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8 Inulin asaPharmaceutical Excipient
169
9
Toxicity andSafety Aspects ofInulin
SanjayKumarGupta andAsthaVerma
Abstract
Inulin has gained considerable attention in academic circles due to its excep-
tional physicochemical properties and diverse range of biological activities,
making it a highly promising and versatile biopolymer. This naturally occurring
polysaccharide can be found in several plant sources, including chicory and
dahlia. It nds extensive applications in the food, pharmaceutical, cosmetic, and
biotechnological industries for a variety of purposes. Of late, inulin has been
utilized as an encapsulating agent in numerous drug formulations and bioactive
preparations, thus enhancing their delivery properties. However, the safety and
toxicity of inulin present signicant concerns in the development of pharmaceu-
tical products. Many studies have reported adverse effects associated with inulin
usage. This chapter aims to provide a concise overview of the toxicity, safety, and
various adverse effects linked to pharmaceutical products containing inulin.
Considering that the United States Food and Drug Administration (USFDA) has
recognized inulin as a safe ingredient within a specic dosage range, this chapter
will focus on delineating the adverse events associated with different dosage
levels. The reported adverse effects of inulin on various organs and tissues will
be comprehensively discussed. By delving into the toxicity and safety aspects of
inulin-based pharmaceutical products, this chapter will prove invaluable to
researchers involved in inulin-based development, as it will help them navigate
potential risks in diverse populations and anticipate long-term complications.
S. K. Gupta (*)
Department of Pharmacology, Rungta College of Pharmaceutical Sciences and Research,
Bhilai, Chhattisgarh, India
A. Verma
Department of Pharmaceutics, Shri Rawatpura Sarkar Institute of Pharmacy,
Kumhari, Chhattisgarh, India
170
Keywords
Inulin · Toxicity · Safety · Fructose polymer · Adverse effect · Recommended doses
9.1 Introduction
Recently, there has been a growing interest in utilizing natural biopolymers for vari-
ous pharmaceutical applications, biotechnology, and medicine applications. Inulin
has emerged as a versatile and promising candidate among these biopolymers due
to its unique physicochemical properties and diverse biological activities (Kishan
etal. 2021). Inulin is a fructan biosynthesized mainly in plants of the Asteraceae
family. It is a naturally occurring polysaccharide, which is primarily found in the
roots and rhizomes of various plants, such as onion, scorzonera, topinambur, aspara-
gus, garlic, ginger, chicory, dahlia, and Jerusalem artichoke (Lin etal. 2024; Sheng
etal. 2023; Akram etal. 2019; Coussement 1999). It was rst discovered by German
scientist, Valentine Rose, in the 1800s from the roots of Inula helenium, naming it
“Inulin” by Thomson in 1817 (Ghali etal. 2024). Many plants are reported to con-
tain a small amount of inulin. It is a type of prebiotic and is not absorbed and
digested in the stomach. Many people are most commonly consuming inulin-based
products for weight loss, constipation, high cholesterol, and diabetes. Inulin is likely
safe for most people in the amounts found in foods (Kishan etal. 2021).
Inulin is a polydisperse β-(2–1) fructan which is made up of residues of β-D-
fructose bound together by glycosidic bonds (Watzl etal. 2005). Inulin is indigest-
ible in the human small intestine due to β-conguration of anomeric carbon,
however, can be fermented by the intestinal microora in the large intestine. Its
β-(2–1) bonds are a special feature of the structure of inulin. These linkages inhibit
the digestion of inulin like a standard carbohydrate and are responsible for its
decreased caloric value and benets of dietary ber (Shoaib etal. 2016).
Inulin is used in the food, pharmaceutical, cosmetic, and biotechnological indus-
tries and exhibits prebiotic properties. Inulin can be used as a thickener, fat replacer,
sweetener, and water-retaining agent in the food industry. Inulin also can be applied
in pharmaceutics as a stabilizer, drug carrier, and auxiliary therapeutic agent for
certain diseases such as constipation and diabetes (Wan etal. 2020). Inulin can be
used as a wall material in the encapsulation process of drugs and other bioactive
compounds and the development of their delivery systems (Gruskiene etal. 2024).
