As a small molecule PDE 4 inhibitor, apremilast has drawn much attention for multiple promising indications. However, apremilast is a poorly water-soluble drug and has multiple polymorphic forms. This study aims to develop a sustained-release (SR) amorphous solid dispersion (ASD) system for apremilast. A streamlined material sparing ASD formulation development approach was utilized to identify candidate polymers and optimize drug loading. HPMCAS-M at a 20% drug loading and Copovidone at a 40% drug loading was selected as the lead formulations. A stable single-phase amorphous system of apremilast via spray drying was generated as revealed by XRPD, DMA, micro-dissolution, and accelerated stability testing. The apparent solubility of apremilast was improved up to 9 folds. HPMC was subsequently utilized to compress the produced ASD system into an SR matrix tablet. Release data demonstrated the capacity of HPMC to gradually hydrate and control drug release while suppressing drug recrystallization during the 20-hours period of sustained drug delivery. The designed SR amorphous based matrix system indicates that the delivery system has the ability to enhance apparent solubility, avoid recrystallization or polymorphic transformation by stabilizing its amorphous form, and provide an opportunity to enhance patient compliance by allowing once-daily administration. / Pharmaceutical Sciences

The most common route of administration is oral, despite absorption barriers leading to variable exposure and therapeutic effect. Preclinical species are used to study this variability, though they are expensive and time-consuming. Modeling and simulation provide an alternative to preclinical studies. In this study, a continuous rodent absorption model was developed and refined to predict drug absorption prior to entering animals. The continuous absorption model describes the change in drug concentration over distance and time. The intestine is defined by a physiologically based pharmacokinetic (PBPK) model, which is attached to a simpler classical compartmental model to represent the rest of the body. Physiological factors and drug physicochemical properties will be incorporated to predict the absorption profiles of amlodipine (AML), glyburide (GLY), and digoxin (DIG). The anatomy of the gastrointestinal tract and therefore, the physiological factors inputted into the model, are species specific. The region lengths, such as the jejunum, and absorptive surface area amplifiers, such as the villi, of the small intestine differ in humans versus rats. In addition, the stomach composition and presence of the gallbladder is not consistent between the two species. Similarly, food alters the physiology of the intestines. Periods of fasting can induce changes in intestinal pH and gastrointestinal motility. Chapter One details the background concerning this project, along with the hypothesis and goals. Chapter Two involves the development and validation for bioanalytical methods for the drugs of interest. Chapter Three discusses the collection of anatomical data, specifically the intestinal pH and gastrointestinal motility under fed and fasted conditions. Chapter Four includes in vitro ADME data collection and in vivo IV pharmacokinetic studies in male Sprague-Dawley rats to determine the systemic disposition functions in for amlodipine (AML), glyburide (GLY) and digoxin (DIG). Chapter Five includes the in vivo pharmacokinetic studies in male Sprague-Dawley rats to determine the effect of food on the absorption of amlodipine (AML), glyburide (GLY) and digoxin (DIG). Chapter Six details the in vivo rat studies involving the influence of particle size on GLY suspension absorption. Chapter Seven discusses the input of physiological factors and prediction of drug absorption using a continuous absorption model in rats. Chapter Eight details future directions and the summary of the project. / Pharmaceutical Sciences

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The objective of this study was to evaluate the stability of vancomycin hydrochloride oral solution prepared using FIRST Vancomycin and FIRVANQ compounding kits, prepared in oral syringes and heat-sealed dosing cups, stored at refrigerated and room temperatures. Triplicate batches of vancomycin hydrochloride oral solution (50 mg/mL) were prepared using FIRST Vancomycin and FIRVANQ kits, aliquoted into plastic oral syringes and sealed dosing cups, stored at refrigerated and room temperatures for a total of eight sample groups. Additionally, remaining samples from FIRVANQ batches were unit-dosed in clear Luer-Lok syringes and stored under refrigeration as a ninth batch. Samples were removed and analyzed for vancomycin recovery using a previously validated high-performance liquid chromatography with ultraviolet detection method over a 30-day period. Recovery was quantitatively assessed by comparing to a freshly prepared United States Pharmacopeia reference standard on each day of sampling. Stability was defined as recovery of 90% to 110% of labeled amount. For all batches and storage conditions tested, the percent recovery of vancomycin remained within the 90% to 110% range throughout the entire 30-day study period. Statistically significant differences based on storage conditions were detected between some test groups, with higher recoveries associated with refrigerated storage. The stability of FIRVANQ is comparable to the solution prepared using the FIRST Vancomycin kit. FIRST Vancomycin and FIRVANQ solutions can be unit dosed, using capped oral syringes or sealed plastic cups, and stored at room temperature or under refrigeration for up to 30 days, which helps improve pharmacy workflow and reduce errors.

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