Download Cyclodextrins and Cyclodextrin Derivatives as

Pre-conference Workshop
Cyclodextrins and Cyclodextrin Derivatives as Pharmaceutical
Excipients: Toxicological and Regulatory Issues
Saturday, June 2nd 2012
Location:
Icelandair Hotel Reykjavik Natura (formerly Hotel Loftleidir)
Program:
9:00 -10:00
Thorsteinn Loftsson
University of Iceland
Cyclodextrin metabolism and pharmacokinetics
10:00 – 11:00
Eva Fenyvesi
CycloLab Ltd.
Cyclodextrin derivatives: substitution degree and
pattern
11:00 – 12:00
Jyrki Heinämäki
University of Tartu
New pharmaceutical excipients: Development and
regulatory perspectives
12:00 – 13:30
Brunch
13:30 – 14:30
Piotr Kozarewicz
European Medicines
Agency
New excipients - regulatory aspects and EMA
experience
14:30 – 15:30
Marcus E. Brewster
Johnson & Johnson
Registration Experiences with Hydroxypropyl-βcyclodextrin
15:30 – 17:00
All
Discussions
Sponsored by
Cyclodextrin metabolism and pharmacokinetics
Thorsteinn Loftsson
Faculty of Pharmaceutical Sciences, University of Iceland, Hofsvallagata 53, IS-107
Reykjavik, Iceland
Cyclodextrins (CDs) possess many of the same physicochemical and biological
characteristics as water-soluble linear dextrins. However, due to their cyclic structure,
they are more resistant towards both enzymatic as well as non-enzymatic hydrolysis
than linear dextrins such as dextran. CDs are resistant to β-amylases that hydrolyze
starch from the non-reducing end, but are slowly hydrolyzed by α-amylases that
hydrolyze starch from within the carbohydrate chain. The hydrolytic rate depends on the
ring size and fraction of free CD. All the natural CDs and their derivatives are
susceptible to bacterial digestion in the gastrointestinal tract. CDs are mainly (more than
about 90%) excreted unchanged with urine via glomerular filtration after parenteral
administration. Most likely any remaining CD is eliminated by other pathways such as
by liver metabolism and biliary excretion via the gastrointestinal tract, analogous to
excretion of the low molecular weight dextrans. The pharmacokinetics of CDs is very
similar to that of linear dextrins of comparable molecular weight. In humans the half-life
(t½) of the elimination phase ranges from about 1.4 to 2 hours and the volume of
distribution (VD) is about 0.2 L/kg for all CDs tested. The pharmacokinetic studies show
that over 90% of parenterally administered CD will be eliminated from the body within
about 6 hours and over 99.9% within 24 hours. Thus, no accumulation of CD will be
observed in individuals with normal kidney function, even at high doses. However, CD
accumulation will be observed in severely renally impaired patients, i.e. individuals with
renal clearance below about 10 ml/min.
References
1. Frömming, K. H., Szejtli, J., 1994. Cyclodextrins in pharmacy, Kluwer Academic
Publishers, Dordrecht.
2. Irie, T., Uekama, K., 1997. Pharmaceutical applications of cyclodextrins. III.
Toxicological issues and safety evaluation. J. Pharm. Sci., 86, 147-162.
3. Stella, V. J., He, Q., 2008. Cyclodextrins. Tox. Pathol., 36, 30-42.
4. Loftsson, T., Brewster, M. E., 2010. Pharmaceutical applications of cyclodextrins:
basic science and product development. J. Pharm. Pharmacol., 62, 1607-1621.
Cyclodextrin derivatives: substitution degree and pattern
Eva Fenyvesi
CycloLab Ltd., H-1097 Budapest, Illatos út 7, Hungary
Cyclodextrin derivatives are usually mixtures of hundreds of isomers. They can be
characterized by the average degree of substitution and a fingerprint of the distribution
of the various isomers. The lecture will cover both the methods for characterization of
these properties in the case of hydroxypropyl and methylated cyclodextrins and the
effect of the degree and pattern of substitution on the pharmaceutically relevant
properties (solubilizing effect on drugs and cell membrane constituents such as
cholesterol and phospholipids). An overview on the regulatory requirements concerning
the degree and pattern of substitution will be given. The mixed derivatives having both
ionic and anionic substituents as a strategy to reduce toxicity will be discussed. The selfaggregation behavior will be also compared.
New pharmaceutical excipients: Development and regulatory perspectives
Jyrki Heinämäki
Department of Pharmacy, Faculty of Medicine, University of Tartu, Nooruse 1, 50411
Tartu, Estonia
Pharmaceutical excipients are chemical substances apart from the active substance and
they are designed to be therapeutically inert. Excipients are “pharmaceutical necessities”
that have various important functions in a medicine. Today, new and specialized areas
of drug delivery (nanoparticles, dendrimers, drug impregnated adhesives and coatings,
tissue repair products, etc.), provide opportunity and necessitate the novel use of
excipients and/or the development of new excipients. New excipients, however, require
a thorough characterisation and documentation with regard to their functionality,
physicochemistry and safety like a new active substance. This lecture will review
development of new pharmaceutical excipients and regulatory actions to approve these
excipients. The differences of European Medicines Agency (EMA) and US Food and
Drug Administration (FDA) guidances on quality and safety testing of new excipients will
be compared and discussed. Four case studies will be presented as examples of
implementation of novel excipients including two new chemical excipients (polyoxyl 15
hydroxystearate and sulfobutyl ether cyclodextrin), a new graft co-polymer (polyvinyl
caprolactam-polyvinyl acetate-PEG), and a new co-processed excipient (silicified
microcrystalline cellulose). Potential toxicological concerns for impurity safety of new
excipients will be also discussed with a special reference set impurity safe limits.
