Innovative Softgel Technology
SPon Sore D b y
PharmTech.com
mage courtesy of Catalent Pharma Solutions. © 2016 Catalent, Inc. All rights reserved
InnovatIve
Softgel
technologIeS
to DelIver
Poorly Soluble
MoleculeS
TOC
SOfTgel
Table of contents
03
11
15
Bioavailability Enhancement
with Lipid-Based
Drug-Delivery Systems
By Adeline Siew, PhD
Advancing Softgel Technology
for Poorly Soluble or Highly
Potent APIs
By Cynthia A. Challener
Opportunities with Softgels
By Stephen Tindal
A custom e-Book from Pharmaceutical Technology and Catalent
bIoavaIlabIlIty enhanceMent wIth
lIPID-baSeD Drug-DelIvery SySteMS
By Adeline Siew, PhD
ARTICLE
lIPID-BASeD
DelIVeRY SYSTeMS
Click to
view link
VIDEO
Softgel Technology to
Deliver Poorly Soluble APIs
Click
to view
video
3 | January 2016
Experts from Capsugel and Catalent discuss
the rationale of using lipid-based formulations
to improv the oral bioavailability of poorly
soluble drugs.
Poor solubility remains an ongoing challenge
in formulation development. “the abundance
of poorly soluble drugs is often attributed to
the manner by which companies build large
compound libraries (usually via combinatorial
chemistry techniques) and/or the use of
high-throughput screening assays to identify
potential candidates,” explain eduardo Jule,
PhD, senior manager, and hywel williams, PhD,
senior scientist, both with capsugel’s Dosage
form Solutions business unit. “In the latter,
the identiication of potential hits will often be
measured by how readily a particular compound
binds to a receptor. because receptor binding
will involve a level of hydrophobic interactions
between the drug and receptor, these assays
may, therefore, preferentially select those drugs
that are intrinsically hydrophobic.”
Julien Meissonnier, vP, Science and
technology, catalent, notes that while poorly
BIOAVAILABILITY
ENHANCEMENT
ADVANCING SOFTGEL
TECHNOLOGY
soluble drugs are here to stay, this issue
is, however, not currently addressed
appropriately due to the multiple existing
and emerging technologies arising in the
area, as well as the lack of clarity around
the beneits and options that these
technologies can provide to formulation
scientists. “also, a large portion
of the current solubility-enhancing
technologies bring incremental
development complexity (such as
increased incompatibilities, complex
scale-up, and clinical acceptability)
resulting in loss of time and additional
risks,” says Meissonnier. “as a result,
achieving a clear picture of the solubilityenhancement space has become
increasingly complex.”
there is a growing interest in lipid-based
drug-delivery systems as a means to
improve the bioavailability of poorly
soluble drugs. Jule, williams, and
Meissonnier discuss the advantages of
this approach and the challenges in
developing lipid-based formulations.
PharmTech: First of all, what is the
rationale of using lipid-based drugdelivery systems?
Jule and Williams (Capsugel): lipidbased drug-delivery systems have the
proven capacity to improve the oral
bioavailability of a drug via several
4 | January 2016
OPPORTUNITIES
WITH SOFTGELS
mechanisms, with the unique potential
to address both physicochemical
and biological obstacles to systemic
exposure. It is, therefore, appropriate to
describe these mechanisms in relation to
the fate of a lipid-based formulation in
the gastrointestinal (gI) tract:
Stomach. lipid-based formulations
containing the drug, either dissolved or
suspended, are typically administered via
hard or soft capsules. following rupture
and disintegration of the capsule shell in
the stomach, the formulation mixes with
gastric luid to an extent that is governed
by formulation composition and stomach
contents. In the fasted state (which is
usually more challenging for poorly
soluble drugs than fed-state conditions),
those formulations containing a mixture
of oil and surfactant(s) will self-emulsify
before entering the small intestine--the
primary site of drug absorption.
Small intestinal lumen. here, a high
dissolved drug concentration at the
intestinal wall will promote passive
drug diffusion across the enterocyte
membrane. for a poorly soluble drug,
enabling technologies are required to
increase solubility and dissolution so that
a high dissolved concentration that drives
intestinal absorption can be attained.
this may be achieved via lipid-based
formulations, wherein the potential to
BIOAVAILABILITY
ENHANCEMENT
ADVANCING SOFTGEL
TECHNOLOGY
administer the drug pre-dissolved in the
formulation matrix is such that dissolution
can be bypassed altogether, while the
lipidic components of the formulation
(dispersed and/or digested) mix with
endogenous bile salts and phospholipids
to form a range of colloidal species that
increase drug solubility and present
the drug in a well-dispersed and
readily absorbable form. Small colloidal
species formed by lipidic excipients and
endogenous solubilizers will also enhance
drug transport through the unstirred
water layer, which can be slow and
potentially limiting to absorption when
the drug is lipophilic.
enterocyte. lipid-based formulations
may also impact post-absorption events
to improve bioavailability of drugs that
are subject to:
■ intestinal eflux—fatty acids and
nonionic surfactants commonly
used in lipid-based technologies
have been shown to reversibly
inhibit P-glycoprotein and breast
cancer resistance protein (bcrP)
eflux transporters or increase
transcellular permeability.
■ high irst-pass metabolism—
surfactants have been shown to
inhibit cytochrome P450 enzymes
known to extensively metabolize
5 | January 2016
OPPORTUNITIES
WITH SOFTGELS
drugs in the intestinal wall, while
lipidic excipients can, for highly
lipophilic drugs, increase the
fraction of absorbed drug that
enters into the lymphatic system
where hepatic metabolic pathways
are avoided.
