Eyes on Lipinski's Rule of Five: A New "Rule of Thumb" for Physicochemical Design Space of Ophthalmic Drugs.

The study objective was to investigate molecular thermodynamic properties of approved ophthalmic drugs and derive a framework outlining physicochemical design space for product development. Unlike the methodology used to obtain molecular descriptors for assessment of drug-like properties by Lipinski's Rule of 5 (Ro5), this work presents a retrospective approach based on in silico analysis of molecular thermodynamic properties beyond Ro5 parameters (ie, free energy of distribution/partitioning in octanol/water, dynamic polar surface area, distribution coefficient, and solubility at physiological pH) by using 145 marketed ophthalmic drugs. The study's focus was to delineate inherent molecular parameters explicitly important for ocular permeability and absorption from topical eye drops. A comprehensive parameter distribution analysis on ophthalmic drugs' molecular properties was performed. Frequencies in distribution analyses provided groundwork for physicochemical parameter limits of molecular thermodynamic properties having impact on corneal permeability and topical ophthalmic drug delivery. These parameters included free energy of partitioning (ΔGo/w) calculated based on thermodynamic free energy equation, distribution coefficient at physiological pH (clog DpH7.4), topological polar surface area (TPSA), and aqueous solubility (Sint, SpH7.4) with boundaries of clog DpH7.4 ≤4.0, TPSA ≤250 Å2, ΔGo/w ≤20 kJ/mol (4.8 kcal/mol), and solubility (Sint and SpH7.4) ≥1 µM, respectively. The theoretical free energy of partitioning model streamlined calculation of changes in the free energy of partitioning, Δ(ΔGo/w), as a measure of incremental improvements in corneal permeability for congeneric series. The above parameter limits are proposed as "rules of thumb" for topical ophthalmic drugs to assess risks in developability.

Discovery of TAK-981, a First-in-Class Inhibitor of SUMO-Activating Enzyme for the Treatment of Cancer.

SUMOylation is a reversible post-translational modification that regulates protein function through covalent attachment of small ubiquitin-like modifier (SUMO) proteins. The process of SUMOylating proteins involves an enzymatic cascade, the first step of which entails the activation of a SUMO protein through an ATP-dependent process catalyzed by SUMO-activating enzyme (SAE). Here, we describe the identification of TAK-981, a mechanism-based inhibitor of SAE which forms a SUMO-TAK-981 adduct as the inhibitory species within the enzyme catalytic site. Optimization of selectivity against related enzymes as well as enhancement of mean residence time of the adduct were critical to the identification of compounds with potent cellular pathway inhibition and ultimately a prolonged pharmacodynamic effect and efficacy in preclinical tumor models, culminating in the identification of the clinical molecule TAK-981.

Ocular biopharmaceutics: impact of modeling and simulation on topical ophthalmic formulation development.

The estimation of ocular pharmacokinetics (PK) in various eye tissues is limited because of sampling challenges. Computational modeling and simulation (M&S) tools underpinning the elucidation of drug access routes and prediction of ocular exposure are essential for the mechanistic assessment of biopharmaceutics in the eye. Therefore, theoretical and experimental evaluation of ocular absorption and transit models is necessary. Biopharmaceutical parameter sensitivity analysis based on permeability and drug dose illustrates utility in ocular drug delivery assessment, which could have innovative and cost-saving impacts on ophthalmic product development and therapeutic bioequivalence (BE) evaluations.

Complex effects of drug/silicate ratio, solid-state equivalent pH, and moisture on chemical stability of amorphous quinapril hydrochloride coground with silicates.

