Pharmaceutical Research

Ekins, Sean; Lane, Thomas R.; Madrid, Peter B.

doi: 10.1007/s11095-020-02799-8pmid: 32215760

For the last 50 years we have known of a broad-spectrum agent tilorone dihydrochloride (Tilorone). This is a small-molecule orally bioavailable drug that was originally discovered in the USA and is currently used clinically as an antiviral in Russia and the Ukraine. Over the years there have been numerous clinical and non-clinical reports of its broad spectrum of antiviral activity. More recently we have identified additional promising antiviral activities against Middle East Respiratory Syndrome, Chikungunya, Ebola and Marburg which highlights that this old drug may have other uses against new viruses. This may in turn inform the types of drugs that we need for virus outbreaks such as for the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Tilorone has been long neglected by the west in many respects but it deserves further reassessment in light of current and future needs for broad-spectrum antivirals.

Schultz, Hayley B.; Joyce, Paul; Thomas, Nicky; Prestidge, Clive A.

doi: 10.1007/s11095-020-02795-ypmid: 32236761

PurposeAbiraterone acetate (AbA) is a poorly water-soluble drug with an oral bioavailability of <10% and a significant pharmaceutical food effect. We aimed to develop a more efficient oral solid-state lipid-based formulation for AbA using a supersaturated silica-lipid hybrid (super-SLH) approach to achieve high drug loading, improve in vitro solubilization and mitigate the food effect, while gaining a mechanistic insight into how super-SLH are digested and release drug.MethodsThe influence of super-SLH saturation level and lipid type on the physicochemical properties and in vitro solubilization during lipolysis of the formulations was investigated and compared to the commercial product, Zytiga.ResultsSuper-SLH achieved significantly greater levels of AbA solubilization compared to Zytiga. Solubilization was influenced by the AbA saturation level, which determined the solid state of AbA and the relative amount of lipid, and the lipid utilized, which determined its degree of digestion and the affinity of the lipid and digestion products to the silica. A fine balance existed between achieving high drug loads using supersaturation and improving performance using the lipid-based formulation approach. The non-supersaturated SLH prepared with Capmul PG8 mitigated the 3-fold in vitro food effect.ConclusionSLH and super-SLH improve in vitro solubilization of AbA, remove the food effect and demonstrate potential to improve oral bioavailability in vivo.Graphical AbstractAbiraterone acetate was formulated as silica-lipid hybrids and demonstrated enhanced in vitro solubilization in comparison to pure abiraterone acetate and commercial product, Zytiga[graphic not available: see fulltext]

Melien, Richard; Garidel, Patrick; Hinderberger, Dariush; Blech, Michaela

doi: 10.1007/s11095-020-02792-1pmid: 32236701

PurposePredicting thermal protein stability is of major interest in the development of protein-based biopharmaceuticals. Therefore, this study provides a predictive tool for determining transition enthalpies, which can be used for ranking different proteins according to their thermal stability.MethodsUnfolding and aggregation profiles of eight different therapeutic monoclonal antibodies (mAbs) of type G, isotype 1 were investigated. The unfolding profiles were determined by intrinsic fluorescence (IF) spectroscopy and differential scanning calorimetry (DSC). A three-state unfolding fitting model was used to determine thermodynamic parameters for macromolecular multi-domain mAbs in IF experiments, like the van’t Hoff enthalpy change (∆Hvh) and the entropy change (∆S) of the unfolding event. The derived values were compared to thermodynamic parameters obtained directly by calorimetry. Moreover, differences in the Fab enthalpies were used to predict aggregation behavior and protein thermal stabilities. To do so, the liquid-formulated mAbs were investigated exemplarily by size exclusion chromatography (SEC) after accelerated thermal-induced stress conditions.ResultsComparing the thermodynamic parameters derived from IF spectroscopy and DSC resulted in similar values. Data generated by thermal-induced stress at 40°C show similar stability ranking as postulated through the Fab enthalpies for mAbs in two different formulations, while at 25°C a meaningful ranking is not possible, because distinct differences in the thermal stability cannot be observed. The additional consideration of Fab enthalpies to predict the 40 °C SEC ranking seems to be more reliable compared to the use of exclusively the melting temperatures or aggregation onset temperatures and times. ConclusionWe show that thermodynamic profiling can help predicting unfolding and aggregation properties of therapeutic mAbs at 40°C. Therefore, analyzing thermodynamic unfolding parameters is a useful and supportive tool discriminating thermal stability profiles of mAbs for further pharmaceutical development and clinical studies.

