Исследование свободных колебаний ортотропных цилиндрических оболочек на основе различных моделей

Досліджуються вільні коливання ортотропних циліндричних оболонок при різних граничних умовах на краях в уточненій постановці з застосуванням теорії Міндліна–Тимошенка та на основі тривимірної теорії пружності. Для розрахунку частот використовується чисельно-аналітичний підхід, який базується на застосуванні сплайн-апроксимації, а також методу колокації, дискретної ортогоналізації разом з методом покрокового пошуку. Проведено порівняння частот циліндричних оболонок з різними граничними умовами на торцях, отриманих в рамках різних моделей.A problem of natural vibrations of orthotropic cylindrical shells under various boundary conditions of its end-faces within the framework of the Mindlin–Timoshenko theory and on the basis of 3-D elasticity theory is considered. Using the method of spline-approximation and collocation, the problems are solved by the steady-state numerical method of discrete orthogonalization with incremental search. The comparison of the frequencies of cylindrical shells with different boundary conditions on their ends within various models is performed

Inherent formulation issues of kinase inhibitors

The small molecular Kinase Inhibitor (smKI) drug class is very promising and rapidly expanding. All of these drugs are administered orally. The clear relationship between structure and function has led to drugs with a general low intrinsic solubility. The majority of the commercial pharmaceutical formulations of the smKIs are physical mixtures that are limited by the low drug solubility of a salt form. This class of drugs is therefore characterized by an impaired and variable bioavailability rendering them costly and their therapies suboptimal. New formulations are sparingly being reported in literature and patents. The presented data suggests that continued research into formulation design can help to develop more efficient and cost-effective smKI formulation. Moreover, it may also be of help in the future design of the formulations of new smKIs

Inherent formulation issues of kinase inhibitors

The small molecular Kinase Inhibitor (smKI) drug class is very promising and rapidly expanding. All of these drugs are administered orally. The clear relationship between structure and function has led to drugs with a general low intrinsic solubility. The majority of the commercial pharmaceutical formulations of the smKIs are physical mixtures that are limited by the low drug solubility of a salt form. This class of drugs is therefore characterized by an impaired and variable bioavailability rendering them costly and their therapies suboptimal. New formulations are sparingly being reported in literature and patents. The presented data suggests that continued research into formulation design can help to develop more efficient and cost-effective smKI formulation. Moreover, it may also be of help in the future design of the formulations of new smKIs

Inventory of oral anticancer agents : Pharmaceutical formulation aspects with focus on the solid dispersion technique

Dissolution from the pharmaceutical formulation is a prerequisite for complete and consistent absorption of any orally administered drug, including anticancer agents (oncolytics). Poor dissolution of an oncolytic can result in low oral bioavailability, high variability in blood concentrations and with that suboptimal or even failing therapy. This review discusses pharmaceutical formulation aspects and absorption pharmacokinetics of currently licensed orally administered oncolytics. In nearly half of orally dosed oncolytics poor dissolution is likely to play a major role in low and unpredictable absorption. Dissolution-limited drug absorption can be improved with a solid dispersion which is a formulation method that induces super-saturated drug dissolution and with that it enhances in vivo absorption. This review discusses formulation principles with focus on the solid dispersion technology and how it works to enhance drug absorption. There are currently three licensed orally dosed oncolytics formulated as a solid dispersion (everolimus, vemurafenib and regorafenib) and these formulations result in remarkably improved dissolution and absorption compared to what can be achieved with conventional formulations of the respective oncolytics. Because of the successful implementation of these three solid dispersion formulations, we encourage the application of this formulation method for poorly soluble oral oncolytics

Pharmaceutical development of an amorphous solid dispersion formulation of elacridar hydrochloride for proof-of-concept clinical studies

Objective: A novel tablet formulation containing an amorphous solid dispersion (ASD) of elacridar hydrochloride was developed with the purpose to resolve the drug’s low solubility in water and to conduct proof-of-concept clinical studies. Significance: Elacridar is highly demanded for proof-of-concept clinical trials that study the drug’s suitability to boost brain penetration and bioavailability of numerous anticancer agents. Previously, clinical trials with elacridar were performed with a tablet containing elacridar hydrochloride. However, this tablet formulation resulted in poor and unpredictable absorption which was caused by the low aqueous solubility of elacridar hydrochloride. Methods: Twenty four different ASDs were produced and dissolution was compared to crystalline elacridar hydrochloride and a crystalline physical mixture. The formulation with highest dissolution was characterized for amorphicity. Subsequently, a tablet was developed and monitored for chemical/physical stability for 12 months at +15–25 °C, +2–8 °C and −20 °C. Results: The ASD powder was composed of freeze dried elacridar hydrochloride–povidone K30–sodium dodecyl sulfate (1:6:1, w/w/w), appeared fully amorphous and resulted in complete dissolution whereas crystalline elacridar hydrochloride resulted in only 1% dissolution. The ASD tablets contained 25 mg elacridar hydrochloride and were stable for at least 12 months at –20 °C. Conclusions: The ASD tablet was considered feasible for proof-of-concept clinical studies and is now used as such

Individual Differences Influencing Immediate Effects of Internal and External Focus Instructions on Children’s Motor Performance

Purpose: A large pool of evidence supports the beneficial effect of an external focus of attention on motor skill performance in adults. In children, this effect has been studied less and results are inconclusive. Importantly, individual differences are often not taken into account. We investigated the role of working memory, conscious motor control, and task-specific focus preferences on performance with an internal and external focus of attention in children. Methods: Twenty-five children practiced a golf putting task in both an internal focus condition and external focus condition. Performance was defined as the average distance toward the hole in 3 blocks of 10 trials. Task-specific focus preference was determined by asking how much effort it took to apply the instruction in each condition. In addition, working memory capacity and conscious motor control were assessed. Results: Children improved performance in both the internal focus condition and external focus condition (ŋp 2 = .47), with no difference between conditions (ŋp 2 = .01). Task-specific focus preference was the only factor moderately related to the difference between performance with an internal focus and performance with an external focus (r = .56), indicating better performance for the preferred instruction in Block 3. Conclusion: Children can benefit from instruction with both an internal and external focus of attention to improve short-term motor performance. Individual, task-specific focus preference influenced the effect of the instructions, with children performing better with their preferred focus. The results highlight that individual differences are a key factor in the effectiveness in children’s motor performance. The precise mechanisms underpinning this effect warrant further research