New Insights into Using Lipid Based Suspensions for ‘Brick Dust’ Molecules: Case Study of Nilotinib

Koehl, Niklas J.; Holm, René; Kuentz, Martin; Griffin, Brendan T.

doi:10.1007/s11095-019-2590-y

Cited by 29 publications

(35 citation statements)

References 37 publications

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“…The amount of venetoclax decreased from 66.5 ± 7.3% upon dispersion to 8.3 ± 2.3% during digestion, which correlated with the amount recovered in the solid phase ( Figure 4 C). This indicated that the venetoclax crystals in the Peceol ® suspension were entrapped in the lipid excipient, an observation which was similar to that previously demonstrated for lipid nilotinib suspensions [ 25 ]. Overall, a comparison between the formulations suggested that the sLBF had the ability to maintain higher concentrations in the lipid and aqueous phase relative to the suspensions, and hence may offer benefits in vivo.…”

Section: Resultssupporting

confidence: 84%

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Supersaturated Lipid-Based Formulations to Enhance the Oral Bioavailability of Venetoclax

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Increasing numbers of beyond Rule-of-Five drugs are emerging from discovery pipelines, generating a need for bio-enabling formulation approaches, such as lipid-based formulations (LBF), to ensure maximal in vivo exposure. However, many drug candidates display insufficient lipid solubility, leading to dose-loading limitations in LBFs. The aim of this study was to explore the potential of supersaturated LBFs (sLBF) for the beyond Rule-of-Five drug venetoclax. Temperature-induced sLBFs of venetoclax were obtained in olive oil, Captex® 1000, Peceol® and Capmul MCM®, respectively. A Peceol®-based sLBF displayed the highest drug loading and was therefore evaluated further. In vitro lipolysis demonstrated that the Peceol®-based sLBF was able to generate higher venetoclax concentrations in the aqueous phase compared to a Peceol®-based suspension and an aqueous suspension. A subsequent bioavailability study in pigs demonstrated for sLBF a 3.8-fold and 2.1-fold higher bioavailability compared to the drug powder and Peceol®-based suspension, respectively. In conclusion, sLBF is a promising bio-enabling formulation approach to enhance in vivo exposure of beyond Rule-of-Five drugs, such as venetoclax. The in vitro lipolysis results correctly predicted a higher exposure of the sLBF in vivo. The findings of this study are of particular relevance to pre-clinical drug development, where maximum exposure is required.

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Section: Resultssupporting

confidence: 84%

“…The system was operated by the Tiamo ® 2.2 software. The in vitro protocol was amended from Williams et al [ 23 , 24 ] as reported previously [ 25 ]. In brief, the buffer contained 2 mM TRIS maleate, 150 mM NaCl, and 1.4 mM CaCl 2 2H 2 O, adjusted to pH 6.5.…”

Section: Methodsmentioning

confidence: 99%

Supersaturated Lipid-Based Formulations to Enhance the Oral Bioavailability of Venetoclax

et al. 2020

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“…For "brick-dust" molecules, those with a relatively high crystal lattice energy, solubilization generally will be limited in the lipid phase and LBFs are not as useful for formulation of these drugs. However, recent work has been carried out to demonstrate the possibility of supersaturating such "brick-dust" molecules in lipid formulations using heat-cool cycles (Koehl, et al 2019). Of course, such formulations may encounter long-term stability issues, which could limit practical application as commercially viable formulations, but they are an attractive option for pre-clinical studies where dose-escalation requires high concentrations in easily deliverable formulations, e.g.…”

Section: Lipid-based Formulationsmentioning

confidence: 99%

“…Of course, such formulations may encounter long-term stability issues, which could limit practical application as commercially viable formulations, but they are an attractive option for pre-clinical studies where dose-escalation requires high concentrations in easily deliverable formulations, e.g. for toxicological studies (Koehl, et al 2019).…”

Section: Lipid-based Formulationsmentioning

confidence: 99%

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Novel in vitro and in silico tools for the development of mesoporous silica formulations with optimal precipitation inhibitors

