In Silico, In Vitro, and In Vivo Evaluation of Precipitation Inhibitors in Supersaturated Lipid-Based Formulations of Venetoclax.

The concept of using precipitation inhibitors (PIs) to sustain supersaturation is well established for amorphous formulations but less in the case of lipid-based formulations (LBF). This study applied a systematic in silico-in vitro-in vivo approach to assess the merits of incorporating PIs in supersaturated LBFs (sLBF) using the model drug venetoclax. sLBFs containing hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone (PVP), PVP-co-vinyl acetate (PVP/VA), Pluronic F108, and Eudragit EPO were assessed in silico calculating a drug-excipient mixing enthalpy, in vitro using a PI solvent shift test, and finally, bioavailability was assessed in vivo in landrace pigs. The estimation of pure interaction enthalpies of the drug and the excipient was deemed useful in determining the most promising PIs for venetoclax. The sLBF alone (i.e., no PI present) displayed a high initial drug concentration in the aqueous phase during in vitro screening. sLBF with Pluronic F108 displayed the highest venetoclax concentration in the aqueous phase and sLBF with Eudragit EPO the lowest. In vivo, the sLBF alone showed the highest bioavailability of 26.3 ± 14.2%. Interestingly, a trend toward a decreasing bioavailability was observed for sLBF containing PIs, with PVP/VA being significantly lower compared to sLBF alone. In conclusion, the ability of a sLBF to generate supersaturated concentrations of venetoclax in vitro was translated into increased absorption in vivo. While in silico and in vitro PI screening suggested benefits in terms of prolonged supersaturation, the addition of a PI did not increase in vivo bioavailability. The findings of this study are of particular relevance to pre-clinical drug development, where the high in vivo exposure of venetoclax was achieved using a sLBF approach, and despite the perceived risk of drug precipitation from a sLBF, including a PI may not be merited in all cases.

Cocrystal Solubility Advantage and Dose/Solubility Ratio Diagrams: A Mechanistic Approach To Selecting Additives and Controlling Dissolution-Supersaturation-Precipitation Behavior.

Two of the main questions regarding cocrystal selection and formulation development are whether the will be stable and how fast can it dissolve the drug dose. Dissolving the drug dose may require cocrystals with a high solubility advantage over drug (SA = SCC/SD), but these may have limited potential to sustain drug supersaturation. Thus, we propose a twofold approach to mitigate the risk of drug precipitation by optimizing thermodynamic (SA) and kinetic factors (nucleation inhibitors). This risk can be evaluated by considering the cocrystal SA and drug dose/solubility ratio (D0D = Cdose/SD), which in tandem represent the maximum theoretical supersaturation that a cocrystal may generate, the driving force for drug precipitation, and the potential for dose-/solubility-limited absorption. cocrystals with SA and D0D values above critical supersaturation are prone to rapid precipitation, often negating their utility as a solubility enhancement tool. This work presents a mechanistic approach to controlling the dissolution-supersaturation-precipitation behavior of cocrystal systems, whereby relationships between SA, D0D, and the drug-solubilizing power of surfactants (SPD = SD,T/SD,aq) are used to fine-tune cocrystal-inherent supersaturation by rational additive selection. Experimental results with danazol-vanillin cocrystal demonstrate how SA, D0D, and SPD are key thermodynamic parameters to understanding the kinetic cocrystal behavior and how the risks of cocrystal development may be mitigated through the mechanistic formulation design.

New supersaturating drug delivery system as strategy to improve apparent solubility of candesartan cilexetil in biorelevant medium.

Candesartan cilexetil (CC) is a poorly soluble antihypertensive drug with in vivo absorption limited by its low aqueous solubility. Aiming to generate CC supersaturation as strategy to improve its absorption and bioavailability, amorphous solid dispersions (ASDs) of CC with hydroxypropylmethylcellulose acetate succinate type M (HPMCAS M) were developed and evaluated by in vitro and in vivo techniques. The ASDs were characterized by several solid-state techniques and evaluated regarding the supersaturation generation and maintenance under non-sink conditions in biorelevant medium. Stability studies at different storage conditions and in vivo pharmacodynamics studies were performed for the best formulation. The ASD developed presented appropriate drug amorphization, confirmed by solid state characterization, and CC apparent solubility increases around 85 times when compared to the pure crystalline drug. Supersaturation was maintained for up to 24 h in biorelevant medium. The in vivo pharmacodynamics studies revealed that ASD of CC with the polymer HPMCAS M presented an onset of action about four times faster when compared to the pure crystalline drug. The CC-HPMCAS ASD were successfully developed and demonstrated good physical stability under different storage conditions as well as promising results that indicated the ASD potential for improvement of CC biopharmaceutical properties.

The Opposed Effects of Polyvinylpyrrolidone K30 on Dissolution and Precipitation for Indomethacin Supersaturating Drug Delivery Systems.