It also possesses various physiological functions such as lowering blood sugar and
blood fat, anticancer, regulating intestinal microbial ora, and promoting mineral
and vitamin absorption (Ghali etal. 2024; Dehghan etal. 2016).
Despite multiple applications of inulin, many people are concerned about the
safety and toxicity of inulin when using it for the development of drug delivery
systems or any food products as recently it has been found that inulin supplementa-
tion can increase the frequency of bowel movements (Liu etal. 2021). Several stud-
ies have reported that inulin-based products are safe when it is consumed under the
recommended dose, but many case studies have reported the side effects and intoler-
ance associated with the use of inulin (Liu etal. 2021; Teferra 2021). The Food and
S. K. Gupta and A. Verma
171
Drug Administration (FDA) accepts the fact that inulin is a safe component at a
given level the adverse events are associated with different dosage levels or condi-
tions of individuals.
In this book chapter, we focused to collect the information related to the safety
and toxicity of inulin and inulin-based pharmaceutical products that may help the
researchers to use inulin within the acceptable limits to reduce the potential risk
caused by the overconsumption of inulin. The acceptable dose range for the inulin
consumption in various populations is studied and the potential risks associated
with inulin intake discussed.
9.2 Inulin-Based Pharmaceutical Applications
In the pharmaceutical industry, the nondigestible function of inulin has made it
attractive. It can be used as a sugar or fat replacer in processed foods to inuence the
desirable characteristics. Regulating blood sugar and acting as antioxidants and
anticancer are some of the biological activities of inulin (Clark 1999). Inulin can
also be a carrier for colon/tumor targeting. Inulin is considered as a prebiotic as it is
fermented by bacteria that normalize the colon. Inulin can be used as a wall material
in the encapsulation process of drugs and other bioactive compounds and the devel-
opment of their delivery systems (Gruskiene etal. 2024). The ongoing research and
development in this eld suggest that inulin will continue to play a vital role in the
advancement of pharmaceutical technologies.
Inulin is a versatile polysaccharide with several applications in drug delivery
systems (Anjuomo etal. 2021), such as the formation of hydrogels, drug conju-
gates, nanoparticles and microparticles, micelles and liposomes, prodrug or drug
complex, and solid dispersion. Hydrogels prepared using inulin are valuable in sus-
tained and controlled drug release due to their biocompatibility and biodegradabil-
ity (Ali et al. 2023). Recently some inulin-based smart hydrogels have been
developed for specic targeting, in which hydrogels can deliver the drug at triggered
stimuli such as pH, enzyme, temperature, etc. (Anjuomo etal. 2019; Liang etal.
2024). Inulin has been used as a conjugate with several drugs to enhance their stabil-
ity and targetability, for instance, Ganie etal., developed an inulin-niacin conjugate
with controllable and sustained release of niacin (Ganie etal. 2022). Shen etal.
developed an oral curcumin-thioketal-inulin conjugate micelles with improved sol-
ubility and stability (Shen etal. 2024).
Recently, researchers have increasingly used inulin to develop nanoparticles and
microparticles for drug delivery, aiming to enhance the therapeutic efcacy and targe-
tability of the drugs (Saud et al. 2023; Ayala-Fuentes et al. 2023). For instance,
Gontrani et al. prepared inulin-coated zinc oxide nanoparticles for biostimulation
applications (Gontrani etal. 2024). Inulin has also been used to develop micelles and
liposomes to encapsulate drug molecules more specically hydrophobic molecules;
to protect them from degradation; to enhance solubility, stability, tissue penetrability,
and bioavailability; or to make them for specic targeting to organs and tissues (Shi
etal. 2023; Xue etal. 2022; Di Prima etal. 2021; Sardo etal. 2022). Tripodo etal.
