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8
Inulin asaPharmaceutical Excipient
VishnuMittal, AnjaliSharma, andDevkantSharma
Abstract
A ubiquitous carbohydrate found in nature, inulin is exible and soluble in water.
The nondigestible nature of inulin has drawn interest from pharmaceutical sec-
tor. The Food and Drug Administration (FDA) has classied inulin as generally
recognized as safe (GRAS), and more than 30,000 plants naturally store it as a
carbohydrate. Some of main plant sources of inulin include dahlia, chicory, and
Jerusalem artichokes. Out of all plants, chicory is main supplier of inulin.
Numerous biological functions of inulin have been discovered via studies,
including acting as a prebiotic to enhance habitat of intestinal microbes, control-
ling blood sugar and cholesterol levels, acting as an antioxidant, preventing can-
cer, regulating immune system, and more. Inulin is now frequently used in
pharmaceutical sector. Pharmaceutics may use inulin as a stabilizer, medication
carrier, and supplemental therapeutic agent for conditions including diabetes and
constipation. It may be added to processed goods as a sugar or fat substitute to
affect desired qualities. Because of its many bioactivities, important chemical
characteristics, and good biocompatibility, inulin is a remarkable natural nutri-
ent. The stabilization of proteins, altered drug delivery, and, nally, inulin’s
physiological and disease-modifying properties are discussed as applications of
inulin. Inulin may be used to provide drugs specically to colon and to stabilize
and adjuvant vaccination formulations. Research on inulin’s many applications
in pharmaceutical industry is currently ongoing, especially with regard to chemi-
cally modied inulins. Therefore, it’s conceivable that this exible oligosaccha-
ride will nd even more uses. When compared to other biodegradable
V. Mittal · A. Sharma (*)
Guru Gobind Singh College of Pharmacy, Yamunanagar, Haryana, India
D. Sharma
Ch. Devi Lal College of Pharmacy, Jagadhri, Haryana, India
148
polysaccharides, inulin’s unique and exible structure, stabilizing and protecting
actions, and organ-targeting capabilities make it an effective drug delivery vehi-
cle. Each fructose unit has three hydroxyl groups that act as an anchor for chemi-
cal modication. Consequently, this aids in attaining targeted, sustained, and
regulated release of medications and biomolecules as well as improved cellular
absorption and bioavailability. Because of its exceptional qualities, chemically
modied inulin is becoming more popular in pharmaceutical industry.
Keywords
Inulin · Physiological functions · Pharmaceutical · Excipient
8.1 Introduction
A naturally occurring fructan-type polysaccharide, inulin is made up of β--
fructosyl residues joined together and generally have an end group of α--glucose
in it. It comes as a white, odourless powder tastes dull to slightly sweet. A exible
ingredient used in many different elds, inulin is also known by trade names and
synonyms such as oligofructose, polyfructose, RaftilineTM, Frutat
®
, and GrafttTM
(Niness 1999). It serves as a ller to increase product volume without losing taste or
texture and as a glue to help components come together. Inulin also works as a
thickening and viscosity-boosting agent, which makes it important in recipes like
soups and creams where accuracy and structure are crucial. Its importance as a bre
source also helps explain why it’s often used in cooking items, giving nutritional
benets, and improving gut health (Clark 1999). All things considered, inulin’s
many uses make it a useful component in cooking, medical, beauty, and other com-
panies. When degree of polymerization is low, inulin is also known as oligofructose
(Franck 2002).
8.1.1 Background ofInulin asaPharmaceutical Excipient
Natural plants store inulin as a carbohydrate in excess of 30,000 different ways.