Amorphous solid dispersions (ASD) are one of the most important supersaturating drug delivery systems (SDDS) for poorly water-soluble drugs to improve their bioavailability. As a result of thermodynamic instability, drug molecules tend to precipitate during storage and dissolution in gastrointestinal tract. Various precipitation inhibitors (PI) have been widely used to improve the stability in the past decade. However, most studies have investigated the inhibiting capability of PI on drug precipitation, rarely considering their potential hindering effect on the drug dissolution. The present study designed an ASD of Indomethacin (IND) and Eudragit® EPO by hot melt extrusion to investigate the influence of the added PI (PVP-K30) into ASD both on dissolution and precipitation. The precipitation study by solvent shift method indicated PVP-K30 could inhibit the precipitation of IND significantly. The dissolution study in different concentrations of PVP-K30 showed when the concentration increased above 50 µg/mL, PVP-K30 displayed an acceptable precipitation inhibition without drug concentration decline but an unexpected dissolution impediment with the reduction of maximum concentration platform. The dissolution tests of physical mixtures (PMs) of ASD and PVP-K30 also showed the precipitation inhibition and dissolution impediment when more than 2% PVP-K30 in PMs. This opposed effect of PVP-K30 was strengthen in ternary systems prepared by hot melt extruding the mixtures of IND, Eudragit® EPO and PVP-K30. All of these results proved the PI may be a double-edged sword for the opposed effects of precipitation inhibition and dissolution impediment, which should be carefully considered in the design and development of SDDS.

Tailored Supersaturable Immediate Release Behaviors of Hypotensive Supersaturating Drug-Delivery Systems Combined with Hot-Melt Extrusion Technique and Self-Micellizing Polymer.

The short-term immediate release of supersaturated drug-delivery systems (SDDSs) presents an interesting process that can be tailored to multi-stage release events including initial release after dosing and dissolution, evolved release over longer dissolution periods for biological absorption, and terminal release following the end of immediate release. However, although comprehensive analysis of these critical release behaviors is often ignored yet essential for understanding the supersaturable immediate-release events for supersaturable solid formations when employing new techniques or polymers matched to a particular API. Hot-melt extrusion (HME) has become a popular continuous thermodynamic disordering technique for amorphization. The self-micellizing polymer Soluplus® is reported to be a potential amorphous and amphiphilic graft copolymer frequently used in many nano/micro supersaturable formulations. Our current work aims to develop hypotensive supersaturating solid dispersion systems (faSDDSHME) containing the BCS II drug, felodipine, when coordinately employing the HME technique and self-micellizing Soluplus®, and to characterize their amorphization as well as immediate release. Other discontinuous techniques were used to prepare control groups (faSDDSSE and faSDDSQC). Tailored initial/evolved/terminal three-stage supersaturable immediate-release behaviors were identified and possible mechanisms controlling the release were explored. HME produced the highest initial release in related faSDDSHME. During the evolved-release period, highly extended "spring-parachute" process was found in HME-induced amorphization owing to its superior supersaturation duration. Due to the enhanced crystallization inhibition effect, faSDDSHME displayed the strongest terminal release as measured by solubility. For release mechanisms associated with HME, molecular interaction is not the likely dominant mechanism responsible for the improved properties induced by faSDDSHME. For release mechanisms involved with the polymer Soluplus® itself, they were found to inhibit drug recrystallization, spontaneously solubilize the drug and lead to improved molecular interactions in all SDDS systems, which were the factors responsible for the improved release. These mechanisms play an important role for the generation of an extended multi-stage immediate release produced via HME or self-micellizing polymer. This study provides a deeper understanding on amorphization and superior multi-stage supersaturable immediate-release behaviors for a particular hypotensive supersaturated delivery system combined with an HME-based continuous manufacturing technique and self-micellizing polymer strategy.

Biorelevant dissolution testing and physiologically based absorption modeling to predict in vivo performance of supersaturating drug delivery systems.

Supersaturating drug delivery systems (SDDS) enhance the oral absorption of poorly water-soluble drugs by achieving a supersaturated state in the gastrointestinal tract. The maintenance of a supersaturated state is decided by the complex interplay among inherent properties of drug, excipients and physiological conditions of gastrointestinal tract. The biopharmaceutical advantage through SDDS can be mechanistically investigated by coupling biopredictive dissolution testing with physiologically based absorption modeling (PBAM). However, the development of biopredictive dissolution methods possess challenges due to concurrent dissolution, supersaturation, precipitation, and possible redissolution of precipitates during gastrointestinal transit of SDDS. In this comprehensive review, our effort is to critically assess the current state-of-knowledge and provide future directions for PBAM of SDDS. The review outlines various methods used to retrieve physiologically relevant values for input parameters like solubility, dissolution, precipitation, lipid-digestion and permeability of SDDS. SDDS-specific parameterization includes solubility values corresponding to apparent physical form, dissolution in physiologically relevant volumes with biorelevant media, and transfer experiments to incorporate precipitation kinetics. Interestingly, the lack of experimental permeability values and modification of absorption flux through SDDS possess the additional challenge for its PBAM. Supersaturation triggered permeability modifications are reported to fit the observed plasma concentration-time profile. Hence, the experimental insights on good fitting with modified permeability can be potential area of future research for the development of in vitro methods to reliably predict oral absorption of SDDS.

