scholarly journals In vitro tools for orally inhaled drug products—state of the art for their application in pharmaceutical research and industry and regulatory challenges

2021 ◽  
Author(s):  
Julia Katharina Metz ◽  
Marius Hittinger ◽  
Claus-Michael Lehr
Keyword(s):  
State Of The Art ◽  
Animal Experiments ◽  
Pharmaceutical Research ◽  
Alternative Methods ◽  
In Vitro Test ◽  
Safety And Efficacy ◽  
Drug Products ◽  
Orally Inhaled Drug Products ◽  
Regulatory Challenges

AbstractThe drug development process is a lengthy and expensive challenge for all involved players. Experience with the COVID-19 pandemic underlines the need for a rapid and effective approval for treatment options. As essential prerequisites for successful drug approval, a combination of high-quality studies and reliable research must be included. To this day, mainly in vivo data are requested and collected for assessing safety and efficacy and are therefore decisive for the pre-clinical evaluation of the respective drug. This review aims to summarize the current state of the art for safety and efficacy studies in pharmaceutical research and industry to address the relevant regulatory challenges and to provide an outlook on implementing more in vitro methods as alternative to animal testing. While the public demand for alternative methods is becoming louder, first examples have meanwhile found acceptance in relevant guidelines, e.g. the OECD guidelines for skin sensitizer. Besides ethically driven developments, also the rather low throughput and relatively high costs of animal experiments are forcing the industry towards the implementation of alternative methods. In this context, the development of orally inhaled drug products is particularly challenging due to the complexity of the lung as biological barrier and route of administration. The replacement of animal experiments with focus on the lungs requires special designed tools to achieve predictive data. New in vitro test systems of increasing complexity are presented in this review. Limits and advantages are discussed to provide some perspective for a future in vitro testing strategy for orally inhaled drug products. Graphical abstract

scholarly journals Testing of aerosolized ciprofloxacin nanocarriers on cystic fibrosis airway cells infected with P. aeruginosa biofilms

2021 ◽  
Author(s):  
Jenny Juntke ◽  
Xabier Murgia ◽  
Nazende Günday Türeli ◽  
Akif Emre Türeli ◽  
Chelsea R. Thorn ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
In Vitro Model ◽  
Time Window ◽  
Animal Experiments ◽  
Pulmonary Delivery ◽  
Barrier Properties ◽  
In Vitro Test ◽  
Safety And Efficacy ◽  
Vitro Model

AbstractThe major pathogen found in the lungs of adult cystic fibrosis (CF) patients is Pseudomonas aeruginosa, which builds antibiotic-resistant biofilms. Pulmonary delivery of antibiotics by inhalation has already been proved advantageous in the clinic, but the development of novel anti-infective aerosol medicines is complex and could benefit from adequate in vitro test systems. This work describes the first in vitro model of human bronchial epithelial cells cultivated at the air–liquid interface (ALI) and infected with P. aeruginosa biofilm and its application to demonstrate the safety and efficacy of aerosolized anti-infective nanocarriers. Such a model may facilitate the translation of novel therapeutic modalities into the clinic, reducing animal experiments and the associated problems of species differences. A preformed biofilm of P. aeruginosa PAO1 was transferred to filter-grown monolayers of the human CF cell line (CFBE41o-) at ALI and additionally supplemented with human tracheobronchial mucus. This experimental protocol provides an appropriate time window to deposit aerosolized ciprofloxacin-loaded nanocarriers at the ALI. When applied 1 h post-infection, the nanocarriers eradicated all planktonic bacteria and reduced the biofilm fraction of the pathogen by log 6, while CFBE41o- viability and barrier properties were maintained. The here described complex in vitro model approach may open new avenues for preclinical safety and efficacy testing of aerosol medicines against P. aeruginosa lung infection. Graphical abstract

Bisphenol A emission factors from industrial sources and elimination rates in a sewage treatment plant

2003 ◽  
Vol 47 (10) ◽  
pp. 117-122 ◽  
Author(s):  
M. Fuerhacker
Keyword(s):  
Bisphenol A ◽  
Estrogenic Activity ◽  
Animal Experiments ◽  
Elimination Rate ◽  
Sewage Treatment Plant ◽  
Treatment Plant ◽  
Emission Factors ◽  
Point Sources ◽  
In Vitro Test

