General Formulation Research Articles

Pharmacokinetics and Safety of Linezolid Tablets of 2 Different Manufacturers in Healthy Chinese Subjects in Fasting and Fed States.

This study aimed to evaluate the pharmacokinetics (PKs) and safety of a generic drug, linezolid, compared to those of a reference drug in healthy Chinese subjects under both fasting and fed conditions. This was a randomized, open-label, 2-period, 2-sequence crossover study. The subjects received a single dose of the test or reference drug, linezolid (600mg), in each period. The PK parameters were calculated using a non-compartmental method and compared between the 2 drugs. Bioequivalence was analyzed using geometric mean ratios (GMRs) of the 2 formulations and their corresponding 90% confidence intervals (CIs). The safety of the 2 formulations was assessed under both fasting and fed conditions. Forty-eight subjects completed the study, 24 each in the fasting and feeding groups. The average plasma concentration-time patterns of linezolid were similar for both medications under both conditions. The GMR and 90% CIs of the maximum plasma concentration and the area under the plasma concentration-time curve of linezolid were ranged from 0.80 to 1.25. Both drugs were well tolerated with a similar incidence of adverse drug reactions. In conclusion, the PK and safety profiles of the 2 formulations were comparable. Food intake did not influence the PK profiles of linezolid. These results suggest that the test drug can be used as an alternative to reference drugs.

Targeted therapies and conventional care for the treatment of ankylosing spondylitis in China: a cost-effectiveness analysis based on the network-meta analysis

ObjectiveThis study aimed to evaluate the long-term cost-effectiveness of conventional care (CC) and seven first-line targeted therapies marketed in China for the treatment of patients with ankylosing spondylitis (AS)–namely secukinumab, ixekizumab, infliximab, etanercept, adalimumab and golimumab and tofacitinib–from the perspective of the Chinese health care system.MethodsThe York model was structured as a 12-week decision tree leading into two Markov models. This study set 1 year as a recurring cycle and a lifetime timeframe for the model. Primary model outcomes included the costs in Chinese yuan (CNY), health outcomes in quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER) under a willingness-to-pay threshold of ¥89,358 (equal to the per capita gross domestic product in China in 2023) per QALY. Parameters in the York model were captured from network meta-analyses and literature including treatment response, short-term disease progression, patient functioning and long-term structural disease progression. Utilities are dependent on indicators such as the BASDAI score, the BASFI score, gender and age. Drug prices were analysed using the median price of the Chinese market from YAOZH net in the basic analysis. Costs and outcomes were discounted at 5.0%. We performed deterministic and probabilistic sensitivity analyses to investigate the robustness of the results. The prices of original drugs and generic drugs were used in the scenario analysis.ResultsCompared with CC, the ICER of golimumab was ¥104,217.4/QALY, which is between 1 and 3 times the GDP per capita, while the ICERs of the other six targeted therapies were less than ¥89,358/QALY. The specific economic rank of the targeted therapy was as follows:secukinumab > ixekizumab > tofacitinib > infliximab > etanercept > adalimumab > golimumab. Treatment response rates such as the BASDAI50, changes in the BASDAI/BASFI scores and the discounting rate were key model drivers. According to the scenario analysis, IL-17 inhibitors were still the most economical intervention when original drugs and generic drugs were used.ConclusionTargeted therapies are cost-effective treatments for AS. Overall, IL-17 inhibitors were the dominant treatment. The choice of the brand-new prices or generic drug prices can greatly affect economics.