Inulin was initially identied by Thomson in 1817, after Valentine Rose isolated it
from roots of Compositae plant Inula helenium in 1804. As a polysaccharide, inulin
is a member of fructans class of carbohydrates. Fructans are structures where
β-(2→1)--fructose-fructose bond helps hold the fructose (sugar) molecules
together in shape of a chain. Inulin is now trending toward culinary and medicine
sectors. It may be added to processed goods as a sugar or fat substitute to affect
desired qualities (Watzl etal. 2005). Compared to sucrose, inulin has a sweetness
level of roughly 10%. Inulin is a great natural nutrient because of its broad variety
of bioactivities, important chemical characteristics, and strong biocompatibility. A
fructan-type oligosaccharide, inulin is present in a large variety of plants. Since its
V. Mittal et al.
149
discovery in the nineteenth century, a great deal of research has been done on its
features (Roberfroid 2005). Chicory root is a source of majority of inulin that is sold
commercially since it has a comparatively high content of this carbohydrate. It has
been shown that inulin is a chemical with many varied uses, mostly in food and
pharmaceutical industries (Shoaib etal. 2016). The degree of polymerization and
processing history have a signicant inuence on inulin’s physicochemical behav-
iour. Because usefulness for various applications is determined by physicochemical
behaviour, these features should be considered while employing inulin (Jimenez
Sanchez etal. 2019).
8.1.2 Objectives ofChapter
Regarding its many roles and applications in creation of pharmacological forms,
inulin seeks to accomplish a variety of objectives as a pharmaceutical excipient. A
summary of inulin’s physiochemical characteristics, such as its solubility, viscosity,
and compatibility with other excipients, might provide readers a thorough grasp of
characteristics of excipients utilized in formulations (Roberfroid etal. 1998). The
subsequent stage involves investigating potential of inulin as a drug retardant and
elucidating any possible consequences, such as increased bioavailability and regula-
tion of release kinetics. It will also discuss pharmacokinetics and pharmacodynam-
ics of inulin-based formulations, shedding light on their efcaciousness and safety
proles. The goal of chapter is to further area of drug delivery science by offering
relevant information on versatile and effective use of inulin as a pharmaceutical
excipient (Roberfroid 2002).
8.1.3 Scope andSignificance
Beyond limitations previously indicated, inulin’s use and signicance as a pharma-
ceutical excipient are multifaceted and provide several benets for both medicine
formulation and delivery. As was already established, inulin is a naturally occurring
polysaccharide with many properties that make it ideal for use in therapeutic con-
texts (Flamm etal. 2001). The rst benet of inulin’s biocompatibility and biode-
gradability is that they reduce possibility of adverse reactions and environmental
effects. Secondly, since inulin is soluble and viscous, it can bind, stabilize, and
emulsify, which is very helpful for making tablets, capsules, and suspensions.
Gelling and matrix forms enhance effects of medicine by enabling controlled and
prolonged release of substance. Interestingly, inulin is also a prebiotic, which makes
it benecial for oral usage in promotion of intestinal health (Ni et al. 2019).
Pharmaceutical uses for inulin vary widely, from conventional drug delivery tech-
niques to innovative nanotechnology-based formulations that provide several
opportunities to improve medicine efcacy, safety, and patient outcomes (Wan etal.
2020). Table8.1 shows the amount of inulin found in various plant sources.
8 Inulin asaPharmaceutical Excipient
150
Table 8.1 Inulin content of different plant sources
Sr.
no.
Source Botanical name Part
Content of inulin
(%)
1 Garlic Allium sativum Tuber, wet 12.5–23.5
Tuber, dried >75%
2 Asparagus raw Asparagus ofcinalis Root, wet 2–3
3 Salsify Tragopogon porrifolius
L.
Root, wet 4–11
4 Jerusalem artichoke/
sunchoke
Helianthus tuberosus
L.
Tubers, wet 8.16–13.46
5 Dahlia Dahlia pinnata Tubers, wet 6–9.5
Tubers, wet 59
6 Chicory yacon Cichorium intybus L. Root, dried 65–79
7 Yacon Smallanthus
sonchifolius
Root, wet 7–8
Tubers, wet 1.1–7.5
8 Onion Allium cepa L. Tubers,
dried
48
8.2 Physicochemical Properties ofInulin
When Inulin (IN) is dry, it is an amorphous, odourless powder. Inulin extracted from
chicory is a white, odourless powder with improved clarity for small particles.
While typical chicory inulin has a sweetness level of around 10% in relation to
sucrose, long- chain inulin is completely sweet. Inulin is a unique food element with
many important nutritional benets as well as certain industrial uses (Roberfroid
1993). The chemical structure of inulin is seen in Fig.8.1.