Simpson, Solange M; Widanapathirana, Lakmini; Su, Jonathan T.; Sung, Samuel; Watrous, David; Qiu, Jiang; Pearson, Elizabeth; Evanoff, Alex; Karunakaran, Dipu; Chacon, Jorge E.; Kiser, Patrick F.

doi: 10.1007/s11095-020-2777-2pmid: 32296951

PurposeSexual transmission of HIV has been clinically proven to be preventable with a once-daily oral tablet; however, missed doses dramatically increase the risk of HIV infection. Long-acting subcutaneous implants do not allow the user to miss a dose. A desirable long-acting drug-eluting implant can deliver a constant amount of drug, adjust the delivered dose, and be readily manufactured. We present a long-acting, subcutaneous implant design composed of tenofovir alafenamide hemifumarate (TAF) pellets loaded in a sealed polyether urethane tube for the prevention of HIV transmission.MethodsImplants were prepared with pressed drug pellets and extruded polyurethane tubing. In vitro release rate of implants using different pellet formulations, rate-controlling membranes, and geometries were measured.ResultsTenofovir alafenamide release appeared to be governed by a pseudo-steady state and followed a mass transport model of release from a cylindrical drug reservoir. Implant seal integrity was tested and confirmed using mechanical testing. The inclusion of sodium chloride in the pellet increased the release rate and reduced initial lag. The release was sustained for 100 days.ConclusionsThe release rate of tenofovir alafenamide mechanistically varied with geometry and rate controlling membrane composition. The polyether urethane implant presented herein is modular and tunable to adjust the release rate and duration of the TAF release.

Baig, Mirza Muhammad Faran Ashraf; Lai, Wing-Fu; Ahsan, Anam; Jabeen, Mehreen; Farooq, Muhammad Asim; Mikrani, Reyaj; Abbas, Muhammad; Naveed, Muhammad; Kassim, Said Abasse; Raza, Faisal; Dar, Afzal Ahmed; Ansari, Muhammad Tayyab

Altaani, Bashar M; Almaaytah, Ammar M; Dadou, Suha; Alkhamis, Khouloud; Daradka, Mousa H; Hananeh, Wael

doi: 10.1007/s11095-020-02793-0pmid: 32253527

PurposeInvestigate the possibility of delivering teriparatide orally using nanoemulsion.MethodTeriparatide was allowed to interact with chitosan in the presence of HPβCD.The formed polyelectrolyte complex (PEC) was characterized by DSC, FTIR, DLS and for entrapment efficiency. PEC was the incorporated in an oil phase consisting of Oleic Acid, Labrasol and Plurol Oleique to form a nanoemulsion. This preparation was characterized for refractive index, viscosity, pH, conductivity, particle size, and morphology.Bioavailability of the preparation was evaluated using rabbits against SC injection. The efficacy of the formula was tested using ovariectomized rats (an osteoporosis animal model) and mechanical and histological tests were conducted on their bones. The stability of the preparation was evaluated by storing samples at 4o C, 25o C and 40o C for three months.ResultsPEC testing demonstrate a complex formation with particle size of 208 nm, zeta potential of +17 mV and entrapment efficiency of 49%. For the nanoemulsion, the results demonstrate the formation of a nano-sized dispersed system (108 nm) with a drug loading of 98% and a percent protection of 90% and 71% in SGF and SIF respectively. Bioavailability results showed a sustained release profile was achieved following the oral formulation administration. Efficacy studies showed improvement in the strength, thickness and connectivity of bones. Short-term stability study demostrated that the nanoemulsion is mostly stable at 4o C.ConclusionThese findings demonstrate the ability of delivering Teriparatide orally using oleic acid based dispersion in combination with chitosan PEC.

Nafee, Noha; Gaber, Dina M.; Elzoghby, Ahmed O.; Helmy, Maged W.; Abdallah, Osama Y.

doi: 10.1007/s11095-020-02794-zpmid: 32291520

PurposeMyricetin (MYR) flavonoid is well-recognized for its antioxidant, anti-inflammatory and anti-tumor potential. Introducing nanomedicine was the ultimate resort to solve the imperfections of this nutraceutical, namely solubility, stability and delivery issues. The study, thus, aims at developing inhalable microparticles comprising MYR solid lipid nanoparticles (SLNs) for lung cancer therapy.MethodsA two-step preparation procedure starting with complexation of MYR with the phospholipid Lipoid-S100, followed by nanoencapsulation in Gelucire-based, surfactant-free SLNs was developed. SLNs were characterized in terms of physicochemical properties, MYR loading, release behavior as well as anti-tumor potential and cellular uptake. Respirable microparticles were then obtained by spray drying SLNs with carbohydrate carriers. Their size, flowability and pulmonary deposition pattern were assessed.ResultsOptimized SLNs were 75.98 nm in diameter with a zeta-potential of −22.5 mV, and an encapsulation efficiency of 84.5%. Attempts to ameliorate drug loading implicate MYR-phospholipid complexation (MYR-PH-CPX) prior to its entrapment in SLNs, which ensured 5-fold increase in drug loading. Viability assays were modified to guarantee MYR chemical stability. Superior antitumor activity of MYR-phospholipid-complex and 3-fold reduction in IC50 were accomplished with MYR-SLNs. This could be related to enhanced cellular uptake revealed by confocal imaging and doubled fluorescence intensity. SLNs entrapping MYR-PH-CPX were spray-dried with carbohydrate carriers to produce respirable microparticles. The latter ensured MMAD of 2.39 μm and span index of 1.84, in addition to good flowability and > 80% release over 8 h. Deposition experiments revealed MMAD of 2.77 μm, FPF of 81.23 and EF of 93% indicating particle deposition in the targeted bronchial region.ConclusionsThe study highlights the ability of phospholipid-complex on the nanoencapsulation, cellular uptake and antitumor activity of MYR. Formulation of respirable microparticles gives promises of efficacious therapy of lung carcinoma.

