286 results on '"Daan J.A. Crommelin"'
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2. Ongoing challenges to develop high concentration monoclonal antibody-based formulations for subcutaneous administration: Quo Vadis?
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David B. Volkin, Tim Menzen, Daan J.A. Crommelin, Andrea Hawe, and Wim Jiskoot
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High concentration ,Viscosity ,medicine.drug_class ,business.industry ,Clinical performance ,Antibodies, Monoclonal ,Biological Availability ,Pharmaceutical Science ,Monoclonal antibody ,Subcutaneous Tissue ,Risk analysis (engineering) ,Biological property ,medicine ,Humans ,Longitudinal Studies ,business ,Protein concentration - Abstract
Although many subcutaneously (s.c.) delivered, high-concentration antibody formulations (HCAF) have received regulatory approval and are widely used commercially, formulation scientists are still presented with many ongoing challenges during HCAF development with new mAb and mAb-based candidates. Depending on the specific physicochemical and biological properties of a particular mAb-based molecule, such challenges vary from pharmaceutical attributes e.g., stability, viscosity, manufacturability, to clinical performance e.g., bioavailability, immunogenicity, and finally to patient experience e.g., preference for s.c. vs. intravenous delivery and/or preferred interactions with health-care professionals. This commentary focuses on one key formulation obstacle encountered during HCAF development: how to maximize the dose of the drug? We examine methodologies for increasing the protein concentration, increasing the volume delivered, or combining both approaches together. We discuss commonly encountered hurdles, i.e., physical protein instability and solution volume limitations, and we provide recommendations to formulation scientists to facilitate their development of s.c. administered HCAF with new mAb-based product candidates.
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- 2021
3. Formulation of cell-based medicinal products
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Karin H. Hoogendoorn, Wim Jiskoot, and Daan J.A. Crommelin
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Advanced therapy medicinal products ,Cell therapy products ,Computer science ,media_common.quotation_subject ,Pharmaceutical Science ,02 engineering and technology ,021001 nanoscience & nanotechnology ,Frozen ,030226 pharmacology & pharmacy ,Stability assessment ,Unmet needs ,Biopharmaceuticals ,Excipients ,03 medical and health sciences ,0302 clinical medicine ,(Non)-off-the shelf ,Risk analysis (engineering) ,Formulation ,Fresh ,Quality (business) ,Cell-based medicinal products ,0210 nano-technology ,Stability ,media_common ,Cell based - Abstract
The formulation of cell-based medicinal products (CBMPs) poses major challenges because of their complexity, heterogeneity, interaction with their environment (e.g., the formulation buffer, interfaces), and susceptibility to degradation. These challenges can be quality, safety, and efficacy related. In this commentary we discuss the current status in formulation strategies of off-the-shelf and non-off-the-shelf (patient-specific) CBMPs and highlight advantages and disadvantages of each strategy. Analytical tools for the characterization and stability assessment of CBMP formulations are addressed as well. Finally, we discuss unmet needs and make some recommendations regarding the formulation of CBMPs. (C) 2020 American Pharmacists Association?. Published by Elsevier Inc. All rights reserved.
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- 2021
4. A progress report on the 3rd International Symposium on Scientific and Regulatory Advances in Biological and Non-Biological Complex Drugs: A to Z in Bioequivalence
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Jon S. B. de Vlieger, Vinod P. Shah, Stefan Mühlebach, Daan J.A. Crommelin, Beat Flühmann, and Imre Klebovich
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Drug Guides ,Political science ,Engineering ethics ,Pharmacy ,Bioequivalence - Published
- 2019
5. Postproduction Handling and Administration of Protein Pharmaceuticals and Potential Instability Issues
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Daan J.A. Crommelin, Christian Schöneich, Theodore W. Randolph, John F. Carpenter, David B. Volkin, M. Reza Nejadnik, and Wim Jiskoot
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0301 basic medicine ,Hospital setting ,Drug Storage ,media_common.quotation_subject ,Pharmaceutical Science ,Self Administration ,Protein degradation ,030226 pharmacology & pharmacy ,Environmental stress ,Protein Aggregates ,03 medical and health sciences ,0302 clinical medicine ,Drug Stability ,Humans ,Quality (business) ,Product (category theory) ,Life history ,media_common ,Photolysis ,Protein Stability ,Proteins ,Therapeutic protein ,030104 developmental biology ,Pharmaceutical Preparations ,Risk analysis (engineering) ,Proteolysis ,Pharmaceutical biotechnology ,Business ,Drug Contamination - Abstract
The safety and efficacy of protein pharmaceuticals depend not only on biological activity but also on purity levels. Impurities may be process related because of limitations in manufacturing or product related because of protein degradation occurring throughout the life history of a product. Although the pharmaceutical biotechnology industry has made great progress in improving bulk and drug product manufacturing as well as company-controlled storage and transportation conditions to minimize the level of degradation, there is less control over the many factors that may subsequently affect product quality after the protein pharmaceuticals are released and shipped by the manufacturer. Routine handling or unintentional mishandling of therapeutic protein products may cause protein degradation that remains unnoticed but can potentially compromise the clinical safety and efficacy of the product. In this commentary, we address some potential risks associated with (mis)handling of protein pharmaceuticals after release by the manufacturer. We summarize the environmental stress factors that have been shown to cause protein degradation and that may be encountered during typical handling procedures of protein pharmaceuticals in a hospital setting or during self-administration by patients. Moreover, we provide recommendations for improvements in product handling to help ensure the quality of protein pharmaceuticals during use.
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- 2018
6. How to select a nanosimilar
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Josefien Knoeff, Jean-Daniel Hecq, Marco Bissig, Daan J.A. Crommelin, Stefan Mühlebach, Alberto Morell-Baladrón, Hans-Peter Lipp, Alain Astier, Amy Barton Pai, and Beat Flühmann
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Health professionals ,Computer science ,Process (engineering) ,General Neuroscience ,Comparability ,Biosimilar ,030226 pharmacology & pharmacy ,Interchangeability ,Rational planning model ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,History and Philosophy of Science ,Risk analysis (engineering) ,030220 oncology & carcinogenesis ,Formulary - Abstract
Nanomedicines in the class of nonbiological complex drugs (NBCDs) are becoming increasingly available. Up to 23 nanomedicines have been approved, and approximately 50 are in clinical development. Meanwhile, the first nanosimilars have entered the market through the generic approval pathway, but clinical differences have been observed. Many healthcare professionals may be unaware of this issue and must be informed of these clinically relevant variances. This article provides a tool for rational decision making for the inclusion of nanomedicines into the hospital formulary, including defined criteria for evaluation of substitutability or interchangeability. The tool was generated by conducting a roundtable with an international panel of experts and follows the same thought process that was developed and published earlier for the selection of biologicals/biosimilars. In addition to the existing criteria for biosimilars, a set of seven criteria was identified that specifically apply to nanosimilars. These include (1) particle size and size distribution, (2) particle surface characteristics, (3) fraction of uncaptured bioactive moiety, (4) stability on storage, (5) bioactive moiety uptake and (6) distribution, and (7) stability for ready-to-use preparation. Pharmacists should utilize their pharmaceutical expertise to use the appropriate criteria to evaluate the comparability of the drug to decide on interchangeability or substitutability.
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- 2017
7. Equivalence of complex drug products: advances in and challenges for current regulatory frameworks
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Jon S. B. de Vlieger, Stefan Mühlebach, Gerrit Borchard, Elena Wolff-Holz, Sesha Neervannan, Daan J.A. Crommelin, Scott E. McNeil, Vinod P. Shah, Leonie Hussaarts, Beat Flühmann, Wenlei Jiang, Elwyn Griffiths, and Vera Weinstein
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Drug ,business.industry ,General Neuroscience ,media_common.quotation_subject ,Biosimilar ,Pharmacology ,Public domain ,030226 pharmacology & pharmacy ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,White paper ,History and Philosophy of Science ,030220 oncology & carcinogenesis ,Agency (sociology) ,Medicine ,Regulatory science ,Engineering ethics ,business ,Equivalence (measure theory) ,Publication ,media_common - Abstract
Biotechnology and nanotechnology provide a growing number of innovator-driven complex drug products and their copy versions. Biologics exemplify one category of complex drugs, but there are also nonbiological complex drug products, including many nanomedicines, such as iron-carbohydrate complexes, drug-carrying liposomes or emulsions, and glatiramoids. In this white paper, which stems from a 1-day conference at the New York Academy of Sciences, we discuss regulatory frameworks in use worldwide (e.g., the U.S. Food and Drug Administration, the European Medicines Agency, the World Health Organization) to approve these complex drug products and their follow-on versions. One of the key questions remains how to assess equivalence of these complex products. We identify a number of points for which consensus was found among the stakeholders who were present: scientists from innovator and generic/follow-on companies, academia, and regulatory bodies from different parts of the world. A number of topics requiring follow-up were identified: (1) assessment of critical attributes to establish equivalence for follow-on versions, (2) the need to publish scientific findings in the public domain to further progress in the field, (3) the necessity to develop worldwide consensus regarding nomenclature and labeling of these complex products, and (4) regulatory actions when substandard complex drug products are identified.
