Computational prediction of formulation strategies for beyond-rule-of-5 compounds

AbstractThe physicochemical properties of some contemporary drug candidates are moving towards higher molecular weight, and coincidentally also higher lipophilicity in the quest for biological selectivity and specificity. These physicochemical properties move the compounds towards beyond rule-of-5 (B-r-o-5) chemical space and often result in lower water solubility. For such B-r-o-5 compounds non-traditional delivery strategies (i.e. those other than conventional tablet and capsule formulations) typically are required to achieve adequate exposure after oral administration. In this review, we present the current status of computational tools for prediction of intestinal drug absorption, models for prediction of the most suitable formulation strategies for B-r-o-5 compounds and models to obtain an enhanced understanding of the interplay between drug, formulation and physiological environment. In silico models are able to identify the likely molecular basis for low solubility in physiologically relevant fluids such as gastric and intestinal fluids. With this baseline information, a formulation scientist can, at an early stage, evaluate different orally administered, enabling formulation strategies. Recent computational models have emerged that predict glass-forming ability and crystallisation tendency and therefore the potential utility of amorphous solid dispersion formulations. Further, computational models of loading capacity in lipids, and therefore the potential for formulation as a lipid-based formulation, are now available. Whilst such tools are useful for rapid identification of suitable formulation strategies, they do not reveal drug localisation and molecular interaction patterns between drug and excipients. For the latter, Molecular Dynamics simulations provide an insight into the interplay between drug, formulation and intestinal fluid. These different computational approaches are reviewed. Additionally, we analyse the molecular requirements of different targets, since these can provide an early signal that enabling formulation strategies will be required. Based on the analysis we conclude that computational biopharmaceutical profiling can be used to identify where non-conventional gateways, such as prediction of ‘formulate-ability’ during lead optimisation and early development stages, are important and may ultimately increase the number of orally tractable contemporary targets

To Give Chinese Children "a Memorable China":the Trend of Chinese Indigenous Picture Books

To investigate if drug solubility in pharmaceutical excipients used in lipid based formulations (LBFs) can be predicted from physicochemical properties. Solubility was measured for 30 structurally diverse drug molecules in soybean oil (SBO, long-chain triglyceride; TG(LC)), Captex355 (medium-chain triglyceride; TG(MC)), polysorbate 80 (PS80; surfactant) and PEG400 co-solvent and used as responses during PLS model development. Melting point and calculated molecular descriptors were used as variables and the PLS models were validated with test sets and permutation tests. Solvation capacity of SBO and Captex355 was equal on a mol per mol scale (R (2) = 0.98). A strong correlation was also found between PS80 and PEG400 (R (2) = 0.85), identifying the significant contribution of the ethoxylation for the solvation capacity of PS80. In silico models based on calculated descriptors were successfully developed for drug solubility in SBO (R (2) = 0.81, Q (2) = 0.76) and Captex355 (R (2) = 0.84, Q (2) = 0.80). However, solubility in PS80 and PEG400 were not possible to quantitatively predict from molecular structure. Solubility measured in one excipient can be used to predict solubility in another, herein exemplified with TG(MC) versus TG(LC), and PS80 versus PEG400. We also show, for the first time, that solubility in TG(MC) and TG(LC) can be predicted from rapidly calculated molecular descriptors

Computational and Experimental Models for the Prediction of Intestinal Drug Solubility and Absorption

New effective experimental techniques in medicinal chemistry and pharmacology have resulted in a vast increase in the number of pharmacologically interesting compounds. However, the number of new drugs undergoing clinical trial has not augmented at the same pace, which in part has been attributed to poor absorption of the compounds. The main objective of this thesis was to investigate whether computer-based models devised from calculated molecular descriptors can be used to predict aqueous drug solubility, an important property influencing the absorption process. For this purpose, both experimental and computational studies were performed. A new small-scale shake flask method for experimental solubility determination of crystalline compounds was devised. This method was used to experimentally determine solubility values used for the computational model development and to investigate the pH-dependent solubility of drugs. In the computer-based studies, rapidly calculated molecular descriptors were used to predict aqueous solubility and the melting point, a solid state characteristic of importance for the solubility. To predict the absorption process, drug permeability across the intestinal epithelium was also modeled. The results show that high quality solubility data of crystalline compounds can be obtained by the small-scale shake flask method in a microtiter plate format. The experimentally determined pH-dependent solubility profiles deviated largely from the profiles predicted by a traditionally used relationship, highlighting the risk of data extrapolation. The in silico solubility models identified the non-polar surface area and partitioned total surface areas as potential new molecular descriptors for solubility. General solubility models of high accuracy were obtained when combining the surface area descriptors with descriptors for electron distribution, connectivity, flexibility and polarity. The used descriptors proved to be related to the solvation of the molecule rather than to solid state properties. The surface area descriptors were also valid for permeability predictions, and the use of the solubility and permeability models in concert resulted in an excellent theoretical absorption classification. To summarize, the experimental and computational models devised in this thesis are improved absorption screening tools applicable to the lead optimization in the drug discovery process

Caco-2 Cell Conditions Enabling Studies of Drug Absorption from Digestible Lipid-Based Formulations