The effects of drug/silicate ratio and moisture content on chemical stability of amorphous quinapril hydrochloride (QHCl) coground with magnesium aluminometasilicates (Neusilin US2 and Neusilin FL2) were investigated. Amorphous QHCl/Neusilin samples containing 0-95% (w/w) Neusilin were prepared by cryogrinding. All samples were found to be amorphous and remained so for the duration of the study. The chemical stability of neat amorphous QHCl and QHCl coground with various percentages of Neusilin was studied at 40°C and at various moisture contents, as dictated by varying storage relative humidity (%RH). QHCl hydrolysis, forming a dicarboxylic acid (DCA) product, slightly increased with increasing percentages of Neusilin in the coground amorphous samples. On the contrary, QHCl cyclization, forming a diketopiperazine (DKP) product, was slow at both lower (e.g., 5%) and higher (e.g., 95%) percentages of Neusilin and markedly faster at intermediate percentages (e.g., 50%) of Neusilin. This complex effect of drug/silicate ratio on cyclization of quinapril was correlated with the surface acidity of the coground amorphous systems. For neat amorphous QHCl, increasing moisture resulted in increased DKP and DCA formation, as expected. Similarly, higher DCA formation was observed in QHCl/Neusilin coground amorphous samples with increasing moisture. However, DKP formation in coground amorphous samples was high both at lower (e.g., 0% RH) and higher (e.g., 75% RH) humidity, and low at intermediate (e.g., 48% RH) humidity. This complex relationship between DKP formation and moisture content for coground amorphous samples can be explained by the competitive adsorption of drug and water molecules on Neusilin surfaces, which was confirmed by Fourier transform infrared (FTIR) spectroscopy. Therefore, drug/silicate ratio, solid-state equivalent pH (surface acidity), and moisture have significant effects on chemical stability and should be considered in formulation and packaging optimization to develop both chemically and physically stable amorphous drug formulations using silicates.

Solid-state surface acidity and pH-stability profiles of amorphous quinapril hydrochloride and silicate formulations.

To determine the surface acidity and stability profiles of quinapril hydrochloride (QHCl) coground with silicates, solid-state equivalent pH (pHeq) of amorphous samples was measured by diffuse reflectance spectroscopy using pH indicator probes. Calibration curves for pH indicators were developed in buffer solutions. Amorphous samples with and without pH indicators were prepared by cryo-grinding. Different pH grades of silicates and various QHCl/silicate ratios were used to make amorphous samples over a range of surface acidity. Diffuse reflectance spectra of amorphous samples were measured and pHeq was determined using the calibration curves of pH indicators developed in solution. Suspension pH of amorphous samples was also measured. The chemical stability of coground amorphous samples was assessed at 40 degrees C and 0% or 48% RH. The chemical stability of neat amorphous quinapril lyophilized from solutions over a range of pH was also assessed at 40 degrees C/0% RH and the reconstituted pH-stability profile of lyophiles was determined. For all silicate and QHCl/silicate amorphous samples, the same pH rank order was obtained based on pHeq and suspension pH. However, the pHeq was significantly lower than the corresponding suspension pH. Discrepancies between pH-stability profiles based on the pHeq and the suspension pH were observed. In general, the pHeq- and reconstituted pH-stability profiles were essentially identical, but the suspension pH-stability profile deviated from the reconstituted pH-stability profile by 2-3 pH units. The results indicate that solid-state surface acidity measurement provides a more accurate prediction of the effective surface acidity of amorphous formulations than the suspension pH. In conclusion, solid-state surface acidity measurement of excipients and solid formulations using pH indicator probes as surrogates can be used to determine the ionization state of the drug and to predict the chemical stability profile of the drug in actual solid formulations.

Effect of the pH grade of silicates on chemical stability of coground amorphous quinapril hydrochloride and its stabilization using pH-modifiers.

The effect of pH grade of silicates on chemical stability of amorphous drugs coground with silicates (Neusilin and Aerosil) was investigated using quinapril HCl (QHCl) as a model drug. The ability of pH-modifiers (ascorbic acid and MgO) to improve chemical stability was explored. PXRD and polarized light microscopy indicated complete amorphization of all samples by cryo-grinding. All samples remained amorphous during stability study at 40 degrees C and 48% RH. In general, drug degradation was greater in the QHCl/silicate (1:3) coground amorphous samples than the neat amorphous QHCl. The rate of diketopiperazine formation by cyclization of QHCl was higher in the presence of lower pH grades than higher pH grades of silicates. However, the pH-stability profile of coground amorphous systems prepared with different pH grades of silicates was not consistent with the pH-stability profile of the drug in solution. A basic pH-modifier (MgO) in a lower pH grade silicate (Neusilin US2) stabilized coground amorphous QHCl. Also, an acidic pH-modifier (ascorbic acid) in a higher pH grade silicate (Neusilin FL2) suppressed QHCl hydrolysis. The pH grade of silicates is a major factor affecting the chemical stability of a coground amorphous drug and pH-modifiers are useful for chemical stabilization without compromising physical stability.