Meissonnier (Catalent): lipid-based
formulations of poorly soluble drugs
generally exist during development
where drug substance solutions remain
itn a solution form in the gI luids prior
to facing the gI walls. this means the
formulation must irst resist its dispersion
in the gI luids by maintaining the
drug in solution. upon dispersion,
the formulation could be present in
different states, ranging from coarse
emulsions to thermodynamically stable
microemulsions, which present different
features. after the lipid components
of the formulation are subjected to the
action of the lipase (pancreatic lipase
being the primary contributor), which
acts speciically at the oil/water interface,
the lipids undergo de-esteriication into
fatty acids and partial glycerides. again
upon digestion, it is important to ensure
that the poorly soluble drugs remains
in solution form before facing the
enterocytes.
lipid systems have the advantage
in that they can present the drug as a
stable liquid solution, but the term ‘lipid
BIOAVAILABILITY
ENHANCEMENT
ADVANCING SOFTGEL
TECHNOLOGY
formulation’ has come to mean one of
a large group of formulations that share
some common features. lipid systems
may include triglycerides, mono- and
diglycerides, lipophilic surfactants,
hydrophilic surfactants and cosolvents-excipients with a wide variety of
physicochemical properties.
In 2000, colin Pouton irst established
an effective classiication system for
lipid-based formulations, which was
completed in 2006 (1). based upon their
qualitative and quantitative composition,
the lipid formulations might exhibit
different behaviors upon dispersion
and digestion. the classiication system
consists of four broad categories (1) .
briely, type I formulations are oils that
require digestion; type II formulations
include water-insoluble self-emulsifying
drug-delivery systems (SeDDS); type
III systems include SeDDS or selfmicroemulsifying drug-delivery systems
(SMeDDS) that contain some watersoluble surfactants and/or cosolvents
(type IIIa) or a greater proportion of
water-soluble components (type IIIb);
and type Iv formulations contain no
oils and represent the most extremely
hydrophilic formulations.
the advantage of moving from
type I toward type Iv formulations is
to enhance the solvent power of the
formulation (hence, majority of high-dose
anti-proteases have been formulated
6 | January 2016
OPPORTUNITIES
WITH SOFTGELS
as type Iv systems). Surfactants offer
much greater food solvent capacity
on dilution (as a micellar solution) than
cosolvents. however, moving in this
direction requires increased proportions
of hydrophilic surfactants with Macrogol
(polyethylene glycol) chains that cover
the oil/water interface and provide steric
hindrance to pancreatic lipase action,
thus inhibiting formulation digestion.
the application of SMeDDS to oral
cyclosporine has revolutionized organ
transplantation therapies, which has
consequently triggered a strong focus on
SMeDDS development. while bringing
more complexity, the development
of microemulsion concentrates is
perfectly suited to enhancing exposure,
while resolving variability issues and
food effect for drugs with narrow
therapeutic windows. Indeed, being
thermodynamically stable by deinition,
those systems are much less sensitive to
change in physiological conditions such
as food intake, bile salts, and ph. those
requisites, however, do not apply to all
target product proiles (tPP) where more
simple, fast-to-develop lipid systems
would apply.
lipid systems enable the resolution of
intrinsic solubility issues associated with
pharmaceutical actives, but unlike other
alternate delivery approaches, enable
more complex biopharmaceutical hurdles
to be overcome and have the ability to
BIOAVAILABILITY
ENHANCEMENT
ADVANCING SOFTGEL
TECHNOLOGY
match some more complex tPPs. the
proper selection of lipid ingredients can
inhibit eflux transporters, extensively
affect presystemic metabolism and
inluence the route of absorption, for
example, by enhancing the lymphatic
uptake of highly lipophilic actives.
PharmTech: What are the beneits
of using lipid-based drug-delivery
systems for solubility/bioavailability
enhancement compared with other
available methods?
Meissonnier (Catalent): lipid systems
allow manufacturing operations to
progress rapidly, and may accelerate
access to early clinical phases and
future scale-up steps. using a rational
approach in preformulation operations
with liquid systems not only enables
accelerated predictability of drug/
ingredient interactions but also, with the
use of in-vitro and in-silico development
tools, assists in tailoring the optimum
lipid formulation system and increasing
predictability of in-vivo performance.
working with liquid and semi-solid
systems, catalent has developed a
standard procedure, whereby low batch
sizes (hundred grams of formulation) are
produced under cgMP conditions using
commercial encapsulation equipment,
enabling quality-by-design integration
from the irst preclinical batches through
7 | January 2016
OPPORTUNITIES
WITH SOFTGELS
to manufacture.
Jule and Williams (Capsugel): as
mentioned previously, lipid-based
technologies offer the possibility to
address both physicochemical and
biological barriers to bioavailability,
which is particularly advantageous
when events post-absorption are such
that bioavailability remains low, in spite
of increased solubility and dissolution
rate. owing to fast capsule rupture and
the absence of dissolution, lipid-based
formulations also may be designed to
provide fast rate of absorption, which is
often desirable when a rapid onset of
action is needed.
aside from performance advantages,
lipid-based formulations offer a
straightforward way of formulating drugs
that are low melting (i.e., < 100 °c)
while avoiding process-related issues
when attempting to mill, granulate,
and produce tablet formulations. the
potential to formulate a drug dissolved in
a non-aqueous vehicle also circumvents
the risk of solid-state polymorphism
(during manufacture and/or on storage).
additionally, liquid-illed hard or soft
capsules offer an optimal approach for
formulating highly potent/low-dose
drugs, ensuring dose uniformity and
reducing exposure risks associated
with handling solids. lastly, liquid-illed
capsules offer an established scale-up
BIOAVAILABILITY
ENHANCEMENT
ADVANCING SOFTGEL
TECHNOLOGY
route, particularly when working with
homogenous solutions.
PharmTech: Can you describe a
stepwise approach for formulation
development of lipid-based drugdelivery systems?
