Visitor engagement with zoo staff and interpretive demonstrations increases visitor stay time in two free-flight aviaries.

Understanding how visitors spend time in zoo exhibits is important as zoological facilities work to enhance visitor experience and conservation education outcomes. We explored a variety of factors we hypothesized would influence visitor stay times in two aviaries at Disney's Animal Kingdom®. Within these aviaries, visitors could utilize educational materials, listen to staff-led demonstrations, or talks, view animal training sessions, or speak directly with animal care or education staff. We observed visitors and recorded the opportunities they utilized in the exhibit. Visitors to either aviary who conversed with exhibit-specific staff stayed between 67% and 89% longer than visitors who did not. In addition, visitors who used a bird guide while in either aviary stayed between 59% and 82% longer than those who did not. Those who listened to an animal care talk or engaged with a staff-led demonstration stayed between 50% and 68% longer than those who did not have the option to participate in such activities. This study provides insight into how exhibit offerings can influence visitor behavior. Implementing strategies used in this study to increase visitors' time in an exhibit may enhance visitor experience and improve learning outcomes.

Mobile eye tracking applied as a tool for customer experience research in a crowded train station.

Train stations have increasingly become crowded, necessitating stringent requirements in the design of stations and commuter navigation through these stations. In this study, we explored the use of mobile eye tracking in combination with observation and a survey to gain knowledge on customer experience in a crowded train station. We investigated the utilization of mobile eye tracking in ascertaining customers' perception of the train station environment and analyzed the effect of a signalization prototype (visual pedestrian flow cues), which was intended for regulating pedestrian flow in a crowded underground passage. Gaze behavior, estimated crowd density, and comfort levels (an individual's comfort level in a certain situation), were measured before and after the implementation of the prototype. The results revealed that the prototype was visible in conditions of low crowd density. However, in conditions of high crowd density, the prototype was less visible, and the path choice was influenced by other commuters. Hence, herd behavior appeared to have a stronger effect than the implemented signalization prototype in conditions of high crowd density. Thus, mobile eye tracking in combination with observation and the survey successfully aided in understanding customers' perception of the train station environment on a qualitative level and supported the evaluation of the signalization prototype the crowded underground passage. However, the analysis process was laborious, which could be an obstacle for its practical use in gaining customer insights.

PolyQ length-based molecular encoding of vocalization frequency in FOXP2.

The transcription factor FOXP2, a regulator of vocalization- and speech/language-related phenotypes, contains two long polyQ repeats (Q1 and Q2) displaying marked, still enigmatic length variation across mammals. We found that the Q1/Q2 length ratio quantitatively encodes vocalization frequency ranges, from the infrasonic to the ultrasonic, displaying striking convergent evolution patterns. Thus, species emitting ultrasonic vocalizations converge with bats in having a low ratio, whereas species vocalizing in the low-frequency/infrasonic range converge with elephants and whales, which have higher ratios. Similar, taxon-specific patterns were observed for the FOXP2-related protein FOXP1. At the molecular level, we observed that the FOXP2 polyQ tracts form coiled coils, assembling into condensates and fibrils, and drive liquid-liquid phase separation (LLPS). By integrating evolutionary and molecular analyses, we found that polyQ length variation related to vocalization frequency impacts FOXP2 structure, LLPS, and transcriptional activity, thus defining a novel form of polyQ length-based molecular encoding of vocalization frequency.

Can the Oral Bioavailability of the Discontinued Prostate Cancer Drug Galeterone Be Improved by Processing Method? KinetiSol® Outperforms Spray Drying in a Head-to-head Comparison.

Galeterone, a novel prostate cancer candidate treatment, was discontinued after a Phase III clinical trial due to lack of efficacy. Galeterone is weakly basic and exhibits low solubility in biorelevant media (i.e., ~ 2 µg/mL in fasted simulated intestinal fluid). It was formulated as a 50-50 (w/w) galeterone-hypromellose acetate succinate spray-dried dispersion to increase its bioavailability. Despite this increase, the bioavailability of this formulation may have been insufficient and contributed to its clinical failure. We hypothesized that reformulating galeterone as an amorphous solid dispersion by KinetiSol® compounding could increase its bioavailability. In this study, we examined the effects of composition and manufacturing technology (Kinetisol and spray drying) on the performance of galeterone amorphous solid dispersions. KinetiSol compounding was utilized to create galeterone amorphous solid dispersions containing the complexing agent hydroxypropyl-ß-cyclodextrin or hypromellose acetate succinate with lower drug loads that both achieved a ~ 6 × increase in dissolution performance versus the 50-50 spray-dried dispersion. When compared to a spray-dried dispersion with an equivalent drug load, the KinetiSol amorphous solid dispersions formulations exhibited ~ 2 × exposure in an in vivo rat study. Acid-base surface energy analysis showed that the equivalent composition of the KinetiSol amorphous solid dispersion formulation better protected the weakly basic galeterone from premature dissolution in acidic media and thereby reduced precipitation, inhibited recrystallization, and extended the extent of supersaturation during transit into neutral intestinal media.

