The News Capsule
issue 4
The World’s preferred CMO partner for the development
and commercial manufacture of Liquid Filled Hard Capsules
inside this edition : EncodeTM… 2nd Oral Drug Delivery Meeting…
Thermosetting Formulations… Yes, we have no leeks!
New drug feasibility screening
services for colon targeted
delivery
ENCODETM pH and bacteria
sensitive coating for targeted
delivery to the colon
Encap is now offering a feasibility
package which will evaluate
the potential to formulate
candidate compounds in liquid fill
formulations suitable for delivery
to the colon
Recently colonic drug delivery has gained increased
importance, mainly for treatment of local diseases
associated with the colon, such as inflammatory bowel
disease and irritable bowel syndrome. Other local
diseases of the large intestine could benefit from
topical delivery to the colonic mucosa and the potential
of the colon for systemic delivery of drugs including
vaccines, proteins and peptides is of renewed interest.
Encap is able to offer clients a range of colonic delivery
systems, promoted under the name ENCODETM,
including the PhloralTM system licensed from the
London School of Pharmacy.
The new PhloralTM technology represents a significant
improvement in colonic delivery providing ‘fail-safe’ delivery of
drug to the target site by employing two mechanisms to trigger
drug release. The technology combines the bacterial and pH
mediated approaches used previously for colonic delivery.
The combination of these independent but complementary
release mechanisms overcomes the limitations associated with
the single trigger systems and improves site specificity. The
technology involves the combination of a pH-sensitive polymer
with resistant starch and this mixture is used as a film coating
matrix, which can be applied to tablets, capsules or pellets.
Encap’s new screening package includes the following:
•
•
•
Assessing the stability of the test compound to metabolism by colonic bacteria using a buffered faecal slurry test
Determining the feasibility of formulating the drug in a stable liquid fill dosage form
An optional evaluation of the candidate compound’s intestinal permeability using a Caco-2 assay
If you would like to find out more, please contact us.
Please email [email protected] if you would like to receive future editions of The News Capsule direct to your mail box.
2nd Oral drug delivery meeting
On March 4th 2011, Encap were delighted to host their second Oral Drug Delivery Meeting at
The Radisson Blu Hotel, Edinburgh.
The meeting gave attendees the opportunity to hear presentations from leading academic and
industrial experts covering a number of topics of interest to those involved in oral drug product
development. The meeting was attended by over 40 delegates from over 20 pharmaceutical
companies based in the USA, the United Kingdom, France, Switzerland, Germany, Japan,
Sweden and Norway.
Solid dispersion as a
promising technique
for dissolution rate
enhancement
Oral Delivery of
Vaccines
Chair in Drug Delivery
Aston Pharmacy School
School of Life and
Health Sciences
Aston University
Birmingham
An interesting presentation to open the
meeting which looked at the history of
vaccines, specifically oral vaccines. Professor
Perrie also presented work that her team
has carried out developing an oral vaccine for
bovine tuberculosis.
Mario Maio
Director
Formulation and
Process Development
R&D
CMC-Development
Merck Serono
A tale of Two Glasses
Polymer Dispersions
for Enhanced Oral
Bioavailability
Prof. D. Craig
Head of School
School of Pharmacy
University of
East Anglia
Professor Craig discussed the research
carried out by his team at the University of
East Anglia studying amorphous polymer
systems and how they could help enhance
oral bioavailability. This included research to
develop new ways to characterise and analyse
such systems.
‘‘‘‘
Analytical Challenges
for Liquid Fill
Capsules
Alyn McNaughton Encap’s Analytical Manager gave an industry
Analytical Chemistry
perspective on the day to day challenges
Manager
that his team face when working with liquid
Encap Drug Delivery
and semi-solid filled capsules. This included
several case studies from work performed at
Encap.
How to integrate
excipients into QbD
It is really a nice format that allows
an easy and friendly discussion with peers
‘‘‘‘
‘‘‘‘
The whole event was excellent.
The mixture of speaker topics was just
right and the Thursday evening meal and
entertainment were great
‘‘‘‘
…Encap look forward to hosting the next event.
Please contact [email protected]
if you are interested in attending
This presentation discussed in detail the
challenges that pharmaceutical companies
face with poor API solubility and how solid
dispersions (through hot-melt extrusion) can
overcome this. Mario also gave a case study
from recent work at Merck Serono which had
utilised this technology.
Dr Brian Carlin
Director
Open Innovation
FMC BioPolymer
Dr Carlin talked about the important role
and influence that excipients can have in
pharmaceutical development and why we
need to understand their impact when
looking at Quality by Design.