Jule and Williams (Capsugel): once a
lipid-based approach is determined to
be the optimal technology for improving
bioavailability, the irst step to the
development of a robust lipid-based
formulation is to further qualify the drug
candidate in terms of physicochemical
and biopharmaceutical properties. this
ensures that a range of lipidic excipients
(oils, cosurfactants, surfactants, and
cosolvents) is selected based on
the drug characteristics. from here,
solubility testing is performed to identify
excipients toward which the compound
exhibits a high afinity. Selected
excipients are then progressed into the
formulation design phase; this stage
of development can often be slow and
rate-limiting given that a wide number
of potential excipients and excipient
combinations can be theoretically
explored. to accelerate the formulation
design process, capsugel uses a lipid
expert system—an in-silico database
based on hundreds of phase diagrams
coupled to a decision tree--to identify
concept formulations based on drug
8 | January 2016
OPPORTUNITIES
WITH SOFTGELS
solubility in lipid excipients, target dose,
and the dispersibility of several hundred
different placebo formulations across a
range of different dilutions.
concept formulations are then
progressed into a performance testing
program. here, formulations are
subjected to dispersion and simulated
digestion tests to ascertain the likely
fate of the incorporated drug as the
lipid formulation is processed via the
highly eficient lipid digestion and
absorption pathway. the most robust
formulations are those that solubilize
high compound concentrations in
both the dispersed and digested state
(i.e., minimizing drug precipitation),
with limited change in performance
on changing certain experimental
factors, such as bile salt concentration
and extent of dilution. our experience
tells us that such formulations are less
likely to show variable and/or poor
performance in-vivo.
alongside a physical and chemical
stability program, lead formulation(s)
undergo capsule compatibility studies
and physical characterization before a
technical batch is manufactured. During
these latter stages of development, our
understanding and capabilities in this
area are also leveraged to ensure rapid
process development and supply of
clinical batches.
BIOAVAILABILITY
ENHANCEMENT
ADVANCING SOFTGEL
TECHNOLOGY
Meissonnier (Catalent): the
development of lipid systems
encompasses the standard steps found
in pharmaceutical development. the
state of excellence is reached through
the internal development of formulationspeciic analytical techniques, enabling
access to a more complete and accurate
dataset earlier and faster to ensure
proper risk mitigation earlier in the
development cycle.
complementing further drug
characterization studies, preformulation
studies are based upon the kinetic
evaluation of drug solubility in various
classes of ingredients, in parallel with
chemical compatibility screens. these
tests are enabled by speciic automated
platforms and predictive tools.
when progressing to the
formulation development stage, to
select a formulation that is resistant
to precipitation under dispersion and
digestion, catalent operates proprietary
9 | January 2016
OPPORTUNITIES
WITH SOFTGELS
in-vitro and in-silico models, including
a computerized database of digestion
proiles, and also pseudo-ternary
diagrams generated at its ive primary
global development sites dedicated
to lipid-based systems development.
these systems improve the eficiency
of formulation determination, as
well as predictability to progress in
further clinical studies. the excipient
selectionprocess is also based upon
careful selection of the ingredients in
light of their global approvability and
existing safety status. a wide majority of
lipid ingredients are generally recognized
as safe (graS) and several studies are
under way on novel functional lipids to
broaden their existing safety data.
Reference
(1) C.W. Pouton et al., Eur J Pharm Sci 29 (3-4) 278-287 (2006).
aDvancIng Softgel technology for
Poorly Soluble (or hIghly Potent) aPIS
The lipid-based method provides a tool for delivery of highly potent, poorly soluble, and
unstable APIs. And new in-process capsule printing and shell technologies expand softgels’
applications further.
By Cynthia A. Challener
VIDEO
Click
to view
video
Optigel™ Bio
Technology- Innovations
for Oral Macromolecule
Delivery
CASE STUDY
Optigel™ Bio Technology
enables IV to Oral
Therapy Conversion
Click to
view PDf
Softgel capsules are a drug-delivery form
that offers pharmaceutical manufacturers a
tool to overcome the growing formulating
challenges presented by poorly soluble drugs
and highly potent APIs. Advances in softgel
technology are making it possible to use this
drug-delivery approach for a wider selection of
APIs, including those that must be processed at
higher temperatures or wider pH ranges. New
printing methods also reduce process time
and make counterfeiting more difficult. Kevin
Li Product Marketing Manager, Rx Softgel
Technologies, spoke with Cynthia Challener,
editor of the Pharmaceutical Technology, about
these developments and future applications of
softgel technology.
Addressing bioavailability concerns
Pharmaceutical Technology: What are the key
trends driving interest in softgel technology?
li (Catalent): bioavailability challenges
associated with poorly soluble aPIs
(biopharmaceutics classiication System (bcS)
class II and Iv) are driving a lot of interest in
11 | January 2016
BIOAVAILABILITY
ENHANCEMENT
ADVANCING SOFTGEL
TECHNOLOGY
lipid-based drug-delivery systems that
are ideal for softgel formulations. as
drug-discovery teams travel deeper into
libraries and derivatives, the resulting,
more complex leading candidates are
typically less soluble and/or permeable
than previously developed drugs. It
is estimated that as many as 70% of
new chemical entities are either poorly
soluble, poorly permeable, or both.
Softgel technology offers a
drug-delivery solution with the
formulation lexibility to overcome
these challenges. for example, lipidbased formulations can be used to
overcome issues created by aPIs
that are practically insoluble in water
and that spontaneously emulsify in
gastric juices by keeping these aPIs in
solution for absorption and preventing
precipitation. the technology offers
good in-vivo performance with fast
release of ill, has good development
proiles, and is compatible with a wide
range of excipients and formulations.
In addition, as clinical trials become
more complicated and expensive,
companies are increasingly looking for
the optimal therapeutic proile; softgels
can in many cases provide the fastest
path and best chance for clinical success.
Expanded applications
Pharmaceutical Technology: When are
softgels an appropriate delivery vehicle?
12 | January 2016
OPPORTUNITIES
WITH SOFTGELS
li (Catalent): Softgels are the ideal
delivery vehicle for an increasing number
of applications. we have demonstrated
that our softgels are particularly suited
for very low dose aPIs where content
uniformity can be problematic (< 3
mg); potent compounds, hormones,
and cytotoxic compounds where safe
handling is required; poorly soluble
or poorly permeable aPIs; oxygenlabile aPIs; aPIs that are unstable in
light or liquids; and in abuse- deterrent
applications. In addition, we have
developed a new technology that allows
semisolid ills with a wider range of
excipients, enhancers, and aPIs, thus
enabling more drug candidates to beneit
from the therapeutic advantages of
softgel technology.
