Download Formulation Strategies for `First-Into-Man` Studies

Formulation
Formulation Strategies
for ‘First-Into-Man’ Studies
By Robert Harris at
Molecular Profiles
Deciding on the best approach for taking a new drug into ‘first-into-man’
studies can be a difficult process – but choosing the right formulation is
critical in ensuring that a new drug is given the best possible chance of
fulfilling its potential in clinical trials.
When a new experimental drug shows great promise
in preclinical studies for the treatment of a disease
which afflicts millions of patients worldwide, there is
one question that raises significant discussion: What
type of formulation would be the most appropriate for
testing in man for the first time? ‘Phase 1 clinical trials’
is a critical stage in any drug development project
and to reach this stage as quickly as possible is of
paramount importance, especially for those companies
with limited budgets or key investor milestones to
meet. Of equal importance is the need to ensure that
the new drug substance is administered in a form that
will give it ‘the best chance of success’ in early clinical
assessment. A poor choice of formulation can lead
to poor clinical data, which in turn can lead to
re-formulation and a prolonged Phase 1 clinical
programme – or even termination of the project. This
article will examine the factors that need to be taken
into consideration when deciding how best to take
a new drug entity into first-into-man studies, and
provides a ‘formulation decision tree’ to offer guidance
on deciding which formulation strategy to follow for
an orally administered drug.
the most suitable approach to providing a dosage form
for the clinic.
More recently, alternative classification systems have
been suggested to replace the BCS, since the purpose of
the BCS is primarily as a drug development tool to help
formulators and sponsors justify requests for biowaivers
(2,3).The developability classification system (DCS),
which was developed using the BCS as its basis, focuses
on intestinal solubility, the compensatory nature of
solubility and permeability in the small intestine, and
an estimate of the particle size needed to overcome
dissolution rate-limited absorption. Observations on test
compounds have demonstrated DCS to be of greater
value in predicting which factors are critical to in vivo
performance compared with the BCS.
Another tool used to predict whether a drug molecule
will have oral bioavailability in humans is Lipinski’s ‘Rule
of 5’ (4).This states that poor absorption of an orallyadministered compound is likely if the compound has a
molecular mass greater than 500 Da, high lipophilicity
(cLogP greater than 5), more than five hydrogen bond
donors and more than ten hydrogen bond acceptors.
Defining the Drug Substance
One of the primary aims of preclinical studies should
be to identify the physicochemical and
Keywords
biological characteristics of a drug in
order to predict oral bioavailability.
According to the biopharmaceutics
First-into-man studies
classification system (BCS), drug
Biopharmaceutics
substances can be classified into four
classification system (BCS)
distinct classes based on their aqueous
Developability classification
solubility and intestinal permeability (1).
system (DCS)
When combined with the dissolution rate
Formulation strategy
of the drug and the unit dose required,
Particle size reduction
this information can be used to decide on
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If a drug molecule has been predicted to exhibit good
oral bioavailability following application of Lipinski’s ‘Rule
of 5’ and/or the DCS, then a simple drug-in-capsule or
drug-in-bottle unformulated approach could be used. On
the other hand, if a drug molecule is predicted to have
poor oral bioavailability, alternative formulation
strategies will need to be considered.
Choosing a Formulation Strategy
Having defined a drug substance according to its
solubility and permeability, the next step is to select the
most appropriate strategy for formulating the drug for
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use in Phase 1 and possibly Phase 2 clinical
trials. Based on the physicochemical and
biological characteristics of the drug,
different formulation strategies may be
applicable. Strategies to consider when
formulating a drug for a first-into-man study
are summarised in the ‘formulation decision
tree’ shown in Figure 1.
A popular strategy is to manually add the
necessary quantity of the drug substance
directly into a capsule or bottle for
reconstitution with a suitable liquid prior to
ingestion.This simple formulation strategy
accelerates progression to first-into-man
studies, while also being cost-effective.
Specialised dosing equipment can be used
to facilitate high precision filling of capsules,
particularly when dosing potent drug
substances (where the required dose is less
than 10mg), or when large quantities of
capsules are required to be filled.
Figure 1:
Formulation
decision tree
Drug
substance
Figure: Molecular
Review
physicochemical
and biological data
Yes
Drug in
capsule/bottle
No
Drug absorption is
solubility limited
Yes
More water soluble
salt available?