"Felodipine-indomethacin" co-amorphous supersaturating drug delivery systems: "Spring-parachute" process, stability, in vivo bioavailability, and underlying molecular mechanisms.

Amorphous solid dispersions (ASD) are one of most commonly used supersaturating drug delivery systems (SDDS) to formulate insoluble active pharmaceutical ingredients. However, the development of polymer-guided stabilization of ASD systems faces many obstacles. To overcome these shortcomings, co-amorphous supersaturable formulations have emerged as an alternative formulation strategy for poorly soluble compounds. Noteworthily, current researches around co-amorphous system (CAS) are mostly focused on preparation and characterization of these systems, but more detailed investigations of their supersaturation ("spring-parachute" process), stability, in vivo bioavailability and molecular mechanisms are inadequate and need to be clarified. In present study, we chose pharmacological relevant BCS II drugs to fabricate and characterize "felodipine-indomethacin" CAS. To enrich the current inadequate but key knowledge on CAS studies, we carried out following highlighted investigations including dissolution/solubility, semi-continuous "spring-parachute" process, long-term stability profile of amorphous state, in vivo bioavailability and underlying molecular mechanisms (molecular interaction, molecular miscibility and crystallization inhibition). Generally, the research provides some key information in the field of current "drug-drug" CAS supersaturable formulations.

HPMCAS as an effective precipitation inhibitor in amorphous solid dispersions of the poorly soluble drug candesartan cilexetil.

Among the strategies to improve the biopharmaceutic properties of poorly soluble drugs, Supersaturating Drug Delivery Systems like polymer-based amorphous solid dispersions (SD) have been successfully applied. The screening of appropriate polymeric carriers to compose SD is a crucial point on their development. In this study, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMCAS) types L, M and H and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SOL) were evaluated by in vitro supersaturation studies regarding their anti-precipitant ability on the poorly soluble drug candesartan cilexetil (CC) under two different media, including biorelevant conditions. According to the results, HPMCAS M was considered the best carrier to develop SD containing CC among all the polymers tested, due to its good anti-precipitant performance in both media. In addition, the medium used in the in vitro supersaturation studies played an important role on the results, and its selection should be carefully done.

Evaluation and optimized selection of supersaturating drug delivery systems of posaconazole (BCS class 2b) in the gastrointestinal simulator (GIS): An in vitro-in silico-in vivo approach.

Supersaturating drug delivery systems (SDDS) have been put forward in the recent decades in order to circumvent the issue of low aqueous solubility. Prior to the start of clinical trials, these enabling formulations should be adequately explored in in vitro/in silico studies in order to understand their in vivo performance and to select the most appropriate and effective formulation in terms of oral bioavailability and therapeutic outcome. The purpose of this work was to evaluate the in vivo performance of four different oral formulations of posaconazole (categorized as a biopharmaceutics classification system (BCS) class 2b compound) based on the in vitro concentrations in the gastrointestinal simulator (GIS), coupled with an in silico pharmacokinetic model to predict their systemic profiles. Recently published intraluminal and systemic concentrations of posaconazole for these formulations served as a reference to validate the in vitro and in silico results. Additionally, the morphology of the formed precipitate of posaconazole was visualized and characterized by optical microscopy studies and thermal analysis. This multidisciplinary work demonstrates an in vitro-in silico-in vivo approach that provides a scientific basis for screening SDDS by a user-friendly formulation predictive dissolution (fPD) device in order to rank these formulations towards their in vivo performance.

Biopharmaceutical classification of poorly soluble drugs with respect to "enabling formulations".

The large number of drug candidates with poor dissolution characteristics seen in the past decade, has fostered interest in so-called "enabling formulations", i.e., formulations which shall make such drugs bio-available. Development of enabling formulations is currently being guided by the following (simplified) hypothesis: If a poorly soluble drug (BCS class II drug) can be transferred into a solubilized state, one can achieve an absorption profile close to that of a soluble drug (BCS class I drug). Thus, formulation development typically endeavors to achieve the most robust solubility enhancement. Here we critically review both common in vitro approaches and experimental data available in literature pertaining to the solubility and permeability of poorly soluble drugs from enabling formulations, and discuss their interplay. Recent in vitro data indicate, that commonly employed surfactants as well as endogenous surfactants present in the intestine, although enhancing drug solubility, mostly hamper drug permeation. Mechanistic studies demonstrate a direct correlation between passive transcellular diffusion and the concentration of molecularly dissolved drug. The latter may be reduced due to partitioning into micelles or other solubilizing carriers, but enhanced in supersaturating formulations. We conclude thus that biopharmaceutical assessment approaches that rely on the amount of molecularly dissolved drug should guide us towards successful enabling formulations.