New printing and ingredient
technologies
Pharmaceutical Technology: What are
some recent advances in softgel capsule
technology?
li (Catalent): the two technologies
that I think are worth noting are inline
printing and the use of new materials in
the shell that impart added performance
properties.
for example, catalent’s proprietary
inline printing technology facilitates
the printing of any required logo or
graphic onto the softgel ribbon prior to
BIOAVAILABILITY
ENHANCEMENT
ADVANCING SOFTGEL
TECHNOLOGY
encapsulation. the advantages of labelling
prior to encapsulation include product
differentiation through branding, processtime reduction, and reduced risk for
counterfeiting because the label is in the
same location on each and every capsule.
the process also ensures a higher level
of quality; mislabelled products may be
outside of speciication in some other
way and can be quickly identiied.
Meanwhile, softgel capsules
manufactured using our [catalent]
new optiShell technology containing
starch and carrageenan in the shell,
makes it possible to use a wider range
of excipients, which in turn, expands
the range of ph values and processing
temperatures (up to 70 °c) that can be
tolerated. as previously mentioned,
these softgels can also be illed with
semisolids.
Technology assessment
Pharmaceutical Technology: What are
the limitations of the technology?
li (Catalent): a key limitation that
we ind is the perception that the
softgel form is a “low” technology
solution. although there are tremendous
advantages to formulating as a softgel,
including a faster formulation time,
improved stability, and a better therapeutic
proile, the balance between the shell,
excipients, and ill formulation is crucial for
13 | January 2016
OPPORTUNITIES
WITH SOFTGELS
the long-term success of therapies. we
are working to overcome this challenge by
developing in-depth expertise in softgel
formulation. In addition, with our in-house
component library, it is possible to rapidly
develop an optimal formulation and
provide a smoother and quicker path to
commercialization.
another perceived limitation of the
technology is that softgels are primarily
an immediate-release technology.
with recent advances in shell and ill
formulations, such as shell technology
with starch and carrageenan, it is
now possible to provide a much wider
range of therapeutic proiles, including
extended-t and modiied-release.
Converting from intravenous
to oral dose
Pharmaceutical Technology: Where
do you see softgel capsule technology
going in the future?
li (Catalent): as the number of lead
candidates that are dificult to formulate
continues to grow and the costs of
commercialization increase, softgel
technology will continue to provide the
industry with a faster, more effective path
to market.
we expect that further advances
will provide even more options to
drug manufacturers that will help them
overcome formulating challenges
BIOAVAILABILITY
ENHANCEMENT
ADVANCING SOFTGEL
TECHNOLOGY
and bring their innovative products
to market. one such example is the
opportunity presented by the conversion
of intravenous formulations to oral dose
14 | January 2016
OPPORTUNITIES
WITH SOFTGELS
forms. Incorporating macromolecules
into softgels may provide tremendous
therapeutic and cost beneits to the
marketplace.
oPPortunItIeS wIth
SoftgelS
By Stephen Tindal
VIDEO
OptiShell Technology
Solves Bioavailability
Challenges
Click
to view
video
TECH NOTE
Click to
view PDf
Better development and
formulation solutions for
challenging compounds
using cutting-edge
softgel innovation
15 | January 2016
Softgel technologies offer an alternative drugdelivery vehicle for lead candidates that are
difficult to formulate.
Softgels are gaining widespread acceptance
as a drug-delivery system for pharmaceuticals,
particularly for lead compounds that present
solubility and permeability challenges during
formulation development. with advances in
softgel technologies ever since the invention of
the manufacturing process by rP Scherer in the
1930s, it is now possible to create solid dosage
forms from liquids, pastes and even powders
that could not be developed into tablet forms,
notes Stephen tindal, director, formulation and
Site r&D lead at catalent Pharma Solutions.
“commonly used in medicines and food
supplements alike, the softgel capsule has
moved on from the simple gelatin shell, with
new materials and modiied delivery proiles
enabling improved drug-delivery forms to be
created,” says tindal. he further explains that
although gelatin is an ideal material for the
shell of a softgel, it is not suitable for vegetarian
diets. “Moreover, the appearance of bovine
BIOAVAILABILITY
ENHANCEMENT
ADVANCING SOFTGEL
TECHNOLOGY
spongiform encephalopathy (bSe) in
the 1990s led to the avoidance of the
commonly used bovine gelatin in favour
of porcine material.”
according to tindal, vegetarian
alternatives have been developed in the
past decade or so, solving all of these
problems in an instant. “they typically
combine a carrageenan with a corn or
potato starch derivative, and shelf-lives
of three years or more are possible with
no loss of shell integrity.” the additional
advantage is that ills can be carried out
at higher temperatures for lipids that are
semi-solid at room temperature, tindal
points out.
enteric coatings can be applied to
softgels to prevent the capsule from
dissolving in the acid environment of
the stomach so that drug release is
delayed until it has moved further down
the gastrointestinal tract. “this feature
is important if the contents are acid
sensitive, if they might cause damage
to the stomach lining, or if absorption
is actively required in the intestines,”
explains tindal. “rapid intestinal
absorption can be achieved if the shell
is designed to dissolve very quickly
and permeation enhancers are added
16 | January 2016
OPPORTUNITIES
WITH SOFTGELS
to the contents, enabling high local
concentrations to be achieved.”
“Softgels can even be made chewable,
making them particularly suitable for
paediatric formulations,” says tindal
“this is achieved by combining the
capsule contents with lavouring and
taste-masking agents and making the
shell out of a ribbon that is made weaker,
perhaps by mixing the gelatin with a
starch. Printed patterns can also be
applied.”
according to tindal, researchers
are currently developing new softgel
formulations to deliver biological
molecules, such as peptides, proteins
and macromolecules. “lipid-based
formulations that self-emulsify are able
to enhance bioavailability, minimising
absorption variability with negligible food
effect, while lipid-based solution and
suspension formulations can have a major
impact on bioavailability, whether that is
by enabling digestion in-vivo by lipolysis
or even modifying the absorption route
to allow lymphatic transport.”
About the Author
Stephen Tindal is director, Formulation and
Site R&D Lead at Catalent Pharma Solutions.