9 Toxicity andSafety Aspects ofInulin
172
developed natural inulin-based micelles loaded with rifampicin and reported enhanced
antibacterial action (Tripodo etal. 2019). Inulin can form complexes with the drugs or
can be used to develop prodrugs, which later can be metabolized and converted into
active drugs in the body (Anjuomo etal. 2021; Li etal. 2021). Inulin has also been
used to develop the solid dispersion of some drugs and phytochemicals to improve
their dissolution and absorption rate, especially for drugs that are classied under
Biopharmaceutical classication system (BCS) class IV, which can be delivered using
inulin-based solid dispersion (Visser etal. 2010; Setyaningsih etal. 2022).
Inulin’s role in pharmaceuticals is not limited to drug delivery; it also includes
stabilization of proteins, modied drug delivery for enhanced dissolution rates, drug
targeting, and physiological and disease-modifying effects. Its potential for colon-
specic drug administration and use in vaccine formulations as a stabilizing and
adjuvant agent are also signicant areas of interest (Mensink etal. 2015).
9.3 Toxicity Studies ofInulin
The long history of mankind’s safe use of inulin-containing foods is reected by the
fact that very little formal toxicity testing in laboratory animals has been reported on
inulin (Coussement 1999). This class of ber has been studied in a series of standard
toxicological test systems. The studies have demonstrated that inulin-type fructans,
when administered in the diet at high levels, do not result in mortality, morbidity,
target organ toxicity, reproductive or developmental toxicity, or carcinogenicity.
Several invitro studies have also shown the absence of mutagenic or genotoxic
potential. The only basis for limiting the use of such ber in the human diet relates
to gastrointestinal tolerance (Carabin and Flamm 1999).
The use of inulin in foods as a ber source has increased recently. Inulin is gener-
ally recognized as safe (GRAS status) by the USFDA, and daily intake of 10g is
well tolerated by young and healthy people. However, the consumption of inulin
can cause gastric distress to some individuals or intake beyond the limit. The com-
mon Gastrointestinal (GI) symptoms are atulence followed by bloating (Bonnema
etal. 2010). Also, recent studies suggest that long-term supplementation with bers
causes changes in hepatic bile acid metabolism, hepatocyte damage, and hepatocel-
lular cancer in dysbiotic mice (Pauly etal. 2020).
Pauly etal. (2020) reported that the supplementation of inulin may disturb the
hepatic cholesterol and bile acid metabolism. They investigated the effect of short-
term dietary inulin supplementation on cholesterol and bile acid metabolism in the
liver using pathogen-free wild-type mice, and their ndings indicated that inulin
provoked cholestasis and showed a detrimental effect on liver functioning and
metabolism of cholesterol and bile acid (Pauly etal. 2020).
On the one hand, it shows that mankind has been exposed to both substances for
centuries. On the other hand, the fact that specic meals and even some diets can
contain considerable amounts of inulin or oligofructose (up to 20 g) provides a
S. K. Gupta and A. Verma
173
history of exposure to such high amounts through the diet (Coussement 1999).
Although inulin dietary ber can ameliorate low-grade inammation and associated
metabolic disease, some negative effects have been reported for inulin consumption
in murine models as well as in humans (Tawck etal. 2022). Recently, the effect of
a high dose of inulin (80mg per mouse) provoked severe allergic and intestinal
inammatory response (Xie etal. 2023).
9.3.1 Reported Adverse Effects ofInulin
9.3.1.1 GIT
Inulin is a type of soluble dietary ber, and the bers are polymer of carbohydrates
that is resistant to hydrolysis by enzymes and make it indigestible by the intestinal
enzymes, and while consuming it, some people may experience digestive discom-
forts such as gas, bloating, nausea, atulence, diarrhea, and abdominal distension
(Sheng etal. 2023; Liu etal. 2021; Teferra 2021). This is because inulin is a fer-
mentable ber that undergoes fermentation by gut bacteria, producing gases as
byproducts (Gunn etal. 2022). Individuals with sensitive digestive systems may
need to introduce inulin gradually to allow their bodies to adjust. It’s worth noting
that individuals with irritable bowel syndrome (IBS) or other gastrointestinal condi-
tions may be more prone to experiencing symptoms related to inulin consumption.