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- 2017
8. Public-Private Partnerships as drivers of innovation in healthcare
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Jon S. B. de Vlieger, Remco L. A. de Vrueh, and Daan J.A. Crommelin
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lcsh:R5-920 ,Editorial ,public-private parternships ,business.industry ,Health care ,Medicine ,healthcare ,General Medicine ,Public relations ,lcsh:Medicine (General) ,business ,innovation - Published
- 2019
9. Report of the AAPS Guidance Forum on the FDA Draft Guidance for Industry: 'Drug Products, Including Biological Products, that Contain Nanomaterials'
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Vinod P. Shah, Sesha Neervannan, Scott E. McNeil, Daryl C. Drummond, Rachael M. Crist, Jon S. B. de Vlieger, Daan J.A. Crommelin, Katherine M. Tyner, and Wenlei Jiang
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Drug ,Biological Products ,Drug Industry ,United States Food and Drug Administration ,Extramural ,media_common.quotation_subject ,Pharmacology toxicology ,Pharmaceutical Science ,Guidelines as Topic ,030226 pharmacology & pharmacy ,United States ,Nanostructures ,Food and drug administration ,03 medical and health sciences ,0302 clinical medicine ,Government regulation ,030220 oncology & carcinogenesis ,Generic drug ,Government Regulation ,Drugs, Generic ,Engineering ethics ,Business ,Critical quality attributes ,Drug Approval ,media_common - Abstract
To guide developers of innovative and generic drug products that contain nanomaterials, the U.S. Food and Drug Administration issued the draft guidance for industry titled: "Drug Products, Including Biological Products, that Contain Nanomaterials" in December 2017. During the AAPS Guidance Forum on September 11, 2018, participants from industry, academia, and regulatory bodies discussed this draft guidance in an open setting. Two questions raised by the AAPS membership were discussed in more detail: what is the appropriate regulatory pathway for approval of drug products containing nanomaterials, and how to determine critical quality attributes (CQAs) for nanomaterials? During the meeting, clarification was provided on how the new FDA center-led guidance relates to older, specific nanomaterial class, or specific product-related guidances. The lively discussions concluded with some clear observations and recommendations: (I) Important lessons can be learned from how CQAs were determined for, e.g., biologics. (II) Publication of ongoing scientific discussions on strategies and studies determining CQAs of drug products containing nanomaterials will significantly strengthen the science base on this topic. Furthermore, (III) alignment on a global level on how to address new questions regarding nanomedicine development protocols will add to efficient development and approval of these much needed candidate nanomedicines (innovative and generic). Public meetings such as the AAPS Guidance Forum may serve as the place to have these discussions.
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- 2019
10. Formulation of Biologics Including Biopharmaceutical Considerations
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Wim Jiskoot, Daan J.A. Crommelin, and Andrea Hawe
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Active ingredient ,Biopharmaceutical ,Computer science ,Process (engineering) ,Biochemical engineering ,Dosage form - Abstract
This chapter describes the various issues a formulator of biologics faces when turning an active pharmaceutical ingredient (API) into a biopharmaceutical product that can be administered to a patient. A well-equipped analytical lab to characterize chemical and physical characteristics of the protein in the formulation process is a first requirement. Then, the proper excipients and conditions (e.g., freeze-dried or not; refrigerated or not) to achieve an acceptable shelf-life of the formulated protein can be selected. Throughout this process one should consider the specific requirements linked to the desired route of administration, e.g., dose, volume, primary container. Alternative routes of administration are briefly discussed and their limitations listed.
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- 2019
11. Biophysical and Biochemical Characteristics of Therapeutic Proteins
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Wim Jiskoot and Daan J.A. Crommelin
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chemistry.chemical_classification ,Protein structure ,Chemistry ,Biophysics ,Protein folding ,Amino acid - Abstract
Pharmaceutical proteins are large, folded structures stabilized by weak physical/chemical forces. An appreciation of the factors that may influence their structure is an absolute requirement when dealing with these complex, fragile compounds.
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- 2019
12. Non-biological complex drugs (NBCDs) and their follow-on versions: time for an editorial section
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Vinod P. Shah, Scott E. McNeil, Sesha Neervannan, Jon S. B. de Vlieger, Stefan Mühlebach, Gerrit Borchard, Beat Flühmann, Vera Weinstein, and Daan J.A. Crommelin
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Computer science ,Drug Guides ,Section (typography) ,Calculus ,Pharmacy - Published
- 2015
13. Physical Stability on Long-Term Storage
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Nicolaas J. Zuidam, Herre Talsma, Mustafa Grit, and Daan J.A. Crommelin
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Control theory ,Environmental science ,Physical stability ,Term (time) - Published
- 2018
14. Sterilization of Liposomes
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Nicolaas J. Zuidam, Daan J.A. Crommelin, and Herre Talsma
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Liposome ,medicine.medical_specialty ,Chemistry ,medicine ,Sterilization (microbiology) ,Surgery - Published
- 2018
15. Absorptie en toedieningswegen
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Daan J.A. Crommelin and J. J. Tukker
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- 2018
16. Equivalence of glatiramer acetate products: challenges in assessing pharmaceutical equivalence and critical clinical performance attributes
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Daan J.A. Crommelin and Gerrit Borchard
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0301 basic medicine ,Drug ,Multiple Sclerosis ,Therapeutic equivalency ,Pharmaceutical equivalence ,media_common.quotation_subject ,Pharmaceutical Science ,Computational biology ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Drugs, Generic ,Humans ,Glatiramer acetate ,Equivalence (measure theory) ,media_common ,business.industry ,Clinical performance ,Drugs generic ,Glatiramer Acetate ,030104 developmental biology ,Therapeutic Equivalency ,business ,030217 neurology & neurosurgery ,Immunosuppressive Agents ,medicine.drug - Abstract
This review discusses the challenges to characterize and evaluate the peptide based drug glatiramer acetate (GA) and its follow-on products used for treatment of multiple sclerosis patients.GA is a highly complex mixture of peptides consisting of four amino acids. The various (physico)-chemical approaches and bioassays used for characterizing this complex drug product are described. It is not possible to link data from preclinical performance to outcomes observed in clinical trials as no critical attributes suitable for predicting the clinical performance in MS patients have been identified yet. The limited insight into the precise mechanism(s) of action of GA may explain why these critical clinical performance attributes still have not been identified.The complexity of GA and lack of understanding of critical clinical performance attributes leads to a number of issues to be resolved as they hamper industry and regulatory bodies in designing and evaluating follow-on/generic applications of GA. The following questions are waiting to be addressed: Preclinical characterization vs clinical outcome: what is the relation? What are possible biomarkers? How to choose the right patient group? What is the experience with existing follow-on versions? Is there a place for GA 'betters'? How to evaluate existing and draft new guidance documents and pharmacopoeial monographs?
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- 2017
17. The similarity question for biologicals and non-biological complex drugs
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Scott E. McNeil, Beat Flühmann, Jon S. B. de Vlieger, Imre Klebovich, Daan J.A. Crommelin, Vinod P. Shah, Vera Weinstein, and Stefan Mühlebach
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Biosimilars ,Non-biological complex drugs ,Manufacturing process ,business.industry ,Management science ,media_common.quotation_subject ,Pharmaceutical equivalence ,Multitude ,Pharmaceutical Science ,Biosimilar ,Nanotechnology ,Biologicals ,Nanomedicines ,Liposomes ,Similarity (psychology) ,Medicine ,Quality (business) ,Product (category theory) ,Glatiramoids ,business ,Equivalence (measure theory) ,Iron–carbohydrate complexes ,media_common - Abstract
For small – low molecular weight – molecule medicines a robust regulatory system has evolved over the years. This system guarantees high and constant quality of our (generic) medicines. Pharmaceutical equivalence and bioequivalence assessment are the pillars under that system. But there are complex medicines where the question of equivalence is more challenging to answer. For biologicals the paradigm of similarity rather than equality (the emergence of ‘biosimilars’) was developed in the past decade. This has been a program where an evolutionary, science based approach has been chosen by the frontrunner regulatory body, the EMA, with a ‘learn and confirm’ character.In addition, there is another group of complex drugs, the non-biological complex drugs, NBCDs, where the generic paradigm can be challenged as well. The NBCDs are defined as: 1. consisting of a complex multitude of closely related structures; 2. the entire multitude is the active pharmaceutical ingredient; 3. the properties cannot be fully characterized by physicochemical analysis and 4. the consistent, tightly controlled manufacturing process is fundamental to reproduce the product. NBCDs encompass product families such as the glatiramoids, liposomes, iron–carbohydrate colloids and many candidates of the group of the upcoming nanoparticulate systems. Following the main principles of regulatory pathways for biologicals (with appropriate product-by-product adjustments), instead of that for small molecules, would be the more logical strategy for these NBCDs.The status and outstanding regulatory issues for biosimilars and NBCD-similars/follow on versions were discussed at a conference in Budapest, Hungary (October 2014) and this commentary touches upon the issues brought up in the presentations, deliberations and conclusions.