Implementation of variable cross-section curved beam in train-turnout dynamic interactions

The abundance of variable cross-section curved rails in railway turnouts emphasizes the necessity of intricately modeling them, which facilitates a more accurate evaluation of train-turnout interactions. This study presents a general formulation for analyzing both free and forced vibrations of a variable cross-section curved Timoshenko beam and its implementation in train-turnout dynamic interactions. First, the natural frequencies and mode shapes for in-plane and out-of-plane free vibrations of the beam are determined through eigenvalue analysis, taking into careful consideration the characteristics of variable cross-section and curvature. Then, the forced vibration solution is derived using modal superposition and orthogonality. Furthermore, comparative analyses using finite element method (FEM) validate the natural frequencies and dynamic responses of a beam under various boundary conditions, confirming the reliability and accuracy of the proposed method. Finally, the developed beam model is then applied to simulate the switch rail and point rail under train-turnout interactions, revealing the differences from existing methods that modeled these components as uniform cross-section straight beams. Numerical analyses provide new insights by comparing wheel-rail forces and rail acceleration. Considering curve and variable cross section characteristics could contribute to a more accurate evaluation of train-turnout dynamic interactions.

Physicians’ opinions on the utilization of generic medications in Gulf Cooperation Council countries: a narrative review

Abstract Objective This review paper explores strategies and recommendations for reducing healthcare expenses in the Gulf Cooperation Council (GCC) by understanding physicians’ attitudes regarding the utilization of generic medicines. Methods A comprehensive search of seven databases yielded 24 437 titles and abstracts. Using inclusion criteria focusing on physicians’ insights into generic prescribing and exclusion criteria, cutting out systematic reviews, case studies, and non-English articles, the review process led to an in-depth analysis of six studies. Results Findings revealed that while physicians generally comprehend terms like “generic”, “brand”, and “bioequivalence”, they face difficulty discussing bioequivalence with patients. Lack of emphasis on generic medicines in medical education and complex patient communication were potential impediments to generic medicine prescribing in the GCC countries. Strategies & Recommendations: Promoting the benefits of generic drugs could support their usage and help decrease healthcare costs. Improving medical education to include a larger focus on generic medications and their benefits, as well as training physicians in effectively communicating bioequivalence concepts to patients, could promote the use of more cost-effective, generic options. Conclusion The review calls for attention to the potential of generic medicine prescribing to reduce healthcare expenses in the GCC. Future research studies should consider broadening the geographical scope to provide global insights into these issues and their possible solutions.

Bioequivalence and Safety of Generic Glecaprevir/Pibrentasvir Compared to a Branded Product: A Randomized, Crossover Study in Healthy Volunteers.

This was an open-label, randomized, single-dose, 2-period, crossover clinical trial with an adaptive design to evaluate the bioequivalence and comparative pharmacokinetics of generic glecaprevir/pibrentasvir versus the brand name product in healthy White male and female volunteers under fed conditions. Safety profiles were also assessed. A total of 56 healthy adult volunteers were enrolled and randomly assigned in a 1:1 ratio to receive a single dose of either the generic or reference formulation. After a 7-day washout period, subjects received the alternate product. Blood samples were collected at pre-specified time points up to 48hours post-dosing. Plasma concentrations of glecaprevir and pibrentasvir were determined using a validated high-performance liquid chromatography-tandem mass spectrometry method. The geometric mean ratios of the test to the reference formulation for maximum plasma concentration (Cmax) and area under the concentration-time curve from drug administration to the last measurable concentration (AUC0-t) fell within the predefined bioequivalence range of 80%-125%. Both formulations demonstrated comparable pharmacokinetic profiles for glecaprevir and pibrentasvir, and can be considered bioequivalent. No adverse events were reported, and both formulations were well tolerated by all participants.

Which factor reduces pharmaceutical expenditure, number of entrants or price variance? Updated generic drug markets in South Korea

