays were used to genotype DNA from buccal swab samples at 15 polymorphic sites in genes implicated in mercury metabolism. Linear regression modeling assessed the ability of polymorphisms to modify the relationship between mercury biomarker levels and exposure sources (e.g., amalgams, fish consumption). Five polymorphisms were significantly associated with urine mercury levels (GSTT1 deletion), hair mercury levels (GSTP1-105, GSTP1-114, GSS 5′), or both (SEPP1 3′UTR). Overall, this study suggests that polymorphisms in selenoproteins and glutathione-related genes may influence elimination of mercury in the urine and hair or mercury retention following exposures to elemental mercury (via dental amalgams) and methylmercury (via fish consumption).     

Role of Particle Size in Translational Research of Nanomedicines for Successful Drug Delivery: Discrepancies and Inadequacies

Despite significant research progress in substantiating the therapeutic merits of nanomedicines and the emergence of sophisticated nanotechnologies, the translation of this knowledge into new therapeutic modalities has been sluggish, indicating the need for a more comprehensive understanding of how the unique physicochemical properties of nanoparticles affect their clinical applications. Particle size is a critical quality attribute that impacts the bio-fate of nanoparticles, yet precise knowledge of its effect remains elusive with discrepancies among literature reports. This review aims to address this scientific knowledge gap from a drug development perspective by highlighting potential inadequacies during the evaluation of particle size effects. We begin with a discussion on the major issues in particle size characterization along with the corresponding remedies. The influence of confounding factors on biological effects of particle size, including colloidal stability, polydispersity, and in vitro drug release, are addressed for establishing stronger in vitro-in vivo correlation. Particle size design and tailoring approaches for successful nanoparticulate drug delivery beyond parenteral administration are also illustrated. We believe a holistic understanding of the effect of particle size on bio-fate, combined with consistent nanoparticle manufacturing platforms and tailored characterization techniques, would expedite the translation of nanomedicines into clinical practice.     

Role of catalase in the oxidation of mercury vapor

In human red blood cells the slow rate of production of hydrogen peroxide limits the rate of oxidation of mercury vapor. When H₂O₂ was added to blood samples, the rate of mercury uptake increased six times, but the inhibitory effect of KCN was less pronounced than in samples without H₂O₂, possibly because H₂O₂ tends to destroy cyanide. Only in the absence of exogenous H₂O₂ did the inhibition of oxidation of mercury vapor by different concentrations of KCN parallel the inhibition of catalase. Addition of peroxide to liver homogenates was without effect. When 20% (w/v) liver homogenates were exposed to mercury vapor at 37°, neither acatalasemia in mice nor pretreatment of rats with 2 g/kg of aminotriazole produced an appreciable decrease in the uptake of mercury during the 90-min incubation period. However, it was clear that catalase was responsible for the oxidation of mercury from the correlation (r² = 0.85) between catalase activity and mercury uptake when 0.4 mg liver in 2 ml of incubation medium was exposed to mercury vapor. With higher concentrations of homogenates the availability of mercury limited the oxidation process. Experiments with horseradish peroxidase, beef liver catalase and inorganic catalysts of H₂O₂ decomposition indicate that the elemental mercury atom serves as an electron donor for complex I of catalase which is formed from the first reaction of catalase with H₂O₂. Other possible pathways of oxidation such as oxidation of elemental mercury by nascent oxygen released from H₂O₂ do not appear to be important.     

Comparative study of different Portuguese samples of propolis: Pollinic,sensorial, physicochemical,microbiological characterization and antibacterial activity

The aim of this work was to study four propolis samples from Trás-os-Montes region of Portugal. The propolis samples’ color was different, which pollen analysis showed to be due to different botanical sources: Populus sp., Pinus sp., Quercus sp. and Castanea sativa. The data from physicochemical analysis (moisture, soluble and insoluble solids content, pH, conductivity, ash content, wax, total phenolics and flavonoids content) was treated using multivariate statistical tools as cluster heat map, principal components analysis and linear discriminant analysis with the purpose of classifying the sample accordingly to the botanical/geographical origin. The discriminant analysis was applied with stepwise to select the variables that most contribute to sample identification accordingly to pollinic profile. The cross-validation technique was applied, using the leave-one-out procedure, which showed good prediction capabilities of the samples. Microbiologically, the commercial quality was satisfactory, since the samples didn’t contain deterioration or pathogenic microorganisms. All the samples studied presented antimicrobial activity against Methicillin-resistant Staphylococcus aureus, in a dose dependent way. The antimicrobial activity was strictly related to the physicochemical composition. This work will allow connecting a particular chemical propolis type to a specific type of biological activity, what is essential for the use in therapeutic applications.     