Bisphenol A (BPA) is widely used for the production of epoxy resins and polycarbonate plastics and is considered an endocrine disruptor. Special in vitro test systems and animal experiments showed a weak estrogenic activity. Aquatic wildlife especially could be endangered by waste water discharges. To manage possible risks arising from BPA emissions the major fluxes need to be investigated and the sources of the contamination of municipal treatment plants need to be determined. In this study, five major industrial point sources, two different household areas and the influent and effluent of the corresponding treatment plant (WWTP) were monitored simultaneously at a plant serving 120,000 population equivalents. A paper producing plant was the major BPA contributor to the influent load of the wastewater treatment plant. All the other emissions from point sources, including the two household areas, were considerably lower. The minimum elimination rate in the WTTP could be determined at 78% with an average of 89% of the total BPA-load. For a possible pollution-forecast, or for a comparison between different point sources, emission factors based on COD-emissions were calculated for industrial and household point sources at BPA/COD-ratios between 1.4 ×10−6-125×10−6 and 1.3×10−6-6.3×10−6, respectively.

scholarly journals Analysis of non-animal methods and models for research in cardiovascular disease

2020 ◽  
Author(s):  
Emanuele Gasparotti ◽  
Margherita Cioffi ◽  
Vincenzo Positano ◽  
Emanuele Vignali ◽  
Benigno Marco Fanni ◽  
...  
Keyword(s):  
In Silico ◽  
Animal Experiments ◽  
Relevant Information ◽  
Information Resources ◽  
Alternative Methods ◽  
Second Phase ◽  
Inclusion Criteria ◽  
In Silico Models ◽  
State Of Art

Cardiovascular diseases (CVD) are disorders of the heart and blood vessels and represent 31% of all global deaths. In the contest of CVD, the use of animal experiments has been a contentious subject for many years. In recent years, in vitro and in silico models and methods have been proposed according to the 3Rs statement. However, an exhaustive report regarding the state of art in terms of in vitro and in silico experiments has not been reported yet. This work is focused on providing a collection of non-animal models and methods in use for basic and applied CVD research. The standardized descriptions of such studies will ultimately feed into EURL ECVAM database on alternative methods. Two are the research main phases. Firstly, the exclusion/ inclusion criteria and the list of relevant information resources of the research have been defined. The second phase regards the search, selection and detailed description of the literature papers by analysing records on Scopus and Pubmed databases.

scholarly journals Adverse Outcome Pathway Development for Assessment of Lung Carcinogenicity by Nanoparticles

2021 ◽  
Vol 3 ◽  
Author(s):  
Penny Nymark ◽  
Hanna L. Karlsson ◽  
Sabina Halappanavar ◽  
Ulla Vogel
Keyword(s):  
Lung Cancer ◽  
Risk Assessment ◽  
Adverse Outcome ◽  
Animal Experiments ◽  
Engineered Nanoparticles ◽  
Alternative Methods ◽  
Weight Of Evidence ◽  
Adverse Outcome Pathway ◽  
Alternative Mechanism

Lung cancer, one of the most common and deadly forms of cancer, is in some cases associated with exposure to certain types of particles. With the rise of nanotechnology, there is concern that some engineered nanoparticles may be among such particles. In the absence of epidemiological evidence, assessment of nanoparticle carcinogenicity is currently performed on a time-consuming case-by-case basis, relying mainly on animal experiments. Non-animal alternatives exist, including a few validated cell-based methods accepted for regulatory risk assessment of nanoparticles. Furthermore, new approach methodologies (NAMs), focused on carcinogenic mechanisms and capable of handling the increasing numbers of nanoparticles, have been developed. However, such alternative methods are mainly applied as weight-of-evidence linked to generally required animal data, since challenges remain regarding interpretation of the results. These challenges may be more easily overcome by the novel Adverse Outcome Pathway (AOP) framework, which provides a basis for validation and uptake of alternative mechanism-focused methods in risk assessment. Here, we propose an AOP for lung cancer induced by nanosized foreign matter, anchored to a selection of 18 standardized methods and NAMs for in silico- and in vitro-based integrated assessment of lung carcinogenicity. The potential for further refinement of the AOP and its components is discussed in relation to available nanosafety knowledge and data. Overall, this perspective provides a basis for development of AOP-aligned alternative methods-based integrated testing strategies for assessment of nanoparticle-induced lung cancer.

