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AS APPEARED IN MAY 2016 Tablets & Capsules WWW.TABLETSCAPSULES.COM

excipients
John K. Tillotson
Abitec

This edition of the column discusses using emulsification of API in the lumen The optimized pre-concentrate is
functional lipids and self-emulsifying and possibly effect para-cellular filled into a soft or hard capsule for
transport; oral administration. Upon contact
drug delivery systems (SEDDS) to over-
• The potential to reduce the P- with GI fluid, the pre-concentrate
come the poor solubility and permeability glycoprotein mediate efflux of cer- forms an emulsion or micro-emul-
of today’s APIs. tain APIs, improving bioavailability; sion, which carries the API until it is
The majority of new chemical • The reduction of fasted and fed absorbed.

Components of a stable SEDDS pre-


entities (NCEs) being evaluated for pharmacokinetic differences of APIs;

concentrate
therapeutic use exhibit low solubility, • APIs that can be readily digested
low permeability, or both, indicating and metabolized;
that they are BCS Class II, Class III, • Formulations that can be easily Solubilizers. These are typically
or Class IV compounds. There are filled into soft and hard capsules fully esterified lipids manufactured
numerous and varying strategies for (gelatin or non-gelatin) for oral by the esterification of glycerol or
improving the solubility of BCS administrations; and propylene glycol with free fatty acids
Class II active pharmaceutical ingre- • Higher-molecular-weight lipids of varying chain lengths. These
dients (APIs), including that are solid at room temperature products are highly lipophilic and
• Micronizing and nano-sizing and have the potential to be readily have no hydrophilic-lipophilic bal-
them to increase the surface area; incorporated into direct-compression ance (HLB).
• Using solid dispersions and tablets while still providing the Secondary surfactants or co-
spray drying to hold the API in a advantages cited above. emulsifiers. These are typically par-
higher energy state; There are two basic approaches to tially esterified lipids manufactured
• Adding surfactant to aid in dis- formulating with functional lipids: by the partial esterification of glyc-
solution; dissolution of the API in a neat lipid erol or propylene glycol with free
• Adjusting micro-environmental or dissolution of the API in a SEDDS fatty acids or oils (via a catalyst).
pH; pre-concentrate. In the former, the These emulsifiers provide a range of
• Using organic salt conjugation API is simply dissolved in a lipid HLB values according to their degree
to create more soluble ion pairs; and excipient and then filled into a soft of esterification, fatty acid chain
• Using flash precipitation. or hard capsule. Once the capsule is length, and saturation, and that
When it comes to improving the ingested, the API-containing lipid is allows you to select a suitable emulsi-
intrinsic permeability of APIs, there released and undergoes digestion fication system for specific APIs. For
are even fewer options. Lipid-based through the actions of lipases. This certain APIs with similar solubility
formulations, however, offer a very results in the body creating an emul- parameters, an emulsifier can be
safe and effective method of poten- sified system containing the API, employed as a solubilizer and used
tially improving both the solubility lipid, bile salts, and phospholipids. alone.
and permeability of APIs. The bene- The API remains in the solubilized Primary surfactants. The produc-
fits of lipid-based formulations state in the emulsion and is thus tion of optimal SEDDS formulations
include: absorbed from the gastrointestinal often requires high concentrations
• A large increase in the solubility (GI) tract. In the latter, a SEDDS (greater than 30 percent) of surfactant
of BCS Class II APIs by incorporat- pre-concentrate is developed by agents. There are many types of sur-
ing them into an oil-water emulsion; employing a combination of func- factants that can be employed in the
• The potential to greatly improve tional lipids, including any permuta- pre-concentrate to emulsify oil and
the permeability of polar APIs by tion of the following: a primary solu- water and even facilitate the forma-
means of stimulating bile salt secre- bilizer, a secondary surfactant/co- tion of nano-emulsions. The most
tion from lipolysis to improve the emulsifier, and a primary surfactant. common types employed for SEDDS
Copyright CSC Publishing
formulations are pegylated esters, to filter and analyze the combina- are plotted on two vertices and water
polyethoxylated sorbitan esters, and tions for API content in order to occupies the third vertex. Next,
polyethoxylated glycerides. Pegylated determine the maximum API solubil- binary mixtures—containing different
esters are manufactured through the ity in each pre-concentrate candidate concentrations of the pre-concentrate
esterification of polyethylene glycol or in selected candidate mixtures. base components and of the pre-con-
with its respective fatty acids, the Determine the emulsion’s charac- centrate surfactant components—are
rearrangement of oils and alcohols, or teristics. After you determine the diluted systematically with water, and
the direct in situ ethoxylation of par- maximum solubility, the SEDDS pre- the phase characteristics of these
tial glycerides. Polyethoxylated castor combinations are observed (usually
oil is prepared by reacting ethylene Figure 1 by eye). You can then evaluate the
oxide with castor oil, and polyethoxy- Time-elapsed photos of simvastatin droplet size where desired in the
lated sorbitan esters are made through dissolving in SEDDS pre-concentrate phase diagram. The most common
the esterification of polyethoxylated phase observations are emulsion for-
sorbitan with its respective fatty acids mation, micro-emulsion formation, or
after cyclization of sorbitol. gel formation. Figure 2 shows an