PharmTech.com
mage courtesy of Catalent Pharma Solutions. © 2016 Catalent, Inc. All rights reserved
InnovatIve
Softgel
technologIeS
to DelIver
Poorly Soluble
MoleculeS
TOC
SOfTgel
Table of contents
03
11
15
Bioavailability Enhancement
with Lipid-Based
Drug-Delivery Systems
By Adeline Siew, PhD
Advancing Softgel Technology
for Poorly Soluble or Highly
Potent APIs
By Cynthia A. Challener
Opportunities with Softgels
By Stephen Tindal
A custom e-Book from Pharmaceutical Technology and Catalent
bIoavaIlabIlIty enhanceMent wIth
lIPID-baSeD Drug-DelIvery SySteMS
By Adeline Siew, PhD
ARTICLE
lIPID-BASeD
DelIVeRY SYSTeMS
Click to
view link
VIDEO
Softgel Technology to
Deliver Poorly Soluble APIs
Click
to view
video
3 | January 2016
Experts from Capsugel and Catalent discuss
the rationale of using lipid-based formulations
to improv the oral bioavailability of poorly
soluble drugs.
Poor solubility remains an ongoing challenge
in formulation development. “the abundance
of poorly soluble drugs is often attributed to
the manner by which companies build large
compound libraries (usually via combinatorial
chemistry techniques) and/or the use of
high-throughput screening assays to identify
potential candidates,” explain eduardo Jule,
PhD, senior manager, and hywel williams, PhD,
senior scientist, both with capsugel’s Dosage
form Solutions business unit. “In the latter,
the identiication of potential hits will often be
measured by how readily a particular compound
binds to a receptor. because receptor binding
will involve a level of hydrophobic interactions
between the drug and receptor, these assays
may, therefore, preferentially select those drugs
that are intrinsically hydrophobic.”
Julien Meissonnier, vP, Science and
technology, catalent, notes that while poorly
BIOAVAILABILITY
ENHANCEMENT
ADVANCING SOFTGEL
TECHNOLOGY
soluble drugs are here to stay, this issue
is, however, not currently addressed
appropriately due to the multiple existing
and emerging technologies arising in the
area, as well as the lack of clarity around
the beneits and options that these
technologies can provide to formulation
scientists. “also, a large portion
of the current solubility-enhancing
technologies bring incremental
development complexity (such as
increased incompatibilities, complex
scale-up, and clinical acceptability)
resulting in loss of time and additional
risks,” says Meissonnier. “as a result,
achieving a clear picture of the solubilityenhancement space has become
increasingly complex.”
there is a growing interest in lipid-based
drug-delivery systems as a means to
improve the bioavailability of poorly
soluble drugs. Jule, williams, and
Meissonnier discuss the advantages of
this approach and the challenges in
developing lipid-based formulations.
PharmTech: First of all, what is the
rationale of using lipid-based drugdelivery systems?
Jule and Williams (Capsugel): lipidbased drug-delivery systems have the
proven capacity to improve the oral
bioavailability of a drug via several
4 | January 2016
OPPORTUNITIES
WITH SOFTGELS
mechanisms, with the unique potential
to address both physicochemical
and biological obstacles to systemic
exposure. It is, therefore, appropriate to
describe these mechanisms in relation to
the fate of a lipid-based formulation in
the gastrointestinal (gI) tract:
Stomach. lipid-based formulations
containing the drug, either dissolved or
suspended, are typically administered via
hard or soft capsules. following rupture
and disintegration of the capsule shell in
the stomach, the formulation mixes with
gastric luid to an extent that is governed
by formulation composition and stomach
contents. In the fasted state (which is
usually more challenging for poorly
soluble drugs than fed-state conditions),
those formulations containing a mixture
of oil and surfactant(s) will self-emulsify
before entering the small intestine--the
primary site of drug absorption.
Small intestinal lumen. here, a high
dissolved drug concentration at the
intestinal wall will promote passive
drug diffusion across the enterocyte
membrane. for a poorly soluble drug,
enabling technologies are required to
increase solubility and dissolution so that
a high dissolved concentration that drives
intestinal absorption can be attained.
this may be achieved via lipid-based
formulations, wherein the potential to
BIOAVAILABILITY
ENHANCEMENT
ADVANCING SOFTGEL
TECHNOLOGY
administer the drug pre-dissolved in the
formulation matrix is such that dissolution
can be bypassed altogether, while the
lipidic components of the formulation
(dispersed and/or digested) mix with
endogenous bile salts and phospholipids
to form a range of colloidal species that
increase drug solubility and present
the drug in a well-dispersed and
readily absorbable form. Small colloidal
species formed by lipidic excipients and
endogenous solubilizers will also enhance
drug transport through the unstirred
water layer, which can be slow and
potentially limiting to absorption when
the drug is lipophilic.
enterocyte. lipid-based formulations
may also impact post-absorption events
to improve bioavailability of drugs that
are subject to:
■ intestinal eflux—fatty acids and
nonionic surfactants commonly
used in lipid-based technologies
have been shown to reversibly
inhibit P-glycoprotein and breast
cancer resistance protein (bcrP)
eflux transporters or increase
transcellular permeability.
■ high irst-pass metabolism—
surfactants have been shown to
inhibit cytochrome P450 enzymes
known to extensively metabolize
5 | January 2016
OPPORTUNITIES
WITH SOFTGELS
drugs in the intestinal wall, while
lipidic excipients can, for highly
lipophilic drugs, increase the
fraction of absorbed drug that
enters into the lymphatic system
where hepatic metabolic pathways
are avoided.