The ECVAM Workshops: A Critical Assessment of their Impact on the Development, Validation and Acceptance of Alternative Methods

2002 ◽  
Vol 30 (2_suppl) ◽  
pp. 151-165 ◽  
Author(s):  
Robert D. Combes
Keyword(s):  
State Of The Art ◽  
Substantial Effect ◽  
Alternative Methods ◽  
Current Status ◽  
In Vitro Tests ◽  
Regulatory Requirements ◽  
Safety Testing ◽  
Task Forces ◽  
Development And Validation

ECVAM initiated its workshop programme in 1994, to enable it to become well informed about the state of the art of non-animal test development and validation, and about the possible incorporation of alternatives into regulatory requirements for safety testing. Fifty-one such workshops had been held on specific topics, up to 2002. In these workshops, the current status of in vitro tests and their potential uses were reviewed and recommendations were made as to the best ways forward to progress and enhance the use of in vitro methods. Reports for 46 of these workshops have been published in ATLA. Most of the workshops focused on in vitro replacement methods, although an increasing number have dealt with reduction and refinement. The recommendations in the ECVAM workshops have been progressed further by: a) the formation of ECVAM task forces; b) the organisation of further workshops; c) the activities of scientific committees; d) the provision of earmarked research funding; and e) the conduct of validation studies. Examples of each of these activities are discussed. Some individual workshops are covered in more detail, and several recommendations that have so far not been acted on are also considered. The workshops and their reports have had a substantial effect on the development and implementation of alternative methods, and have been a major factor in contributing to the success of the first nine years of ECVAM's existence. It is strongly recommended that ECVAM continues to organise workshops and to publish their findings, and suggestions are made for topics for future workshops.

Metabolite Detection and Profiling Using Analytical Methods

2020 ◽  
Vol 17 (1) ◽  
pp. 2-9
Author(s):  
Lovekesh Mehta ◽  
Parul Grover ◽  
Tanveer Naved ◽  
Debaraj Mukherjee
Keyword(s):  
Pharmaceutical Research ◽  
In Vitro Test ◽  
In Vitro Techniques ◽  
Lead Compounds ◽  
Modern Drug ◽  
Short Period ◽  
Living Organisms ◽  
Metabolite Detection

To develop effective and safe drugs and to take them to the market in short period of time is the mission of pharmaceutical research companies. A selection of few of the lead compounds are done for the evaluation of safety and their ADMET (absorption, distribution, metabolism, excretion and toxicology) properties are tested in in-vitro (test systems), in-vivo (living organisms) and in-silico (computational methods). From initial stages to final stages of modern drug discovery processes, the vital tool for detecting and characterizing metabolites is MS (Mass spectrometry) hyphenated with other techniques. The methods used for generation of metabolites are in vitro techniques and cell lines (containing expressing drug metabolizing enzymes and heterologous genes). The use of HPLC-MS/UPLC-MS and high resolution MS, enables the in depth metabolite detection and profiling studies and it may also be likely to identify and characterize the site and types of biotransformation.

scholarly journals Optimization of the Transwell® System for Assessing the Dissolution Behavior of Orally Inhaled Drug Products through In Vitro and In Silico Approaches

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1109
Author(s):  
Elham Amini ◽  
Abhinav Kurumaddali ◽  
Sharvari Bhagwat ◽  
Simon M. Berger ◽  
Günther Hochhaus
Keyword(s):  
In Silico ◽  
Mass Effect ◽  
Dissolution Behavior ◽  
Experimental Conditions ◽  
Drug Products ◽  
Starting Point ◽  
Orally Inhaled Drug Products ◽  
Model Drug ◽  
The Impact

The aim of this study was to further evaluate and optimize the Transwell® system for assessing the dissolution behavior of orally inhaled drug products (OIDPs), using fluticasone propionate as a model drug. Sample preparation involved the collection of a relevant inhalable dose fraction through an anatomical mouth/throat model, resulting in a more uniform presentation of drug particles during the subsequent dissolution test. The method differed from previously published procedures by (1) using a 0.4 µm polycarbonate (PC) membrane, (2) stirring the receptor compartment, and (3) placing the drug-containing side of the filter paper face downwards, towards the PC membrane. A model developed in silico, paired with the results of in vitro studies, suggested that a dissolution medium providing a solubility of about 5 µg/mL would be a good starting point for the method’s development, resulting in mean transfer times that were about 10 times longer than those of a solution. Furthermore, the model suggested that larger donor/receptor and sampling volumes (3, 3.3 and 2 mL, respectively) will significantly reduce the so-called “mass effect”. The outcomes of this study shed further light on the impact of experimental conditions on the complex interplay of dissolution and diffusion within a volume-limited system, under non-sink conditions.

