Topical drug delivery by Sepineo P600 emulgel: Relationship between rheology, physical stability, and formulation performance.

The objective of this present work was to develop and optimize oil-in-water (O/W) emulsion-based gels, namely emulgels that allow maximum topical drug delivery while having desired microstructure and acceptable physical stability. Emulgels containing 2.0 wt% lidocaine were prepared using various concentrations (0.75-5.0 wt%) of Sepineo P600. Their droplet size distribution, physical stability, rheological behaviors, in vitro drug release, and skin permeation profiles were evaluated. Results show that the concentration of Sepineo P600 significantly influenced the microstructure, rheology, and physical stability of the emulgel formulations. The physico-chemical properties also reveals that at least 1.0 wt% Sepineo P600 was needed to produce stable emulgel formulations. All formulations exhibited non-Newtonian shear-thinning properties which are desirable for topical applications. Both the release and permeation rates decreased with increasing viscosity and rigidity of the formulation. The lower the complex modulus of the emulgels, the higher the steady-state flux of the drug through the skin. Adding Sepineo P600 to emulgel systems resulted in increased rheological properties, which in turn slowed the diffusion of the drug for in vitro release. Although as expected skin permeation was rate limiting since in vitro release was 3 to 4 log-fold faster than skin flux. However, an interesting finding was that the derived skin/vehicle partition coefficient suggested the ionic interaction between lidocaine and Sepineo polymer reducing the free drug, i.e., thermodynamic activity and hence the flux with increasing Sepineo P600 concentration. Overall, this study has provided us with valuable insights into understanding the relationship between the microstructure (rheology), physical stability and skin drug delivery properties which will help to design and optimize topical emulgel formulations.

Sustainable Alternatives to Petroleum-Derived Excipients in Pharmaceutical Oil-in-Water Creams.

Recently, vast efforts towards sustainability have been made in the pharmaceutical industry. In conventional oil-in-water (O/W) cream formulations, various petroleum-based excipients, namely mineral oil and petrolatum, are commonly used. Natural or synthetic excipients, derived from vegetable sources, were explored as alternatives to petroleum-based excipients in prototype topical creams, with 1% (w/w) lidocaine. A conventional cream comprised of petroleum-derived excipients was compared to creams containing sustainable excipients in terms of key quality and performance attributes, physicochemical properties, and formulation performance. The petrolatum-based control formulation had the highest viscosity of 248.0 Pa·s, a melting point of 42.7°C, a low separation index at 25°C of 0.031, and an IVRT flux of 52.9 µg/cm2/h. Formulation SUS-4 was the least viscous formulation at 86.9 Pa·s, had the lowest melting point of 33.6°C, the highest separation index of 0.120, and the highest IVRT flux of 139.4 µg/cm2/h. Alternatively, SUS-5 had a higher viscosity of 131.3 Pa·s, a melting point of 43.6°C, a low separation index of 0.046, and the lowest IVRT flux of 25.2 µg/cm2/h. The cumulative drug permeation after 12 h from SUS-4, SUS-5, and the control were 126.2 µg/cm2, 113.8 µg/cm2, and 108.1 µg/cm2, respectively. The composition of the oil-in-water creams had influence on physicochemical properties and drug release; however, skin permeation was not impacted. Sustainable natural or synthetic excipients in topical cream formulations were found to be suitable alternatives to petroleum-based excipients with comparable key quality attributes and performance attributes and should be considered during formulation development.

Demographic and Clinical Predictors of Pharmacist-Administered Pediatric Influenza Immunization.

