The Selection of a Pharmaceutical Salt—The Effect of the Acidity of the Counterion on Its Solubility and Potential Biopharmaceutical Performance

A roadmap for the selection of a pharmaceutical salt form for a development candidate is presented. The free base of the candidate did not have sufficient chemical stability for development. The initially selected salt form turned out to be undevelopable because it was unstable during scale-up synthesis and storage. The rationale for the new solid form screening and the criteria for selection are discussed. Before the final selection, the pH solubility profiles of the 2 new salts, a benzoate and a besylate, were compared. Atypical solubility behavior was observed for the benzoate salt in hydrochloric acid with and without normal saline. A scheme is proposed illustrating how the pKas of the counterion and active pharmaceutical ingredient, the medium composition, and final pH affect the solubility and solution equilibria of the 2 selected salt forms. This scheme also includes the equilibria between solution and solid phases in different pH ranges. The pharmaceutical importance of this research is that it sheds light on how the acidity of the counterion can affect the solubility of the selected salt form in the gastric environment. With a well-designed formulation strategy, this property potentially can be translated to optimal biopharmaceutical performance of the drug product.     

Population Pharmacokinetics and Dosing Simulations of Ceftazidime in Chinese Neonates

An accurate dosage determination is required in neonates when antibiotics are used. The adult data cannot be simply extrapolated to the pediatric population due to significant individual differences. We aimed to identify factors impacting ceftazidime exposure in neonates and to provide drug dosing guidance to clinicians. Forty-three neonates aged less than 60 days with proven or suspected infections were enrolled in this study. After intravenous administration, blood samples were collected, and plasma ceftazidime concentration was determined using a HPLC method. Pharmacokinetic data were fitted using a nonlinear mixed-effects model approach. One-compartmental model could nicely characterize the ceftazidime in vivo behavior. The covariate test found that the postmenstrual age (day) was strongly associated with systemic drug clearance (L/h), and the effect of body weight (kg) was identified as the covariate on distribution volume (L). Compared with the base model, the addition of covariates improved the goodness-of-fit of the final model. Model validation (bootstrap, visual predictive check, and prediction-corrected visual predictive check) suggested a robust and reliable pharmacokinetic model was developed. Personalized dosage regimens were provided based on model simulations. The intravenous dose should be adjusted according to postmenstrual age, body weight, and minimum inhibitory concentration.     

Bottom-Up and Top-Down Approaches to Explore Sodium Dodecyl Sulfate and Soluplus on the Crystallization Inhibition and Dissolution of Felodipine Extrudates

The objectives of this study were to explore sodium dodecyl sulfate (SDS) and Soluplus on the crystallization inhibition and dissolution of felodipine (FLDP) extrudates by bottom-up and top-down approaches. FLDP extrudates with Soluplus and SDS were prepared by hot melt extrusion, and characterized by polarized light microscopy, differential scanning calorimetry, and fourier transform infrared spectroscopy. Results indicated that Soluplus inhibited FLDP crystallization, and the whole amorphous solid dispersions (ASDs) were binary FLDP-Soluplus (1:3) and ternary FLDP-Soluplus-SDS (1:2:0.15～0.3 and 1:3:0.2～0.4) extrudates. Internal SDS (5%-10%) decreased glass transition temperatures of FLDP-Soluplus-SDS ternary ASDs without presenting molecular interactions with FLDP or Soluplus. The enhanced dissolution rate of binary or ternary Soluplus-rich ASDs in the nonsink condition of 0.05% SDS was achieved. Bottom-up approach indicated that Soluplus was a much stronger crystal inhibitor to the supersaturated FLDP in solutions than SDS. Top-down approach demonstrated that SDS enhanced the dissolution of Soluplus-rich ASDs via wettability and complexation with Soluplus to accelerate the medium uptake and erosion kinetics of extrudates, but induced FLDP recrystallization and resulted in incomplete dissolution of FLDP-rich extrudates. In conclusion, top-down approach is a promising strategy to explore the mechanisms of ASDs' dissolution, and small amount of SDS enhances the dissolution rate of polymer-rich ASDs in the nonsink condition.     

Health service utilization,unmet healthcare needs,and the potential of telemedicine services among Korean expatriates

Background

With the significant growth of migration and expatriation, facilitated by increased global mobility, the number of Koreans living abroad as of 2016 is approximately 7.4 million (15% of the Korean population). Healthcare utilization or health problems, especially among expatriates in developing countries, have not been well researched despite the various health risks these individuals are exposed to. Consequently, we identified the health utilization patterns and healthcare needs among Korean expatriates in Vietnam, Cambodia, and Uzbekistan.

Methods

This cross-sectional survey examined 429 Korean expatriates living in Vietnam (n?=?208), Cambodia (n?=?60), and Uzbekistan (n?=?161) who had access to the Internet and were living abroad for at least 6?months. A 67-item questionnaire was used, and feedback was received via an online survey program. Stepwise logistic regression analyses were performed to evaluate factors associated with unmet healthcare needs and preferences of certain type of telemedicine.

