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

Basics of advanced therapy medicinal product development in academic pharma and the role of a GMP simulation unit

Following successes of authorized chimeric antigen receptor T-cell products being commercially marketed in the United States and European Union, product development of T-cell-based cancer immunotherapy consisting of cell-based advanced therapy medicinal products (ATMPs) has gained further momentum. Due to their complex characteristics, pharmacological properties of living cell products are, in contrast to classical biological drugs such as small molecules, more difficult to define. Despite the availability of many new advanced technologies that facilitate ATMP manufacturing, translation from research-grade to clinical-grade manufacturing in accordance with Good Manufacturing Practices (cGMP) needs a thorough product development process in order to maintain the same product characteristics and activity of the therapeutic product after full-scale clinical GMP production as originally developed within a research setting. The same holds true for transferring a fully developed GMP-grade production process between different GMP facilities. Such product development from the research to GMP-grade manufacturing and technology transfer processes of established GMP-compliant procedures between facilities are challenging. In this review, we highlight some of the main obstacles related to the product development, manufacturing process, and product analysis, as well as how these hinder rapid access to ATMPs. We elaborate on the role of academia, also referred to as ‘academic pharma’, and the added value of GMP production and GMP simulation facilities to keep innovation moving by reducing the development time and to keep final production costs reasonable

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