BackgroundIntroducing more generics has been a successful strategy for lowering pharmaceutical prices and expenditure. However, the effect of the strategy depends on the pricing schemes for generics. We aimed to update the South Korean generic markets in terms of effective competition, and to examine the effects of number of manufacturers and price variance on pharmaceutical expenditure.MethodsWe constructed balanced panel data provided by the Health Insurance Review and Assessment Service covering 726 reimbursed substances from 2019 to 2023. We developed original indicators to analyze the generic markets: the maximum-minimum price variance (MMPV) and the maximum-weighted price variance (MWPV). Panel regression with fixed and time-fixed effects was used.ResultsOver the study period, the number of manufacturers increased from 17.81 in 2019 to 20.98 in 2020 and then decreased to 18.70 in 2023. The MMPV increased from 204.70 in 2019 to 230.07 in 2022 and then decreased slightly to 225.34 in 2023. The MWPV increased from 59.70 in 2019 to 72.58 in 2023. Two types of segmented markets were noteworthy: low use of low-cost generics with sufficient manufacturers and high use of low-cost generics with insufficient manufacturers. In the fixed and time-fixed effects panel analyses, the MWPV presented a negative association with the number of manufacturers and a positive association with the MMPV.ConclusionsA newly introduced tiered pricing scheme, designed to differentiate generic prices, was associated with a decrease in the number of manufacturers and an increase in price dispersion. The pricing schemes for generics should be designed with price variance in mind and limit the number of too many generics in South Korea.

A Review on Consumer Patterns and Behaviours’ Towards Generic Medicines

Generic medicines have become an important topic in healthcare due to their potential to reduce costs while providing equivalent treatment to branded drugs. This review article investigates consumer patterns and behaviors related to generic medicines, focusing on awareness, purchasing factors, and satisfaction levels. The research employs a systematic literature review methodology, analyzing peer-reviewed journals, government reports, and industry studies on generic medicines and consumer behavior. Various statistical techniques, such as percentage analysis, chi-square tests, factor analysis, Garrett ranking, and Likert scales, are used to summarize demographic profiles, examine relationships, identify influencing factors, prioritize purchase constraints, and measure satisfaction levels. Key findings reveal that consumer awareness of generic medicines varies widely, influenced by factors such as age, education, and exposure to information from healthcare providers. Government initiatives like India's Pradhan Mantri Jan Aushadhi Yojana aim to increase access to affordable generics, yet awareness remains limited in some areas. Price is a major motivator for purchasing generics, but other factors like perceived quality, doctor recommendations, availability, and prior experience also play significant roles. Generally, consumers express positive experiences with generics, citing effectiveness, cost savings, and quality. However, some consumers and healthcare providers harbor concerns about the safety and efficacy of generics compared to branded versions. This review underscores the need for ongoing efforts to enhance consumer confidence in generics through education and awareness campaigns, ensuring the success of initiatives aimed at making essential medicines affordable and accessible to all.

Pharmacy practice and policy research in Türkiye: a systematic review of literature.

In recent decades, there has been an interest in clinical pharmacy practice in Türkiye with emerging studies in this area. Despite the recent emergence of diverse pharmacy practice studies in Türkiye, a comprehensive assessment of overall typology of studies and impact has not been conducted thus far. This systematic review aims to document and assess pharmaceutical policy and practice literature published within the last 5 years in Türkiye. The other aim is to summarise the expected impact of published studies on policy and practice research. The systematic review was conducted according to the guidelines described in the PRISMA Statement. A comprehensive search approach, incorporating Medical Subject Headings (MeSH) queries and free-text terms was employed to locate pertinent literature related to pharmacy practice and policy in Türkiye. The search covered the period from January 1, 2019, to January 1, 2024, and involved electronic databases including PubMed, Medline Ovid, Scopus, ScienceDirect, Springer Link, PlosOne, and BMC. In the final grouping, 73 articles met the inclusion criteria and were selected for this review. Among the quantitative studies, majority studies were cross-sectional survey studies. Through the rigorous thematic content analysis seven research domains were developed from the selected literature: drug utilisation and rational drug use, the emerging role of pharmacist, access to medicines and generic medicines, community pharmacy practice, pharmacovigilance/adverse drug reactions, and pharmacoeconomic studies. The pharmacist role is evolving; however, several challenges remain in fully realising the potential of pharmacists. These include regulatory barriers, limited public awareness of pharmacists' expanded roles, workforce capacity issues, and the need for ongoing professional development and training. Research studies are needed in the areas of generic prescribing, medicine adherence, intervention studies in community and hospital pharmacy practice, and on pharmacoeconomics and pharmacovigilance.