Results

We found that 45.5% (195/429) of respondents had used medical services in their country of stay. Among those who visited health institutions >?3 times, the most popular choice was general hospitals (39.4%, 15/38); however, they initially visited Korean doctors’ or local doctors’ offices. The most essential criteria for healthcare service facilities was a “skilled professional” (39.3%, 169/429), 42% wanted a health program for chronic disease management, and 30% wanted specialized internal medicine. A substantial number wanted to access telemedicine services and were willing to pay for this service. They were particularly interested in experts’ second opinion (61.5%, 264/429) and quick, 24-h medical consultations (60.8%, 261/429). Having unmet healthcare needs and being younger was strongly associated with all types of telemedicine networks.

Conclusions

Nearly half of the expatriates in developing countries had unmet healthcare needs. Telemedicine is one potential solution to meet these needs, especially in developing countries.

     

PM<Subscript>10</Subscript> concentration in relation to clinic visits for anxiety disorders: a population-based study of a high river-dust episode region in Taiwan

PM₁₀ exposure has been found to have significant effects on a variety of physical conditions. However, whether it acts on psychopathology remains unclear. This study used 8-year data to examine the relationship between PM₁₀ concentration and daily clinic visits of anxiety disorders. All residents of Yunlin County, Taiwan, which is a high river-dust exposure area, were selected as subjects. Data from the Taiwan National Health Insurance Research Database (NHIRD), 2002–2009, were analyzed. Individuals with any ICD code of 300.0 and 300.2 were categorized as with anxiety disorders. PM₁₀ data were based on the Lunbei station (located at Yunlin County) of EPA, Taiwan. Time-series analysis showed that, during the observed 8 years, the number of daily clinic visits for anxiety disorders increased with PM₁₀ levels, and the relationship remained significant after unemployment rate, and the Weighted Price Index of Taiwan Stock Exchange in the same period were controlled for. In particular, we found that there is a linear dose-response effect between daily clinic visits and PM₁₀ levels when PM₁₀ <?300 μg/m³; whereas a dramatically elevated daily clinic visits of anxiety disorders was found when PM₁₀ >?300 μg/m³. Findings from this study highlight that high level of PM₁₀ exposure derived from severe weather or environment condition may affect the occurrence of anxiety disorders. In addition, there seems to have a threshold of PM₁₀ in elevating the risk of anxiety disorders.     

Visceral adipose tissue is more strongly associated with insulin resistance than subcutaneous adipose tissue in Chinese subjects with pre-diabetes

Aims: To investigate the value of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in a cohort of a community’s residents who were diagnosed as pre-diabetes, and to evaluate the association of VAT and SAT with insulin resistance.

Methods: This study was based on cross-sectional analysis of data from 107 adults. VAT and SAT were assessed by computed tomography. Insulin resistance was defined by homeostasis model assessment of insulin resistance >2.69. The relationship of VAT and SAT with insulin resistance were examined by linear regression. Logistic regression was used to analyze the association of VAT and SAT with insulin resistance.

Results: A total of 87 subjects had VAT ≥100?cm². Thirty-six out of 107 (33.6%) subjects were detected to have insulin resistance, 71 were normal (66.4%), and all had insulin resistance with VAT ≥100?cm². VAT (r?=?0.378, p?r?=?0.357, p?p?=?.003), but that of SAT was lost.

Conclusion: Pre-diabetic subjects with insulin resistance had elevated levels of VAT. VAT was more strongly associated with insulin resistance than SAT in Chinese subjects with pre-diabetes.     

RhPDCD5 combined with dexamethasone increases antitumor activity in multiple myeloma partially via inhibiting the Wnt signalling pathway

Multiple myeloma (MM) is one of the most common hematological malignancies and characterized by the clonal accumulation of malignant plasma cells. Significant progress has been made in MM treatment recently, while MM still remains incurable. Our previous studies showed that the recombined human programmed cell death 5 (rhPDCD5) can promote MM apoptosis induced by dexamethasone (Dex). Here, we expanded the findings by showing that the rhPDCD5 alone could not induce an obvious growth inhibition of U266 cells (a MM cell line). Of note, with the combination of dexamethasone (Dex), the growth of MM cells was significantly inhibited and accompanied with the cell cycle arrest in G0/G1. For mechanism study, we found that the combination treatment of rhPDCD5 plus Dex downregulated the mRNA and protein expressions of Wnt effectors including β‐catenin, β‐catenin (Ser675), TCF4, survivin and c‐Myc when compared to Dex only. Moreover, the activation of WNT pathway induced by LiCl can also be inhibited by this combination treatment. Taken together, our study demonstrated that the combination of rhPDCD5 and Dex can suppress the proliferation of multiple myeloma cells partially via inhibiting the WNT signalling pathway.     

The vial kit formulation for preparation of no‐carrier‐added 131I‐MIBG

We have developed a new set of lyophilized kits, composed of 3 different kits, for the instant preparation of no‐carrier‐added ¹³¹I‐MIBG in the clinic. We here discussed the formulation of the kits, optimization of radiolabelling, quality control of radiolabeled ¹³¹I‐MIBG, and studies of animal biodistribution. The no‐carrier‐added (nca) ¹³¹I‐MIBG injection could be prepared within 30 minutes in the clinic with the help of the lyophilized kits. The radiochemical purity and specific activity (SA) could achieve above 98% and 6700 MBq/mg, respectively.