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- 2015
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18. Towards more effective advanced drug delivery systems1
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Alexander T. Florence and Daan J.A. Crommelin
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Targeted drug delivery ,Risk analysis (engineering) ,business.industry ,Drug delivery ,Pharmaceutical Science ,Position paper ,Medicine ,Profiling (information science) ,business ,Target organ ,Design for manufacturability ,Biotechnology - Abstract
This position paper discusses progress made and to be made with so-called advanced drug delivery systems, particularly but not exclusively those in the nanometre domain. The paper has resulted from discussions with a number of international experts in the field who shared their views on aspects of the subject, from the nomenclature used for such systems, the sometimes overwrought claims made in the era of nanotechnology, the complex nature of targeting delivery systems to specific destinations in vivo, the need for setting standards for the choice and characterisation of cell lines used in in vitro studies, to attention to the manufacturability, stability and analytical profiling of systems and more relevant studies on toxicology. The historical background to the development of many systems is emphasised. So too is the stochastic nature of many of the steps to successful access to and action in targets. A lacuna in the field is the lack of availability of data on a variety of carrier systems using the same models in vitro and in vivo using standard controls. The paper asserts that greater emphasis must also be paid to the effective levels of active attained in target organs, for without such crucial data it will be difficult for many experimental systems to enter the clinic. This means the use of diagnostic/imaging technologies to monitor targeted drug delivery and stratify patient groups, identifying patients with optimum chances for successful therapy. Last, but not least, the critical importance of the development of science bases for regulatory policies, scientific platforms overseeing the field and new paradigms of financing are discussed.
- Published
- 2013
19. Scientific considerations for complex drugs in light of established and emerging regulatory guidance
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J. Michael Nicholas, Chris Holloway, Jan Mueller-Berghaus, Sau Larry Lee, Janet S. Wyatt, Beatriz Silva Lima, and Daan J.A. Crommelin
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Structure (mathematical logic) ,medicine.medical_specialty ,business.industry ,General Neuroscience ,Alternative medicine ,Biosimilar ,Pharmacology ,Interchangeability ,General Biochemistry, Genetics and Molecular Biology ,Variety (cybernetics) ,Consistency (negotiation) ,History and Philosophy of Science ,medicine ,Engineering ethics ,business - Abstract
On March 9, 2012, the New York Academy of Sciences brought together experts representing a variety of perspectives--including academic, industrial, regulatory, as well as those from physicians and consumers--to discuss considerations for the non-biological complex drug (NBCD) regulatory approval pathway, given the emerging regulatory guidelines for biosimilars (follow-on biological complex drugs). Some of the organizers of the conference expressed their belief that NBCDs share a number of characteristic features with biologicals: the structure cannot be fully defined by the available (physicochemical) analytical tests, and quality assurance is based on in-depth knowledge, consistency, and control of the production process. However, their view on NBCDs was not universally accepted among the experts who participated in the conference. Plenary sessions addressed the most recent regulatory developments, experimental design, interchangeability, and immunogenicity issues for follow-on versions of complex drugs from the perspective of key audiences, including industry, regulatory agencies, physicians, and consumers. This report summarizes these various perspectives on NBCDs and the scientific and regulatory considerations associated with complex drug categories.
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- 2012
20. Impact of the Pharmaceutical Sciences on Health Care: A Reflection over the Past 50 Years
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Carl C. Peck, Christian R. Noe, Geoffrey T. Tucker, Malcolm Rowland, Luc Besançon, Dennis A. Smith, Mario L. Rocci, Vinod P. Shah, and Daan J.A. Crommelin
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Pharmacology ,Drug Utilization ,business.industry ,Chemistry, Pharmaceutical ,MEDLINE ,Pharmaceutical Science ,Globe ,Historical Article ,History, 20th Century ,Public relations ,History, 21st Century ,medicine.anatomical_structure ,Drug Discovery ,Health care ,Medicine ,Pharmacokinetics ,Pharmaceutical sciences ,Translational science ,business - Abstract
During the last century, particularly the latter half, spectacular progress has been made in improving the health and longevity of people. The reasons are many, but the development of medicines has played a critical role. This report documents and reflects on the impressive contribution that those working in the pharmaceutical sciences have made to healthcare over the past 50 years. It is divided into six sections (drug discovery; absorption, distribution, metabolism, and excretion; pharmacokinetics and pharmacodynamics; drug formulation; drug regulation; and drug utilization), each describing key contributions that have been made in the progression of medicines, from conception to use. A common thread throughout is the application of translational science to the improvement of drug discovery, development, and therapeutic application. Each section has been coordinated by a leading scientist who was asked, after consulting widely with many colleagues across the globe, to identify “The five most influential ideas/concepts/developments introduced by ‘pharmaceutical scientists’ (in their field) over the past 50 years?” Although one cannot predict where the important breakthroughs will come in the future to meet the unmet medical needs, the evidence presented in this report should leave no doubt that those engaged in the pharmaceutical sciences will continue to make their contributions heavily felt. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:4075–4099, 2012
- Published
- 2012
21. Non-Biological Complex Drugs : The Science and the Regulatory Landscape
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Daan J.A. Crommelin, Jon S. B. de Vlieger, Daan J.A. Crommelin, and Jon S. B. de Vlieger
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- Bioactive compounds, Drugs, Pharmaceutical technology, Nanomedicine, Drug interactions
- Abstract
The rise of bio- and nano-technology in the last decades has led to the emergence of a new and unique type of medicine known as non-biological complex drugs (NBCDs). This book illustrates the challenges associated with NBCD development, as well as the complexity of assessing the effects of manufacturing changes on innovator and follow-on batches of NBCDs. It also touches upon proven marketing authorization requirements for biosimilars that could be effective in evaluating follow-on NBCDs, including a demonstration of control over the manufacturing process and a need for detailed physico-chemical characterization and (pre)clinical tests.This book is meant to be used for years to come as a standard reference work for the development of NBCDs. Moreover, this book aims to stimulate discussions and further our thinking to ensure that decisions regarding the approval of complex drugs are made with relevant scientific data on the table.
- Published
- 2015
22. Erratum: Cancer nanomedicine: is targeting our target?
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Wim E. Hennink, Daan J.A. Crommelin, Gert Storm, Marianne Ashford, Twan Lammers, and Fabian Kiessling
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0301 basic medicine ,medicine.medical_specialty ,business.industry ,Cancer ,02 engineering and technology ,021001 nanoscience & nanotechnology ,medicine.disease ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,Biomaterials ,03 medical and health sciences ,030104 developmental biology ,Materials Chemistry ,medicine ,Nanomedicine ,Medical physics ,0210 nano-technology ,business ,Energy (miscellaneous) - Abstract
Nature Reviews Materials 1, 16069 (2016). Published 7 September 2016; corrected 9 September 2016. In the originally published HTML version of this article, Gert Storm's surname was incorrectly spelled. This has been corrected in the HTML version.
- Published
- 2016
23. Cancer nanomedicine: Is targeting our target?
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Gerrit Storm, Wim E. Hennink, Daan J.A. Crommelin, Marianne Ashford, Twan Lammers, Fabian Kiessling, Faculty of Science and Technology, and Biomaterials Science and Technology
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medicine.medical_specialty ,Engineering ,MEDLINE ,Nanotechnology ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Article ,Biomaterials ,InformationSystems_GENERAL ,Materials Chemistry ,medicine ,Medical physics ,METIS-320803 ,business.industry ,Cancer ,IR-103724 ,021001 nanoscience & nanotechnology ,medicine.disease ,3. Good health ,0104 chemical sciences ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,Patient benefit ,Nanomedicine ,0210 nano-technology ,business ,Energy (miscellaneous) - Abstract
Nanomedicine may have a delivery problem. Rigorous, realistic and holistic rethinking is needed to improve nanomedicine performance and increase patient benefit.
- Published
- 2016
24. Pharmaceutical Biotechnology
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Bernd Meibohm, Robert D. Sindelar, and Daan J.A. Crommelin
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Engineering ,business.industry ,Pharmaceutical biotechnology ,Engineering ethics ,business - Published
- 2016
25. Hydrolysis of Phospholipids in Liposomes and Stability- Indicating Analytical Techniques
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Nicolaas J. Zuidam and Daan J.A. Crommelin
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Hydrolysis ,Liposome ,Chromatography ,Chemistry ,Stability indicating - Published
- 2016
26. Hematopoietic Growth Factors
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Bernd Meibohm, Daan J.A. Crommelin, and Robert D. Sindelar
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Haematopoiesis ,business.industry ,Cancer research ,Medicine ,business - Published
- 2016
27. Public-private partnerships in translational medicine: Concepts and practical examples
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Peter R. Luijten, Daan J.A. Crommelin, Gert Storm, Chrit T. W. Moonen, Guus A.M.S. van Dongen, Otolaryngology / Head & Neck Surgery, Radiology and nuclear medicine, and CCA - Innovative therapy
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Drug Industry ,Universities ,MEDLINE ,Pharmaceutical Science ,Nanotechnology ,Translational research ,Public-Private Sector Partnerships ,Translational Research, Biomedical ,Multidisciplinary approach ,Blueprint ,Animals ,Humans ,Medicine ,Netherlands ,business.industry ,Translational medicine ,HIFU ,Image guided drug delivery ,Magnetic Resonance Imaging ,Molecular Imaging ,Engineering management ,PET ,Drug development ,Positron-Emission Tomography ,General partnership ,Participatory medicine ,Public-private partnerships ,business ,MRI - Abstract
The way forward in multidisciplinary research according to former NIH's director Elias Zerhouni is to engage in predictive, personalized, preemptive and participatory medicine. For the creation of the optimal innovation climate that would allow for such a strategy, public-private partnerships have been widely proposed as an important instrument. Public-private partnerships have become an important instrument to expedite translational research in medicine. The Netherlands have initiated three large public-private partnerships in the life sciences and health area to facilitate the translation of valuable basic scientific concepts to new products and services in medicine. The focus of these partnerships has been on drug development, improved diagnosis and regenerative medicine. The Dutch model of public-private partnership forms the blueprint of a much larger European initiative called EATRIS [1]. This paper will provide practical examples of public-private partnerships initiated to expedite the translation of new technology for drug development towards the clinic. Three specific technologies are in focus: companion diagnostics using nuclear medicine, the use of ultra high field MRI to generate sensitive surrogate endpoints based on endogenous contrast, and MRI guidance for High Intensity Focused Ultrasound mediated drug delivery.