Physiologically-based pharmacokinetic model of in vitro porcine ear skin permeation for drug delivery research.

In silico techniques, such as physiologically based pharmacokinetic modeling (PBKP), are recently gaining importance. Computational methods in drug discovery and development and the generic drugs industry enhance research effectiveness by saving time and money and avoiding ethical issues. One key advantage is the ability to conduct toxicology studies without risking harm to living beings. This study aimed to repurpose the multi-phase multi-layer mechanistic dermal absorption (MPML MechDermA) PBPK model for simulation permeation through porcine ear skin under in vitro conditions. The work was divided into four steps: (1) the development of a pig ear skin model based on a previously collected dataset; (2) testing the model's ability to discriminate permeation between pig ear, human abdomen, and human back skin; (3) development of a caffeine permeation model; and (4) testing the caffeine model's performance against in vitro generated data sourced from the scientific literature. Data from 31 manuscripts were used for the development of the pig skin model. Based on these data, values specific to pig skin were found for 22 parameters of the MPML MechDermA model. The model was able to discriminate permeation between pig and human skin. A caffeine model was developed and used to simulate seven experiments identified in the literature. The model's performance was assessed by comparing simulated to observed results. Based on a visual check, all simulations were considered acceptable, whereas three out of seven experiments met the twofold difference criterion. The variability of the experimental data was considered the biggest challenge for reliable model assessment.

Deep reinforcement learning as multiobjective optimization benchmarks: Problem formulation and performance assessment

The successful deployment of Deep learning in several challenging tasks has been translated into complex control problems from different domains through Deep Reinforcement Learning (DRL). Although DRL has been extensively formulated and solved as single-objective problems, nearly all real-world RL problems often feature two or more conflicting objectives, where the goal is to obtain a high-quality and diverse set of optimal policies for different objective preferences. Consequently, the development of Multi-Objective Deep Reinforcement Learning (MODRL) algorithms has gained a lot of traction in the literature. Generally, Evolutionary Algorithms (EAs) have been demonstrated to be scalable alternatives to the classical DRL paradigms when formulated as an optimization problem. Hence it is reasonable to employ Multi-objective Evolutionary Algorithms (MOEAs) to handle MODRL tasks. However, there are several factors constraining the progress of research along this line: first, there is a lack of a general problem formulation of MODRL tasks from an optimization perspective; second, there exist several challenges in performing benchmark assessments of MOEAs for MODRL problems. To overcome these limitations: (i) we present a formulation of MODRL tasks as general multi-objective optimization problems and analyze their complex characteristics from an optimization perspective; (ii) we present an end-to-end framework, termed DRLXBench, to generate MODRL benchmark test problems for seamless running of MOEAs (iii) we propose a test suite comprising of 12 MODRL problems with different characteristics such as many-objectives, degenerated Pareto fronts, concave and convex optimization problems, etc. (iv) Finally, we present and discuss baseline results on the proposed test problems using seven representative MOEAs.

Duloxetine enhances PAX6 expression and suppresses innate immune responses in murine LPS-induced corneal inflammation

Background-aimPAX6 is a key regulator of eye development and epithelial homeostasis in the cornea. When deficient, chronic corneal inflammation, neovascularization and limbal stem cell deficiency can occur. Here we investigated the potential of duloxetine, a generic serotonin reuptake inhibitor that can upregulate PAX6 in vitro, for its in vivo activity in the context of corneal inflammation. MethodsDuloxetine tolerance was tested in a human limbal stem cell line and isogenic CRISPR-knockout PAX6+/− cells. C57BL/6-Wildtype mice were administered duloxetine eye drops at concentrations of 1 μM - 2 mM and tested for toxicity and corneal PAX6 expression. In LPS-induced corneal inflammation in mice, duloxetine's effect on PAX6 expression, corneal opacification and inflammatory responses were evaluated by in vivo corneal imaging, immunostaining, and whole-transcriptome microarray analysis. ResultsNo toxicity was observed in vitro for duloxetine concentrations up to 10μΜ. In vivo, duloxetine drops were well-tolerated up to 50 μM. Duloxetine drops at 10μΜ significantly upregulated PAX6 protein levels in the cornea by 30 % within 2 days. In the LPS model, duloxetine resulted in a sustained 33 % PAX6 protein upregulation in the cornea at 7 days, and in reduced opacity within 2 days, accompanied by a significant dampening of IL-17A signaling, neutrophil degranulation, microglial activation, macrophage markers, and MMP expression, despite non-significant changes in total inflammatory cell infiltration. ConclusionShort-term administration of a repurposed generic drug, duloxetine, upregulates PAX6 protein levels in the cornea of mice and exerts an anti-inflammatory activity by dampening innate immune responses.

