International Journal of Biological Macromolecules

International Journal of Biological Macromolecules 159 (2020) 804–822
Contents lists available at ScienceDirect
International Journal of Biological Macromolecules
journal homepage: http://www.elsevier.com/locate/ijbiomac
Highlighting the impact of chitosan on the development of

gastroretentive drug delivery systems
Maurício Palmeira Chaves de Souza, Rafael Miguel Sábio, Tais de Cassia Ribeiro, Aline Martins dos Santos,
Andréia Bagliotti Meneguin, Marlus Chorilli ⁎
São Paulo State University (UNESP), School of Pharmaceutical Sciences, Araraquara, Department of Drugs and Medicines, Rodovia Araraquara-Jaú, km 1, - Campos Ville, Araraquara, São Paulo
14800-903, Brazil
a r t i c l e i n f o a b s t r a c t
Article history: The development of gastroretentive systems have been growing lately due to the high demand for carriers that
Received 11 February 2020 increase drug bioavailability and therapeutic effectiveness after oral administration. Most of systems reported up
Received in revised form 6 May 2020 to now are based on chitosan (CS) due to its peculiar properties, such as cationic nature, biodegradability, bio-
Accepted 14 May 2020
compatibility and important mucoadhesiveness, which make CS a promising biopolymer to design effective
Available online 18 May 2020
gastroretentive systems. In light of this, we reported in this review the CS versatility to fabricate different types
Keywords:
of nano- and microstructured gastroretentive systems. For a better understanding of the gastric retention mech-
Gastroretentive systems anisms, we highlighted expandable, density-based, magnetic, mucoadhesive and superporous systems. The bio-
Chitosan logical and chemical properties of CS, anatomophysiological aspects related to gastrointestinal tract (GIT) and
Drug delivery systems some applications of these systems are also described here. Overall, this review may assist researchers to explore
Stomach new strategies to design safe and efficient gastroretentive systems in order to popularize them in the treatment of
Biopolymer diseases and clinical practices.
© 2020 Published by Elsevier B.V.
1. Introduction Despite the numerous advantages of controlled drug delivery sys-

tems, many drugs with high solubility at stomach pH, instability in in-
Chitosan (CS) is a biopolymer obtained from the deacetylation of testinal pH, as well as those with narrow absorption window and that
chitin that presents several applications in photography [1], cosmetic/ are intended for the local treatment of stomach disorders, require ad-
skin regeneration [2], food and nutrition [3], environmental protection ditional mechanisms for spatial control of the release, for which
[4] and drug delivery systems [5]. Specifically, CS is very useful for phar- GRDDSs classification has been attributed. This topic has been ex-
maceutical applications due its non-toxic nature, biodegradability, tremely relevant according to the number of preclinical and clinical
bioadhesivity, biocompatibility besides the capability to form films, [13,14] studies in which their effectiveness have been demonstrated
gels, nano and microparticles [6,7]. Thus, floating, mucoadhesive, po- by increasing the drugs absorption despites the low absorption win-
rous and gastric pH resistant pharmaceutical systems may be originated dow [15].
using pristine CS or associated with other materials [8,9]. Many characteristics attributed to CS are directly related to the
Investigations have been carried out with the purpose of suggesting, preservation of protonable amino groups in the polymeric chain,
developing and testing microspheres, micelles, hydrogels and nanopar- which are nucleophilic and reactive regions of the molecule. Therefore,
ticles using this biopolymer [10–12]. An innovative application of CS is being able to interact with a large number of materials, and therefore
to develop systems with the capacity to remain and release drugs in be widely applied in the most diverse fields, from water treatment to
the stomach. These systems are labelled gastroretentive drug delivery the development of controlled drug release systems, its versatility
systems (GRDDSs), which demarcate an important frontier in gastric can be explored individually or in combination with other materials
and drug transport therapies that require gastric absorption and/or [16].
local action. Consequently, these systems circumvent the short reten- This review highlights recent works addressing to the CS-based ma-
tion time caused by gastric emptying and some physicochemical limita- terials to fabricate GRDDSs. In the Scopus database, when requested to
tion, such as low solubility of some drugs. search using the keywords “chitosan”, “gastroretentive” and “drug de-
livery”, 1544 documents were found from 2009 to 2019, (Fig. 1). It is
worth noting that since 2013 the number of publications on this topic
⁎ Corresponding author. has increased, showing great interest on the part of scientific
E-mail address: marlus.chorilli@unesp.br (M. Chorilli). community.
https://doi.org/10.1016/j.ijbiomac.2020.05.104
0141-8130/© 2020 Published by Elsevier B.V.
M.P.C. Souza et al. / International Journal of Biological Macromolecules 159 (2020) 804–822 805
2. Chitin and chitosan
Discovered in 1811 by Henri Braconot, chitin is a polysaccharide