Meissonnier (Catalent): lipid-based
formulations of poorly soluble drugs
generally exist during development
where drug substance solutions remain
itn a solution form in the gI luids prior
to facing the gI walls. this means the
formulation must irst resist its dispersion
in the gI luids by maintaining the
drug in solution. upon dispersion,
the formulation could be present in
different states, ranging from coarse
emulsions to thermodynamically stable
microemulsions, which present different
features. after the lipid components
of the formulation are subjected to the
action of the lipase (pancreatic lipase
being the primary contributor), which
acts speciically at the oil/water interface,
the lipids undergo de-esteriication into
fatty acids and partial glycerides. again
upon digestion, it is important to ensure
that the poorly soluble drugs remains
in solution form before facing the
enterocytes.
lipid systems have the advantage
in that they can present the drug as a
stable liquid solution, but the term ‘lipid
BIOAVAILABILITY
ENHANCEMENT
ADVANCING SOFTGEL
TECHNOLOGY
formulation’ has come to mean one of
a large group of formulations that share
some common features. lipid systems
may include triglycerides, mono- and
diglycerides, lipophilic surfactants,
hydrophilic surfactants and cosolvents-excipients with a wide variety of
physicochemical properties.
In 2000, colin Pouton irst established
an effective classiication system for
lipid-based formulations, which was
completed in 2006 (1). based upon their
qualitative and quantitative composition,
the lipid formulations might exhibit
different behaviors upon dispersion
and digestion. the classiication system
consists of four broad categories (1) .
briely, type I formulations are oils that
require digestion; type II formulations
include water-insoluble self-emulsifying
drug-delivery systems (SeDDS); type
III systems include SeDDS or selfmicroemulsifying drug-delivery systems
(SMeDDS) that contain some watersoluble surfactants and/or cosolvents
(type IIIa) or a greater proportion of
water-soluble components (type IIIb);
and type Iv formulations contain no
oils and represent the most extremely
hydrophilic formulations.
the advantage of moving from
type I toward type Iv formulations is
to enhance the solvent power of the
formulation (hence, majority of high-dose
anti-proteases have been formulated
6 | January 2016
OPPORTUNITIES
WITH SOFTGELS
as type Iv systems). Surfactants offer
much greater food solvent capacity
on dilution (as a micellar solution) than
cosolvents. however, moving in this
direction requires increased proportions
of hydrophilic surfactants with Macrogol
(polyethylene glycol) chains that cover
the oil/water interface and provide steric
hindrance to pancreatic lipase action,
thus inhibiting formulation digestion.
the application of SMeDDS to oral
cyclosporine has revolutionized organ
transplantation therapies, which has
consequently triggered a strong focus on
SMeDDS development. while bringing
more complexity, the development
of microemulsion concentrates is
perfectly suited to enhancing exposure,
while resolving variability issues and
food effect for drugs with narrow
therapeutic windows. Indeed, being
thermodynamically stable by deinition,
those systems are much less sensitive to
change in physiological conditions such
as food intake, bile salts, and ph. those
requisites, however, do not apply to all
target product proiles (tPP) where more
simple, fast-to-develop lipid systems
would apply.
lipid systems enable the resolution of
intrinsic solubility issues associated with
pharmaceutical actives, but unlike other
alternate delivery approaches, enable
more complex biopharmaceutical hurdles
to be overcome and have the ability to
BIOAVAILABILITY
ENHANCEMENT
ADVANCING SOFTGEL
TECHNOLOGY
match some more complex tPPs. the
proper selection of lipid ingredients can
inhibit eflux transporters, extensively
affect presystemic metabolism and
inluence the route of absorption, for
example, by enhancing the lymphatic
uptake of highly lipophilic actives.
PharmTech: What are the beneits
of using lipid-based drug-delivery
systems for solubility/bioavailability
enhancement compared with other
available methods?
Meissonnier (Catalent): lipid systems
allow manufacturing operations to
progress rapidly, and may accelerate
access to early clinical phases and
future scale-up steps. using a rational
approach in preformulation operations
with liquid systems not only enables
accelerated predictability of drug/
ingredient interactions but also, with the
use of in-vitro and in-silico development
tools, assists in tailoring the optimum
lipid formulation system and increasing
predictability of in-vivo performance.
working with liquid and semi-solid
systems, catalent has developed a
standard procedure, whereby low batch
sizes (hundred grams of formulation) are
produced under cgMP conditions using
commercial encapsulation equipment,
enabling quality-by-design integration
from the irst preclinical batches through
7 | January 2016
OPPORTUNITIES
WITH SOFTGELS
to manufacture.
Jule and Williams (Capsugel): as
mentioned previously, lipid-based
technologies offer the possibility to
address both physicochemical and
biological barriers to bioavailability,
which is particularly advantageous
when events post-absorption are such
that bioavailability remains low, in spite
of increased solubility and dissolution
rate. owing to fast capsule rupture and
the absence of dissolution, lipid-based
formulations also may be designed to
provide fast rate of absorption, which is
often desirable when a rapid onset of
action is needed.
aside from performance advantages,
lipid-based formulations offer a
straightforward way of formulating drugs
that are low melting (i.e., < 100 °c)
while avoiding process-related issues
when attempting to mill, granulate,
and produce tablet formulations. the
potential to formulate a drug dissolved in
a non-aqueous vehicle also circumvents
the risk of solid-state polymorphism
(during manufacture and/or on storage).
additionally, liquid-illed hard or soft
capsules offer an optimal approach for
formulating highly potent/low-dose
drugs, ensuring dose uniformity and
reducing exposure risks associated
with handling solids. lastly, liquid-illed
capsules offer an established scale-up
BIOAVAILABILITY
ENHANCEMENT
ADVANCING SOFTGEL
TECHNOLOGY
route, particularly when working with
homogenous solutions.
PharmTech: Can you describe a
stepwise approach for formulation
development of lipid-based drugdelivery systems?