Fast Algorithms for \(\ell_p\)-Regression

The ℓ p -norm regression problem is a classic problem in optimization with wide ranging applications in machine learning and theoretical computer science. The goal is to compute \(\boldsymbol {\mathit {x}}^{\star } =\arg \min _{\boldsymbol {\mathit {A}}\boldsymbol {\mathit {x}}=\boldsymbol {\mathit {b}}}\Vert \boldsymbol {\mathit {x}}\Vert _p^p \) , where \(\boldsymbol {\mathit {x}}^{\star }\in \mathbb {R}^n,\boldsymbol {\mathit {A}}\in \mathbb {R}^{d\times n},\boldsymbol {\mathit {b}} \in \mathbb {R}^d \) and d ≤ n . Efficient high-accuracy algorithms for the problem have been challenging both in theory and practice and the state-of-the-art algorithms require \(poly(p)\cdot n^{\frac{1}{2}-\frac{1}{p}} \) linear system solves for p ≥ 2. In this paper, we provide new algorithms for ℓ p -regression (and a more general formulation of the problem) that obtain a high-accuracy solution in O ( pn ( p − 2)/(3 p − 2) ) linear system solves. We further propose a new inverse maintenance procedure that speeds-up our algorithm to \(\widetilde{O}(n^{\omega }) \) total runtime, where O ( n ω ) denotes the running time for multiplying n × n matrices. Additionally, we give the first Iteratively Reweighted Least Squares (IRLS) algorithm that is guaranteed to converge to an optimum in a few iterations. Our IRLS algorithm has shown exceptional practical performance, beating the currently available implementations in MATLAB/CVX by 10-50x.

AN OVERVIEW OF THE COMMUNITY KNOWLEDGE LEVEL TOWARDS THE USE OF GENERIC DRUGS IN TUPA VILLAGE, NORTH BULANGO DISTRICT, BONE BOLANGO REGENCY, GORONTALO PROVINCE, IN 2022

Generic drugs are medications with generic names, as defined by the Indonesian Pharmacopoeia and International Non-proprietary Names (INN) from the WHO, and they do not use trade names or manufacturer logos. Examples of these include amoxicillin and metformin. The public often perceives generic drugs to be inferior to patented drugs because of their relatively lower prices. The purpose of this study is to describe the knowledge level of the community about the use of generic drugs in Desa Tupa, Kecamatan Bulango Utara, Kabupaten Bone Bolango in 2022. This study employs a descriptive method using a quantitative approach. Data were collected through questionnaires that were distributed to 30 randomly selected respondents. A univariate analysis was conducted by creating frequency distributions to determine the community's awareness level regarding generic drugs. The survey results indicated that most residents of Desa Tupa have limited information about the use of generic drugs. The study concluded that, in terms of knowledge level about generic drugs, 30% of respondents had heard of generic drugs, 22% knew that generic drugs were named according to INN (International Non-proprietary Names), 11% understood that generic drugs are those that have expired patents, 9% recognize that generic drugs do not use brand names, and 28% are aware that generic drugs are more affordable than branded drugs.

Bioequivalence Analysis of Terazosin Hydrochloride Tablets Based on Parallel Artificial Membrane Permeability Analysis.