Pre-Processing a Polymer Blend into a Polymer Alloy by KinetiSol Enables Increased Ivacaftor Amorphous Solid Dispersion Drug Loading and Dissolution.

This study compares the effects of pre-processing multiple polymers together to form a single-phase polymer alloy prior to amorphous solid dispersion formulation. KinetiSol compounding was used to pre-process a 1:1 (w/w) ratio of hypromellose acetate succinate and povidone to form a single-phase polymer alloy with unique properties. Ivacaftor amorphous solid dispersions comprising either a polymer, an unprocessed polymer blend, or the polymer alloy were processed by KinetiSol and examined for amorphicity, dissolution performance, physical stability, and molecular interactions. A polymer alloy ivacaftor solid dispersion with a drug loading of 50% w/w was feasible versus 40% for the other compositions. Dissolution in fasted simulated intestinal fluid revealed that the 40% ivacaftor polymer alloy solid dispersion reached a concentration of 595 µg/mL after 6 h, 33% greater than the equivalent polymer blend dispersion. Fourier transform infrared spectroscopy and solid-state nuclear magnetic resonance revealed changes in the ability of the povidone contained in the polymer alloy to hydrogen bond with the ivacaftor phenolic moiety, explaining the differences in the dissolution performance. This work demonstrates that the creation of polymer alloys from polymer blends is a promising technique that provides the ability to tailor properties of a polymer alloy to maximize the drug loading, dissolution performance, and stability of an ASD.

Minimization of Acid-Catalyzed Degradation in KinetiSol Processing through HPMCAS Neutralization.

Hypromellose acetate succinate (HPMCAS) is an enteric polymer that has been successfully employed as a carrier in amorphous solid dispersions (ASDs). Deprotonation of succinic acid substituents at intestinal pH levels results in solubilization of the polymer. However, the acidic moieties responsible for favorable pH-dependent solubility can also result in incompatibilities between acid-sensitive drugs and HPMCAS. Solution-state conversion of the carboxylic acid substituents of enteric polymers into carboxylate salts to reduce acid-mediated drug degradation is a demonstrated effective strategy for generating ASDs in enteric polymers. This work aimed to extend the use of a pre-ionized enteric polymer to KinetiSol solvent-free processing to reduce acid- or base-mediated drug degradation during processing. Pre-ionization of HPMCAS was accomplished by reaction with a stoichiometric quantity of sodium carbonate (Na2CO3) delivered as a saturated aqueous solution. The resulting ionized polymer, HPMCAS-Na, was dried thoroughly before processing. Tetrabenazine (TBZ) was chosen as a model drug for its susceptibility to degradation via both acid- and base-catalyzed reaction mechanisms and for its tendency to form a single impurity by these mechanisms. The use of HPMCAS-Na in KinetiSol solid dispersions (KSDs) of TBZ resulted in a 6- to 8-fold reduction of the acid- and base-generated TBZ impurity compared with KSDs formulated with untreated HPMCAS.

Facial Appearance Dissatisfaction Explains Differences in Zoom Fatigue.

Viewing self-video during videoconferences potentially causes negative self-focused attention that contributes to virtual meeting (VM) or "Zoom" fatigue. The present research examines this proposition, focusing on facial dissatisfaction-feeling unhappy about one's own facial appearance-as a potential psychological mechanism of VM fatigue. A study of survey responses from a panel of 613 adults found that VM fatigue was 14.9 percent higher for women than for men, and 11.1 percent higher for Asian than for White participants. These gender and race/ethnicity differences were found to be mediated by facial dissatisfaction. This study replicates earlier VM fatigue research, extends the theoretical understanding of facial dissatisfaction as a psychological mechanism of VM fatigue, and suggests that practical approaches to mitigating VM fatigue could include implementing technological features that reduce self-focused attention during VMs (e.g., employing avatars).

The effect of drug loading on the properties of abiraterone-hydroxypropyl beta cyclodextrin solid dispersions processed by solvent free KinetiSol® technology.