8.2.1 Structure ofMolecules
A polydisperse β-(2-1) fructan is inulin. It consists of β--fructose residues joined
by glycosidic linkages. Like sucrose, each fructose chain ends with a glucose mol-
ecule connected by an α--glucopyranosyl or α-(1→2) bond. Chicory inulin has a
range of 2–60 fructose units, which indicate a combination of oligomers and poly-
mers (Devine and Marsh 2009). The formula for IN is often written as GFn, where
n is number of fructose residues, G is terminal glucose unit, and F is fructosyl resi-
due. IN polymerization ranges in degree from 2 to 60, with an average of 10–12
(Gupta etal. 2019). Oligofructose is another name for IN with a low degree of
polymerization (n<10). The source, harvest period, and extraction method have
greatest effects on structural characteristics of IN, such as chain length and content.
The value and industrial uses of IN are signicantly impacted by changes in its
degree of polymerization (Kim etal. 2001).
V. Mittal et al.
151
Fig. 8.1 Chemical
structure of inulin
8.2.2 Properties ofSolubility andHydration
At 25°C, inulin dissolves about 10% of itself in water, making it possible to apply
it to an aqueous media without any precipitation. It is recommended to use hot water
between 50 and 100°C to create an inulin solution (Imran etal. 2012). Due to its
hydrophilic nature, inulin is very weakly soluble in ethanol or cold water but sub-
stantially soluble in hot water. Crystallinity may have an impact on inulin’s solubil-
ity. Beta inulin has a signicant water solubility at 23 °C (Slavin 2013). The
dissolving temperatures of other polymorphs must be raised. Natural IN has a solu-
bility of around 6% at 10°C and 33% at 90°C.Generally speaking, solubility of IN
rises with temperature and falls with increasing polymerization degree. On the other
hand, solubility dramatically rises to 35% at 90°C.The solubility of IN may be
greatly impacted by its crystal shape. Initially, four crystalline IN polymorphs (α, ß,
γ, and δ) were discovered based on their dissolving behaviour. For certain poly-
morphs to dissolve, a greater temperature is needed. Inulin’s strong hygroscopicity
is a great attribute for food sector. Because of its ability to absorb water, inulin may
lower water activity. In order to prevent product odour and increase shelf life, this
function may effectively decrease evaporation of water during food production pro-
cess (Carabin and Gary 1999).
8.2.3 Anatomical Characteristics
At low concentrations, inulin solution exhibited Newtonian uid behaviour. Inulin
solution’s rheological characteristics at various solid content (Xs) between 1% and
8 Inulin asaPharmaceutical Excipient
152
Fig. 8.2 Extraction of inulin powder from chicory
12% in a broad temperature range between 10 and 85°C (Karimi etal. 2015). Based
on concentration and temperature examined, viscosity (η) of inulin solution varied
between 2.0998 and 3.2439 mPa s, exhibiting Newtonian liquid behaviour. The
Arrhenius equation explained temperature dependence of Newtonian viscosity of
inulin solution, and activation energy (Ea) for viscous ow varied according to solid
concentration, ranging from 2.111 to 3.013 kJ/mol. Depending on temperature,
effect of solid content on Newtonian viscosity was either power law or linear (Liu
etal. 2015). The procedure for extracting inulin from chicory is shown in Fig.8.2.
8.2.4 Thermodynamic Stability
The inulin does not break down easily, not even at 100°C.It has excellent thermal
stability as a result. Because IN gels don’t contain any free water, they are very
stable and difcult to hydrolyse. Compared to other three crystalline inulin forms,
sigma crystalline inulin has a greater degree of heat stability. Crystalline inulin has
thermodynamic stability in beta\alpha\gama (Xiong etal. 2019).
8.3 Inulin asaBinder andDisintegrant
The pharmaceutical industry’s tablet manufacture is still a developing sector. Over
last several decades, many excipients with unique benets in compaction process
have been created and used (Pasqualetti etal. 2014). The qualities of ller-binder
V. Mittal et al.
153
are critical to nal tablet’s attributes since contents are only dry-mixed prior to com-
pression. Plants that contain inulin include Jerusalem artichoke tubers, dahlia tubers,
and chicory roots (Hines and Kaplan 2013). There are many reasons why inulin
might be a promising ller-binder for direct compaction based on previously listed
criteria:
• Inulin is a nonreducing carbohydrate that is stable and inert, with relatively mild
hygroscopicity. Thus, there is little chance of unintended interactions with active
medication.