Background: Pediatricians' offices are primary locations for pediatric influenza vaccination; however, pharmacists are also well-positioned as immunizers. Considering the current COVID-19 pandemic and Public Readiness and Emergency Preparedness (PREP) Act, pharmacists' authority to vaccinate children has been recently expanded. Methods: We used the de-identified Optum ClinformaticsTM Data Mart database to identify demographic and clinical predictors of pharmacist-administered pediatric influenza vaccination compared with influenza vaccination in pediatricians' offices. Procedures codes for influenza vaccinations among children were captured for the 2016-2017 influenza season. Logistic regression was used to identify significant predictors. Results: We included 336 841 children receiving influenza vaccines by a pharmacist (5.2%) or in pediatricians' offices (94.8%). The following significant predictors were identified: older pediatric age groups (13-17 years odds ratio [OR] 91.51, 5-12 years OR 35.41), states allowing pharmacist-administered influenza vaccination at younger ages (no age restrictions OR, 26.68, minimum age 2-4 years old OR, 33.76), influenza vaccination outside of pediatricians' offices in the previous year (pharmacist-administered OR, 22.18, convenience care OR 4.15, emergency care OR 1.69), geographic region (South OR, 2.02, Midwest OR 1.60, and West OR 1.38), and routine health exam or follow-up in the prior 6-months (OR, 1.59). Conclusions: The strongest drivers of pharmacist-administered pediatric influenza vaccination were older pediatric age, more lenient minimum age restrictions, and previous influenza vaccination in a pharmacy. Due to the COVID-19 pandemic, the PREP Act, and forthcoming pediatric COVID-19 vaccines for children, pharmacists may play a greater role in pediatric vaccination resulting in sustained changes in pediatric vaccination practices.

Pediatric influenza vaccination rates lower than previous estimates in the United States.

BACKGROUND: Annually, pediatric influenza vaccination coverage estimates are ascertained from health surveys, such as the National Immunization Survey (NIS-Flu). From 2010 to 2017, vaccination coverage among children ranged from 51 to 59 %. Recognizing the limitations of national health survey data, we sought to describe temporal trends in pediatric influenza vaccination coverage, and demographic differences among a commercially insured large national cohort from 07/01/2010 to 06/30/2017. METHODS: Influenza vaccination coverage was assessed among children (<18 years) with continuous enrollment in the de-identified Optum Clinformatics® Data Mart database, and from NIS-Flu. Time trends in vaccination coverage were assessed using Joinpoint regression, overall and stratified by age group, sex, and geographic region. RESULTS: The average annual pediatric influenza vaccination coverage was 33.4 % in our study population versus 56.5 % reported from NIS-Flu during the same period (p-value < 0.0001). Vaccination coverage was highest in children 6 months-4-years old at 52.6 % (versus 68.8 % NIS-Flu, p-value < 0.0001), and lowest in the 13-17-year-old age group at 20.1 % (versus 42.8 % NIS-Flu, p-value < 0.0001). Vaccination coverage over time remained stable in our study population (average annual percent change 1.8 %, 95 % confidence interval [CI] -2.3 % to 6.0 %) versus significantly increasing by 2.8 % in NIS-Flu (95 % CI 0.3 % to 5.3 %). CONCLUSIONS: Vaccination coverage in our commercially insured pediatric population was 51.4% lower than estimates from NIS-Flu during the same period, suggesting the need for more accurate vaccination coverage surveillance, which will also be critical in future COVID-19 vaccination efforts. Effective interventions are needed to increase pediatric influenza vaccination rates to the Healthy People 2020 target of 70%.

Pharmacist-Administered Influenza Vaccination in Children and Corresponding Regulations.

In our retrospective cohort study, we evaluated trends in pharmacist-administered pediatric influenza vaccination rates in the United States and corresponding state-level pharmacist pediatric vaccination authorization models, including minimum age requirements, vaccination protocols, and/or prescription requirements. An administrative health claims database was used to capture influenza vaccinations in children less than 18 years old with 1 year of continuous enrollment and joinpoint regression was used to assess trends. Of the 3,937,376 pediatric influenza vaccinations identified over the study period, only 3.2% were pharmacist-administered (87.7% pediatrician offices, 2.3% convenience care clinics, 0.8% emergency care, and 6.0% other locations). Pharmacist-administered pediatric influenza vaccination was more commonly observed in older children (mean age 12.65 ± 3.26 years) and increased significantly by 19.2% annually over the study period (95% confidence interval 9.2%-30.2%, p < 0.05). The Northeast, with more restrictive authorization models, represented only 2.2% (n = 2816) of all pharmacist-administered pediatric influenza vaccinations. Utilization of pharmacist-administered pediatric influenza vaccination remains low. Providing children with greater access to vaccination with less restrictions may increase overall vaccination rates. Due to the COVID-19 pandemic and the Public Readiness and Emergency Preparedness Act, pharmacists will play a major role in vaccinating children.