Differential elemental distribution of retained particles along the respiratory tract

Context: Prolonged exposure to ambient particles is associated with premature mortality due to cardio-respiratory diseases and lung cancer. The size and composition of these particles determine their toxicity, which is aggravated by their long-term retention in the lungs.

Objective: To compare the elemental profile of particles retained along the bronchial tree and lymph nodes by combining laser capture microdissection (LCM) and elemental composition analysis through energy dispersive x-ray (EDX) and scanning electron microscopy (SEM).

Material and methods: Twenty-four right lung middle lobes from autopsied cases were obtained from two cities with different pollution backgrounds. Lung samples were collected from three distinct sites within the lung at the time of autopsy: peribronchial tissue, peripheral parenchyma and hilar lymph nodes. Areas of potentially increased particle deposition were microdissected using LCM and analyzed for elemental composition through EDX “allied” with SEM.

Results: Elemental analyses of the particles retained along the bronchial tree showed two groups of distribution: peribronchiolar or lymph node deposition. The elemental profile of peribronchial areas were significantly different between the two cities and were better discriminators of past air pollution exposure.

Conclusion: Our data suggest that particle uptake varies along the bronchial tree and human lung tissue retains particles indicative of regional air pollution background.     

Exploration and insights into the cellular internalization and intracellular fate of amphiphilic polymeric nanocarriers

The beneficial or deleterious effects of nanomedicines emerge from their complex interactions with intracellular pathways and their subcellular fate. Moreover, the dynamic nature of plasma membrane accounts for the movement of these nanocarriers within the cell towards different organelles thereby not only influencing their pharmacokinetic and pharmacodynamic properties but also bioavailability, therapeutic efficacy and toxicity. Therefore, an in-depth understanding of underlying parameters controlling nanocarrier endocytosis and intracellular fate is essential. In order to direct nanoparticles towards specific sub-cellular organelles the physicochemical attributes of nanocarriers can be manipulated. These include particle size, shape and surface charge/chemistry. Restricting the particle size of nanocarriers below 200 nm contributes to internalization via clathrin and caveolae mediated pathways. Similarly, a moderate negative surface potential confers endolysosomal escape and targeting towards mitochondria, endoplasmic reticulum (ER) and Golgi. This review aims to provide an insight into these physicochemical attributes of nanocarriers fabricated using amphiphilic graft copolymers affecting cellular internalization. Fundamental principles understood from experimental studies have been extrapolated to draw a general conclusion for the designing of optimized nanoparticulate drug delivery systems and enhanced intracellular uptake via specific endocytic pathway.KEY WORDS: Amphiphilic, Copolymer, Nanoparticles, Internalization, Intracellular fate     

Analysis of the Postoperative Periarticular Environment and Influence on Sustained Drug Delivery From a Gel Formulation

Regional intraarticular delivery of local anesthetics is effective in treating postoperative pain following total knee or hip replacement. Recent research efforts have been only partially successful in achieving sustained release of the analgesic agent, in part due to limited understanding of the biological environment into which these formulations are administered. This study aimed to detail the composition and properties of postoperative periarticular fluid (PO-PAF). PO-PAF was collected from 8 patients, and the composition and physicochemical properties were determined. A number of components were identified which are lacking from phosphate buffered saline (PBS) or other synthetic media. The differences in composition led to variation in the physicochemical properties of PO-PAF compared with PBS. Notably, significantly lower surface tension (p <0.05) and higher buffer capacity (p <0.05) were observed in the biological fluid. We demonstrated that the solubility of lidocaine is almost double in PO-PAF compared to PBS (p <0.05) and that lidocaine release from a poloxamer gelling system occurred faster into PO-PAF under both sink and nonsink conditions. Collectively, these data indicate PBS is inappropriate for the in vitro evaluation of intraarticular drug delivery systems. The presented data describe that PO-PAF and will support the future development of biorelevant media to ultimately improve in vivo–in vitro correlation.     

