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[Display omitted] • Dissolution behavior of an ASD of a weak base is pH dependent. Drug loading at which optimal dissolution performance is observed increases with increase in ionization. • Unique association behavior of atazanavir-PVPVA is purported to occur in both unionized and ionized states of atazanavir. The impact of this associated phase on the overall ASD dissolution performance is drastically different. Ionized atazanavir-PVPVA phase positively influences dissolution. • At unionized conditions, a relatively drastic decline in the ASD dissolution performance is observed with increase in drug loading whereas, a gradual decline in ASD dissolution behavior was seen for ionized conditions. Amorphous solid dispersions (ASDs) are widely employed as a strategy to improve oral bioavailability of poorly water soluble compounds. Typically, optimal dissolution performance from a polyvinylpyrrolidone vinyl acetate (PVPVA) based ASD is observed at relatively low drug loading limit. Above a certain drug load, termed limit of congruency (LoC), the release from ASDs significantly decreases. So far, the majority of the dissolution behavior has been tested in conditions where the drug primarily exists in unionized form. In this work, the impact of pH of the dissolution environment on the release performance of ASDs of an ionizable drug was studied. Atazanavir (ATZ), a weakly basic drug with a pK a of 4.5 was used as a model compound and PVPVA was used as a non-ionizable matrix polymer. Dissolution rate was measured using Wood's apparatus which normalizes the surface area of the dissolving tablet. The pH of the dissolution media was varied between 1 and 6.8, to cover a range where ATZ exists as >99 % ionized or unionized species. At pH 6.8, near complete release was observed only when the drug load was ≤ 6 %. Unlike typically observed drastic decline in release behavior for PVPVA based ASDs above LoC, ATZ ASDs underwent gradual decline in dissolution behavior when the DL was increased to 8 %. This was attributed to potential formation of an ATZ-PVPVA associated phase with dissolution rate slower than neat PVPVA. However, the 10 % DL ASD showed negligible ATZ release. On another extreme (pH 1) where ATZ is ∼100 % ionized, the dissolution rate of ATZ was faster than that of PVPVA. ASD dissolution rate was found to be slower than that of the neat drug but faster than PVPVA and interestingly, did not change with DL. This can be attributed to formation of an ionized ATZ-PVPVA phase which controls the dissolution rate of the ASD. At pH 3, where the drug is ∼97 % ionized, near complete release was observed for drug loads ≤ 8 %. To observe significant increase in drug loading with near complete release, >98 % ionization of ATZ was required. At pH 2 where ATZ is ∼99.7 % ionized, near complete release was observed for drug loads up to 30 %. Furthermore, the deterioration in dissolution performance with an increase in drug load continued to be gradual at pH 2. The enhancement in dissolution performance did not correlate with solubility enhancement of ATZ due to ionization. We theorize that the enhancement in the dissolution performance due to ionization is the result of formation of an ionized ATZ-PVPVA phase which increases the hydrophilicity and the miscibility of the ASD. This can help resist water induced phase separation during ASD dissolution and therefore, result in continuous, and congruent dissolution of the drug and polymer. [ABSTRACT FROM AUTHOR]