Jule and Williams (Capsugel): once a
lipid-based approach is determined to
be the optimal technology for improving
bioavailability, the irst step to the
development of a robust lipid-based
formulation is to further qualify the drug
candidate in terms of physicochemical
and biopharmaceutical properties. this
ensures that a range of lipidic excipients
(oils, cosurfactants, surfactants, and
cosolvents) is selected based on
the drug characteristics. from here,
solubility testing is performed to identify
excipients toward which the compound
exhibits a high afinity. Selected
excipients are then progressed into the
formulation design phase; this stage
of development can often be slow and
rate-limiting given that a wide number
of potential excipients and excipient
combinations can be theoretically
explored. to accelerate the formulation
design process, capsugel uses a lipid
expert system—an in-silico database
based on hundreds of phase diagrams
coupled to a decision tree--to identify
concept formulations based on drug
8 | January 2016
OPPORTUNITIES
WITH SOFTGELS
solubility in lipid excipients, target dose,
and the dispersibility of several hundred
different placebo formulations across a
range of different dilutions.
concept formulations are then
progressed into a performance testing
program. here, formulations are
subjected to dispersion and simulated
digestion tests to ascertain the likely
fate of the incorporated drug as the
lipid formulation is processed via the
highly eficient lipid digestion and
absorption pathway. the most robust
formulations are those that solubilize
high compound concentrations in
both the dispersed and digested state
(i.e., minimizing drug precipitation),
with limited change in performance
on changing certain experimental
factors, such as bile salt concentration
and extent of dilution. our experience
tells us that such formulations are less
likely to show variable and/or poor
performance in-vivo.
alongside a physical and chemical
stability program, lead formulation(s)
undergo capsule compatibility studies
and physical characterization before a
technical batch is manufactured. During
these latter stages of development, our
understanding and capabilities in this
area are also leveraged to ensure rapid
process development and supply of
clinical batches.
BIOAVAILABILITY
ENHANCEMENT
ADVANCING SOFTGEL
TECHNOLOGY
Meissonnier (Catalent): the
development of lipid systems
encompasses the standard steps found
in pharmaceutical development. the
state of excellence is reached through
the internal development of formulationspeciic analytical techniques, enabling
access to a more complete and accurate
dataset earlier and faster to ensure
proper risk mitigation earlier in the
development cycle.
complementing further drug
characterization studies, preformulation
studies are based upon the kinetic
evaluation of drug solubility in various
classes of ingredients, in parallel with
chemical compatibility screens. these
tests are enabled by speciic automated
platforms and predictive tools.
when progressing to the
formulation development stage, to
select a formulation that is resistant
to precipitation under dispersion and
digestion, catalent operates proprietary
9 | January 2016
OPPORTUNITIES
WITH SOFTGELS
in-vitro and in-silico models, including
a computerized database of digestion
proiles, and also pseudo-ternary
diagrams generated at its ive primary
global development sites dedicated
to lipid-based systems development.
these systems improve the eficiency
of formulation determination, as
well as predictability to progress in
further clinical studies. the excipient
selectionprocess is also based upon
careful selection of the ingredients in
light of their global approvability and
existing safety status. a wide majority of
lipid ingredients are generally recognized
as safe (graS) and several studies are
under way on novel functional lipids to
broaden their existing safety data.
Reference
(1) C.W. Pouton et al., Eur J Pharm Sci 29 (3-4) 278-287 (2006).
aDvancIng Softgel technology for
Poorly Soluble (or hIghly Potent) aPIS
The lipid-based method provides a tool for delivery of highly potent, poorly soluble, and
unstable APIs. And new in-process capsule printing and shell technologies expand softgels’
applications further.
By Cynthia A. Challener
VIDEO
Click
to view
video
Optigel™ Bio
Technology- Innovations
for Oral Macromolecule
Delivery
CASE STUDY
Optigel™ Bio Technology
enables IV to Oral
Therapy Conversion
Click to
view PDf
Softgel capsules are a drug-delivery form
that offers pharmaceutical manufacturers a
tool to overcome the growing formulating
challenges presented by poorly soluble drugs
and highly potent APIs. Advances in softgel
technology are making it possible to use this
drug-delivery approach for a wider selection of
APIs, including those that must be processed at
higher temperatures or wider pH ranges. New
printing methods also reduce process time
and make counterfeiting more difficult. Kevin
Li Product Marketing Manager, Rx Softgel
Technologies, spoke with Cynthia Challener,
editor of the Pharmaceutical Technology, about
these developments and future applications of
softgel technology.
Addressing bioavailability concerns
Pharmaceutical Technology: What are the key
trends driving interest in softgel technology?
li (Catalent): bioavailability challenges
associated with poorly soluble aPIs
(biopharmaceutics classiication System (bcS)
class II and Iv) are driving a lot of interest in
11 | January 2016
BIOAVAILABILITY
ENHANCEMENT
ADVANCING SOFTGEL
TECHNOLOGY
lipid-based drug-delivery systems that
are ideal for softgel formulations. as
drug-discovery teams travel deeper into
libraries and derivatives, the resulting,
more complex leading candidates are
typically less soluble and/or permeable
than previously developed drugs. It
is estimated that as many as 70% of
new chemical entities are either poorly
soluble, poorly permeable, or both.
Softgel technology offers a
drug-delivery solution with the
formulation lexibility to overcome
these challenges. for example, lipidbased formulations can be used to
overcome issues created by aPIs
that are practically insoluble in water
and that spontaneously emulsify in
gastric juices by keeping these aPIs in
solution for absorption and preventing
precipitation. the technology offers
good in-vivo performance with fast
release of ill, has good development
proiles, and is compatible with a wide
range of excipients and formulations.
In addition, as clinical trials become
more complicated and expensive,
companies are increasingly looking for
the optimal therapeutic proile; softgels
can in many cases provide the fastest
path and best chance for clinical success.
Expanded applications
Pharmaceutical Technology: When are
softgels an appropriate delivery vehicle?
12 | January 2016
OPPORTUNITIES
WITH SOFTGELS
li (Catalent): Softgels are the ideal
delivery vehicle for an increasing number
of applications. we have demonstrated
that our softgels are particularly suited
for very low dose aPIs where content
uniformity can be problematic (< 3
mg); potent compounds, hormones,
and cytotoxic compounds where safe
handling is required; poorly soluble
or poorly permeable aPIs; oxygenlabile aPIs; aPIs that are unstable in
light or liquids; and in abuse- deterrent
applications. In addition, we have
developed a new technology that allows
semisolid ills with a wider range of
excipients, enhancers, and aPIs, thus
enabling more drug candidates to beneit
from the therapeutic advantages of
softgel technology.