‘‘‘‘
Thank you very much again for this
interesting meeting and adjoining program,
which indeed I enjoyed very much. It was a
very interesting mix of topics as well as of
people
‘‘‘‘
Prof. Y. Perrie
article by Professor Geoff Rowley
Hard Gelatin Capsules, Liquid filled
with Thermosetting Formulations
In the thermosoftening process, the formulation is heated to
produce a mobile liquid at the capsule filling temperature,
normally up to 70°C, followed by cooling in the capsule to form a
solid dispersion. The technique was pioneered commercially over
30 years ago by Bowtle et al1 when very hygroscopic vancomycin
was successfully formulated with PEG 6000 and liquid filled into
hard gelatin capsules. If the active substance dissolves or melts
in the molten excipient at the capsule filling temperature, then
the physical properties of the raw materials have little effect on
filling, however the properties of the recrystallized active and
excipient on cooling in the capsule will influence drug dissolution
and stability of the product. In cases where the active substance
remains as a particulate dispersion in the molten excipient,
then the rheology of the formulation becomes of considerable
importance during capsule filling. It is thus possible to formulate
a liquid filled capsule containing poorly water soluble and
hydrophobic drugs with improved dissolution characteristics, as
demonstrated in the considerable literature on solid dispersions.
In addition, active substances with specific formulation problems
such as hygroscopicity and unpalatability may be formulated as
thermosoftened formulations for oral use2.
Research at The University of Sunderland2 investigated excipients
in the polyoxyethylene group (PEGs) and the poly(oxyethylene)
poly(oxypropylene) block polymer group (poloxamers) to formulate
active substances with a range of physicochemical properties.
This research included thermal analysis to investigate the stability
of active, excipient and the formulation during temperature cycles
typical of the capsule filling process and also after storage, in
order to detect possible ageing of the solid dispersion. Information
from differential scanning calorimetry (DSC), hot stage
microscopy (HSM) and cooling curves of formulation temperature
versus time from fill temperature to solidification in the capsule,
enables the most suitable excipient to be selected. DSC provided
essential information on melting temperature range, enthalpy
and physicochemical stability, whereas HSM provided additional
information on the behaviour of the microcrystalline structure
during melting, cooling and after storage. HSM was also used
profitably to follow penetration of aqueous media at 37°C into the
formuIation, thus simulating dissolution behaviour and hence
providing information to elucidate the mechanisms of drug
release. The cooling curves provide the rate of cooling and time
for solidification of the formulation in the capsule, as well as
detection of supercooling. Ideally, rapid solidifcation will eliminate
leakage of the formulation prior to sealing the capsule, whereas
slow solidifcation and/or supercooling will increase the propensity
for leakage. It was shown that excipients from the PEG and
poloxamer groups are suitable candidates for liquid filling by the
thermosoftening process.
The maximum possible concentration of active substance in
a thermosoftened formulation will depend on the solubility of
active in the molten excipient. For example, ibuprofen forms
a Newtonian solution at 70°C with PEG 6000, PEG 10000 or a
poloxamer, Lutrol F683, has a negligible effect on the viscosity
of the molten formulation and thus could be liquid filled with
high drug concentration e.g. 90% w/w. However, when the active
substance forms a particulate dispersion in the molten excipient,
there will be a critical disperse phase concentration above
which, the apparent viscosity of the non-Newtonian formulation
increases abruptly, resulting in unsatisfactory filling properties4.
Thus, the maximum concentration of active substances in nonNewtonian dispersions will depend upon the disperse phase
particle properties and concentration, as well as the viscosity of
the molten excipient at the filling temperature. Further research
into these systems could lead to predictions of filling capability
and dispersion stability from the physical properties of the
formulation components and the rheology of the dispersion.
There is no doubt that two component solid dispersions, when
liquid filled in hard gelatin capsules can produce rapid drug
release for immediate release products or slow release for a
controlled delivery system. Despite all the research2 on the
thermosoftening technique for liquid filled capsules, there is
still scope for research aimed to produce formulations from a
model, based on the physicochemical properties of bioactives and
excipients, with respect not only to drug delivery, but also capsule
integrity, filling and stability.
References
1. Bowtle, W.J., Barker, N.J. and Woodhams, J. (1988), Pharm. Technol.,
12 (6), 86-91.
2. Rowley, G., (2004), Pharmaceutical Capsules (2nd Ed.), Pharmaceutical Press, Chapter 9, 169-194.
3. Hawley, A.R., Rowley, G., Lough, W.J. and Chatham, S.M., (1992), Drug. Dev. Ind. Pharm., 18(16), 1719-1739.
4. Rowley, G., Hawley, A.R., Dobson, C.L. and Chatham, S.M., (1998), Drug. Dev. Ind. Pharm., 24, 605-611.
Our presence in Japan
Encap’s drug delivery
technology is proving
to be an attractive
global offering.