With an increasing number of Biopharmaceutical Classification System (BCS) II/IV pipeline compounds, solubilizing and supersaturating formulation strategies are becoming prevalent. Beyond formulation and solid form strategies, prodrugs are also employed to overcome solubility-limited absorption of poorly water-soluble compounds. Prodrugs can potentially yield supersaturated systems upon conversion to the parent drug intraluminally and thus enhance absorption. However, supersaturation also increases the driving force for crystallization, resulting in low solution concentrations, which can potentially negate the advantage of prodrugs. In this work, two unique solubility-enhancing prodrugs, phosphate and glycine esters, were investigated for a rapidly crystallizing parent drug. Ex vivo absorption studies using rat tissue and in vivo studies in dogs were performed. Conversion rate of the phosphate prodrug to the parent was dependent on the milieu and increased ∼24-fold in the presence of intestinal contents as medium and tissue relative to neat buffer. In contrast, conversion of the glycine prodrug was minimal under any conditions tested, suggesting that the conversion occurs after absorption into the enterocytes. Phosphate prodrug showed a non-linear increase in parent drug absorptive flux across rat intestinal tissue with concentration when intestinal contents were used as donor media. This was attributed to rapid conversion and high supersaturation of the parent drug which subsequently resulted in crystallization at high doses in the donor chamber. Glycine prodrug did not undergo complete conversion at high doses and was absorbed unchanged on the basolateral side, indicating saturation of the converting enzymes in the enterocytes. The combined flux (parent drug and glycine) showed a linear increase with dose and crystallization was not observed. Under physiological conditions , glycine prodrug that is absorbed unchanged from the intestine can potentially undergo complete conversion in hepatocytes after absorption and make the parent drug systemically available. Thus, glycine prodrug provided overall higher absorption compared to phosphate prodrug. The observed flux levels for both the prodrugs were higher compared to the parent drug alone, highlighting an advantage to use of a prodrug strategy to improve absorption of such compounds. Oral dosing in a dog PK study revealed that the bioavailability using the phosphate prodrug was ∼50% whereas, it was ∼100% with glycine prodrug, supporting the in vitro observations. [Display omitted] • Impact of two unique prodrugs of a poorly soluble, rapidly crystallizing compound on oral absorption is studied. • Role of conversion enzymes and site, permeability, solubility and crystallization tendency is demonstrated. • Considerations for in vitro evaluation and in silico modeling of prodrugs are put forth. [ABSTRACT FROM AUTHOR]

It has been observed that certain amorphous solid dispersions (ASDs), upon dissolution, generate drug-rich amorphous nanodroplets. These nanodroplets, present as a dispersed phase, can potentially enhance oral bioavailability of poorly soluble drugs by serving as a drug reservoir that efficiently feeds the continuous aqueous solution phase following absorption of drug. The purpose of this study is to probe the formation mechanism of the nanodroplets. The model system studied was nifedipine (NFD) formulated as an ASD with hydroxypropyl methylcellulose E5 Premium LV or polyvinylpyrrolidone/vinyl acetate. Dissolution of ASDs prepared with proteated nifedipine (H-NFD) was carried out in a medium saturated with deuterated nifedipine (D-NFD) at the amorphous solubility. Upon dissolution, the H/D composition of NFD aqueous solution was determined using nuclear magnetic resonance spectroscopy. The results suggested that isotopic scrambling (equilibrium in the distribution of deuterated and proteated form of the drug) had occurred. Thus, as the H-NFD was brought into the aqueous solution via ASD dissolution, the drug concentration in solution exceeded the amorphous solubility. Subsequent precipitation of the drug, a process which does not differentiate H-NFD from D-NFD, generated NFD nanodroplets and resulted in redistribution of the isotopes. Thus, nanodroplets of NFD are formed due to dissolution of these homogenous ASDs followed by precipitation of the drug from aqueous solutions. [ABSTRACT FROM AUTHOR]

Abstract: The present study was designed with the objective to investigate the stability and potential of glucomannan-modified bilosomes (GM-bilosomes) in eliciting immune response following oral administration. GM-bilosomes exhibited desired quality attributes simultaneously maintaining the chemical and conformation stability of the tetanus toxoid (TT) entrapped in to freeze dried formulations. The GM-bilosomes exhibited excellent stability in different simulated biological fluids and sustained release profile up to 24h. GM-bilosomes elicited significantly higher (P <0.05) systemic immune response (serum IgG level) as compared to bilosomes, niosomes and alum adsorbed TT administered through oral route. More importantly, GM-bilosomes were found capable of inducing mucosal immune response, i.e. sIgA titre in salivary and intestinal secretions as well as cell mediated immune response (IL-2 and IFN-γ levels in spleen homogenate) which was not induced by i.m. TT, the conventional route of immunization. Conclusively, GM-bilosomes could be considered as a promising carrier and adjuvant system for oral mucosal immunization. From the Clinical Editor: This team reports on the development and effects of a glucomannan-modified bilosome as an oral vaccine vector, using tetanus toxoid in the experiments. These GM-bilosomes not only elicited significantly higher systemic immune response as compared to bilosomes, niosomes and alum adsorbed orally administered TT, but also demonstrated mucosal immune response induction as well as cell mediated immune responses, which were not induced by the conventional route of immunization. [Copyright &y& Elsevier]