Abiraterone is a poorly water-soluble drug used in the treatment of prostate cancer. In our previous study, we reported that KinetiSol® processed solid dispersions (KSDs) based on hydroxypropyl ß-cyclodextrin (HPBCD) showed improved dissolution and pharmacokinetics of abiraterone. However, the nature of abiraterone-HPBCD interaction within the KSDs or the effect of drug loading on the physicochemical properties and in vivo performance of HPBCD-based KSDs remain largely unknown. We hypothesize that KinetiSol technology can prepare abiraterone-HPBCD complexes within KSDs and that increasing the drug loading beyond an optimal point reduces the in vitro and in vivo performance of these KSDs. To confirm our hypothesis, we developed KSDs with 10-50% w/w drug loading and analyzed them using X-ray diffractometry and modulated differential scanning calorimetry. We found that KSDs containing 10-30% drug were amorphous. Interestingly, two-dimensional solid-state nuclear magnetic resonance and Raman spectroscopy indicated that the abiraterone-HPBCD complexes were formed. At elevated temperatures, the 10% and 20% drug-loaded KSDs were physically stable, while the 30% drug-loaded KSD showed recrystallization of abiraterone. In vitro dissolution and in vivo pharmacokinetic performances improved as the drug loading decreased; we attribute this to increased noncovalent interactions between abiraterone and HPBCD at lower drug loadings. Overall, the 10% drug loaded KSD showed a dissolution enhancement of 15.7-fold compared to crystalline abiraterone, and bioavailability enhancement of 3.9-fold compared to the commercial abiraterone acetate tablet Zytiga®. This study is first to confirm that KinetiSol, a high-energy, solvent-free technology, is capable of forming abiraterone-HPBCD complexes. Furthermore, in terms of in vitro and in vivo performance, a 10% drug load is optimal.

Formulating a heat- and shear-labile drug in an amorphous solid dispersion: Balancing drug degradation and crystallinity.

We seek to further addresss the questions posed by Moseson et al. regarding whether any residual crystal level, size, or characteristic is acceptable in an amorphous solid dispersion (ASD) such that its stability, enhanced dissolution, and increased bioavailability are not compromised. To address this highly relevant question, we study an interesting heat- and shear-labile drug in development, LY3009120. To study the effects of residual crystallinity and degradation in ASDs, we prepared three compositionally identical formulations (57-1, 59-4, and 59-5) using the KinetiSol process under various processing conditions to obtain samples with various levels of crystallinity (2.3%, 0.9%, and 0.1%, respectively) and degradation products (0.74%, 1.97%, and 3.12%, respectively). Samples with less than 1% crystallinity were placed on stability, and we observed no measurable change in the drug's crystallinity, dissolution profile or purity in the 59-4 and 59-5 formulations over four months of storage under closed conditions at 25 °C and 60% humidity. For formulations 57-1, 59-4, and 59-5, bioavailability studies in rats reveal a 44-fold, 55-fold, and 62-fold increase in mean AUC, respectively, compared to the physical mixture. This suggests that the presence of some residual crystals after processing can be acceptable and will not change the properties of the ASD over time.

A rapid review of Indigenous boys' and men's sexual health in Canada.

Indigenous boys and men in Canada face adverse social and structural circumstances that affect their ability to achieve and maintain sexual health. Research about Indigenous sexual health, however, is largely limited to matters relating to women and statistics on sexually transmitted infections. A rapid review of research was conducted to determine what is currently known about Indigenous boys' and men's sexual health in Canada. Given the prevalence of research documenting quantitative disparities, the current review included qualitative research only. Thirteen included studies explored a wide range of topics relating to sexual health and an overarching intersection between social conditions and individual health outcomes was observed. The results of this review reveal significant gaps in the literature relating to the holistic sexual health of Indigenous boys and men and highlight important domains of sexual health to consider in future research. Findings suggest that sexual health programmes that promote traditional Indigenous knowledge and intergenerational relationships may be effective for promoting sexual health among Indigenous boys and men.

Rheumatoid arthritis related interstitial lung disease - improving outcomes over 25 years: a large multicentre UK study.