Xi, Hanmi; Ren, Jie; Novak, Julie M.; Kemp, Eric; Johnson, Gregory; Klinzing, Gerard; Johnson, Mary Ann; Xu, Wei

doi: 10.1007/s11095-020-2772-7pmid: 32185516

PurposeWhile including amorphous solid dispersion (ASD) in tablet formulations is increasingly common, tablets containing high ASD loading are associated with slow disintegration, which presents a challenge to control pill burden for less potent compounds.MethodsWe use a model ASD, composed of a hydrophobic drug with copovidone and a non-ionic surfactant, to explore formulation options that can prevent slow disintegration.ResultsIn addition to the ASD loading, the pH of the disintegration medium and the inclusion of inorganic salts in the tablet also have an impact on the tablet disintegration time. Certain kosmotropic salts, when added in the formulation, can significantly accelerate tablet disintegration, though the rank order in their effectiveness does not exactly follow the Hofmeister series at pH 1.8. The particle size and dissolution rate of the salt can contribute to its overall effectiveness.ConclusionWe provided a mechanistic explanation of the disintegration process: fast-dissolving kosmotropic salt results in a concentrated salt solution inside the restrained tablet matrix, thus inhibiting the dissolution of copovidone and preventing polymer gelling which is the main cause leading the slow disintegration. The outcome of this study has enabled the design of a higher ASD loading platform formulation for copovidone based ASD.Graphical AbstractMicroCT aids the mechanistic understanding of the role of inorganic salt in the tablet disintegration of amorphous solid dispersion based formulation[graphic not available: see fulltext]

Zdravkovic, Steven A.

doi: 10.1007/s11095-020-02805-zpmid: 32232571

PurposeRubber stoppers that seal the primary packaging systems of parenteral pharmaceutical products have the potential to introduce impurities into the drug during storage. While this interaction has been well characterized for products stored as an aqueous liquid, it is not well understood how the interaction is affected when the product is stored as a lyophilized solid. Accordingly, the goal of this study was to determine how lyophilization affects the propensity for impurity migration (leaching) into the product.MethodsThe concentration of substances in the stopper and the concentration of these substances that had leached into the product at equilibrium were measured and used to calculate equilibrium constants, which quantifies the degree of partitioning of each compound between each unique stopper and drug matrix, for twelve lyophilized and twelve liquid commercial drug products.ResultsLyophilized products were shown to have a significantly increased propensity to contain substances that migrated from their stopper as compared to liquid products, as supported both by the general qualitative/quantitative leachable profile and the equilibrium constants obtained.ConclusionsThe conversion of a liquid drug formulation to a lyophilized solid during storage will increase the number and concentration of impurities leached from the stopper.

Sodhi, Jasleen K.; Liu, Shuaibing; Benet, Leslie Z.

doi: 10.1007/s11095-020-02797-wpmid: 32215750

PurposeTo examine the theoretical/practical utility of the liver-to-blood partition coefficient (Kpuu) for predicting drug-drug interactions (DDIs), and compare the Kpuu-approach to the extended clearance concept AUCR-approach.MethodsThe Kpuu relationship was derived from first principles. Theoretical simulations investigated the impact of changes in a single hepatic-disposition process on unbound systemic (AUCB,u) and hepatic exposure (AUCH,u) versus Kpuu. Practical aspects regarding Kpuu utilization were examined by predicting the magnitude of DDI between ketoconazole and midazolam employing published ketoconazole Kpuu values.ResultsThe Kpuu hepatic-disposition relationship is based on the well-stirred model. Simulations emphasize that changes in influx/efflux intrinsic clearances result in Kpuu changes, however AUCH,u remains unchanged. Although incorporation of Kpuu is believed to improve DDI-predictions, utilizing published ketoconazole Kpuu values resulted in prediction errors for a midazolam DDI.ConclusionsThere is limited benefit in using Kpuu for DDI-predictions as the AUCR-based approach can reasonably predict DDIs without measurement of intracellular drug concentrations, a difficult task hindered by experimental variability. Further, Kpuu changes can mislead as they may not correlate with changes in AUCB,u or AUCH,u. The well-stirred model basis of Kpuu when applied to hepatic-disposition implies that nuances of intracellular drug distribution are not considered by the Kpuu model.