Dry Powder Aerosols Generated by Standardized Entrainment Tubes from Alternative Sugar Blends: 3. Trehalose Dihydrate and d-Mannitol Carriers

The relationship between physicochemical properties of drug/carrier blends and aerosol drug powder delivery was evaluated. Four pulmonary drugs each representing the major pulmonary therapeutic classes and with a different pharmacological action were employed. Specifically, the four pulmonary drugs were albuterol sulfate, ipratropium bromide monohydrate, disodium cromoglycate, and fluticasone propionate. The two carrier sugars, each representing a different sugar class, were D-mannitol and trehalose dihydrate. Dry powder aerosols (2%, w/w, drug in carrier) delivered using standardized entrainment tubes (SETs) were characterized by twin-stage liquid impinger. The fine particle fraction (FPF) was correlated with SET shear stress, τ_s, and the maximum fine particle fraction (FPF_max) was correlated with a deaggregation constant, k_d, by using a powder aerosol deaggregation equation (PADE) by nonlinear and linear regression analyses applied to pharmaceutical inhalation aerosol systems in the solid state. For the four pulmonary drugs representing the major pulmonary therapeutic classes and two chemically distinct pulmonary sugar carriers (non-lactose types) aerosolized with SETs having well-defined shear stress values, excellent correlation and predictive relationships were demonstrated for the novel and rigorous application of PADE for dry powder inhalation aerosol dispersion within a well-defined shear stress range, in the context of pulmonary drug/sugar carrier physicochemical and interfacial properties.     

Designing Dendrimers for Drug Delivery and Imaging: Pharmacokinetic Considerations

Dendrimers have well-organized high branches with a layered architecture providing a series of versatile chemical modification for various purposes. Consequently, this dendrimer nanotechnology explores a new promising class of nanoscale carriers for therapeutic drugs and imaging reagents using passive and active targeting approaches. By controlling dendritic structures, the biological fate of dendrimer/dendrimer-based drugs can be significantly altered based on their intrinsic physicochemical properties, including the hydrophilicity of the unit molecules, particle size, surface charge, and modification. Accordingly, pharmacokinetic aspects play an important role in the design and development of dendrimer systems for successful in vivo application and clinical translation. This review focuses on the recent progress regarding dendritic architectures, structure-related toxicity, and critical factors affecting the pharmacokinetics and biodistribution of dendrimer/dendrimer-based drugs. A better understanding of the basic aspects of dendritic systems and their pharmacokinetics will help to develop a rationale for the design of dendrimers for the controlled delivery of drugs and imaging reagents for therapeutic or diagnostic purposes.     

Corticosteroid solubility and lipid polarity control release from solid lipid nanoparticles

Solid lipid nanoparticles (SLN) show promise as a drug delivery system for skin administration. The solid state of the lipid particle enables efficient drug encapsulation and controlled drug release. The present study addresses the influence of lipid composition and drug substance lipid solubility on the in vitro release profile of corticosteroids from SLN for topical administration. Firstly, the effect of lipid composition on the lipid solubility and in vitro release of betamethasone-17-valerate (BMV) was determined by varying the lipid monoglyceride content and the chain length of the fatty acid moiety. Secondly, the effect of drug substance physicochemical properties was determined by studying five different corticosteroid derivatives with different lipophilicity. A high concentration of monoglyceride in SLN increased the amount of BMV released. The corticosteroid release rate depended on the drug substance lipophilicity and it was clear that the release profiles depended on drug partitioning to the aqueous phase as indicated by zero order kinetics. The results emphasize that the corticosteroid solubility in the lipid phase greatly influence drug distribution in the lipid particles and release properties. Thus knowledge of drug substance solubility and lipid polarity contributes to optimize SLN release properties.     