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Formulation scientists have developed a toolkit of strategies that can improve the solubility and subsequent bioavailability of poorly soluble candidates. Amorphous formulations are especially appealing due to the significant improvement in solubility the amorphous form can provide, but must be stabilized for effective performance (Timpe, 2007). 2. The Importance of Drug Polymer Interactions in Precipitation Inhibition Polymeric “precipitation inhibitors” have seen widespread usage in the literature (Warren, 2010). The precipitation inhibition effect of polymers on precipitations is related to interference with nucleation and crystal growth (Xu, 2013). Many techniques have been reported in the literature to predict these interactions, however, they are not suitable to screening due to API and time resources required, which are not amenable to early stage pharmaceutical development. 3. Mesoporous Silica: An Emerging Formulation Technology Mesoporous silicon dioxide has emerged in recent years as a new option for stabilizing the amorphous form. Upon impregnation of the silica with a concentrated drug solution, the drug can be molecularly adsorbed and locally and sterically confined, preventing recrystallization (Ditzinger, 2018). Upon administration of mesoporous silica formulations to the body the amorphous formulation generates supersaturation which must be stabilized using precipitation inhibitors (Guzman, 2007). 4. Co-incorporation: A New Method to Combine Precipitation Inhibitors with Mesoporous Silica There has been no systematic study of how best to incorporate precipitation inhibitors into mesoporous silica formulations. The current standard practice involves combining inhibitors in a physical mixture with the drug-loaded silica, either by pestle and mortar or overhead stirring. Due to the lack of a defined protocol, there is uncertainty about how reliably the precipitation inhibitor is combined with the drug-loaded silica on a batch to batch basis. In this work, a novel co-incorporated formulation of glibenclamide and the precipitation inhibitor, HPMCAS, onto mesoporous silica was described. By co-incorporating the precipitation inhibitor, the formulation significantly outperformed the commonly applied simple physical blend due to the formation of drug-polymer interactions in the solid state. 5. In Silico Pharmaceutics: A New Method to Select Precipitation Inhibitors for Mesoporous Silica An approach that can incorporate understanding of the drug-polymer interactions with a quick and efficient screening process would be very useful. The COnductor like Screening MOdel for Real Solvents (COSMO-RS) is a quantum mechanical theory, which can be used to derive thermodynamic properties of interest. (Klamt, 1993, 1995, 2003). We proposed excess mixing enthalpies of drug and polymer could be calculated using the COSMO-RS theory. This new approach was applied to screen precipitation inhibitors for three model compounds, all of which showed a strong positive correlation between the rank assigned based on the calculated free enthalpy of mixing and the overall formulation performance. 6. Conclusion This body of work aimed to improve the processes underpinning the design and development of mesoporous silica with precipitation inhibitors. Firstly, this involved two extensive literature reviews in the area of solubility enhancement formulation technologies and precipitation inhibition. Secondly, a mechanistic rational and experimental approach was developed to improve the formulation of precipitation inhibitors with mesoporous silica, the “co-incorporation” approach significantly improved process efficiency and formulation performance. Finally, combining insights from the aforementioned review, and learnings from the mechanistic analysis of the “co-incorporation” approach, an in silico screening protocol was developed to calculate the enthalpy of interaction between drug and polymer, to identify the most optimal precipitation inhibitor for a given formulation.

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Supersaturated-Silica Lipid Hybrids Improve in Vitro Solubilization of Abiraterone Acetate

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New Insights into Using Lipid Based Suspensions for ‘Brick Dust’ Molecules: Case Study of Nilotinib

Cited by 29 publications

References 37 publications

Supersaturated Lipid-Based Formulations to Enhance the Oral Bioavailability of Venetoclax

Supersaturated Lipid-Based Formulations to Enhance the Oral Bioavailability of Venetoclax

Novel in vitro and in silico tools for the development of mesoporous silica formulations with optimal precipitation inhibitors

Supersaturated-Silica Lipid Hybrids Improve in Vitro Solubilization of Abiraterone Acetate

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