Or
No
Conventional capsule
formulation (powder
blend or granules)
Use solubilityenhancing vehicle
Liquid/semi-solid matrix
in capsules (for example,
SEDDS or SMEDDS)
Yes
Although the drug-in-capsule or drug-inbottle approach is time- and cost-efficient, it
is not suitable for all types of drug substance.
If a drug substance does not ‘wet’ easily, or if
its solubility in water is not sufficient, then
it may be poorly absorbed from the
gastrointestinal (GI) tract – and this will
influence the pharmacokinetic data
obtained. For drug substances that have poor
water-solubility and have exhibited poor or variable
absorption when tested in animal models, a watersolubility enhancing formulation strategy should be
considered for Phase 1 clinical evaluation.There are
several such strategies that can be implemented, ranging
from particle size reduction to using inclusion complexes
such as cyclodextrins.The most commonly used
strategies are discussed briefly below.
Particle Size Reduction
The dissolution rate of the drug substance can be
significantly accelerated by reducing the particle size of
the active pharmaceutical ingredient (API). Particle size
reduction can be efficiently achieved down to 2-10µm
through the use of micronising equipment such as fluid
energy mills, in which particle size reduction is achieved
by collision between the particles at high speed. Over the
last 10 to 15 years, the processing of drugs as nanocrystals
(<1µm) has rapidly evolved into a reliable drug delivery
strategy, enabling the production of formulations with
rapid drug dissolution characteristics and enhanced
bioavailability after oral administration. Precipitation
(‘bottom up’) or wet milling (‘top down’) techniques
can be used to produce submicron nanocrystals (5,6).
No
Reduce particle size
(for example, micronise
or nano-mill)
Conventional capsule
formulation (powder
blend/granule)
Or
Drug in lipid-based
vehicle in capsule
Required dose is soluble
in liquid/wax vehicle
Melt granulation – using
water soluble polymer as
binding agent
No
Required dose is
miscible with polymer
Or
No
Solid dispersion (drug
dispersed in polymer or
self-emulsifying wax matrix)
Fill formulation
into capsules
Yes
Drug miscible with
polymer at greater
than 150ºC
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Change
salt form
Yes
Melt extrusion with
water-soluble polymer.
Mill the extrudate
Yes
Spray-dry to produce
drug-polymer** solid
solution or co-precipitate
Fill milled extrudate
into capsules
No
Drug and polymer*
soluble in common
volatile solvent
Or
Spray solution onto
carrier (for example,
lactose) and granulate
* or cyclodextrin
** or drug-cyclodextrin complex
Fill into capsules
(blend with excipients
if necessary)
Solution Capsule Formulations
Some drugs can be dissolved in a suitable,
pharmaceutically acceptable solvent and the resulting
solution can be filled into capsules.The key advantage of
pre-dissolving the drug compound is elimination of the
initial rate-limiting step of particulate dissolution in the
aqueous environment within the GI tract. Nevertheless,
this formulation strategy may result in the drug
precipitating out of the solution when the formulation
disperses in the GI tract, especially in cases when a
water-miscible solvent has been used, such as
polyethylene glycol.
The problem of precipitation on dilution in the GI tract
can be overcome if the drug compound is sufficiently
lipophilic to dissolve in a lipid vehicle; in such a case,
partitioning kinetics will enable the drug to remain in
the lipid droplets. An additional advantage made
possible by this approach is that lipidic vehicles are
usually well absorbed from the GI tract, resulting in
significantly improved oral bioavailability compared
with administration of the solid drug substance (7,8).
However, the ability of individuals to digest lipid-based
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formulations may cause significant inter- and intrasubject variation in drug uptake.
Mixtures of lipidic excipients and surfactants are
increasingly being used to produce self-emulsifying drug
delivery systems (SEDDS) and self-microemulsifying drug
delivery systems (SMEDDS) for oral administration of
drugs exhibiting poor water-solubility (9). SEDDS and
SMEDDS formulations act by forming emulsions or
microemulsions spontaneously on contact with
aqueous media. Both of these types of formulation use
pharmaceutically acceptable surfactant excipients to
achieve self-emulsification. In this way, emulsification of
the lipids in the formulation no longer depend on GI
secretions such as bile salts, and therefore inter- and intrasubject variability in drug absorption can be reduced.