- Published
- 2012
28. Respiratory sensitization: Advances in assessing the risk of respiratory inflammation and irritation
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Emiel Rorije, Hub Noteborn, Erwin Ludo Roggen, David Roberts, Berend Glazenburg, Frans P. Nijkamp, Frieke Kuper, Conchita Callant Cransveld, Jacqueline van Engelen, Rosette Van Den Heuvel, Henk Van Loveren, Katharina Sewald, Andreas Natsch, Raymond Pieters, Sandra Verstraelen, Daan J.A. Crommelin, Zuzana Diamant, Rob J. Vandebriel, Guy Joos, Martin Seed, Toxicogenomics, RS: GROW - School for Oncology and Reproduction, and Publica
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Cellular immunity ,respiratory sensitization ,Respiratory Tract Diseases ,Respiratory tract ,medicine.disease_cause ,Toxicology ,sensitization ,immunoglobulin E ,airway remodeling ,Life ,immunopathology ,Respiratory system ,Sensitization ,Rhinitis ,Risk assessment ,predictive value ,quantitative analysis ,QSAR ,quantitative structure activity relation ,General Medicine ,bronchus hyperreactivity ,cell assay ,reaction analysis ,medicine.anatomical_structure ,risk factor ,Irritation ,QS - Quality & Safety ,EELS - Earth, Environmental and Life Sciences ,occupational asthma ,Occupational asthma ,functional genomics ,immunoreactivity ,Healthy Living ,Integrated testing ,medicine.medical_specialty ,in vitro study ,dendritic cell ,respiratory tract inflammation ,review ,cellular immunity ,Animal Testing Alternatives ,Hazardous Substances ,process model ,In vitro ,Toxicity Tests ,In vivo ,medicine ,Respiratory Hypersensitivity ,Animalia ,Humans ,human ,Intensive care medicine ,ASAT ,Asthma ,nonhuman ,business.industry ,disease predisposition ,biosafety ,medicine.disease ,contact allergen ,respiratory tract injury ,process development ,animal testing alternative ,Immunology ,mucosal immunity ,Healthy for Life ,business ,mathematical model - Abstract
Respiratory sensitization provides a case study for a new approach to chemical safety evaluation, as the prevalence of respiratory sensitization has increased considerably over the last decades, but animal and/or human experimental/predictive models are not currently available. Therefore, the goal of a working group was to design a road map to develop an ASAT approach for respiratory sensitisers. This approach should aim at (i) creating a database on respiratory functional biology and toxicology, (ii) applying data analyses to understand the multi-dimensional sensitization response, and how this predisposes to respiratory inflammation and irritation, and (iii) building a systems model out of these analyses, adding pharmacokinetic-pharmacodynamic modeling to predict respiratory responses to low levels of sensitisers. To this end, the best way forward would be to follow an integrated testing approach. Experimental research should be targeted to (i) QSAR-type approaches to relate potential as a respiratory sensitizer to its chemical structure, (ii) in vitro models and (iii) in vitro-in vivo extrapolation/validation. © 2011 Elsevier Ltd.
- Published
- 2011
29. How to screen non-viral gene delivery systems in vitro?
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Roel van Eijk, Wim E. Hennink, Ronald S. Oosting, Ethlinn V.B. van Gaal, Daan J.A. Crommelin, Enrico Mastrobattista, and Robbert J. Kok
- Subjects
Protocol (science) ,business.industry ,Transgene ,Genetic Vectors ,Pharmaceutical Science ,Context (language use) ,DNA ,Transfection ,Computational biology ,Biology ,Gene delivery ,In vitro transfection ,Viral gene ,In vitro ,Biotechnology ,Animals ,Humans ,Polyethyleneimine ,business ,Plasmids - Abstract
Screening of new gene delivery candidates regarding transfection efficiency and toxicity is usually performed by reading out transgene expression levels relative to a reference formulation after in vitro transfection. However, over the years and among different laboratories, this screening has been performed in a variety of cell lines, using a variety of conditions and read-out systems, and by comparison to a variety of reference formulations. This makes a direct comparison of results difficult, if not impossible. Reaching a consensus would enable placing new results into context of previous findings and estimate the overall contribution to the improvement of non-viral gene delivery. In this paper we illustrate the sensitivity of transfection outcomes on testing conditions chosen, and propose a screening protocol with the aim of standardization within the field.
- Published
- 2011
30. Potential inaccurate quantitation and sizing of protein aggregates by size exclusion chromatography: Essential need to use orthogonal methods to assure the quality of therapeutic protein products
- Author
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C. Russell Middaugh, John F. Carpenter, Wim Jiskoot, Theodore W. Randolph, Daan J.A. Crommelin, and Gerhard Winter
- Subjects
Quality Control ,Chromatography ,Protein Stability ,Chemistry ,media_common.quotation_subject ,Size-exclusion chromatography ,Pharmaceutical Science ,Therapeutic protein ,Protein aggregation ,Recombinant Proteins ,Sizing ,Protein stability ,Drug Stability ,Pharmaceutical Preparations ,Chromatography, Gel ,Quality (business) ,Physical stability ,media_common - Published
- 2010
31. Peptide nanocarriers for intracellular delivery of photosensitizers
- Author
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Marjan M. Fretz, Wim E. Hennink, Daan J.A. Crommelin, Albert J. van Hell, and Enrico Mastrobattista
- Subjects
Indoles ,Pharmaceutical Science ,Peptide ,Isoindoles ,Photosensitizers ,Drug Delivery Systems ,Cellular internalization ,Cell Line, Tumor ,Chlorocebus aethiops ,Animals ,Nanotechnology ,Photosensitizer ,Vesicles ,Amino Acid Sequence ,Transport Vesicles ,Peptide sequence ,chemistry.chemical_classification ,Drug Carriers ,Oligopeptide ,Photosensitizing Agents ,Chemistry ,Vesicle ,Pinocytosis ,Carcinoma ,Farmacie ,Self-assembly ,Cell killing ,Photodynamic therapies ,Photochemotherapy ,Biochemistry ,COS Cells ,Colonic Neoplasms ,Adsorption ,Nanocarriers ,Hydrophobic and Hydrophilic Interactions ,Oligopeptides - Abstract
Previously we have shown that recombinantly produced amphiphilic oligopeptides with amino acid sequence Ac-Ala-Ala-Val-Val-Leu-Leu-Leu-Trp-Glu-Glu spontaneously assemble into nano-sized vesicles with an average diameter of 120 nm. Moreover, peptide vesicles could be stabilized by introducing multiple cysteine residues within the hydrophobic domain of these amphiphilic oligopeptides, allowing the formation of intermolecular disulfide bridges. In this study, the cellular association and internalization of peptide vesicles were assessed. Flow cytometry and confocal laser-scanning microscopy showed that peptide vesicles were internalized by cells predominantly via adsorptive macropinocytosis. Furthermore, the potential of these peptide vesicles as delivery system for photosensitizers was explored. Water-insoluble phthalocyanines could be quantitatively entrapped within the hydrophobic domains of these peptide vesicles. Confocal laser-scanning microscopy analysis showed that internalized peptides co-localized with the phthalocyanine, suggesting that peptide vesicles are internalized in their intact form. Upon illumination, the phthalocyanine-containing peptide vesicles showed an active photodynamic response towards the cells leading to effective cell killing. In contrast, the free phthalocyanine or empty peptide vesicles did not show any cytotoxicity. In conclusion, this is the first demonstration that peptide vesicles show promise as delivery systems for photosensitizers to be used in photodynamic therapy.
- Published
- 2010
32. The Pharmaceutical Sciences in 2020: Report of a Conference Organized by the Board of Pharmaceutical Sciences of the International Pharmaceutical Federation (FIP)
- Author
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Geoffrey T. Tucker, Pieter Stolk, Vinod P. Shah, Daan J.A. Crommelin, and Luc Besançon
- Subjects
Societies, Pharmaceutical ,Operations research ,Drug Industry ,education ,Pharmacology toxicology ,Pharmaceutical Science ,Pharmacy ,Business model ,Drug Discovery ,Medicine ,Technology, Pharmaceutical ,Pharmaceutical engineering ,Pharmacology (medical) ,Pharmaceutical sciences ,Drug industry ,health care economics and organizations ,Pharmacology ,business.industry ,Organic Chemistry ,Health technology ,Congresses as Topic ,Venture capital ,Pharmaceutical Sciences in 2020 ,Paradigm shift ,Commentary ,Molecular Medicine ,Engineering ethics ,business ,Biotechnology - Abstract
In accordance with its missions, the Board of Pharmaceutical Sciences (BPS) of the International Pharmaceutical Federation (FIP) has developed a view on the future of pharmaceutical sciences in 2020. This followed an international conference with invited participants from various fields (scientists, academicians, regulators, industrialists, venture capitalists…) who shared their views on the forces that might determine how the pharmaceutical sciences will look in 2020. The participants of the conference identified major research activities which will drive drug discovery and development, the enabling technologies, as well as likely paradigm shifts in drug discovery, development, regulation and usage. In addition, they discussed the translation of these changes into the education of pharmaceutical scientists and the potential role of FIP. The outcome of this exercise could serve as a starting point for a scenario analysis of the future of pharmaceutical sciences and the challenges that await the pharmaceutical scientist.