scholarly journals Development of an Aerosol Dose Collection Apparatus for In Vitro Dissolution Measurements of Orally Inhaled Drug Products

2020 ◽  
Vol 22 (2) ◽  
Author(s):  
Robert Price ◽  
Jagdeep Shur ◽  
William Ganley ◽  
Gonçalo Farias ◽  
Nikoletta Fotaki ◽  
...  
Keyword(s):  
In Vitro Dissolution ◽  
Drug Products ◽  
Orally Inhaled Drug Products

scholarly journals Partial Least Square Model (PLS) as a Tool to Predict the Diffusion of Steroids Across Artificial Membranes

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1387
Author(s):  
Eleni Tsanaktsidou ◽  
Christina Karavasili ◽  
Constantinos K. Zacharis ◽  
Dimitrios G. Fatouros ◽  
Catherine K. Markopoulou
Keyword(s):  
Animal Experiments ◽  
Pharmaceutical Research ◽  
Partial Least Square ◽  
Least Square ◽  
Predictive Tool ◽  
Apparent Permeability ◽  
Internal Validation ◽  
Candidate Drug ◽  
Apparent Permeability Coefficient

One of the most challenging goals in modern pharmaceutical research is to develop models that can predict drugs’ behavior, particularly permeability in human tissues. Since the permeability is closely related to the molecular properties, numerous characteristics are necessary in order to develop a reliable predictive tool. The present study attempts to decode the permeability by correlating the apparent permeability coefficient (Papp) of 33 steroids with their properties (physicochemical and structural). The Papp of the molecules was determined by in vitro experiments and the results were plotted as Y variable on a Partial Least Squares (PLS) model, while 37 pharmacokinetic and structural properties were used as X descriptors. The developed model was subjected to internal validation and it tends to be robust with good predictive potential (R2Y = 0.902, RMSEE = 0.00265379, Q2Y = 0.722, RMSEP = 0.0077). Based on the results specific properties (logS, logP, logD, PSA and VDss) were proved to be more important than others in terms of drugs Papp. The models can be utilized to predict the permeability of a new candidate drug avoiding needless animal experiments, as well as time and material consuming experiments.

Development and Evaluation of a Novel Artificial Catheter-Deliverable Prosthetic Heart Valve and Method for in Vitro Testing

2009 ◽  
Vol 32 (5) ◽  
pp. 262-271 ◽  
Author(s):  
Thomase Claiborne ◽  
Danny Bluestein ◽  
Richard T. Schoephoerster
Keyword(s):  
Heart Valve ◽  
State Of The Art ◽  
Prosthetic Heart Valve ◽  
Test Methods ◽  
In Vitro Testing ◽  
In Vitro Test ◽  
Vitro Test ◽  
Percutaneous Heart Valve

Background This work presents a novel artificial prosthetic heart valve designed to be catheter or percutaneously deliverable, and a method for in vitro testing of the device. The device is intended to create superior characteristics in comparison to tissue-based percutaneous valves. Methods The percutaneous heart valve (PHV) was constructed from state-of-the-art polymers, metals and fabrics. It was tested hydrodynamically using a modified left heart simulator (LHS) and statically using a tensile testing device. Results The PHV exhibited a mean transvalvular pressure gradient of less than 15 mmHg and a mean regurgitant fraction of less than 5 percent. It also demonstrated a resistance to migration of up to 6 N and a resistance to crushing of up to 25 N at a diameter of 19 mm. The PHV was crimpable to less than 24 F and was delivered into the operating LHS via a 24 F catheter. Conclusion An artificial PHV was designed and optimized, and an in vitro methodology was developed for testing the valve. The artificial PHV compared favorably to existing tissue-based PHVs. The in vitro test methods proved to be reliable and reproducible. The PHV design proved the feasibility of an artificial alternative to tissue based PHVs, which in their traditional open-heart implantable form are known to have limited in vivo durability.

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