Loose stools and diarrhea are also reported in some individuals consuming inulin.
Miles etal. reported that diets enriched with inulin did not protect but further exac-
erbated the severity of dextran sulfate sodium (DSS)-induced colitis in mice (Miles
et al. 2017). In another study, inulin has been reported to have the potential in
improving intestinal immunity and decrease the edema in stress-recurrent inam-
matory bowel disease (Du etal. 2024).
9.3.1.2 CNS
There is limited information are available on toxicity of inulin in the central nervous
system (CNS). It has been shown that increased intake of inulin may induce head-
ache, chemoreceptor trigger zone (CTZ) stimulation, or stress-like conditions, and
it has been recommended that the intake of inulin should be consumed below the
upper limit of the range (Table9.1).
Table 9.1 Acceptable dose
range for inulin consumption
in different population
(Sheng etal. 2023; Teferra
2021; Bonnema etal. 2010;
Oswari etal. 2019; Kim etal.
2007; Vajdi etal. 2023)
Type of population Acceptable dose range (in g/day)
Infants/child 2–10
Adult 10–40
Overweight/obese
adults
10–20
Diabetic people 10–25
Patient on dialysis <10
Older people 5–15
Pregnant women 5–10
9 Toxicity andSafety Aspects ofInulin
174
9.3.1.3 CVS
In a study, it has been reported that inulin can increase the plasma cholesterol level
and exacerbate the atherosclerosis development characterized by enhanced lesion
formation and outward vascular remodeling (Hoving etal. 2018). However, the
effect of inulin on plasma triglycerides and cholesterol levels is still controversial
(Hiel etal. 2018). In a randomized controlled trial, the effect of inulin has been
investigated for cardiovascular risks, and it was reported that the inulin can reduce
the low-density lipoproteins and triglycerides. The reduction in these lipids is ben-
ecial for the cardiac health (Talukdar etal. 2024).
9.3.1.4 Hypersensitivity Reactions
Although rare, some individuals may be allergic to inulin or may experience an
allergic reaction. Symptoms can range from mild to severe and may include itching,
hives, swelling, difculty breathing, and anaphylaxis. If any individual suspects an
allergy, it’s important to seek medical attention immediately. Recently, Xie etal.
(2023) reported that high insulin dietary supplementation can be detrimental to
allergic individuals and highlighted the importance for personalized use of inulin-
type dietary supplementation to safely improve human health. They found that high-
inulin supplementation (80mg per mouse) provoked severe allergic and intestinal
inammatory responses, which were characterized by elevated serum allergic
inammation-related factor levels, dysfunctional gut barrier, unbalanced luminal
pH value, decrease in intestinal antioxidant capacity, and disordered gut microecol-
ogy (Xie etal. 2023). For individuals with pollen allergy, intake of inulin-containing
chicory may trigger oral allergy syndrome (OAS) (Cadot etal. 2003).
9.3.1.5 Other Reported Adverse Effects
Dietary bers can have other unwanted side effects, such as a negative inuence on
vitamin or mineral absorption, allergic reactions, and an undesirable inuence on
the gut ora and its metabolism. In most of the studies, inulin also has been reported
to produce some side effects on an individual basis (Mysonhimer and Holscher
2022). Inulin supplementation can also affect the hepatic metabolism of cholesterol
and bile acid, which can affect the normal functioning of the liver and other adverse
events associated with long-term intake or overdosage of inulin shown in Fig.9.1
(Pauly etal. 2020).