OBJECTIVE: This study explores whether the prognosis of interstitial lung disease in rheumatoid arthritis (RA-ILD) has improved over time and assesses the potential influence of drug therapy in a large multicentre UK network. METHODS: We analysed data from 18 UK centres on patients meeting criteria for both RA and ILD diagnosed over a 25-year period. Data included age, disease duration, outcome and cause of death. We compared all cause and respiratory mortality between RA controls and RA-ILD patients, assessing the influence of specific drugs on mortality in four quartiles based on year of diagnosis. RESULTS: A total of 290 RA-ILD patients were identified. All cause (respiratory) mortality was increased at 30% (18%) compared with controls 21% (7%) (P =0.02). Overall, prognosis improved over quartiles with median age at death rising from 63 years to 78 years (P =0.01). No effect on mortality was detected as a result of DMARD use in RA-ILD. Relative risk (RR) of death from any cause was increased among patients who had received anti-TNF therapy [2.09 (1.1-4.0)] P =0.03, while RR was lower in those treated with rituximab [0.52(0.1-2.1)] or mycophenolate [0.65 (0.2-2.0)]. Patients receiving rituximab as their first biologic had longer three (92%), five (82%) and seven year (80%) survival than those whose first biologic was an anti-TNF agent (82%, 76% and 64%, respectively) (P =0.037). DISCUSSION: This large retrospective multicentre study demonstrates survival of patients with RA-ILD has improved. This may relate to the increasing use of specific immunosuppressive and biologic agents.

Thermally Conductive Excipient Expands KinetiSol® Processing Capabilities.

We report for the first time that incorporation of a thermally conductive excipient (TCE) modifies the thermal conductivity of the ternary drug-polymer-TCE compositions such that high-energy mixing can occur for prolonged periods at a selected steady-state temperature during the KinetiSol process. In this study, candurin, a TCE, is incorporated within a composition that is processed by high-energy mixing from the KinetiSol process to increase the thermal conductivity of the ternary composition. The improved thermal conductivity promotes heat transfer and enables the high-energy mixing applied during the KinetiSol process to be continued for prolonged time intervals at a selected steady-state temperature, instead of undergoing a continued increase in temperature when the TCE is not present in the composition. The addition of candurin does not impact the molecular structure and mixing of the drug and polymer in ASDs from solid-state NMR characterizations. Compositions with candurin achieved a steady-state processing temperature with + 5°C of the target temperature, and these compositions demonstrated the ability to mix for prolonged time periods while maintaining within this steady-state temperature range, thus enabling the formation of an ASD at a temperature that the drug does not chemically degrade. This study demonstrated that inclusion of the TCE modified the composition's thermal conductivity to efficiently dissipate heat to achieve a selected steady-state temperature during the KinetiSol process, thus providing prolonged mixing times at a lower temperature for dissolving the drug into the polymer to achieve an ASD without sacrificing product performance.

Innovations in Thermal Processing: Hot-Melt Extrusion and KinetiSol® Dispersing.

Thermal processing has gained much interest in the pharmaceutical industry, particularly for the enhancement of solubility, bioavailability, and dissolution of active pharmaceutical ingredients (APIs) with poor aqueous solubility. Formulation scientists have developed various techniques which may include physical and chemical modifications to achieve solubility enhancement. One of the most commonly used methods for solubility enhancement is through the use of amorphous solid dispersions (ASDs). Examples of commercialized ASDs include Kaletra®, Kalydeco®, and Onmel®. Various technologies produce ASDs; some of the approaches, such as spray-drying, solvent evaporation, and lyophilization, involve the use of solvents, whereas thermal approaches often do not require solvents. Processes that do not require solvents are usually preferred, as some solvents may induce toxicity due to residual solvents and are often considered to be damaging to the environment. The purpose of this review is to provide an update on recent innovations reported for using hot-melt extrusion and KinetiSol® Dispersing technologies to formulate poorly water-soluble APIs in amorphous solid dispersions. We will address development challenges for poorly water-soluble APIs and how these two processes meet these challenges.

In Vitro and In Vivo Behaviors of KinetiSol and Spray-Dried Amorphous Solid Dispersions of a Weakly Basic Drug and Ionic Polymer†.