• Using inulin, both orally and parenterally, is safe. Inulin given parenterally has
been widely used as a renal function (glomerular ltration) diagnostic tool.
Inulin is not absorbed when taken orally; however, bacteria in the colon’s ora
may partly metabolize it (Lim etal. 2009).
• The majority of regulatory bodies approve use of inulin since it is outlined in
monographs in many pharmacopoeias, including USP and BP.Additionally, this
outlines chemical specications for material.
• The physical stability of amorphous inulin is excellent when kept in dry circum-
stances. Inulin is available from many sources at a fair price (Tardif etal. 2016).
8.3.1 Role inTablet Formulations
There are researches that show use of inulin as a binder for solid pharmaceutical
forms. Inulin solution has been tested as a binder in comparison to typical starch
slime for active compounds with distinct physical-chemical characteristics, and its
usage as a binder in medication manufacturing has been proven to be efcient.
Every inulin exhibited a strong ability for bonding (Liu etal. 2008). Nonetheless,
there was a signicant variation in lubricant sensitivity between various inulin
forms. Amorphous materials, like starches, often exhibit a ductile tendency upon
compaction, making them very sensitive to lubricants. Conversely, since they frac-
ture during compaction, crystalline minerals like dicalcium phosphate dihydrate
have a low lubrication sensitivity (Torres etal. 2019). In contrast, when particles
containing a lot of air were crushed, amorphous inulin’s lubricant sensitivity was
low. When incubated in water, inulin-prepared tablets dissolved rather than disinte-
grating. As inulin’s chain length decreased, so did disintegration/dissolution period.
The disintegration period was shortened by inclusion of a disintegrant. Chewable
pills or lozenges may benet from longer-chain inulin’s somewhat slower dissolu-
tion (Kaur and Gupta 2002; Mensink etal. 2015).
8.3.2 Impact onTablet Mechanical Properties
We looked at tableting characteristics of many varieties of amorphous inulin. The
kinds differed in terms of quantity of air contained in particles, size of particles, and
chain length. The various varieties’ densities and powder ow characteristics were
8 Inulin asaPharmaceutical Excipient
154
examined (Van Arkel etal. 2013). It was discovered that when material’s particle
size rose, ow characteristics became better as predicted. The study of compact-
ibility included compressing tablets using a compaction simulator, which replicated
process of compression using high-speed tabletting machines (Mutanda etal. 2014).
8.3.3 Enhancement ofDrug Dissolution
For solid oral preparations, drug has to dissolve in order for it to be absorbed. As a
result, medications with subpar release patterns and disintegration rates have low
bioavailability. Techniques like solid dispersion (SD) may improve medications’
release prole and ease of disintegration (Barclay etal. 2010). The solid dispersion
dissolves more quickly when hydrophilic carriers are used, which boosts bioavail-
ability. Additionally, since inulin is hydrophilic, dosage forms use it as a carrier to
progressively improve medication release, solubility, and bioavailability
(Saengthongpinit and Sajjaanantakul 2005). Inulin considerably enhanced dissolv-
ing proles in a research on rate of medication dissolution when compared to
sucrose or other sugars. Merely 10–15% of medication is discharged from physical
blends; however, 80–85% of release was seen from solid dispersions including inu-
lin (Koch etal. 1999).
8.4 Inulin asaSustained Release Agent
When compared to other biodegradable polysaccharides, inulin’s unique and exi-
ble structure and stabilizing/protective properties aid in attaining targeted, sus-
tained, and regulated release of medications and biomolecules as well as improved
cellular absorption and bioavailability (Leyva-Porras etal. 2015). The potential use
of inulin as an entrapment material was investigated in relation to its prolonged and
regulated drug release behaviour as well as its breakdown by enzymes in intestinal
microbiota. Since inulin is nontoxic, blood-compatible, and biodegradable and has
therapeutic value, it is a desirable drug carrier when employing prodrug method
(Keenan et al. 2014). The bio-based, naturally occurring polysaccharide inulin,
which comes from plant roots, has garnered a lot of attention lately as a carrier
matrix for production of controlled-release medications. For a longer period of
time, inulin matrix formulation aids in controlling release of active pharmaceutical
ingredient (API). This feature is benecial, particularly for a continuous release
system that increases patient adherence, minimizes frequency of treatment, and
optimizes medication efciency (Rodriguez Furlan etal. 2014; Kocer etal. 2007).