Parallel artificial membrane permeability analysis (PAMPA) is used to determine the permeability of compounds through concentrated negatively charged phospholipid bilayer barriers. We employed MacroFlux (a scaled-up version of PAMPA) to test the permeation rate of terazosin hydrochloride (TH) tablets and predict in vivo bioequivalence. The dissolution profiles and permeability of one reference formulation, and seven generic TH tablets, were compared. The dissolution profiles of these generic tablets were equivalent to that of the reference drug in four different media. However, the flux and the total permeated amount of some generic TH tablets were below the lower limit of the confidence interval of the original acceptance range in MacroFlux, which implied risk in the bioequivalence test in vivo. We further evaluated potential factors responsible for this discrepancy by µFlux, including active pharmaceutical ingredient (API) permeability and excipient prescriptions. The analysis showed that different properties of API were a main factor leading to biological inequivalence in the MacroFlux assay, while excipient prescriptions did not have an impact on bioequivalence risk. These data indicated that the flux assay may be a helpful as an auxiliary method for predicting bioequivalence of generic drugs and analyze the factors responsible for bioequivalence risk.

Analysis of thermally-induced fracture of Callovo-Oxfordian claystone: From lab tests to field scale

Argillaceous rocks are a suitable host rock for the deep geological disposal of exothermic High-Level Radioactive Waste (HLW) and Spent Fuel (SF). Excess pore pressures develop in this type of rocks when subject to increased temperatures that, in some circumstances, may lead to the fracturing of the rock. The paper explores this phenomenon by means of coupled numerical analyses carried out within a fully coupled thermo-hydro-mechanical (THM) framework. The general THM formulation is described as well as the anisotropic elastic and anisotropic elastoviscoplastic constitutive laws employed. Thermal extension triaxial tests are simulated as a check on the performance of the numerical formulation and to provide calibration data for the tensile strength of the material. Selected results from a comprehensive set of three-dimensional analyses of a large-scale field heating test, designed to study the possibility of thermal-induced failure in the rock, are presented and discussed. The analyses reproduce satisfactorily the observed patterns of behaviour. The effects of the constitutive law, material parameters and the presence of the excavation damage zone (EDZ) around the main drift and around the heater boreholes are studied. In particular, their effects on the state of the stress in the heated area are examined in the context of the potential for thermal fracturing of the rock.

The Intersection of Intellectual Property and Public Health

Purpose: The general objective of this study was to investigate the intersection of intellectual property and public health. Methodology: The study adopted a desktop research methodology. Desk research refers to secondary data or that which can be collected without fieldwork. Desk research is basically involved in collecting data from existing resources hence it is often considered a low cost technique as compared to field research, as the main cost is involved in executive’s time, telephone charges and directories. Thus, the study relied on already published studies, reports and statistics. This secondary data was easily accessed through the online journals and library. Findings: The findings reveal that there exists a contextual and methodological gap relating to the intersection of intellectual property and public health. Preliminary empirical review revealed that intellectual property laws, while designed to promote innovation, often created barriers to accessing essential medicines and technologies, particularly in low-income regions. It highlighted how patent protections, while incentivizing pharmaceutical development, led to high drug prices that limited access and exacerbated health disparities. The study emphasized the need for a balanced approach to IP regulations that would encourage innovation while ensuring that new treatments are affordable and accessible. It called for a re-evaluation of IP frameworks to align better with public health objectives and promote global health equity. Unique Contribution to Theory, Practice and Policy: The Theory of Intellectual Property as a Public Good, Theory of Technological Determinism and the Theory of Access to Medicines and Health Equity may be used to anchor future studies on the intersection of intellectual property and public health. The study recommended several key actions to address the issues identified. It suggested revising IP policies to include more flexibility, such as compulsory licensing and support for generic drug production, to improve access to essential medicines. The study advocated for international collaboration to balance IP protections with health needs and proposed that policymakers craft regulations that support both innovation and accessibility. It also emphasized the importance of ongoing research and evidence-based decision-making to guide IP reforms and promote global health equity. Additionally, it recommended fostering partnerships between governments, international organizations, and pharmaceutical companies to enhance healthcare access and address disparities.