The mechanisms of drug release from amorphous solid dispersions (ASDs) are complex and not fully explored, making it difficult to optimize for in vivo performance. A recurring behavior has been the limit of congruency (LoC), a drug loading above which the ASD surface forms an amorphous drug-rich barrier in the presence of water, which hinders release, especially in non-sink conditions. Drug-polymer interactions and drug glass transition temperature were reported to affect the LoC. However, the effect of polymer molecular weight has not been explored. ASDs of clotrimazole and different molecular weight grades of poly (vinylpyrrolidone) (PVP) were studied for their release to obtain their LoC drug loadings. Failure modes underpinning the LoC were investigated using fluorescence confocal microscopy to analyze the ASD/solution interface and phase behavior of ASD films at high relative humidity. ASDs with good release formed stable drug-rich nanodroplets at the ASD/solution interface, while ASDs with poor release were limited by one of two failure modes, depending on PVP molecular weight. In Failure Mode I the nanodroplets quickly agglomerated, while in Failure Mode II the system underwent phase inversion. This work highlights the importance of identifying the mechanisms underlying the LoC to improve the release of higher drug loading ASDs. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] Amorphous solid dispersion formulations (ASD) are increasingly being used as a formulation strategy to improve bioavailability of poorly soluble drugs. One of the limitations of ASDs, in particular for high glass transition temperature (T g) compounds, is the drug loading threshold (termed the limit of congruency, LoC) below which rapid, complete and congruent release of drug and polymer is achieved. In this study, several ionic and non-ionic surfactants were added to atazanavir-copovidone ASDs with the main goal of increasing the limit of congruency. Atazanavir (ATZ) is a relatively high T g compound with a LoC of 5 % drug loading (DL). Surface normalized dissolution studies revealed that addition of 5 % w/w of surfactant, sodium dodecyl sulfate (SDS) or cetrimonium bromide (CTAB), to the binary copovidone-based ASD doubled the LoC (from 5 to 10 % DL), resulting in a more than 30-fold increase in total release compared to the corresponding binary ASD. Moreover, addition of 5 % of Span®80 increased the LoC to 15 % DL. ASD T g was found to decrease upon addition of surfactants and water sorption extent was found to increase. We speculate that surfactants act as plasticizers, which may facilitate polymer release from ASDs containing a high T g drug, providing a possible explanation for the observed enhancement in drug release from ternary ASDs and the increase in LoC. [ABSTRACT FROM AUTHOR]

Chemically induced, targeted protein degradation with proteolysis targeting chimeras (PROTACs) has shown to be a promising pharmacological strategy to circumvent the poor "druggability" of intracellular targets. However, the favorable pharmacology comes with complex molecular properties limiting the oral bioavailability of these drugs. To foster the translation of PROTACs into the clinics it is of high importance to establish sensitive bioanalytical methods that enable the assessment of absorption, bioavailability, and disposition of PROTACs after oral dosing. In this study, two highly sensitive LC-MS/MS methods (LLOQ = 0.5 ng/mL) were developed and validated for the quantification of bavdeglutamide (ARV-110) and vepdegestrant (ARV-471) in rat plasma. Plasma samples were processed by protein precipitation and separated on a C18 column over a gradient of acetonitrile and water with 0.1 % formic acid. Selected reaction monitoring in positive ESI mode was applied to quantify ARV-110 and ARV-471. Both methods showed linearity, accuracy, and precision as well as matrix effects and carry-over within the predefined acceptance criteria. High stability of the compounds in plasma was demonstrated at long-term storage for seven weeks at −20 °C, three freeze-thaw cycles, up to 20 min at room temperature, and as extracts in the autosampler. The plasma concentration-time curves after intravenous and intraduodenal bolus single-dose administrations in rats could be successfully quantified at clinically relevant doses per body weight. The highly sensitive bioanalytical assays presented in this work enable the application of a broad spectrum of in vivo studies to elucidate the oral absorption, bioavailability, and disposition of PROTACs. [Display omitted] • Highly sensitive LC-MS/MS methods for novel PROTACs ARV-110 and ARV-471 in rat plasma. • Bioanalytical method validation criteria according to EMA and FDA guidelines passed. • Methods applicable across a broad concentration range in pharmacokinetic studies. • First in vivo concentration-time profiles for ARV-471. [ABSTRACT FROM AUTHOR]