Solid Solutions and Dispersions
Solid solutions are molecular dispersions of drug
molecules in a polymer or wax matrix, whereas in
the case of solid dispersions, the drug exists in the
form of discrete particles dispersed within a polymer
or wax matrix – although the terms are often used
interchangeably (10).The solid solution strategy employs
two separate principles to enhance the water-solubility
of a drug: first, conversion of the drug substance into its
amorphous state, making it easier for the substance to
dissolve; and second, incorporation of the amorphous
drug substance in a hydrophilic carrier matrix, such as
polyvinyl pyrrolidone (PVP) or polyethylene glycol (for
example, PEG 6000). Solid solutions can be prepared
either by dissolving the drug directly in molten polymer,
or by dissolving both the drug and the polymer in a
suitable volatile solvent. When the solvent is removed, an
amorphous drug-polymer complex is produced with the
drug being trapped in an amorphous state within the
water-soluble polymer matrix – thereby enhancing the
water-solubility of the drug.
The efficiency of this formulation strategy may be
impaired if the drug substance is triggered to return to
its more thermodynamically stable crystalline state.This
can result in the drug compound crystallising in the
polymer matrix, which can lead to a deterioration in
dissolution properties. Recently, surfactants have been
used to stabilise solid solution formulations, avoiding
drug recrystallisation and further enhancing watersolubility. In addition, the physical stability of a
formulation can be tested by a combination of rapid
screening techniques, such as differential scanning
calorimetry (DSC), Raman spectroscopy and x-ray
crystallography.
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recently, such methods are being increasingly employed
in pharmaceutical applications, having demonstrated
their efficiency in preparing several types of dosage
form and drug delivery system. HME techniques offer a
number of key benefits compared with conventional
pharmaceutical processing methods, including the
absence of solvents, few processing steps, continuous
operation, formation of solid molecular dispersions and
improved bioavailability. Dosage forms that have been
produced using an HME technique are complex mixtures
of active drug, functional excipients and processing
aids (11).
As well as providing a platform for enhancing drug
solubility, HME techniques are also capable of providing
sustained, modified and targeted drug delivery, and can
be used in various drug delivery applications such as
granules, pellets, immediate and modified release tablets,
transmucosal and transdermal systems, and implants (12).
The HME formulation strategy can be considered an
extension to the ‘solid solution’ approach. It requires
that a co-melt of the drug substance and a polymer
are extruded using a heated screw to produce a solid
extrudate; this can then be milled to produce granules
for encapsulation or compression into tablets. Producing
a melt extruded drug/polymer matrix serves as an
efficient method of increasing the water-solubility of a
poorly water-soluble drug substance.The efficacy of this
approach depends on the miscibility of the drug and
polymer substances, and on their exhibiting similar
melting points.
Melt Granulation
Melt granulation is a process by which pharmaceutical
powder mixtures are efficiently agglomerated using a
water-soluble polymer as a binding agent.The resulting
granule blend is heated to a temperature at which the
polymer-binding agent softens without completely
melting. As a result, aggregates comprised of the
drug and excipient are formed.The granule mass is
subsequently cooled, sieved and becomes suitable for
either filling into capsules or compressing into tablets.
Compared with traditional granulation, melt granulation
offers several advantages; it does not require the use of
water or organic solvents, and elimination of the granule
drying stage makes the process more time- and energyefficient (13). As a drug formulation strategy, melt
granulation has proved to be an easy, fast and effective
technique for enhancing the dissolution rate of several
poorly water-soluble drugs (13,14).
Hot Melt Extrusion
Cyclodextrins
Hot-melt extrusion (HME) techniques have been used
extensively in the plastics industry for many years. More
Cyclodextrins are doughnut-shaped functional
excipients with a lipophilic surface on the inside ring and
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a hydrophilic surface on the outside ring (15).These
molecules have been extensively used in pharma
formulation owing to their ability to interact with poorly
water-soluble drugs, resulting in an increase in their
water-solubility.This formulation strategy works by
fitting the poorly soluble drug molecule into the
inner ring while the outer hydrophilic surface of the
cyclodextrin retains the complex in solution.The
inclusion complex can be prepared by dissolving the
drug and cyclodextrin in a common solvent, or by solidstate mixing of the materials using a high attrition
technique, such as ball milling.