Approach to using mechanism-based structure activity relationship (SAR) analysis to assess human health hazard potential of nanomaterials

With the increasing use and development of engineered nanoparticles in electronics, consumer products, pesticides, food and pharmaceutical industries, there is a growing concern about potential human health hazards of these materials. A number of studies have demonstrated that nanoparticle toxicity is extremely complex, and that the biological activity of nanoparticles will depend on a variety of physicochemical properties such as particle size, shape, agglomeration state, crystal structure, chemical composition, surface area and surface properties. Nanoparticle toxicity can be attributed to nonspecific interaction with biological structures due to their physical properties (e.g., size and shape) and biopersistence, or to specific interaction with biomolecules through their surface properties (e.g., surface chemistry and reactivity) or release of toxic ions. The toxic effects of most nanomaterials have not been adequately characterized and currently, there are many issues and challenges in toxicity testing and risk assessment of nanoparticles. Based on the possible mechanisms of action and available in vitro and in vivo toxicity database, this paper proposes an approach to using mechanism-based SAR analysis to assess the relative human health hazard/risk potential of various types of nanomaterials.     

Influence of the drying method in the antioxidant potential and chemical composition of four shrubby flowering plants from the tribe Genisteae (Fabaceae)

Flowers from several common Mediterranean shrubs, such as those from the Cytisus genus and Genista genus (tribe Genisteae/Fabaceae) have long been used for medicinal purposes and seasoning in the northeastern Portuguese region. Despite, the shade-drying traditionally used to process these plants, freeze-drying is claimed to better preserve the quality of medicinal plants. Herein, the effects of drying process in the antioxidants composition and properties of Cytisus multiflorus, Cytisus scoparius, Cytisus striatus and Pterospartum tridentatum were evaluated. Freeze-dried P. tridentatum revealed the highest antioxidant properties (EC₅₀ values ?0.15 mg/ml). Freeze-drying benefits were confirmed showing, the samples submitted to this process, higher antioxidant activity and higher concentrations of hydrophilic (phenolics, ascorbic acid and sugars) and lipophilic (tocopherols, chlorophylls and lycopene) compounds. This process could be applied in scale-up treatments of the studied plants for cosmetic or pharmaceutical applications.     

Impact of chitosan composites and chitosan nanoparticle composites on various drug delivery systems: A review

Chitosan is a promising biopolymer for drug delivery systems. Because of its beneficial properties, chitosan is widely used in biomedical and pharmaceutical fields. In this review, we summarize the physicochemical and drug delivery properties of chitosan, selected studies on utilization of chitosan and chitosan-based nanoparticle composites in various drug delivery systems, and selected studies on the application of chitosan films in both drug delivery and wound healing. Chitosan is considered the most important polysaccharide for various drug delivery purposes because of its cationic character and primary amino groups, which are responsible for its many properties such as mucoadhesion, controlled drug release, transfection, in situ gelation, and efflux pump inhibitory properties and permeation enhancement. This review can enhance our understanding of drug delivery systems particularly in cases where chitosan drug-loaded nanoparticles are applied.     

The influence of lipophilicity in drug discovery and design

Introduction: The role of lipophilicity in drug discovery and design is a critical one. Lipophilicity is a key physicochemical property that plays a crucial role in determining ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties and the overall suitability of drug candidates. There is increasing evidence to suggest that control of physicochemical properties such as lipophilicity, within a defined optimal range, can improve compound quality and the likelihood of therapeutic success.

Areas covered: This review focuses on understanding lipophilicity, techniques used to measure lipophilicity, and summarizes the importance of lipophilicity in drug discovery and development, including a discussion of its impact on individual ADMET parameters as well as its overall influence on the drug discovery and design process, specifically within the past 15 years.

Expert opinion: A current review of the literature reveals a continued reliance on the synthesis of novel structures with increased potency, rather than a focus on maintaining optimal physicochemical properties associated with ADMET throughout drug optimization. Particular attention to the optimum region of lipophilicity, as well as monitoring of lipophilic efficiency indices, may contribute significantly to the overall quality of candidate drugs at different stages of discovery.     