Oral delivery of poorly water-soluble, weakly basic drugs may be problematic based on the drugs' intrinsic properties. Many drugs in this subset have overcome barriers to delivery following successful formulation as amorphous solid dispersions (ASDs). To process drugs as ASDs, multiple commercially relevant technologies have been developed and become well understood. However, ASD-producing technologies like spray drying and KinetiSol produce ASDs with vastly differing particle characteristics. Ultimately, the objective of this study was to assess whether processing an ASD of identical composition utilizing two different ASD-producing technologies (KinetiSol and spray drying) may impact the oral bioavailability of a weakly basic drug. For this study, we selected a weakly basic drug (Boehringer Ingelheim research compound 639667, BI 667) and processed it with an anionic polymer (hypromellose acetate succinate MMP grade (HPMCAS-MMP)) to evaluate whether the processing technology could modulate drug release in acidic and neutral media. Multiple characterization techniques (specific surface area (SSA), particle size distribution (PSD), scanning electron microscopy (SEM)) were utilized to evaluate the surface characteristics and differences in particles produced by KinetiSol and spray drying. Molecular interactions and drug-polymer miscibility of the processed particles were assessed using Fourier transform infrared spectroscopy and solid-state nuclear magnetic resonance, respectively. In vitro nonsink, pH-shift dissolution in biorelevant media and dissolution/permeation studies were conducted to better understand the release of BI 667 based on processing technology and particle size distribution. Finally, an in vivo male Beagle dog study was conducted to assess the impact of processing technology on oral bioavailability. In this study, we demonstrate that particles produced by KinetiSol have enhanced oral bioavailability compared with spray-dried particles when delivering a weakly basic drug processed with an anionic polymer. The findings of this study demonstrate that by utilizing KinetiSol, drug release may be controlled such that supersaturation in acidic media is inhibited and supersaturation of the drug is designed to occur in neutral media, ultimately enhancing oral bioavailability.

Improved Dissolution and Pharmacokinetics of Abiraterone through KinetiSol® Enabled Amorphous Solid Dispersions.

Abiraterone is a poorly water-soluble drug. It has a high melting point and limited solubility in organic solvents, making it difficult to formulate as an amorphous solid dispersion (ASD) with conventional technologies. KinetiSol® is a high-energy, fusion-based, solvent-free technology that can produce ASDs. The aim of this study was to evaluate the application of KinetiSol to make abiraterone ASDs. We developed binary KinetiSol ASDs (KSDs) using both polymers and oligomers. For the first time, we reported that KinetiSol can process hydroxypropyl-ß-cyclodextrin (HPBCD), a low molecular-weight oligomer. Upon X-ray diffractometry and modulated differential scanning calorimetry analysis, we found the KSDs to be amorphous. In vitro dissolution analysis revealed that maximum abiraterone dissolution enhancement was achieved using a HPBCD binary KSD. However, the KSD showed significant abiraterone precipitation in fasted state simulated intestinal fluid (FaSSIF) media. Hence, hypromellose acetate succinate (HPMCAS126G) was selected as an abiraterone precipitation inhibitor and an optimized ternary KSD was developed. A pharmacokinetic study revealed that HPBCD based binary and ternary KSDs enhanced abiraterone bioavailability by 12.4-fold and 13.8-fold, respectively, compared to a generic abiraterone acetate tablet. Thus, this study is the first to demonstrate the successful production of an abiraterone ASD that exhibited enhanced dissolution and bioavailability.

Harnessing the therapeutic potential of anticancer drugs through amorphous solid dispersions.

The treatment of cancer is still a major challenge. But tremendous progress in anticancer drug discovery and development has occurred in the last few decades. However, this progress has resulted in few effective oncology products due to challenges associated with anticancer drug delivery. Oral administration is the most preferred route for anticancer drug delivery, but the majority of anticancer drugs currently in product pipelines and the majority of those that have been commercially approved have inherently poor water solubility, and this cannot be mitigated without compromising their potency and stability. The poor water solubility of anticancer drugs, in conjunction with other factors, leads to suboptimal pharmacokinetic performance. Thus, these drugs have limited efficacy and safety when administered orally. The amorphous solid dispersion (ASD) is a promising formulation technology that primarily enhances the aqueous solubility of poorly water-soluble drugs. In this review, we discuss the challenges associated with the oral administration of anticancer drugs and the use of ASD technology in alleviating these challenges. We emphasize the ability of ASDs to improve not only the pharmacokinetics of poorly water-soluble anticancer drugs, but also their efficacy and safety. The goal of this paper is to rationalize the application of ASD technology in the formulation of anticancer drugs, thereby creating superior oncology products that lead to improved therapeutic outcomes.

Homogeneity of amorphous solid dispersions - an example with KinetiSol®.