9.3.2 Inulin Interactions
Inulin may interact with certain medications, particularly those that affect blood
sugar levels. Individuals taking medications for diabetes or other blood sugar-
related conditions should consult their healthcare provider before incorporating inu-
lin into their diet. Specically, it has been reported to interact with lactulose and
linaclotide, but the interactions are not typically serious, but attention is required
while using these medications (Bărboi etal. 2022). Additionally, there are certain
S. K. Gupta and A. Verma
175
Fig. 9.1 The adverse events associated with long-term intake or overdosage of inulin
disease interactions with inulin, particularly for individuals with inammatory
bowel disease or intestinal obstruction disorders (Akram etal. 2019).
9.4 Safety Considerations forInulin-Based
Pharmaceutical Products
Inulin has been reported for its signicant antioxidant and protective effect by
reducing the reactive oxygen species (ROS) and apoptosis of cells. A study shown
that the inulin has the potential to reverse the hepatotoxic effect caused due to intake
of some narrow therapeutic indexed drugs, for example, methotrexate-induced hep-
atotoxicity can be revered by intake of inulin (Kalantari etal. 2019).
9.4.1 Acceptable Daily Intake
The daily effective intake is 5g, and the recommended maximum daily intake is
15–20g. Inulin consumption under 40g per day in healthy adults is safe (Sheng
etal. 2023). Inulin is present in the daily diet of many of the world’s populations,
and several grams per day may be ingested through the normal diet that fact is the
cornerstone of safety evaluation of inulin (Hiel etal. 2018). However, Intestinal
acceptability of nondigestible fermentable carbohydrates differs from person to
9 Toxicity andSafety Aspects ofInulin
176
person. Many people can consume ≥10g without noticeable side effects, whereas
some people experience intestinal discomfort that they consider too much after
ingestion of even small amounts of nondigestible fermentable carbohydrates
(Mysonhimer and Holscher 2022). Inulin is likely safe for most people in the
amounts found in foods. It is possibly safe in adults when taken as a supplement,
short-term. Doses of 8–18g daily have been used safely for up to 24weeks. The
adverse effects such as bloating, constipation, cramps, back pain, headache, etc. are
reported with high intake of inulin, i.e., more than 30g/day. A series of clinical stud-
ies has been reported which shows that up to 20g/day of inulin and/or oligofructose
is well tolerated (Rubin etal. 2022). A number of previous studies mentioned the
different dose ranges for the intake of inulin in different population, and based on
various studies, a general dose range has been mentioned in Table9.1.
9.4.2 Regulatory Guidelines andStandards
Regulatory guidelines and standards for inulin intake may vary by country and
region. In the United States, inulin is generally recognized as safe (GRAS) when
used in accordance with good manufacturing practices. The FDA has established
regulations for dietary bers, and inulin falls under this category. Food products
containing inulin must adhere to the FDA’s regulations on nutrition labeling, and
inulin content may be declared as part of the total dietary ber content (Stribling
and Ibrahim 2023).
In the European Union, inulin is considered a dietary ber, and its intake is regu-
lated under the European Food Safety Authority (EFSA) guidelines. The EFSA pro-
vides scientic opinions and recommendations on the safety and efcacy of various
food ingredients, including inulin (Theis 2018). National food safety authorities in
different countries may have specic regulations and guidelines regarding the use of
inulin in food products. Regulatory bodies often dene maximum allowable intake
levels for certain food ingredients, including dietary bers like inulin. These levels
are determined based on safety assessments and scientic evidence
(Coussement 1999).
9.4.3 Potential Risks inSpecial Populations
Inulin is safer to intake by all populations if it is consumed within the range of the
average daily recommended dose (Fig.9.2), if used higher than the range, can lead
to several risks, and it can vary depending on the specic population which has been
discussed below.
9.4.3.1 Children andInfants
Inulin supplementation is considered safe for children when it is consumed at an
appropriate dose; however, certain risks are associated with some children as the
children’s tolerance to inulin varies on an individual basis. It has been reported that
S. K. Gupta and A. Verma