New printing and ingredient
technologies
Pharmaceutical Technology: What are
some recent advances in softgel capsule
technology?
li (Catalent): the two technologies
that I think are worth noting are inline
printing and the use of new materials in
the shell that impart added performance
properties.
for example, catalent’s proprietary
inline printing technology facilitates
the printing of any required logo or
graphic onto the softgel ribbon prior to
BIOAVAILABILITY
ENHANCEMENT
ADVANCING SOFTGEL
TECHNOLOGY
encapsulation. the advantages of labelling
prior to encapsulation include product
differentiation through branding, processtime reduction, and reduced risk for
counterfeiting because the label is in the
same location on each and every capsule.
the process also ensures a higher level
of quality; mislabelled products may be
outside of speciication in some other
way and can be quickly identiied.
Meanwhile, softgel capsules
manufactured using our [catalent]
new optiShell technology containing
starch and carrageenan in the shell,
makes it possible to use a wider range
of excipients, which in turn, expands
the range of ph values and processing
temperatures (up to 70 °c) that can be
tolerated. as previously mentioned,
these softgels can also be illed with
semisolids.
Technology assessment
Pharmaceutical Technology: What are
the limitations of the technology?
li (Catalent): a key limitation that
we ind is the perception that the
softgel form is a “low” technology
solution. although there are tremendous
advantages to formulating as a softgel,
including a faster formulation time,
improved stability, and a better therapeutic
proile, the balance between the shell,
excipients, and ill formulation is crucial for
13 | January 2016
OPPORTUNITIES
WITH SOFTGELS
the long-term success of therapies. we
are working to overcome this challenge by
developing in-depth expertise in softgel
formulation. In addition, with our in-house
component library, it is possible to rapidly
develop an optimal formulation and
provide a smoother and quicker path to
commercialization.
another perceived limitation of the
technology is that softgels are primarily
an immediate-release technology.
with recent advances in shell and ill
formulations, such as shell technology
with starch and carrageenan, it is
now possible to provide a much wider
range of therapeutic proiles, including
extended-t and modiied-release.
Converting from intravenous
to oral dose
Pharmaceutical Technology: Where
do you see softgel capsule technology
going in the future?
li (Catalent): as the number of lead
candidates that are dificult to formulate
continues to grow and the costs of
commercialization increase, softgel
technology will continue to provide the
industry with a faster, more effective path
to market.
we expect that further advances
will provide even more options to
drug manufacturers that will help them
overcome formulating challenges
BIOAVAILABILITY
ENHANCEMENT
ADVANCING SOFTGEL
TECHNOLOGY
and bring their innovative products
to market. one such example is the
opportunity presented by the conversion
of intravenous formulations to oral dose
14 | January 2016
OPPORTUNITIES
WITH SOFTGELS
forms. Incorporating macromolecules
into softgels may provide tremendous
therapeutic and cost beneits to the
marketplace.
oPPortunItIeS wIth
SoftgelS
By Stephen Tindal
VIDEO
OptiShell Technology
Solves Bioavailability
Challenges
Click
to view
video
TECH NOTE
Click to
view PDf
Better development and
formulation solutions for
challenging compounds
using cutting-edge
softgel innovation
15 | January 2016
Softgel technologies offer an alternative drugdelivery vehicle for lead candidates that are
difficult to formulate.
Softgels are gaining widespread acceptance
as a drug-delivery system for pharmaceuticals,
particularly for lead compounds that present
solubility and permeability challenges during
formulation development. with advances in
softgel technologies ever since the invention of
the manufacturing process by rP Scherer in the
1930s, it is now possible to create solid dosage
forms from liquids, pastes and even powders
that could not be developed into tablet forms,
notes Stephen tindal, director, formulation and
Site r&D lead at catalent Pharma Solutions.
“commonly used in medicines and food
supplements alike, the softgel capsule has
moved on from the simple gelatin shell, with
new materials and modiied delivery proiles
enabling improved drug-delivery forms to be
created,” says tindal. he further explains that
although gelatin is an ideal material for the
shell of a softgel, it is not suitable for vegetarian
diets. “Moreover, the appearance of bovine
BIOAVAILABILITY
ENHANCEMENT
ADVANCING SOFTGEL
TECHNOLOGY
spongiform encephalopathy (bSe) in
the 1990s led to the avoidance of the
commonly used bovine gelatin in favour
of porcine material.”
according to tindal, vegetarian
alternatives have been developed in the
past decade or so, solving all of these
problems in an instant. “they typically
combine a carrageenan with a corn or
potato starch derivative, and shelf-lives
of three years or more are possible with
no loss of shell integrity.” the additional
advantage is that ills can be carried out
at higher temperatures for lipids that are
semi-solid at room temperature, tindal
points out.
enteric coatings can be applied to
softgels to prevent the capsule from
dissolving in the acid environment of
the stomach so that drug release is
delayed until it has moved further down
the gastrointestinal tract. “this feature
is important if the contents are acid
sensitive, if they might cause damage
to the stomach lining, or if absorption
is actively required in the intestines,”
explains tindal. “rapid intestinal
absorption can be achieved if the shell
is designed to dissolve very quickly
and permeation enhancers are added
16 | January 2016
OPPORTUNITIES
WITH SOFTGELS
to the contents, enabling high local
concentrations to be achieved.”
“Softgels can even be made chewable,
making them particularly suitable for
paediatric formulations,” says tindal
“this is achieved by combining the
capsule contents with lavouring and
taste-masking agents and making the
shell out of a ribbon that is made weaker,
perhaps by mixing the gelatin with a
starch. Printed patterns can also be
applied.”
according to tindal, researchers
are currently developing new softgel
formulations to deliver biological
molecules, such as peptides, proteins
and macromolecules. “lipid-based
formulations that self-emulsify are able
to enhance bioavailability, minimising
absorption variability with negligible food
effect, while lipid-based solution and
suspension formulations can have a major
impact on bioavailability, whether that is
by enabling digestion in-vivo by lipolysis
or even modifying the absorption route
to allow lymphatic transport.”
About the Author
Stephen Tindal is director, Formulation and
Site R&D Lead at Catalent Pharma Solutions.