Solid Lipid Particles for Oral Delivery of Peptide and Protein Drugs III — the Effect of Fed State Conditions on the In Vitro Release and Degradation of Desmopressin

The effect of food intake on the release and degradation of peptide drugs from solid lipid particles is unknown and was therefore investigated in vitro using different fed state media in a lipolysis model. Desmopressin was used as a model peptide and incorporated into solid lipid particles consisting of trimyristin (TG14), tripalmitin (TG16), and tristearin (TG18), respectively. Fasted state and fed state media with varying phospholipid and bile salt concentrations, as well as fed state media with milk and oleic acid glycerides, respectively, were used as the release media. The presence of oleic acid glycerides accelerated the release of desmopressin significantly from all solid lipid particles both in the presence and absence of lipase. The presence of oleic acid glycerides also reduced the degradation rate of desmopressin, probably due to the interactions between the lipids and the protease or desmopressin. Addition of a medium chain triglyceride, trilaurin, in combination with drug-loaded lipid particles diminished the food effect on the TG18 particles, and trilaurin is therefore proposed to be a suitable excipient for reduction of the food effect. Overall, the present study shows that strategies to reduce food effect, such as adding trilaurin, for lipid particle formulations should be considered as drug release from such formulations might be influenced by the presence of food in the gastrointestinal tract.     

Oral Delivery of Highly Lipophilic,Poorly Water-Soluble Drugs: Self-Emulsifying Drug Delivery Systems to Improve Oral Absorption and Enable High-Dose Toxicology Studies of a Cholesteryl Ester Transfer Protein Inhibitor in Preclinical Species

BMS-A is an inhibitor of cholesteryl ester transfer protein and is a highly lipophilic compound (clogP 10.5) with poor aqueous solubility (<0.0001 mg/mL at pH 6.5). The compound exhibits low oral exposure when dosed as cosolvent solution formulations. The purpose of this study was to evaluate lipid-based formulations for enabling high-dose toxicology studies and enhancing toxicology margins of BMS-A in preclinical studies in nonrodent species. The solubility of BMS-A was screened in lipid and cosolvent/surfactant excipients, and prototype formulations were developed. In vitro tests showed that fine/microemulsions were formed after aqueous dilution of lipid formulations, and BMS-A was transferred from oil phase to aqueous phase with enhanced solubility following lipid digestion. When dosed in dogs at 200 mg/kg, a Gelucire-based formulation exhibited more than 10-fold higher exposure compared to the solution formulation and was thus selected for toxicology studies in dogs. For monkeys, an olive oil formulation was developed, and the exposure was about 7-fold higher than that from the solution. In summary, lipid-based drug delivery could be applied in early stages of drug discovery to enhance oral exposure and enable preclinical toxicology studies of highly lipophilic compounds, while facilitating the candidate selection of a molecule which is more specifically designed for bioperformance in a lipid-based drug delivery strategy.     

The Effect of HIV Protease Inhibitors on Amyloid-β Peptide Degradation and Synthesis in Human Cells and Alzheimer’s Disease Animal Model

Combined antiretroviral therapy (ART) tremendously improved the lifespan and symptoms associated with AIDS-defining illness in affected individuals. However, chronic ART-treated patients frequently develop age-dependent complications, including dementia, diabetes, and hyperlipidemia: all risk factors of Alzheimer??s disease. Importantly, the effect of ART compounds on amyloid generation and clearance has never been systematically examined. Nine prescribed HIV protease inhibitors were tested for their effect on amyloid-?? peptide (A??) clearance in primary cultured human monocyte-derived macrophages. Atazanavir, ritonavir, and saquinavir modestly inhibited of A?? degradation, while lopinavir, nelfinavir, and ritonavir enhanced secretion of undigested A?? after phagocytosis. Lopinavir, nelfinavir, ritonavir, and saquinavir inhibited endogenous A??40 production from primary cultured human cortical neurons, which were associated with reduction in Beta-site APP Converting Enzyme 1 (BACE1) and ??-secretase enzyme activities. However, ART compounds showed little inhibition of purified BACE1 activity in vitro, suggesting the indirect effect of ART compounds on BACE1 activity in neurons. Finally, nefinavir or lopinavir/ritonavir (Kaletra) were orally administered for 30?days into APP SCID mice expressing a double mutant form of APP 695 (KM670/671NL + V717F) in homozygosity for the scid allele of Prkdc. There was no difference in beta-amyloidosis by ART drug administration as determined by both immunohistochemistry and ELISA measurements although the therapeutic doses of the ART compounds was present in the brain. These data demonstrated that ART drugs can inhibit A?? clearance in macrophages and A?? production in neurons, but these effects did not significantly alter A?? accumulation in the mouse brain.     