- Published
- 2010
33. Optimization and quantification of protein synthesis inside liposomes
- Author
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Maryam Amidi, Markus de Raad, Helma de Graauw, Wim E. Hennink, Enrico Mastrobattista, Daan J.A. Crommelin, and Dave van Ditmarsch
- Subjects
Cell-free protein synthesis ,Pyrophosphatase ,Liposome ,Cell-Free System ,Transcription, Genetic ,Artificial cell ,Cells ,Proteins ,Pharmaceutical Science ,DNA-Directed RNA Polymerases ,Biology ,beta-Galactosidase ,Cell-free system ,Viral Proteins ,chemistry.chemical_compound ,chemistry ,Biochemistry ,Protein Biosynthesis ,Liposomes ,medicine ,Protein biosynthesis ,T7 RNA polymerase ,DNA ,medicine.drug - Abstract
Synthetic biology aims at reprogramming existing, or creating new, biological systems, with the ultimate aim to obtain artificial cells whose functions can be tailored. For the latter, encapsulation of complex biochemical reactions into cell-sized compartments, such as liposomes, is required. Recently, several groups have demonstrated that proteins of interest can be produced de novo within liposomes by entrapping cell-free protein-synthesis systems and DNA templates inside liposomes. Although detectable, intraliposomal protein synthesis was generally poor. Here, we have optimized intraliposomal cell-free protein synthesis by changing several variables, including lipid composition as well as liposome, pyrophosphatase, and T7 RNA polymerase concentration. Further, by using an activity-based assay, we have quantified the amount of full-length protein that was produced from DNA templates inside liposomes before and after optimization of aforementioned variables. Based on the model protein beta-galactosidase, it is demonstrated that liposomal protein synthesis can yield microgram quantities of protein (30-40 microg/mL liposomes).
- Published
- 2009
34. Stabilization of Peptide Vesicles by Introducing Inter-Peptide Disulfide Bonds
- Author
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Wim E. Hennink, Enrico Mastrobattista, Albert J. van Hell, and Daan J.A. Crommelin
- Subjects
Light ,Stereochemistry ,Pharmaceutical Science ,Peptide ,macromolecular substances ,Microscopy, Atomic Force ,Microscopy, Electron, Transmission ,Amphiphile ,Scattering, Radiation ,crosslinking ,Pharmacology (medical) ,Disulfides ,recombinant ,Peptide sequence ,vesicle ,Pharmacology ,chemistry.chemical_classification ,Oligopeptide ,Aqueous solution ,Vesicle ,Organic Chemistry ,technology, industry, and agriculture ,self-assembly ,Fluoresceins ,chemistry ,Covalent bond ,Molecular Medicine ,Electrophoresis, Polyacrylamide Gel ,Self-assembly ,amphiphilic oligopeptides ,Peptides ,Research Paper ,Biotechnology - Abstract
Purpose Previously, we have shown that the amphiphilic oligopeptide SA2 (Ac-Ala-Ala-Val-Val-Leu-Leu-Leu-Trp-Glu-Glu-COOH) spontaneously self-assemble into nano-sized vesicles in aqueous environment. Relative weak individual intermolecular interactions dominate such oligopeptide assemblies. In this study we aimed at improving the stability of such peptide vesicles by covalently crosslinking the oligopeptide vesicles using disulfide bonds. Two and three cysteines were introduced in the SA2 peptide sequence to allow crosslinking (Ac-Ala-Cys-Val-Cys-Leu-(Leu/Cys)-Leu-Trp-Glu-Glu-COOH). Results Upon disulfide formation the crosslinked vesicles remained stable under conditions that disrupted the non-crosslinked peptide vesicles. The stabilized vesicles were more closely examined in terms of particle size (distribution) using atomic force microscopy, cryogenic electron microscopy, as well as dynamic light scattering analysis, showing an average particle radius in number between 15 and 20 nm. Using entrapment of calcein it was shown that intermolecular crosslinking of peptides within the vesicles did not affect the permeability for calcein. Conclusion Introduction of cysteines into the hydrophobic domain of the SA2 amphiphilic oligopeptides is a feasible strategy for crosslinking the peptide vesicles. Such small crosslinked oligopeptide vesicles may hold promise for drug delivery applications. Electronic supplementary material The online version of this article (doi:10.1007/s11095-009-9933-z) contains supplementary material, which is available to authorized users.
- Published
- 2009
35. The EUFEPS workshop on institutional peer review 'The ultimate tool to advance the pharmaceutical sciences?'
- Author
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Daan J.A. Crommelin and Ole J. Bjerrum
- Subjects
business.industry ,Pharmaceutical Science ,Medicine ,Engineering ethics ,Pharmaceutical sciences ,business - Published
- 2008
36. Efficacy of pulmonary insulin delivery in diabetic rats: Use of a model-based approach in the evaluation of insulin powder formulations
- Author
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Oscar Della Pasqua, Wim Jiskoot, Cor J. Snel, Wim E. Hennink, K M Krudys, Maryam Amidi, and Daan J.A. Crommelin
- Subjects
Blood Glucose ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Population ,Pharmaceutical Science ,Pharmacology ,Models, Biological ,Diabetes Mellitus, Experimental ,Rats, Sprague-Dawley ,Chitosan ,chemistry.chemical_compound ,Diabetes mellitus ,medicine ,Animals ,Hypoglycemic Agents ,Insulin ,Microparticle ,education ,Lung ,education.field_of_study ,Drug Administration Routes ,Dextrans ,medicine.disease ,Rats ,Surgery ,Bioavailability ,Dextran ,chemistry ,Pharmacodynamics ,Powders - Abstract
The potential of N-trimethyl chitosan (TMC) with two degrees of quaternization (DQ), TMC20 (DQ 20%, as a mucoadhesive) and TMC60 (DQ 60%, as a mucoadhesive and a permeation enhancer), and dextran (as a non-mucoadhesive and non-permeation enhancer) microparticles as carriers for pulmonary delivery of insulin was studied in diabetic rats. The impact of the powder formulation on insulin bioavailability and its pharmacological effect was evaluated using a population pharmacokinetic-pharmacodynamic (PKPD) model. Insulin-loaded microparticles were prepared by a supercritical fluid (SCF) drying technique. They had a median volume diameter and median volume aerodynamic diameter of about 6-10 microm and 4 microm, respectively. The PK of insulin in the diabetic rats was analyzed by a one-compartment disposition model and the PD was described by the minimal model of glucose disappearance. The bioavailability of the pulmonarily administered dextran-, TMC20- and TMC60-insulin microparticles relative to subcutaneously (SC) administered insulin, was 0.48, 0.59 and 0.95, respectively. Histological examinations of the rats' lungs did not show any local adverse reactions after single administration of insulin powders. The pharmacodynamic model could describe the insulin-glucose relationship and pharmacodynamic efficiency of insulin formulations, which was about 0.6(*)10(-5) ml/microU, irrespective of the formulations. The current findings suggest that TMC microparticles are a promising vehicle for pulmonary delivery of insulin.
- Published
- 2008
37. Ways of manipulating the polymorphism of glycine during supercritical fluid crystallisation
- Author
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Nataša Jovanović, Andréanne Bouchard, Gerard W. Hofland, Wim Jiskoot, Daan J.A. Crommelin, and Geert-Jan Witkamp
- Subjects
Supercritical carbon dioxide ,Aqueous solution ,Precipitation (chemistry) ,Chemistry ,General Chemical Engineering ,Drop (liquid) ,Supercritical fluid extraction ,Condensed Matter Physics ,Supercritical fluid ,law.invention ,Crystallography ,Chemical engineering ,law ,Mass transfer ,Physical and Theoretical Chemistry ,Crystallization - Abstract
The precipitation of glycine from aqueous solution was studied using a mixture of supercritical carbon dioxide and ethanol as drying medium and as anti-solvent. Glycine, which has three polymorphs, was precipitated by a direct spraying process using a coaxial nozzle under high pressure. By simple manipulation of the solute concentration, the process could be tuned to selectively precipitate either pure α or β-glycine, as determined by X-ray powder diffraction. When decreasing the solute concentration or increasing the ethanol fraction in the system, the precipitation of the metastable β-glycine was preferred over the precipitation of α-glycine. Modelling of the mass transfer around a drop showed that the ethanol fraction inside the drop can reach significant values, and that the evaporation occurs in less than a second, leaving little space for recrystallisation. Even though the crystal growth rate was extreme (up to 800 μm/s), the product was crystalline.