Simultaneous Assessment of Transporter-Mediated Drug-Drug Interactions Using a Probe Drug Cocktail in Cynomolgus Monkey.

We aim to establish an in vivo preclinical model to enable simultaneous assessment of inhibition potential of an investigational drug on clinically relevant drug transporters, organic anion-transporting polypeptide (OATP)1B, breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), and organic anion transporter (OAT)3. Pharmacokinetics of substrate cocktail consisting of pitavastatin (OATP1B substrate), rosuvastatin (OATP1B/BCRP/OAT3), sulfasalazine (BCRP), and talinolol (P-gp) were obtained in cynomolgus monkey-alone or in combination with transporter inhibitors. Single-dose rifampicin (30 mg/kg) significantly (P < 0.01) increased the plasma exposure of all four drugs, with a marked effect on pitavastatin and rosuvastatin [area under the plasma concentration-time curve (AUC) ratio ∼21-39]. Elacridar, BCRP/P-gp inhibitor, increased the AUC of sulfasalazine, talinolol, as well as rosuvastatin and pitavastatin. An OAT1/3 inhibitor (probenecid) significantly (P < 0.05) impacted the renal clearance of rosuvastatin (∼8-fold). In vitro, rifampicin (10 µM) inhibited uptake of pitavastatin, rosuvastatin, and sulfasalazine by monkey and human primary hepatocytes. Transport studies using membrane vesicles suggested that all probe substrates, except talinolol, are transported by cynoBCRP, whereas talinolol is a cynoP-gp substrate. Elacridar and rifampicin inhibited both cynoBCRP and cynoP-gp in vitro, indicating potential for in vivo intestinal efflux inhibition. In conclusion, a probe substrate cocktail was validated to simultaneously evaluate perpetrator impact on multiple clinically relevant transporters using the cynomolgus monkey. The results support the use of the cynomolgus monkey as a model that could enable drug-drug interaction risk assessment, before advancing a new molecular entity into clinical development, as well as providing mechanistic insights on transporter-mediated interactions.

In Vitro-In Vivo Extrapolation of OATP1B-Mediated Drug-Drug Interactions in Cynomolgus Monkey.

Hepatic organic anion-transporting polypeptides (OATP) 1B1 and 1B3 are clinically relevant transporters associated with significant drug-drug interactions (DDIs) and safety concerns. Given that OATP1Bs in cynomolgus monkey share >90% degree of gene and amino acid sequence homology with human orthologs, we evaluated the in vitro-in vivo translation of OATP1B-mediated DDI risk using this preclinical model. In vitro studies using plated cynomolgus monkey hepatocytes showed active uptake Km values of 2.0 and 3.9 µM for OATP1B probe substrates, pitavastatin and rosuvastatin, respectively. Rifampicin inhibited pitavastatin and rosuvastatin active uptake in monkey hepatocytes with IC50 values of 3.0 and 0.54 µM, respectively, following preincubation with the inhibitor. Intravenous pharmacokinetics of 2H4-pitavastatin and 2H6-rosuvastatin (0.2 mg/kg) and the oral pharmacokinetics of cold probes (2 mg/kg) were studied in cynomolgus monkeys (n = 4) without or with coadministration of single oral ascending doses of rifampicin (1, 3, 10, and 30 mg/kg). A rifampicin dose-dependent reduction in i.v. clearance of statins was observed. Additionally, oral pitavastatin and rosuvastatin plasma exposure increased up to 19- and 15-fold at the highest dose of rifampicin, respectively. Use of in vitro IC50 obtained following 1 hour preincubation with rifampicin (0.54 µM) predicted correctly the change in mean i.v. clearance and oral exposure of statins as a function of mean unbound maximum plasma concentration of rifampicin. This study demonstrates quantitative translation of in vitro OATP1B IC50 to predict DDIs using cynomolgus monkey as a preclinical model and provides further confidence in application of in vitro hepatocyte data for the prediction of clinical OATP1B-mediated DDIs.