Several Japanese companies have
chosen Encap to perform formulation
development and manufacture of
clinical supplies. We work closely with
our customers to meet the demands
of the Japanese Pharmacopeia and
regulatory authorities. Our Japanese
clients have adopted liquid fill hard
shell capsules for:
•
•
We will be participating in CPhI Japan
in Osaka 13th – 15th July 2011 and
are looking forward to continuing our
expansion in this market.
Compounds with low bioavailability where we have been able to enhance absorption particularly for water soluble compounds
Low dose compounds to avoid
potential content uniformity challenges with other oral dosage forms
• Highly potent compounds which require safe handling in high containment facilities.
Yes, we have no leeks!
second in a series of articles
by Dr Vic Young on filling and
sealing issues …02/ Capsule
pressurisation and leaking
Following the ‘Yes, we have no bananas’ article in Newsletter
No. 3, we now turn to leeks! Leeks are the friend of the gardener
but the enemy of the pharmaceutical industry (leaks). Leaks are to
liquid fill what capping, chipping and lamination are to tabletting
and are unacceptable in products.
Liquids, as filled into hard capsule shells, are defined as materials
that can be pumped at the point of encapsulation. These may
be thermosetting materials, thixotropic mixes, suspensions
(commonly carrying 30% or more of suspended solids), and room
temperature liquids or have a combination of these properties.
Most thermosetting materials that solidify above 45°C remain
solids during all practical use and thus can not leak. All other
‘liquids’ encapsulated may be able to leak if seal defects are
present. It is apparent from discussions within the industry
that this is a perceived issue with the liquid fill technology that
many have experienced in reality either in their own hands or at
contractors.
Sealing may be performed by banding, a process of placing a
band of gelling solution (gelatin or HPMC, as appropriate to the
capsules), bridging the cap body interface which ‘welds’ the two
parts together or may be carried out by a micro spray process
(Capsugel LEMS™ system). Both systems have their advantages.
Encap chooses to use banding as a band can be visually inspected
during and after application, even on opaque capsules, and the
checking of capsules for ‘leakers’ is straightforward.
pressure. This forces capsule content out through any defect, via
the capsule vents, and allows all leaking capsules to be detected
and removed. This was once an automatic process at Encap when
all product was 100% leak tested. This was followed by a QC
test for leaking capsules that had to be passed before the batch
could be released. Development over the years allowed the Encap
process to be refined to the point where the requirement for full
scale leak testing was successfully discontinued. For more than 10
years, the vast majority of product batches have been the subject
of QC leak-testing only. Encap does, however, retain the facility to
perform 100% leak testing as this can be particularly useful during
product development and scale-up and for clients whose products
require this to be part of the manufacturing process.
In over 15 years of manufacture of product at Encap, no field
complaints of leaking capsules are on file. Leak-free product can
be achieved through careful formulation design, optimisation of
Both softgel capsules and hard shell capsules have the potential
equipment and processing parameters and, most important of all,
to leak. The drying of softgels causes the shell to contract and the skilled scientific, technical and operational staff. Encap have more
contents to become pressurised forcing content out through any
than 50 technical and scientific staff dedicated to the technology,
defects. This allows faulty capsules to be detected and removed
three separate cleanroom suites each with multiple processing
following a tray drying process. Hard shell capsules can be
rooms and four commercial filling and banding lines for standard
challenged by placing on witness-paper and subjecting to reduced and high containment products.
Exhibitions and conferences 2011
Encap will be attending, exhibiting or presenting at the following events in 2011.
Please feel free to stop by for a chat, or arrange an appointment to discuss your requirements.
•Bio Dundee, 8th – 9th June, Hilton Hotel, Dundee, UK.
•Bio 2 Business, 16th June, Sohuset Conference Centre, Copenhagen, Denmark.
•CPhI Japan 2011, 13th – 15th July, Intex, Osaka, Japan.
•Controlled Release Society, 30th July – 3rd August, Gaylord National Resort and Convention Center,
National Harbor, Maryland, USA.
•UK Pharm Sci 2011, 31st August – 2nd September, East Midlands Conference Centre, UK.
•CPhI, ICSE Europe show 2011, 25th – 27th October, Messe Frankfurt, Germany (Booth 40J54).
•AAPS 2011, 23rd – 27th October, Washington Convention Centre, USA (Booth 1751).
Contact us:
Units 4, 5 & 6 Oakbank Park Way
Livingston West Lothian EH53 0TH
Scotland
t: (+44) (0)1506 448080
f: (+44) (0)1506 448081
e:[email protected]
www.encapdrugdelivery.com
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