- Published
- 2008
38. Effect of the modifier on the particle formation and crystallisation behaviour during precipitation from aqueous solutions
- Author
-
Geert-Jan Witkamp, Nataša Jovanović, Gerard W. Hofland, Wim Jiskoot, Ángel Martín, Andréanne Bouchard, and Daan J.A. Crommelin
- Subjects
Aqueous solution ,Chemistry ,Precipitation (chemistry) ,General Chemical Engineering ,Inorganic chemistry ,Condensed Matter Physics ,Supercritical fluid ,law.invention ,chemistry.chemical_compound ,law ,Phase (matter) ,Acetone ,Methanol ,Physical and Theoretical Chemistry ,Crystallization ,Solubility - Abstract
Ethanol is a commonly added modifier to supercritical CO2 for particle formation from aqueous solutions. Four modifiers – methanol, ethanol, 2-propanol and acetone – were studied to determine the extent of the effect of the modifier selection on the particles produced and to determine more precisely the precipitation mechanisms. The strong anti-solvent effect of methanol on the solute was shown by the production of metastable β-glycine, phenylalanine anhydrate and lysozyme agglomerated nanoparticles. Ethanol showed such an anti-solvent effect only when use at higher fraction in the supercritical phase, followed by 2-propanol and acetone. 2-Propanol and acetone mainly contributed to the precipitation of the solute by increasing the solubility of the water in the supercritical phase. In such precipitation conditions the more stable α-glycine, phenylalanine monohydrate and lysozyme microspheres were produced by the evaporation of the solution into the CO2 phase. The putative anti-solvent effect of CO2 in the systems studied was not clearly observed, but it remains that CO2 is essential to the SCF-drying process.
- Published
- 2008
39. Supercritical fluid drying of carbohydrates: Selection of suitable excipients and process conditions
- Author
-
Wim Jiskoot, Andréanne Bouchard, Geert-Jan Witkamp, Daan J.A. Crommelin, Gerard W. Hofland, Eduardo Mendes, and Nataša Jovanović
- Subjects
Carbohydrates ,Pharmaceutical Science ,Excipient ,law.invention ,Excipients ,X-Ray Diffraction ,law ,Spectroscopy, Fourier Transform Infrared ,medicine ,Technology, Pharmaceutical ,Particle Size ,Crystallization ,Supersaturation ,Aqueous solution ,Supercritical carbon dioxide ,Chromatography ,Calorimetry, Differential Scanning ,Ethanol ,Chemistry ,General Medicine ,Supercritical fluid ,Amorphous solid ,Freeze Drying ,Chemical engineering ,Thermogravimetry ,Microscopy, Electron, Scanning ,Powders ,Glass transition ,Biotechnology ,medicine.drug - Abstract
The processibility of 15 carbohydrates, more or less commonly used, was investigated as excipients in supercritical fluid drying. The focus was on the ability to produce amorphous powder, the stability of the powders towards crystallisation, and the residual water and ethanol content. The aqueous solutions were sprayed into a pressurised carbon dioxide-ethanol mixture flowing cocurrently through a coaxial two-fluid nozzle. The powder characteristics appeared to be influenced by the supersaturation level reached during the SCF-drying process and by the properties of the sugar species, such as water solubility and glass transition temperature, or the solution viscosities. The stability and the residual solvent content of a selected set of sugars and some mixtures were further analysed. The stability of amorphous powders was investigated at 4 degrees C, room temperature, 40 and 50 degrees C. Lactose, maltose, trehalose, raffinose, cyclodextrin, low-molecular-weight dextran and inulin could form free-flowing powders that remained amorphous during the 3-month stability study. Sucrose had to be mixed with other sugars to form a stable amorphous powder. Ethanol could be entrapped in supercritical fluid dried low-molecular-weight sugars, whereas polysaccharide powders were free of ethanol. Measures to prevent or overcome the presence of ethanol are discussed.
- Published
- 2008
40. The effect of core composition in biodegradable oligomeric micelles as taxane formulations
- Author
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Wim E. Hennink, Cornelus F. van Nostrum, Leo G.J. de Leede, Johan Kemmink, Pascal H.J.L.F. de Jong, Ruud Verrijk, Daan J.A. Crommelin, and Myrra G. Carstens
- Subjects
Magnetic Resonance Spectroscopy ,Paclitaxel ,Chemistry, Pharmaceutical ,Dispersity ,Pharmaceutical Science ,Docetaxel ,Oligomer ,Micelle ,Mice ,chemistry.chemical_compound ,Drug Stability ,Animals ,Organic chemistry ,Particle Size ,Cytotoxicity ,Micelles ,General Medicine ,End-group ,chemistry ,Colonic Neoplasms ,Proton NMR ,Taxoids ,Drug carrier ,Biotechnology ,Nuclear chemistry - Abstract
Docetaxel (DCTX) and paclitaxel (PTX) are very potent anti-cancer drugs, but the currently marketed formulations, Taxotere ® and Taxol ® , respectively, are associated with vehicle-related toxicity. An attractive alternative to formulate these hydrophobic cytotoxic agents are polymeric micelles. In this study, the loading of taxanes into oligomeric micelles composed of mPEG750- b -oligo(e-caprolactone) 5 (mPEG750- b -OCL 5 ) with a hydroxyl (OH), benzoyl (Bz) or naphthoyl (Np) end group was investigated. Next, the release characteristics and cytotoxicity of the loaded micelles were studied. MPEG750- b -OCL 5 -OH micelles loaded with taxanes formed unstable particles with rapid leakage of the drug. In contrast, the presence of an aromatic end group (Bz or Np) resulted in the formation of small (10 nm), almost monodisperse micelles with stable encapsulation of 10% (w/w) of PTX or DCTX. This was ascribed to a better compatibility between the micellar core and the drug as compared to the oligomers with the hydroxyl end group. 1 H NMR studies showed that the micellar core was liquid, and that PTX was molecularly dissolved in the core. The in vitro stability was studied in PBS at 37 °C, which showed that leakage of PTX from 10% and 5% (w/w) loaded mPEG750- b -OCL 5 -Bz micelles started after 8 and 24 h, respectively. The presence of albumin did not affect the stability, suggesting that the micelles are not destabilised and the drug was not extracted from the micellar core by this protein. The in vitro cytotoxic effect of the taxane-loaded micelles on C26 carcinoma cells was comparable to that of the commercial formulations, but the empty micelles were far less toxic than the Cremophor EL ® vehicle. The results show that mPEG- b -oligo(e-caprolactone) micelles hold good promise for the formulation of taxanes.
- Published
- 2008
41. Stabilization of IgG by supercritical fluid drying: Optimization of formulation and process parameters
- Author
-
Gerard W. Hofland, Andréanne Bouchard, Daan J.A. Crommelin, Wim Jiskoot, Nataša Jovanović, and Geert-Jan Witkamp
- Subjects
Circular dichroism ,Chromatography ,Scanning electron microscope ,Spectrum Analysis ,Pharmaceutical Science ,General Medicine ,Fluorescence spectroscopy ,Supercritical fluid ,Inclusion compound ,chemistry.chemical_compound ,chemistry ,Immunoglobulin G ,Chromatography, Gel ,Microscopy, Electron, Scanning ,Humans ,Electrophoresis, Polyacrylamide Gel ,Titration ,Fourier transform infrared spectroscopy ,Lysozyme ,Biotechnology - Abstract
The aim of this study was to stabilize human serum immunoglobulin G (IgG) by a supercritical fluid (SCF) drying process. Solutions containing IgG (20mg/ml) and trehalose or hydroxypropyl-beta-cyclodextrin in a 1:4 (w/w) ratio were sprayed into a SCF phase consisting of CO(2) and ethanol at 100bar and 37 degrees C. Initially, a set of drying conditions previously developed to successfully stabilize lysozyme and myogobin formulations was used [N. Jovanović, A. Bouchard, G.W. Hofland, G.J. Witkamp, D.J.A. Crommelin, W. Jiskoot, Eur. J. Pharm. Sci. 27 (2006) 336-345]. Dried formulations were analyzed by Karl Fisher titration, scanning electron microscopy, X-ray powder diffraction, and modulated DSC. Protein structure in the solid-state was studied by FTIR and after reconstitution by UV/Vis, circular dichroism and fluorescence spectroscopy, GPC and SDS-PAGE. When IgG was dried under the above-mentioned conditions, substantial amounts of insoluble aggregates were formed. Addition of buffer helped to reduce the fraction of insoluble material but not of soluble aggregates. Full stabilization could be achieved by adjusting the process conditions: drying without ethanol while keeping the other conditions the same, or drying with ethanol at a temperature below the critical point (20 degrees C). In conclusion, it is possible to stabilize human IgG by SCF drying provided that the formulation and process conditions are tailored to meet the specific requirements of the protein.