Coating Solid Dispersions on Microneedles via a Molten Dip‐Coating Method: Development and In Vitro Evaluation for Transdermal Delivery of a Water‐Insoluble Drug

This study demonstrates for the first time the ability to coat solid dispersions on microneedles as a means to deliver water‐insoluble drugs through the skin. Polyethylene glycol (PEG) was selected as the hydrophilic matrix, and lidocaine base was selected as the model hydrophobic drug to create the solid dispersion. First, thermal characterization and viscosity measurements of the PEG–lidocaine mixture at different mass fractions were performed. The results show that lidocaine can remain stable at temperatures up to ∼130°C and that viscosity of the PEG–lidocaine molten solution increases as the mass fraction of lidocaine decreases. Differential scanning calorimetry demonstrated that at lidocaine mass fraction less than or equal to 50%, lidocaine is well dispersed in the PEG–lidocaine mixture. Uniform coatings were obtained on microneedle surfaces. In vitro dissolution studies in porcine skin showed that microneedles coated with PEG–lidocaine dispersions resulted in significantly higher delivery of lidocaine in just 3 min compared with 1 h topical application of 0.15 g EMLA®, a commercial lidocaine–prilocaine cream. In conclusion, the molten coating process we introduce here offers a practical approach to coat water‐insoluble drugs on microneedles for transdermal delivery. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3621–3630, 2014     

Lung effects of 7- and 28-day inhalation exposure of rats to emissions from 1st and 2nd generation biodiesel fuels with and without particle filter – The FuelHealth project

Increased use of 1st and 2nd generation biofuels raises concerns about health effects of new emissions. We analyzed cellular and molecular lung effects in Fisher 344 rats exposed to diesel engine exhaust emissions (DEE) from a Euro 5-classified diesel engine running on B7: petrodiesel fuel containing 7% fatty acid methyl esters (FAME), or SHB20 (synthetic hydrocarbon biofuel): petrodiesel fuel containing 7% FAME and 13% hydrogenated vegetable oil. The Fisher 344 rats were exposed for 7 consecutive days (6 h/day) or 28 days (6 h/day, 5 days/week), both with and without diesel particle filter (DPF) treatment of the exhaust in whole body exposure chambers (n = 7/treatment). Histological analysis and analysis of cytokines and immune cell numbers in bronchoalveolar lavage fluid (BALF) did not reveal adverse pulmonary effects after exposure to DEE from B7 or SHB20 fuel. Significantly different gene expression levels for B7 compared to SHB20 indicate disturbed redox signaling (Cat, Hmox1), beta-adrenergic signaling (Adrb2) and xenobiotic metabolism (Cyp1a1). Exhaust filtration induced higher expression of redox genes (Cat, Gpx2) and the chemokine gene Cxcl7 compared to non-filtered exhaust. Exposure time (7 versus 28 days) also resulted in different patterns of lung gene expression. No genotoxic effects in the lungs were observed. Overall, exposure to B7 or SHB20 emissions suggests only minor effects in the lungs.     

Reasons for supply side driven drug shortages – A mixed-methods study on first-level,higher-level,and root causes from the perspective of marketing authorization holders

BackgroundDrug shortages impact multiple stakeholders and are detrimental to patient safety. Additionally, drug shortages are an extensive financial burden. In Germany, drug shortages, according to data from the federal ministry for drug and medical products (BfArM), have been increasing by 18% between 2018 and 2021. Studies show that shortages are most frequently supply side driven and that often reasons remain unknown.ObjectiveThe aim is to develop a holistic understanding of supply side causes for drug shortages in Germany from marketing authorization holders’ perspectives and to derive implications for shortage mitigation.MethodsA mixed-methods research design, with a grounded theory approach based on a structured literature review, BfArM data analysis, and semi-structured interviews, was used.ResultsInput factor supply issues, manufacturing issues, logistics issues, product recalls, and product discontinuations were identified as first-level causes. Furthermore, a theory on their connection to higher-level causes related to business decision-making, as well as root causes linked to regulations, company values, internal processes, market dynamics, external shocks, and macroeconomic factors, was developed.ConclusionActions to mitigate drug shortages in Germany (e.g., improving business processes, diversifying tender criteria) were derived. These may thus increase patient safety and decrease the financial burden on the healthcare system.     

“Someone who is in this thing that I am suffering from”: The role of peers and other facilitators for task sharing substance use treatment in South African HIV care

South Africa is home to the largest number of people living with HIV/AIDS in the world. Alongside the HIV/AIDS epidemic, problematic alcohol and other drug (AOD) use is prevalent and associated with poor HIV treatment and secondary HIV prevention outcomes. International guidelines and local policy both support the integration of mental health care and AOD treatment into HIV care, yet barriers exist to implementation. This study aimed to explore patient and provider perspectives on the integration of HIV and AOD treatment services in Cape Town, South Africa. This included barriers and facilitators to task sharing AOD treatment in HIV care and preferences for a task shared approach to integrating AOD treatment in HIV care, including who should deliver the behavioural intervention. We conducted thirty semi-structured qualitative interviews with HIV and AOD treatment staff, providers, and people living with HIV/AIDS (PLWH) with moderate, problematic AOD use and difficulties (personal or structural) adhering to HIV treatment. Findings illustrated several key themes: (1) the separation between AOD and HIV services (a “siloed treatment experience”), even in the context of geographic co-location; (2) low AOD treatment literacy among HIV patients and providers, including a low awareness of existing AOD use services, even when co-located; (3) substance use stigma as a barrier to HIV and AOD treatment integration; (4) a strong patient preference for peer interventionists; and (5) the role of community health workers (CHWs) in detecting AOD use among some PLWH who had not followed up in HIV care. These findings will inform a future type 1 hybrid effectiveness-implementation trial, guided by the RE-AIM framework, to evaluate a task shared, evidence-based intervention to address problematic AOD use and improve HIV medication adherence in this setting.