Physicochemical and morphological characterisation of nanoparticles from photocopiers: implications for environmental health

Abstract

Several reports link printing and photocopying with genotoxicity, immunologic and respiratory diseases. Photocopiers and printers emit nanoparticles, which may be involved in these diseases. The physicochemical and morphological composition of these emitted nanoparticles, which is poorly understood and is critical for toxicological evaluations, was assessed in this study using both real-time instrumentation and analytical methods. Tests included elemental composition (40 metals), semi-volatile organics (100 compounds) and single particle analysis, using multiple high-sensitivity/resolution techniques. Identical analyses were performed on the toners and dust collected from copier's exhaust filter. Engineered nanoparticles, including titanium dioxide, iron oxide and fumed silica, and several metals were found in toners and airborne nanoscale fraction. Chemical composition of airborne nanoscale fraction was complex and reflected toner chemistry. These findings are important in understanding the origin and toxicology of such nanoparticles. Further investigation of their chemistry, larger scale exposure studies and thorough toxicological characterisation of emitted nanoparticles is needed.     

Dry powder inhalers: mechanistic evaluation of lactose formulations containing salbutamol sulphate

The purpose of this study was to evaluate the relationships between physicochemical properties and aerosolisation performance of different grades of lactose. In order to get a wide range of physicochemical properties, various grades of lactose namely Flowlac^®100 (FLO), Lactopress anhydrous^®250 (LAC), Cellactose^®80 (CEL), Tablettose^®80 (TAB), and Granulac^®200 (GRA) were used. The different lactose grades were carefully sieved to separate 63-90 μm particle size fractions and then characterised in terms of size, shape, density, flowability, and solid state. Formulations were prepared by blending each lactose with salbutamol sulphate (SS) at ratio of 67.5:1 (w/w), and then evaluated in terms of SS content uniformity, lactose-SS adhesion properties, and in vitro aerosolisation performance delivered from the Aerolizer^®. Sieved lactose grades showed similar particle size distributions (PSDs) and good flow properties but different particle shape, particle surface texture, and particle solid state. Content uniformity assessments indicated that lactose particles with rougher surface produced improved SS homogeneity within DPI formulation powders. Lactose-SS adhesion assessments indicated that lactose particles with more elongated shape and the rougher surface showed smaller adhesion force between lactose and salbutamol sulphate. Lactose powders with higher bulk density and higher tap density produced smaller emission (EM) and higher drug loss (DL) of SS. In vitro aerosolisation for various lactose grades followed the following rank order in terms of deposition performance: GRA > TAB > LAC ≈ CEL > FLO. Linear relationships were established showing that in order to maximize SS delivery to lower airway regions, lactose particles with more elongated shape, more irregular shape, and rougher surface are preferred. Therefore, considerable improvement in DPI performance can be achieved by careful selection of grade of lactose included within DPI formulations.     

Novel continuous flow technology for the development of a nanostructured Aprepitant formulation with improved pharmacokinetic properties

The oral bioavailability of Aprepitant is limited by poor dissolution of the compound in the gastrointestinal tract which is more prominent in the fasted state resulting in significant positive food effect. Due to the low aqueous solubility of the active substance the product development has been focused on decreasing the particle size of the active compound down to the submicron range in order to overcome this disadvantageous pharmacokinetic property. The marketed drug consisting of wet-milled nanocrystals exhibits significantly higher oral bioavailability in the fasted state and reduced food effect when compared to the unformulated compound. We have developed a novel process for the production of a nanostructured Aprepitant formulation in which the generation of the nanosized particles takes place at molecular level. The process relies on controlled continuous flow precipitation of the compound from its solution in the presence of stabilizers. The precise control of the production parameters (mixing geometry, flow rates, temperature, etc.) allows to tailor the physicochemical properties and biological performance of the active compound. We have prepared a novel nanostructured Aprepitant formulation using this method and compared its physicochemical and pharmacokinetic properties with the reference compound and the marketed nanoformula. We found that our method produces a stable amorphous solid form comprising novel nanostructured particles having a particle size of less than 100 nm with instantaneous redispersibility characteristics and improved apparent solubility and permeability. In vivo beagle dog pharmacokinetic studies showed that the novel formula exhibited greatly improved pharmacokinetic characteristics when compared to the reference compound, while serum blood concentrations for the nanostructured formula and the wet-milled formula were similar. The marked food effect observed for the reference compound was practically eliminated by our formulation method. These results indicate that the novel continuous flow precipitation technology is a suitable tool to prepare nanostructured formulations with similar, or even superior in vitro and in vivo characteristics when compared to the industrial standard milling technology.     