Purpose To identify conditions allowing the use of cell-based models for studies of drug absorption during in vitro lipolysis of lipid-based formulations (LBFs). Methods Caco-2 was selected as the cell-based model system. Monolayer integrity was evaluated by measuring mannitol permeability after incubating Caco-2 cells in the presence of components available during lipolysis. Pure excipients and formulations representing the lipid formulation classification system (LFCS) were evaluated before and after digestion. Porcine mucin was evaluated for its capacity to protect the cell monolayer. Results Most undigested formulations were compatible with the cells (II-LC, IIIB-LC, and IV) although some needed mucin to protect against damaging effects (II-MC, IIIB-MC, LC, and IIIA-LC). The pancreatic extract commonly used in digestion studies was incompatible with the cells but the Caco-2 monolayers could withstand immobilized recombinant lipase. Upon digestion, long chain formulations caused more damage to Caco-2 cells than their undigested counterparts whereas medium chain formulations showed better tolerability after digestion. Conclusions Most LBFs and components thereof (undigested and digested) are compatible with Caco-2 cells. Pancreatic enzyme is not tolerated by the cells but immobilized lipase can be used in combination with the cell monolayer. Mucin is beneficial for critical formulations and digestion products

Förskollärares sätt att arbeta med matematik i utomhuspedagogiken

Vi undersöker hur förskollärare arbetar med matematiken i förskolans utomhusverksamhet och hur de synliggör matematiken så att barnen lär och utvecklas. Syftet med vår studie är att få en djupare förståelse kring hur förskollärare synliggör matematiken i utomhuspedagogiken. Bakgrunden till vår studie utgår från de dåliga resultaten i matematik som visades i en undersökning av PISA, Programme for International Student Assessment som gjordes 2013. De teoretiska utgångspunkterna inspireras av de sociokulturella teoribildningarna där de tre teoretikerna Friedrich Fröbel, John Dewey och Alan Bishop varit de centrala. De teoretiska utgångspunkterna och de tre centrala teoretikerna kommer tillsammans med begrepp och tidigare forskning att hjälpa oss att stödja analysen av vår empiri. Empirin har samlats in genom 13 enkäter från förskollärare och observationer från tre förskolor. Slutsatsen av studien visar på att det krävs att man som förskollärare är medveten, närvarande och synliggör matematiken i tidig ålder. Även att man som förskollärare är medveten om vad som står i Läroplanen (Lpfö98, rev 2010). Faktorer som närvarande och medvetenhet spelar roll för vilken matematik man arbetar med och hur man synliggör den

En grundsärskola möter en grundskola : En fallstudie om hur personal från två olika skolformer ser på en samverkan som kan gynna elever med läs- och skrivsvårigheter

Detta examensarbete undersöker olika kontaktytor som kan utvecklas till samverkan mellan en grundsärskola och en grundskola. Denna samverkan fokuserar på elever med läs- och skrivsvårigheter i skolår 1-5. Examensarbetet framhåller också likheter och olikheter mellan metoder och arbetssätt i skolformerna gällande läs- och skrivinlärning. Undersökningen bygger på personalens och ledningens åsikter. Av resultatet kan man utläsa att all personal vill samverka och att ledningen är positivt inställd. Alla har dock inte samma syn på vad samverkan är och personalen är oroliga för att tid och resurser inte räcker till. Skolformerna har olika styrdokument och undervisningen är mer individualiserad på grundsärskolan

Perspectives in solubility measurement and interpretation

Several key topics in solubility measurement and interpretation are briefly summarized and illustrated with case studies drawing on published solubility determinations as a function of pH. Featured are examples of ionizable molecules that exhibit solubility-pH curve distortion from that predicted by the traditionally used Henderson-Hasselbalch equation and possible interpretations for these distortions are provided. The scope is not exhaustive; rather it is focused on detailed descriptions of a few cases. Topics discussed are limitations of kinetic solubility, 'brick-dust and grease-balls,' applications of simulated and human intestinal fluids, supersaturation and the relevance of pre-nucleation clusters and sub-micellar aggregates in the formation of solids, drug-buffer/excipient complexation, hydrotropic solubilization, acid-base 'supersolubilization,' cocrystal route to supersaturation, as well as data quality assessment and solubility prediction. The goal is to highlight principles of solution equilibria - graphically more than mathematically - that could invite better assay design, to result in improved quality of measurements, and to impart a deeper understanding of the underlying solution chemistry in suspensions of drug solids. The value of solid state characterizations is stressed but not covered explicitly in this mini-review

Contemporary formulation development for inhaled pharmaceuticals

Pulmonary delivery has gained increased interests over the past few decades. For conditions within the respiratory tract, targeted drug delivery directly to the site of action can achieve a high local concentration for efficacy with reduced unwanted systemic exposure and adverse effect. For systemic conditions, the unique physiology of the lung evolutionarily designed for rapid gaseous exchange presents an entry route for systemic drug delivery. Although the development of inhaled formulations has come a long way over the last few decades, many aspects of it remain to be elucidated. In particular, a reliable and well-understood method for in vitro-in vivo correlations remains to be established. With the rapid and ongoing advancement of technology, there is much potential to better utilise computational methods including different types of modelling and simulation approaches to support inhaled formulation development. This review intends to provide an introduction on some fundamental concepts in pulmonary drug delivery and inhaled formulation development followed by discussions on some challenges and opportunities in the translation of inhaled pharmaceuticals from preclinical studies to clinical development. The review concludes with some recent advancements in modelling and simulation approaches that could play an increasingly important role in contemporary formulation development of inhaled pharmaceuticals