KinetiSol® is a high-shear, fusion-based technology capable of producing stable amorphous solid dispersions (ASDs) without the assistance of solvent. KinetiSol® has proven successful with multiple challenging BCS class II and IV drugs, where drug properties like thermal instability or lack of appreciable solubility in volatile solvents make hot melt extrusion or spray drying unfeasible. However, there is a necessity to characterize the ASDs like those made by the KinetiSol® process, in order to better understand whether KinetiSol® is capable of homogeneously dispersing drug throughout a carrier in a short (<40 s) processing time. Our study utilized the high melting point, BCS class II drug, meloxicam, in order to evaluate the degree of homogeneity of 1, 5, and 10% w/w KinetiSol®-processed samples. Powder blend homogeneity and content uniformity were evaluated, and all samples demonstrated a meloxicam concentration % relative standard deviation of ≤2.0%. SEM/EDS was utilized to map elemental distribution of the processed samples, which confirmed KinetiSol®-processed materials were homogeneous at a 25 µm2 area. Utilizing Raman spectroscopy, we were able to verify the amorphous content of the processed samples. Finally, we utilized ssNMR 1 H spin-lattice relaxation measurement to evaluate the molecular miscibility of meloxicam with the polymer at 1% w/w drug load, for the first time, and determined the processed sample was highly miscible at ∼200 nm scale. In conclusion, we determined the KinetiSol® process is capable of producing ASDs that are homogeneously and molecularly well-dispersed drug-in-polymer at drug concentrations as low as 1% w/w.

Analysis of spinal and muscle pathology in transgenic mice overexpressing wild-type and ALS-linked mutant MATR3.

Mutations in MATR3 have been associated with amyotrophic lateral sclerosis (ALS) as well as a form of distal myopathy termed vocal cord pharyngeal distal myopathy (VCPDM). To begin to understand how mutations in MATR3 may cause disease, here we provide initial characterization of transgenic (Tg) mice expressing human wild-type (WT) MATR3 (MATR3WT) and ALS-mutant F115C MATR3 (MATR3F115C) proteins under the control of the mouse prion promoter (MoPrP). For each construct, we established multiple independent lines of mice that stably transmitted the transgene. Unexpectedly, for all stably-transmitting lines examined, MATR3 transgenic mRNA expression was more robust in muscle, with minimal expression in spinal cord. The levels of transgenic mRNA in muscle did not differ between mice from our lead MATR3F115C line and lead MATR3WT line, but mice from the lead MATR3F115C line had significantly higher levels of MATR3 protein in muscle over the lead MATR3WT line. Mice from the three independent, established lines of MATR3F115C mice developed weakness in both fore- and hind-limbs as early as < 1 months of age; whereas, MATR3WT mice aged to > 20 months were not overtly distinguishable from non-transgenic (NT) littermates based on basic motor phenotype. Muscle of both MATR3WT and MATR3F115C mice showed vacuoles by 2 months of age which worsened by ~ 10 months, but vacuolation was noticeably more severe in MATR3F115C mice. Overall, our results indicate that increasing the levels of MATR3 in muscle can cause pathologic changes associated with myopathy, with MATR3F115C expression causing overt muscle atrophy and a profound motor phenotype. The findings suggest that analysis of muscle pathology in individuals harboring ALS-linked MATR3 mutations should be routinely considered.

Erratum: Author Correction: Breast-cancer-specific mortality in patients treated based on the 21-gene assay: a SEER population-based study.

[This corrects the article DOI: 10.1038/npjbcancer.2016.17.].

Generation of a Weakly Acidic Amorphous Solid Dispersion of the Weak Base Ritonavir with Equivalent In Vitro and In Vivo Performance to Norvir Tablet.

Ritonavir is an anti-viral compound that has also been employed extensively as a CYP3A4 and P-glycoprotein (Pgp) inhibitor to boost the pharmacokinetic performance of compounds that undergo first pass metabolism. For use in combination products, there is a desire to minimize the mass contribution of the ritonavir system to reduce patient pill burden in these combination products. In this study, KinetiSol® processing was utilized to produce an amorphous solid dispersion of ritonavir at two times the drug load of the commercially available form of ritonavir, and the composition was subsequently developed into a tablet dosage form. The amorphous intermediate was demonstrated to be amorphous by X-ray powder diffraction and 13C solid-state nuclear magnetic resonance and an intimately mixed single-phase system by modulated differential scanning calorimetry and 1H T1/1H T1ρ solid-state nuclear magnetic resonance relaxation. In vitro transmembrane flux analysis showed similar permeation rates for the KinetiSol-made tablet and the reference tablet dosage form, Norvir®. In vivo pharmacokinetic comparison between the two dosage forms resulted in equivalent exposure with approximately 20% Cmax reduction for the KinetiSol tablet. These performance gains were realized with a concurrent reduction in dosage form mass of 45%.