References
1. European Medicines Agency (EMA). Committee for Medicinal Products for
Human Use (CMPH). Guideline on excipients in the dossier for application for
marketing authorisation 2008: 1-12
2. Osterberg RE, DeMerlis CC, Hobson DW et al. Trends in excipient safety
evaluation. Int J Toxicol 2011;30:600-10
3. Koo MY, Varia SA. Case studies with new excipients: development,
implementation and regulatory approval. Therapeutic Delivery 2011;2(7):949-56.
New excipients – regulatory aspects and EMA experience
Piotr Kozarewicz
European Medicines Agency, 7 Westferry Circus, Canary Wharf, London E14 4HB,
United Kingdom
Excipients constitute necessary and important components of medicinal products.
Although not pharmacologically active, they can enhance product performance by
assuring the stability of the active substance, or to protect against microbial
contamination during use, or to optimise the delivery or the kinetics of the active
substance and therefore can influence the bioavailability.
It is not a homogenous group of substances, and various subgroups can be
distinguished based on their function in medicinal products or by the length of their use,
e.g. well established excipients vs novel (or new) ones. The nature of excipients used in
pharmaceutical formulations is changing from traditional, compendial substances to
more complex or sophisticated compounds designed to perform specific functions within
the medicinal product. These substances, classified as novel excipients, are increasingly
being developed purely for pharmaceutical use.
In accordance with the current guidelines, a novel excipient is an excipient which is used
for the first time in a drug product, or by a new route of administration (ICH). It may be a
new chemical entity or a well established one which has not yet been used for human
administration and/or for a particular human administration pathway in the EU and/or
outside the EU.
Why the novel excipients are being developed? The need for more focused or targeted
drug delivery and use of new technology to meet these needs, new lipophilic and high
molecular weight compounds, compounds with low permeability, innovative proteins or
micro-/nano-sized carrier systems trigger development of more sophisticated delivery
systems and/or use of novel excipients.
The use of novel excipients can be seen as a challenge, as the amount of information
required in support of a marketing authorization is much more comprehensive than for
an established excipient. According to the EU legislation, novel excipient is regarded as
a new substance which must be subjected to the full evaluation, similar to new active
substances. Full details of manufacture, characterisation, and controls, with cross
references to supporting safety data, both non-clinical and clinical, are expected to be
provided according to the active substance format and to be presented as a stand-alone
document. Additional information on toxicity studies with the novel excipient is expected
to be provided in non-clinical part of the dossier. This requires acute toxicity studies,
subchronical and chronical studies, genotoxicity studies, reproductive toxicity studies
and ADME. As for any active substance, the principles of risk-benefit assessment apply
to excipients included in medicinal products.
Although novel excipients are developed for pharmaceutical use, they are not frequently
seen in medicinal products. Stricter requirements lead to perception that the use of novel
excipients makes evaluation more complex and may cause delays in the approval
process. However if everything is done properly, using a novel excipient is no more risky
than an established one.
This presentation aims to provide guidance on regulatory requirements for novel
excipients in the EU (what needs to be provided) and characterise the impact on the
approval process caused by inclusion of novel excipients in medicinal products (what the
process will look like).
References:
1. Annex 1 of the Directive 2001/83/EC of the European Parliament and of the
Council on the Community code relating to medicinal products for human use.
2. Guideline on excipients in the dossier for application for marketing authorisation
of a medicinal product (EMEA/CHMP/QWP/396951/2006).
3. CHMP Scientific Article 5(3) opinion on the potential risks of carcinogens,
mutagens and substances toxic to reproduction when these substances are used
as
excipients
of
medicinal
products
for
human
use
(EMEA/CHMP/SWP/146166/2007).
Registration Experiences with Hydroxypropyl-β-cyclodextrin
Marcus E. Brewster
Pharmaceutical Development and Manufacturing Sciences, Janssen Research and
Development, Johnson & Johnson, Turnhoutseweg 30, Beerse 2340 Belgium
In order to achieve appropriate levels of solubilization, dissolution rate and potential
supersaturation, excipients are often required. Excipients are components of a dosage
form which are included for a variety of reasons and are usually not directly associated
with the activity of the selected drug substance. These materials, unlike the active
pharmaceutical ingredient (API), have no regulatory status in and of themselves. In the
US, their use is generally supported by widespread experience with these materials
based on: (1) being recognized as “generally regarded as safe (GRAS)” by the FDA and
other agencies (USA 21CFR182, 184 and 186), (2) being approved as a food additive by
the FDA or other agencies (21CFR171), (3) being present in an approved drug product.
In this instance, the use of the excipient, without additional data, is limited to
circumstances where the same material is used in the same administration route, at the
same level of exposure, for the same duration and in the same patient population. The
nature and extent of toxicology needed to use an excipient is included in “Guidance for
Industry – Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients”
(FDA 2005).
Hydroxypropyl-β-cyclodextrin is compendial in the European Pharmacopeia (EP) as well
as the United States Pharmacopeia (USP/NF) where its official designation is
hydroxypropylbetadex. The compound is also available in the FDA List of Inactive
Ingredients. Janssen Pharmaceutical maintains a drug master file (DMF) containing
information on this material which has allowed its successful use as an excipients in
multiple products. Information that was considered important in this regard include
analytical data as well as toxicology evaluation - mutagenicity, single and multiple doses
to various animal species, reproductive and embryotoxicology, carcinogenicity
assessments, pharmacodynamics, pharmacokinetics and toxicokinetics, local irritation
and tolerance as well as a number of specialty studies. A brief description and history of
the regulatory submission of the data package will be provided.
References
1. M. Brewster, T. Loftsson. Cyclodextrins as pharmaceutical solubilizers.
Drug Deliv Rev 2007;59:645-666.
Adv