- Published
- 2008
42. A mechanistic Study on the Chemical and Enzymatic Degradation of PEG‐Oligo(ε‐caprolactone) Micelles
- Author
-
Myrra G. Carstens, Cornelus F. van Nostrum, Leo G.J. de Leede, Daan J.A. Crommelin, R. Verrijk, and Wim E. Hennink
- Subjects
Spectrometry, Mass, Electrospray Ionization ,Magnetic Resonance Spectroscopy ,Polyesters ,Kinetics ,Pharmaceutical Science ,Micelle ,Polyethylene Glycols ,Hydrolysis ,chemistry.chemical_compound ,Polymer chemistry ,Electrochemistry ,Lipase ,Chromatography, High Pressure Liquid ,Micelles ,Drug Carriers ,biology ,Chemistry ,Substrate (chemistry) ,Hydrogen-Ion Concentration ,biology.protein ,Degradation (geology) ,Pharmaceutical Vehicles ,Drug carrier ,Ethylene glycol ,Algorithms ,Half-Life - Abstract
The chemical and enzymatic degradation of monodisperse oligo(e‐caprolactone) (OCL) and its amphiphilic block oligomer with methoxy poly(ethylene glycol) (mPEG) were investigated in order to obtain insight into the degradation of mPEG‐ b ‐OCL micelles. Hydrolytic degradation was studied as function of pH and dielectric constant of the medium, and enzymatic degradation was investigated at different enzyme and substrate concentrations. The degradation was monitored by HPLC and MS, and the micelle destabilization with DLS. It was found that the hydrolytic degradation followed pseudo first order kinetics, and that the rate depended on the pH and dielectric constant. Degradation essentially occurred via a random scission process, and induced micelle destabilization after approximately 1.5 degradation half‐lives. At physiological pH and temperature, OCLs are very stable, reflected by an estimated degradation half‐life of mPEG‐ b ‐OCL micelles of several years. However, the presence of lipase resulted in an accelerated degradation with half‐lives of a few days to hours. The enzymatic degradation of mPEG‐ b ‐OCL followed Michaelis–Menten kinetics. The results indicate that mPEG‐ b ‐OCL micelles are very stable in vitro , but their susceptibility to enzymes such as lipase makes these systems suitable for the hydrolysis controlled release of drugs in vivo . © 2007 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:506–518, 2008
- Published
- 2008
43. Quality control of routine, experimental and real-time aged diphtheria toxoids by in vitro analytical techniques
- Author
-
Wim Jiskoot, Bernard Metz, Dirk Mekkes, Robert Kingma, Daan J.A. Crommelin, Wim E. Hennink, and Gideon F.A. Kersten
- Subjects
Quality Control ,Time Factors ,Diphtheria Toxoid ,Protein Conformation ,chemical and pharmacologic phenomena ,Biosensing Techniques ,complex mixtures ,Mice ,Chlorocebus aethiops ,medicine ,Animals ,Potency ,Vero Cells ,Diphtheria toxin ,Chromatography ,General Veterinary ,General Immunology and Microbiology ,Chemistry ,Circular Dichroism ,Diphtheria ,Public Health, Environmental and Occupational Health ,Toxoid ,medicine.disease ,Infectious Diseases ,Immunology ,Molecular Medicine ,Electrophoresis, Polyacrylamide Gel - Abstract
Physicochemical and immunochemical techniques can be used to assess the quality of diphtheria toxoid vaccines. In a previous paper [Metz B, Jiskoot W, Hennink WE, Crommelin DJA, Kersten GFA. Physicochemical and immunochemical techniques predict the quality of diphtheria toxoid vaccines. Vaccine 2003;22(2):156-67], techniques were introduced which indicated toxoid quality with respect to safety and potency: SDS-PAGE, primary amino group determination, fluorescence/denaturation, circular dichroism and biosensor analyses. These analyses were performed with experimental toxoids from one toxin batch. In the present study, the quality of regular vaccine batches of different manufacturers, the properties of real-time aged products and a number of experimental toxoids were investigated, using the above-mentioned analytical techniques. We had the unique opportunity to analyse toxoids that were up to 40 years old. The real-time aged diphtheria toxoids showed hardly any structural differences as compared to the recently prepared products in both the analytical chemical techniques and the conventional potency and safety tests. The analytical assays discriminated between regular diphtheria toxoids and experimental toxoids prepared by methylation, acetylation or glutaraldehyde treatment. The analytical data showed a clear correlation with potency and safety of these toxoids. Based on the results, we refined the described physicochemical and immunochemical criteria that a standard diphtheria toxoid has to meet. We recommend further validation of these techniques for quality control of diphtheria toxoid vaccine because of their high precision and easy performance as compared to conventional in vivo procedures.
- Published
- 2007
44. Diphtheria toxoid-containing microparticulate powder formulations for pulmonary vaccination
- Author
-
Anne H. de Boer, Hubert C. Pellikaan, Gideon F.A. Kersten, Maryam Amidi, Daan J.A. Crommelin, Hoang Hirschberg, Wim E. Hennink, Wim Jiskoot, and Pharmaceutical Technology and Biopharmacy
- Subjects
Male ,Guinea Pigs ,TRIMETHYL CHITOSAN CHLORIDE ,Immunoglobulins ,INTRANASAL VACCINATION ,DENDRITIC CELLS ,Microbiology ,INHALATION AEROSOLS ,Chitosan ,chemistry.chemical_compound ,Antigen ,supercritical carbon dioxide ,In vivo ,Animals ,Particle Size ,Neutralizing antibody ,Lung ,N-Trimethyl chitosan (TMC) microparticles ,Diphtheria-Tetanus-Pertussis Vaccine ,IN-VIVO ,Diphtheria toxin ,Chromatography ,General Veterinary ,General Immunology and Microbiology ,biology ,SUPERCRITICAL-FLUID TECHNOLOGY ,Vaccination ,PARTICULATE ANTIGENS ,Public Health, Environmental and Occupational Health ,Toxoid ,Laser diffraction analysis ,diphtheria toxoid ,INFLUENZA SUBUNIT ANTIGEN ,Infectious Diseases ,Dextran ,chemistry ,pulmonary vaccine delivery ,DELIVERY-SYSTEM ,MUCOSAL IMMUNITY ,Microscopy, Electron, Scanning ,biology.protein ,Nanoparticles ,Molecular Medicine ,Female ,Powders - Abstract
this study, the potential of N-Trimethyl chitosan (TMC, degree of quaternization 50%) and dextran microparticles for pulmonary delivery of diphtheria toxoid (DT) was investigated. The antigen-containing microparticles were prepared by drying of an aqueous solution of polymer and DT through a supercritical fluid (SCF) spraying process. The median volume diameter of the dry particles, as determined by laser diffraction analysis, was between 2 and 3 mu m and the fine particle mass fractions smaller than 5 mu m, as determined by cascade impactor analysis, were 35 and 56% for the dextran and TMC formulations, respectively. The water content of the particles as measured by Karl-Fischer titration was 2-3% (w/w). Pulmonary immunization with DT-TMC microparticles containing 2 or 10 Lf of DT resulted in a strong immunological response as reflected by the induction of IgM, IgG, IgG subclasses (IgG1 and IgG2) antibodies as well as neutralizing antibody titers comparable to or significantly higher than those achieved after subcutaneous (SC) administration of alum-adsorbed DT (2 Lf). Moreover, the IgG2/IgG1 ratio after pulmonary immunization with DT-TMC microparticles was substantially higher as compared to SC administered alum-adsorbed DT. In contrast, pulmonarily administered DT-dextran particles were poorly immunogenic. Among the tested formulations only pulmonarily administered DT-contairling TMC microparticles induced detectable pulmonary secretory IgA levels. In conclusion, in this paper it is demonstrated that TMC microparticles are a potent new delivery system for pulmonary administered DT antigen. (c) 2007 Elsevier Ltd. All rights reserved.
- Published
- 2007
45. Self-Assembly of Recombinant Amphiphilic Oligopeptides into Vesicles
- Author
-
Albert J. van Hell, Wim Jiskoot, Marc Sutter, Enrico Mastrobattista, Wim E. Hennink, Daan J.A. Crommelin, Frits M. Flesch, and Cristina I. C. A. Costa
- Subjects
Polymers and Plastics ,Dispersity ,Fluorescence Polarization ,Bioengineering ,Biomaterials ,Surface-Active Agents ,Amphiphile ,Escherichia coli ,Materials Chemistry ,Organic chemistry ,Static light scattering ,chemistry.chemical_classification ,Oligopeptide ,Aqueous solution ,Chemistry ,Vesicle ,Gene Expression Regulation, Bacterial ,Hydrogen-Ion Concentration ,Fluoresceins ,Amino acid ,Microscopy, Electron ,Spectrometry, Fluorescence ,Biophysics ,Self-assembly ,Genetic Engineering ,Oligopeptides - Abstract
The aim of the present study was to design amphiphilic oligopeptides that can self-assemble into vesicular structures. The ratio of hydrophilic to hydrophobic block length was varied, and peptides were designed to have a hydrophobic tail in which the bulkiness of the amino acid side groups increases toward the hydrophilic domain (Ac-Ala-Ala-Val-Val-Leu-Leu-Leu-Trp-Glu(2/7)-COOH). These peptides were recombinantly produced in bacteria as an alternative to solid-phase synthesis. We demonstrate with different complementary techniques (dynamic and static light scattering, tryptophan fluorescence anisotropy, and electron microscopy) that these amphiphilic peptides spontaneously form vesicles with a radius of approximately 60 nm and a low polydispersity when dispersed in aqueous solution at neutral pH. Morphology and size of the vesicles were relatively insensitive to the variations in hydrophilic block length. Exposure to acidic pH resulted in formation of visible aggregates, which could be fully reversed to vesicles upon pH neutralization. In addition, it was demonstrated that water-soluble molecules can be entrapped inside these peptide vesicles. Such peptide vesicles may find applications as biodegradable drug delivery systems with a pH-dependent release profile.