4. Lipinski CA et al, Experimental and computational
approaches to estimate solubility and permeability in
drug discovery and development settings, Adv Drug
Deliv Rev 23: pp3-25, 1997
5. Kesisoglou F et al, Nanosizing – Oral formulation
development and biopharmaceutical evaluation,
Adv Drug Deliv Rev 59: pp631-644, 2007
6. Eerdenbrugh BV et al, Top-down production of drug
nanocrystals: Nanosuspension stabilisation,
miniturization and transformation into solid products,
Int J Pharm 364: pp64-75, 2008
7.
Hauss DJ, Oral lipid-based formulations, Adv Drug Deliv
Rev 59: pp667-676, 2007
Conclusion
8. O’Driscoll CM and Griffin BT, Biopharmaceutical
challenges associated with drugs with low aqueous
Deciding on the best approach for taking a new drug
entity into ‘first-into-man’ studies can be a difficult
process. The first vital step is to accurately characterise
the drug molecule by investigating and determining
its physicochemical and biological characteristics. An
appropriate delivery strategy can then be selected
according to predictions of the oral bioavailability
of the drug. The drug-in-capsule or drug-in-bottle
approach is a simple, cost-effective and time-saving
dosing strategy. However, it may not be suitable
for drug compounds exhibiting poor watersolubility/bioavailability, as is the case for more than
40 per cent of new drug entities. Poor water-solubility
represents a major hurdle in achieving adequate oral
bioavailability for a large percentage of drug
compounds in development. In these cases, a watersolubility enhancing formulation strategy is necessary
in order to give the molecule the best chance of
success in clinical evaluation. Different formulation
strategies can be implemented based on the
characteristics of the specific drug molecule; for
example, lipid-based formulations are able to facilitate
GI absorption of many poorly water-soluble drugs. The
preparation of solid dispersions and solid solutions, as
well as the use of melt granulation techniques, can also
increase water solubility significantly.
References
1. FDA Guidance for Industry, Waiver of in vivo
bioavailability and bioequivalence studies for
immediate release solid oral dosage forms based on a
biopharmaceutics classification system, August, 2000
2. Wu CY and Benet LZ, Predicting drug disposition via
application of BCS: transport/absorption/elimination
interplay and development of a biopharmaceutics drug
disposition classification system, Pharm Res 22:
pp11-23, 2005
3. Butler JM and Dressman JB, The developability
classification system: application of biopharmaceutics
concepts to formulation development, J Pharm Sci 99:
solubility – the potential impact of lipid-based
formulations, Adv Drug Deliv Rev 60: pp617-624, 2008
9. Pouton CW and Porter CJH, Formulation of lipid-based
delivery systems for oral administration: Materials,
methods and strategies, Adv Drug Deliv Rev 60:
pp625-637, 2008
10. Vasconcelos T et al, Solid dispersions as strategy to
improve oral bioavailability of poor water soluble drugs,
Drug Discovery Today 12: pp1,068-1,075, 2007
11. Crowley MM et al, Pharmaceutical applications of
hot-melt extrusion: Part 1, Drug Dev Ind Pharm 33:
pp909-926, 2007
12. Repka MA et al, Pharmaceutical applications of hotmelt extrusion: Part 2, Drug Dev Ind Pharm 33:
pp1,043-1,057, 2007
13. Yang D et al, Effect of the melt granulation technique
on the dissolution characteristics of griseofulvin, Int J
Pharm 329: pp72-80, 2007
14. Passerini N et al, Preparation and characterisation of
ibuprofen-poloxamer 188 granules obtained by melt
granulation, Eur J Pharm Sci 15: pp71-78, 2002
15. Brewster ME and Loftsson T, Cyclodextrins as
pharmaceutical solubilizers, Adv Drug Deliv Rev 59:
pp645-666, 2007
Robert Harris, PhD, CChem, FRSC, is
Director, Early Development, at Molecular
Profiles (Nottingham, UK). He joined
the company in 2010 and leads the
pharmaceutical development services
team which is responsible for integrating
preclinical chemistry, manufacturing and controls (CMC),
solid state form optimisation and formulation development
for early clinical trials through to the end of Phase 2. Rob
has 30 years’ experience in product development of both
commercial and investigational medicinal products with
blue chip and contract pharma companies. During
his career, he has successfully managed the
development of over 50 new chemical entities.
Email: [email protected]
pp4,940-4,954, 2010
Innovations in Pharmaceutical Technology Issue 38
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