Competitive Bidding in Drug Procurement: Evidence from China

We study the equilibrium effects of introducing competitive bidding in drug procurement. In 2019, China introduced a competitive bidding program where drug companies bid for a prespecified procurement quantity in nine provinces. Using a difference-in-differences design, we show the program reduced average drug prices by 47.4 percent. Generic drugs won most bids and cut prices by 75.0 percent. We develop an equilibrium model to quantify the trade-off between lower prices and potential choice distortions. Competitive bidding increases consumer welfare if policymakers believe consumers should value branded and bioequivalent generic drugs equally. The program also reduced government expenditure on insurance by 19.8 percent. (JEL D44, G22, I18, L13, L65, P25, P31)

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Raltegravir Potassium

The present monograph discusses the possibility of BCS-based biowaivers for immediate release pharmaceutical products containing raltegravir potassium, which is used to treat human immunodeficiency virus (HIV) infections. Raltegravir potassium can be assigned to BCS class II or IV since this compound has low solubility and uncertain permeability. Therefore, according to the ICH M9 guideline, it is not recommended to apply BCS-based biowaiver to approval of immediate release solid dosage forms of raltegravir potassium, either for new generic versions or when moderate to major changes in composition and/or the manufacturing method of the product are made.

3D electro-elastic static analysis of advanced plates and shells

The proposed three-dimensional (3D) coupled electro-elastic shell model allows the static analysis of smart structures embedding classical piezoelectric and functionally graded piezoelectric layers. Plates, cylindrical and spherical panels are investigated in both sensor and actuator configurations. The primary variables of the coupled model are displacement components and the electric potential. Therefore, displacements, stresses, strains, electric potential and electric displacements are calculated for smart structures used as sensors (applied mechanical load) and smart structures used as actuators (applied electric potential). In the case of spherical shells, 3D equilibrium equations are coupled with the 3D divergence electric displacement equation. The obtained coupled system is also valid for cylindrical shells and plates thanks to the use of a mixed curvilinear orthogonal reference system. The partial differential governing equations are solved using the Navier harmonic form and the exponential matrix method for simply supported structures. Preliminary assessments are proposed to validate the model and further benchmarks are analyzed to discuss the effects connected with the thickness ratio, the lamination scheme, the load conditions, the geometry of the structures and the employed materials. The main innovation point of the proposed model is the possibility to analyze several geometries including different materials and applied loads by means of a unique and general formulation where partial differential equations are solved in closed form. The use of functionally graded piezoelectric materials allows to eliminate all stress component discontinuities at each layer interface.

Relevance of distinctions and parallels between the US and EU guidelines for determination of comparative effectiveness and safety of the orally inhaled drug products

Approval of drug products for market registration warrants, among other data, evidence to support their safety and effectiveness in the target populations. The extent of investigations to provide the supporting evidence varies between the new innovator products and their follow-on versions generally referred to as Generic Drugs Products in the United States and Hybrids in the Europe. The new drug applications entail large data sets encompassing both nonclinical and clinical product developments. Safety and effectiveness in man is studied in sequentially phased clinical trials, including post marketing evaluations (Where applicable). However, for the generic/hybrid products the safety and effectiveness are established through determination of bioequivalence in head-to-head comparison between the originator and the follow-ons. Methods for documentation of bioequivalence for drug products that reach target site(s) through systemic circulation are aligned worldwide. However, establishing bioequivalence of orally inhaled drug products is complex as drug delivery to the local site(s) of action is independent of the systemic circulation. Documentation of bioequivalence gets further complicated due to the Drug-Device combination nature of these products. The guidelines for establishment of BE of locally acting orally inhaled drugs products vary among certain geographies. This article examines the scientific underpinning of distinctions and similarities between the US and EU guidelines.