- Published
- 2007
46. Selective Production of Polymorphs and Pseudomorphs Using Supercritical Fluid Crystallization from Aqueous Solutions
- Author
-
Geert-Jan Witkamp, Gerard W. Hofland, Wim Jiskoot, Daan J.A. Crommelin, Andréanne Bouchard, Eduardo Mendes, and Nataša Jovanović
- Subjects
Aqueous solution ,Precipitation (chemistry) ,Inorganic chemistry ,Supercritical fluid extraction ,General Chemistry ,Condensed Matter Physics ,Supercritical fluid ,law.invention ,Volumetric flow rate ,Solvent ,chemistry.chemical_compound ,chemistry ,law ,Carbon dioxide ,General Materials Science ,Crystallization - Abstract
A number of supercritical fluid technologies are known to enable the selective production of polymorphs, only by changing the process conditions. These techniques use either supercritical CO2 or organics as solvent. In this work, the precipitation of small organic molecules from aqueous solution was studied using a mixture of supercritical CO2 and ethanol as drying medium and as anti-solvent. Glycine, which has three polymorphs, was precipitated by a direct spraying process. By simple manipulation of the flow rates, the process could be tuned to selectively precipitate either pure α- or β-glycine. When increasing the ethanol concentration in the system, the precipitation of the metastable β-glycine was preferred over the precipitation of α-glycine. Small portions of γ-glycine could be found when choosing slow drying conditions. The same process route was applicable to selectively precipitate pseudomorphs as well. Increasing the ethanol concentration in the extractant phase favored the precipitation of phe...
- Published
- 2007
47. Cellular Uptake of Cationic Polymer-DNA Complexes Via Caveolae Plays a Pivotal Role in Gene Transfection in COS-7 Cells
- Author
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Regine Peschka-Süss, Rolf Schubert, Gerben A. Koning, Ronald S. Oosting, S. Y. Häfele, Wim E. Hennink, M. A. E. M. van der Aa, Ulrich S. Huth, Daan J.A. Crommelin, Enrico Mastrobattista, Advanced drug delivery systems/drug targeting, Dierexperimenteel, and Dep Farmaceutische wetenschappen
- Subjects
viruses ,Pharmaceutical Science ,Beta-Cyclodextrins ,Biomedische technologie en medicijnen ,Farmacie/Biofarmaceutische wetenschappen (FARM) ,Caveolae ,Chlorocebus aethiops ,Polyamines ,Polyethyleneimine ,Pharmacology (medical) ,Enzyme Inhibitors ,Luciferases ,COS cells ,Nocodazole ,beta-Cyclodextrins ,Genetic transfer ,Transferrin ,Farmacie(FARM) ,Clathrin-Coated Vesicles ,Transfection ,Flow Cytometry ,Genistein ,Polyelectrolytes ,Cell biology ,Biochemistry ,COS Cells ,Methacrylates ,Molecular Medicine ,Wortmannin ,cationic polymers ,Intracellular ,Research Paper ,Biotechnology ,Cholera Toxin ,Chlorpromazine ,Macromolecular Substances ,Biology ,Gene delivery ,Endocytosis ,Medical technology ,endocytosis ,Animals ,gene delivery ,Fluorescent Dyes ,Pharmacology ,Organic Chemistry ,Biological Transport ,DNA ,Androstadienes ,Nylons ,Microscopy, Fluorescence - Abstract
Purpose Knowledge about the uptake mechanism and subsequent intracellular routing of non-viral gene delivery systems is important for the development of more efficient carriers. In this study we compared two established cationic polymers pDMAEMA and PEI with regard to their transfection efficiency and mechanism of cellular uptake. Materials and Methods The effects of several inhibitors of particular cellular uptake routes on the uptake of polyplexes and subsequent gene expression in COS-7 cells were investigated using FACS and transfection. Moreover, cellular localization of fluorescently labeled polyplexes was assessed by spectral fluorescence microscopy. Results Both pDMAEMA- and PEI-complexed DNA showed colocalization with fluorescently-labeled transferrin and cholera toxin after internalization by COS-7 cells, which indicates uptake via the clathrin- and caveolae-dependent pathways. Blocking either routes of uptake with specific inhibitors only resulted in a marginal decrease in polyplex uptake, which may suggest that uptake routes of polyplexes are interchangeable. Despite the marginal effect of inhibitors on polyplex internalization, blocking the caveolae-mediated uptake route resulted in an almost complete loss of polyplex-mediated gene expression, whereas gene expression was not negatively affected by blocking the clathrin-dependent route of uptake. Conclusions These results show the importance of caveolae-mediated uptake for successful gene expression and have implications for the rational design of non-viral gene delivery systems.
- Published
- 2007
48. Lysozyme particle formation during supercritical fluid drying: Particle morphology and molecular integrity
- Author
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Geert-Jan Witkamp, Andréanne Bouchard, Wim Jiskoot, Nataša Jovanović, Eduardo Mendes, Daan J.A. Crommelin, and Gerard W. Hofland
- Subjects
Supercritical carbon dioxide ,Chromatography ,Materials science ,Aqueous solution ,Precipitation (chemistry) ,General Chemical Engineering ,Extraction (chemistry) ,Nanoparticle ,Condensed Matter Physics ,Supercritical fluid ,Volumetric flow rate ,Chemical engineering ,Particle ,Physical and Theoretical Chemistry - Abstract
Studies have shown that diverse types of particles can be obtained when processing aqueous protein solutions into powders by using supercritical fluids, however, without identifying the mechanism behind these variations. Therefore, the particle formation of lysozyme by supercritical fluid drying was more systemically studied by varying the flow rates of protein solution, supercritical carbon dioxide and ethanol, co-currently sprayed through a coaxial nozzle. Three different morphologies were identified: agglomerated nanoparticles, microspheres and irregular microparticles. These morphologies could be related to the process conditions, in particular to the fraction of ethanol in the extraction medium: agglomerated nanoparticles were produced under anti-solvent precipitation conditions; microspheres under water extraction conditions; and microparticles under competitive rates of both mechanisms. A slight increase in intermolecular β-sheets was observed in powders (
- Published
- 2007
49. N-Trimethyl chitosan (TMC) nanoparticles loaded with influenza subunit antigen for intranasal vaccination
- Author
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Wim Jiskoot, Anke Huckriede, J. Coos Verhoef, Hans E. Junginger, Laura Bungener, Maryam Amidi, Daan J.A. Crommelin, Stefan Romeijn, and Translational Immunology Groningen (TRIGR)
- Subjects
Hemagglutinin Glycoproteins, Influenza Virus ,Antibodies, Viral ,medicine.disease_cause ,Chitosan ,Mice ,chemistry.chemical_compound ,influenza subunit vaccine ,Drug Delivery Systems ,EPITHELIAL-CELLS CACO-2 ,ABSORPTION ENHANCEMENT ,Influenza A virus ,IMMUNE-RESPONSE ,ACID) MICROSPHERES ,DRUG-DELIVERY ,Antigens, Viral ,IN-VIVO ,Chemistry ,Immunogenicity ,Vaccination ,NASAL DELIVERY-SYSTEM ,Hemagglutinin ,Infectious Diseases ,Influenza Vaccines ,Drug delivery ,Molecular Medicine ,Female ,Antigenicity ,Microbiology ,Antigen ,A VIRUS ,medicine ,Animals ,Humans ,Administration, Intranasal ,CLEARANCE CHARACTERISTICS ,General Veterinary ,General Immunology and Microbiology ,Influenza A Virus, H3N2 Subtype ,nasal vaccine delivery ,Public Health, Environmental and Occupational Health ,HEAT-LABILE ENTEROTOXIN ,Molecular biology ,N-trimethyl chitosan (TMC) nanoparticles ,Mice, Inbred C57BL ,Disease Models, Animal ,Immunoglobulin G ,Immunoglobulin A, Secretory ,Nanoparticles ,Nasal administration - Abstract
In this study, the potential of N-trimethyl chitosan (TMC) nanoparticles as a carrier system for the nasal delivery of a monovalent influenza subunit vaccine was investigated. The antigen-loaded nanoparticles were prepared by mixing a solution containing TMC and monovalent influenza A subunit H3N2 with a tripolyphosphate (TPP) solution, at ambient temperature and pH 7.4 while stirring. The nanoparticles had an average size of about 800 nm with a narrow size distribution and a positive surface charge. The nanoparticles showed a loading efficiency of 78% and a loading capacity of 13% (w/w). It was shown that more than 75% of the protein remained associated with the TMC nanoparticles upon incubation of the particles in PBS for 3 h. The molecular weight and antigenicity of the entrapped hemagglutinin was maintained as shown by polyacrylamide gel electrophoresis and Western blotting, respectively. Single i.n. or i.m. immunization with antigen-loaded TMC nanoparticles resulted in strong hemagglutination inhibition and total IgG responses. These responses were significantly higher than those achieved after i.m. administration of the subunit antigen, whereas the IgG1/IgG2a profile did not change substantially. The i.n. administered antigen-TMC nanoparticles induced higher immune responses compared to the other i.n. antigen formulations, and these responses were enhanced by i.n. booster vaccinations. Moreover, among the tested formulations only i.n. administered antigen-containing TMC nanoparticles induced significant IgA levels in nasal washes of all mice. In conclusion, these findings demonstrate that TMC nanoparticles are a potent new delivery system for i.n. administered influenza antigens. (c) 2006 Elsevier Ltd. All rights reserved.
- Published
- 2007
50. Non-Biological Complex Drugs
- Author
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Jon S. B. de Vlieger and Daan J.A. Crommelin
- Subjects
Computer science - Published
- 2015
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