Table8.2 shows various applications of inulin.
V. Mittal et al.
155
Table 8.2 Various applications of inulin
Inulin and its derivatives
Model drug Dosage form
Applications
Aminated inulin Folic acid
complex
Modied release Controlled
Hydrophobically
modied inulin
Cinnamaldehyde Nano-emulsions Improved solubility of
nanoparticles
Inulin Fiseten Inulin nanoparticles Improved solubility and
stability
Inulin Anthocyanins Microparticles Improved stability
Inulin--α-tocopherol
succinate
Curcumin Self-assembling
micelles
Improved solubility
8.4.1 Mechanisms ofSustained Release
These days majority of time-release medications are made with active pharmaceuti-
cal ingredient (API) incorporated in an insoluble matrix, such chitin or acrylics. In
this case drug’s dissolution depends on pores allowing it to escape. Some medica-
tion formulations with prolonged release dissolve active ingredient into a matrix
(Rodríguez-García etal. 2014). A polymer for glycoside bonds in polysaccharides,
inulin has been used as a matrix to deliver drugs with controlled release. Micro-
encapsulation is another widely used technique that entails coating an inner core
with an API and then covering it with layers of insoluble chemicals (Mittal and
Bajwa 2011). This results in the formation of a microsphere with predictable rates
of dissolution, which, if necessary, may be combined with additional microcapsules
in a gelatine capsule for combination treatment. The physicochemical characteris-
tics of API, administration route, kind of delivery system, patient, disease process,
and anticipated duration of treatment are all important considerations in design of
sustained release dosage forms. The medications or active ingredients that work
best in these dose formulations have moderate rates of absorption or elimination
(Pintor etal. 2013). A fair margin of safety must be maintained when using potential
actives for sustained release (SR) delivery methods. It should be noted that physio-
chemical characteristics of inulin and its interactions with drug molecules dictate
functioning of sustained-release mechanism. Inulin is a linear polysaccharide com-
posed of fructose units connected by β(2-1) glycosidic connections that creates a
porous matrix when wet. As a result, drug particles become caught and dispersed
across same network (Van Loo etal. 1995). Inulin has the ability to gel and coat
drug particles under correct circumstances, forming a barrier. As a result inhibitory
layer limits drug diffusion and solubility, gradually postponing release of active
ingredient. Additionally, mucoadhesive properties promote a prolonged residence
in gastrointestinal tract, ensuring continued absorption of drugs (Rodriguez Furlan
etal. 2015). Figure8.3 illustrates the uses of inulin.
8 Inulin asaPharmaceutical Excipient
156
Fig. 8.3 Applications of inulin
8.4.2 Formulation Strategies
When employing inulin in sustained-release formulations, a number of strategies
may be used to enhance drug release kinetics and improve therapeutic effects. These
methods involve in situ inclusion of pharmaceuticals with homogeneous drug dis-
persion for extended drug release into inulin matrices produced by solvent evapora-
tion, spray-drying, or extrusion (Rezaei etal. 2014). Inulin may be mixed with
different polymers and other excipients to create an effective sustained-release for-
mulation that primarily focuses on targeted therapeutic purpose (Laguna et al.
2013). The surface characteristics of formulations based on inulin may also vary
when coating methods or cross-linking agents are used, which might have an impact
on drug release. These formulation paths often provide adaptable methods for build-
ing rational continuous drug release systems, enhancing therapeutic results and
patient compliance (Kelly 2008).
8.5 Inulin inParenteral Formulations
Parenteral techniques, such as intramuscular, subcutaneous, and intravenous injec-
tions, are preferable to oral and external approaches for medication administration.
Because they don’t have to travel through the stratum corneum or epidermis, which
V. Mittal et al.