Profiling biopharmaceutical deciding properties of absorption of lansoprazole enteric-coated tablets using gastrointestinal simulation technology

The aim of the present study was to correlate in vitro properties of drug formulation to its in vivo performance, and to elucidate the deciding properties of oral absorption. Gastrointestinal simulation technology (GST) was used to simulate the in vivo plasma concentration–time curve and was implemented by GastroPlus™ software. Lansoprazole, a typical BCS class II drug, was chosen as a model drug. Firstly, physicochemical and pharmacokinetic parameters of lansoprazole were determined or collected from literature to construct the model. Validation of the developed model was performed by comparison of the predicted and the experimental plasma concentration data. We found that the predicted curve was in a good agreement with the experimental data. Then, parameter sensitivity analysis (PSA) was performed to find the key parameters of oral absorption. The absorption was particularly sensitive to dose, solubility and particle size for lansoprazole enteric-coated tablets. With a single dose of 30 mg and the solubility of 0.04 mg/ml, the absorption was complete. A good absorption could be achieved with lansoprazole particle radius down to about 25 μm. In summary, GST is a useful tool for profiling biopharmaceutical deciding properties of absorption of lansoprazole enteric-coated tablets and guiding the formulation optimization.     

The effect of the source and the concentration of polymers on the release of chlorhexidine from mucoadhesive buccal tablets

In the current work, two groups of chlorhexidine mucoadhesive buccal tablets were prepared, using either rod or irregularly-shaped spherical particles of hydroxypropyl methylcellulose and different ratios of poloxamer 407 (P407). The tablets were designed to release the drug over two hours. Their physicochemical properties and drug release profiles were investigated. The impact on dry granulation, the ex-vivo mucoadhesion, the swelling index, the morphology of swollen tablets and the drug release kinetic were investigated. Drug-polymers chemical interaction was studied using Fourier Transforms Infrared Spectroscopy (FTIR) and differential scanning calorimetry (DSC). Due to different particle shapes, the preparation of dry granules required a 40 KN force for rod-shaped particles compared to 10 KN for the irregularly-shaped spherical particles. All formulations showed at least two-hours residence time using ex-vivo mucoadhesion. Statistically, there was no significant difference in the swelling index, drug release nor its kinetic for both groups. However, the microscopical morphology of the swollen tablet and the size of the pores were affected by particle shape. Increasing the ratio of P407 to 62.5% resulted in a pronounced increase in drug release from around 60% to >90% after two hours. Following the FTIR and DSC analyses, no chemical interaction was noted apart from the steric hindrance effect of P407, which was observed even with the physical mixtures.     

Stability and solubility of trans-resveratrol are strongly influenced by pH and temperature

Recently trans-resveratrol (trans-RSV) has received great attention due to its prophylactic and therapeutic properties. Its limited bioavailability provides compelling evidence of the need for more suitable formulations in order to attain better clinical effectiveness. Some physicochemical properties of trans-RSV are still unknown or research findings are contradictory. Therefore, this paper presents newly determined trans-RSV solubility and stability at various pH and temperatures, and the importance of such data for the studies of novel trans-RSV-loaded nanofibers. In acidic pH trans-RSV was stable, whereas its degradation started to increase exponentially above pH 6.8. Consequently, it is worthwhile to note that special consideration has to be dedicated to long dissolution testing or biological assays on cell lines in order to obtain relevant data. Measurements were done by validated UV/VIS spectroscopy, HPLC, and newly developed UPLC methods. Specificity was confirmed for HPLC and UPLC method, whereas UV/VIS spectroscopy resulted in false higher trans-RSV concentrations in conditions under which it was not stable (alkaline pH, light, increased temperature). The study is of interest because it draws attention to the importance of careful selected experimental conditions, their influence on the trans-RSV stability and the implications this has for formulation development, storage, and maintenance of therapeutic doses.