Pre-concentrate formulation
example of a phase diagram [2].
The emulsion’s characteristics can
There are four general steps in for- be very important to bioavailability
mulating a pre-concentrate for a
0 seconds
considerations. This has been shown
SEDDS: 1) select the pre-concentrate in the case of cyclosporine A, where
component candidates, 2) determine the micro-emulsion was much more
the maximum API solubility in the bioavailable than the emulsion [3].
pre-concentrate components, 3) The optimization of SEDDS pre-con-
determine the emulsion’s characteris- centrate components focuses on both
tics upon pre-concentrate dilution, maximizing the solubility of the API
and 4) conduct in vitro evaluation of in the SEDDS pre-concentrate and
126 seconds
the pre-concentrate, including disso- on the emulsion performance of the
lution testing and other physiochemi- pre-concentrate upon dilution with
cal characterization. water. The emulsion’s droplet size and
Select component candidates. its stability are of specific interest
First, determine the aqueous solubil- because they will ultimately affect the
ity, log P, melting point, and solubil- absorption of the API and, subse-
ity parameter of the API. Typically, a quently, the API’s bioavailability.

252 seconds
log P greater than four indicates that Table 1 provides a classification sys-
a fully esterified solubilizer should be tem for lipid formulations according
included in the pre-concentrate [1]. to their makeup and droplet size [1].
By matching the required HLB of the Conduct in vitro evaluation,
solubilized API to the HLB values of including dissolution testing. In
the proposed SEDDS components, vitro dissolution testing is important
you can select SEDDS pre-concen- to demonstrate the API’s superior
trate candidates for a solubility study. aqueous solubility in the optimized
Determine maximum API solubil- 378 seconds SEDDS system compared to the same
ity. Once you identify candidate API in a non-SEDDS formulation.
SEDDS pre-concentrate compo- Additionally, in vitro testing can
nents, determine the maximum API allow you to analyze the pre-concen-
solubility in all candidates. This can trate behavior under sink conditions.
be done by adding an excess of API The dissolution parameters you
to each of the SEDDS pre-concen- choose can be adjusted based upon
504 seconds
trate candidate components individu- each individual formulation project.
ally or in combination, if desired. Researchers at St. John’s University
These combinations are then vor- have suggested an in vitro dispersion
texed in order to adequately disperse test [4], a method that employs a dis-
the API in the SEDDS pre-concen- concentrate components that can dis- solution tester outfitted with USP
trate candidates. Next, the vortexed solve the greatest amount of the API Apparatus 2 (0.01 M HCl, 37°C, 50
combinations are shaken by wrist are plotted in various concentrations rpm). Both API concentration and
action for 24 hours at 37°C, and the on a phase diagram. Typically, indi- emulsion droplet size are analyzed
solutions are then allowed to stand vidual known combinations of the over time as a means of determining
for 24 hours at 25°C. The last step is SEDDS pre-concentrate components API release and how the SEDDS per-
Copyright CSC Publishing
Figure 2 Solid lipid formulations
Example of a pseudo-ternary phase diagram [2]
Higher-molecular-weight lipids,
which are solid at room temperature,
may also be employed in lipid formu-

Poly-ethoxylated castor oil


lations. Typically, these lipids are

0 100
melted and the API is dissolved in
the liquefied lipid while heating. It’s

10 90
also possible to formulate a solid dis-
persion by melting the lipid and the
20
80
API together. The most common

30
methods of generating a solid disper-
70
sion with lipids are spray congealing,

40
Mic
hot-melt granulation, and hot-melt
60

%w
r

roe
te

extrusion. In these formulations, it is


wa

50

/w
mul s
50
desirable that the melting point of

s ur
/w
%w

i on

fa c
60
the lipid materials be as close as pos-
l 40

ta n
Ge
sible to the melting point of the API.

t
70
In certain cases, however, the API’s
30 melting point can be higher and the
80 n 20
lsio
API will still dissolve in the molten
u
em
icro
lipid(s). Additionally, you must not
90 n 10
M Emulsio
exceed the degradation temperatures

100 0
of the lipid excipients during the

0 10 20 30 40 50 60 70 80 90 100
melt formation.

% w/w lipid mixture


Once the API is melted with the
Water 1:1 PG lipids, the materials should be rapidly
monolaurate/
PG dilaurate
cooled to solidify them to ensure the
API is dispersed amorphously
throughout the lipid matrix. One
form of solid lipid formulations is
solid lipid nano-particles (SLNs).
TAble 1
Lipid formulation classification system [1]
These nano-sized lipid carrier parti-
cles are generated by melting that is
Emulsion type
followed by high-pressure homoge-
Typical Type I Type II Type IIIA Type IIIB
nization and subsequent cooling.
composition SLNs have been reported to provide
(%)
Triglycerides or 100 40 to 80 40 to 80 < 20
a means for controlling drug delivery,
mixed glycerides
enhancing bioavailability through
Surfactants - 20 to 60 20 to 40 20 to 50
both dissolution modification and
Hydrophilic - - 0 to 40 20 to 50
enhanced tissue distribution, and tar-
cosolvents
geting drug delivery through various
Particle size of Coarse 100 to 250 100 to 250 50 to 100 application routes [5]. SLNs have
dispersion (nm) been proposed as potential carriers
Significance of Limited Solvent Some loss of Significant phase
aqueous dilution importance capacity solvent capacity changes and
for cyclosporin A, insulin, calcitonin,

unaffected potential loss of


and somatostatin. Formulation of
solvent capacity
proteins in SLNs can improve the
Significance of Crucial Not crucial but Not crucial but Not required
stability of the protein, reduce prote-
digestibility requirement likely to occur may be and not likely olytic degradation, and provide sus-
inhibited to occur tained release of the protein [6].

Conclusion
The majority of NCEs exhibit solu-
forms under simulated gastric condi- consider including simulated gastric bility and/or permeability challenges.
tions. It is important to understand and intestinal fluid, which includes Functional lipid formulations, including
the nature of a proposed SEDDS sys- lipases and bile salts, because the neat SEDDS, can overcome these chal-
tem before designing in vitro testing. lipid system only generates an emul- lenges. Specific APIs can be dissolved
For example, if an API were dissolved sion under biological conditions. in neat lipids or formulated in a
in a neat lipid, you would need to SEDDS pre-concentrate containing an
Copyright CSC Publishing
optimized mixture of functional lipids, as a predictive method for assessing
which form an emulsion upon dilution performance of lipid-based drug
with GI fluids. The development of a delivery systems. J. Excipients and
SEDDS pre-concentrate focuses on Food Chem. 4 (4). 2013, 111-125.
optimizing API solubility in the 5. Patil, H. et al. Continuous pro-
SEDDS while still generating a stable duction of fenofibrate solid lipid
micro-emulsion that increases API nanoparticles by hot-melt extrusion
aqueous solubility. Both neat lipid for- technology: a systematic study based
mulations and SEDDS formulations on a quality by design approach. The
can be loaded in either soft or hard AAPS Journal. (17) 1. 2015.
capsules for oral administration. 6. Almeida, AJ and Souto E. Solid
Additionally, SEDDS pre-concentrates lipid nanoparticles as a drug delivery
are candidates for loading in or on vari- system for peptides and proteins.
ous multi-particulate systems for incor- Adv. Drug Deliv. Rev. (59) 6. 2007,
poration into hard capsules or tablets. 478-490.
Furthermore, lipid-based excipients
are being used in a variety of new areas John K. Tillotson, R.Ph., Ph.D., is
of drug delivery, ranging from spray pharmaceutical technical business direc-
congealing for solid oral dosages to
the application of nano-structured tor at Abitec, 501 West 1st Avenue,
lipid carriers for the non-invasive Columbus, OH 43215. Tel: 614 429
delivery of macromolecules. The ver- 6464. Email: jtillotson@abiteccorp.com.
satility and functionality of the lipid His research areas include functional
excipients available today provides lipids, SEDDS system development, and
drug formulators with numerous
options and capabilities to address and direct-compression tabletting.
overcome many historic delivery and
performance challenges. While there
is an ongoing requirement to further
understand the physical and chemical
stability of various API classes within
lipid-based systems, it is clear that
lipids will play an expanding and piv-
otal role in enhancing bioavailability
of poorly soluble NCEs. T&C

References
1. Pouton, Colin W. Lipid formu-
lations for oral administration of
drugs: non-emulsifying, self-emulsi-
fying, and “self-microemulsifying”
drug delivery systems. Eur. J. Pharm.
Sci. 11 Suppl. 2. 2000, S93-S98.
2. Prajapati, Hetal N. et al. Effect
of difference in fatty acid chain
lengths of medium chain lipids on
lipid-surfactant-water phase diagrams
and drug solubility. J. Excipients and
Food Chem. 2 (3). 2011, 73-88.
3. Keown P. and Niese D. Cyclo-
sporine microemulsion increases drug
exposure and reduces acute rejection
without incremental toxicity in de
novo renal transplantation. Kidney Int.
Sep 54 (3). 1998, 938-944.
4. Prajapati, Hetal N. et al. In
vitro dispersion test that could serve

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