formed by β(1 β(1 → 4)-2-acetamide-2-deoxy-D-glucopyranose units
[17]. The orientation of these polymeric chains gives rise to different
allomorphs of chitin, forming anti-parallel and parallel arrangements
known as alpha, beta and gamma-chitin. Chitin is a hydrophobic poly-
mer, with fewer applications than CS, because it is not dispersible in
aqueous, acids and alkaline media, being possible its dispersion only
in hexafluoroisopropanol and chloroalcohols. Chitin is usually found in
exoskeletons of invertebrate animals as crabs, lobsters, shrimps, cock-
roaches and scorpions. In addition to these sources, chitin and CS also
occur naturally in some fungi like Mucor rouxii (30% of total mass) and
Choanephora cucurbitarum (28% of total mass) [18,19].
CS was first observed in 1859 by Rouget [20]. Later, authors showed
that CS is obtained by alkaline deacetylation of chitin (Fig. 2) under
heating [20]. CS consists of monomeric units of β(1 → 4)-2-acet-
amide-2-deoxy-D-glucopyranose and β(1 → 4)-2-amino-2-deoxy-D-
Fig. 1. Publications from the last 10 years containing the terms “chitosan”,
glucopyranose, predominantly the last one [17,21,22].
“gastroretentive” and “drug delivery”. CS presents interesting characteristics like biocompatibility, biode-
gradability and low toxicity being a versatile biomaterial used in many
research areas like textiles, food industry, environmental, agriculture,
Fig. 2. Deacetylation of chitin producing CS.

806 M.P.C. Souza et al. / International Journal of Biological Macromolecules 159 (2020) 804–822
medical products, cosmetics and mainly, in pharmaceutical applications the chemical reactivity of the hydroxyl and amino groups from the
[23–26]. C-6 and C-2 carbons, respectively [58]. Substitutions performed on
In relation to the different CS applications, its dispersion in acidified CS by reducing the DD promote the exposure of more amino groups
aqueous media promotes the increase of liquid formulations viscosity, in the polymer chain increasing its antioxidant activity. The bio-
making CS also applicable as a thickener. Additionally, the high viscosity polymer chain reduction (MW) also exerts a positive effect on the
of these systems associated with their polycationic nature gives to the CS antioxidant activity. Smaller biopolymer chains are very rigid,
CS impressive mucoadhesive properties. This can be attributed to the so the intra-chain hydrogen bonds that involve hydroxyl groups
CS interaction with sialic acid, an anionic component presents in the and amino acids are less intense than the same interactions in
mucin [27]. The properties above mentioned make CS a special biopoly- larger chains with more conformational freedom [45]. Thus, smaller
mer used to develop specific (mucoadhesive) drug delivery systems polymer chains can interact more efficiently with oxidant molecules
[28]. inhibiting their action.
CS amino groups in acidified aqueous media can become protonated, CS hypolipidemic activity is associated with its polycationic nature,
giving rise to a positively charged material, which can interact with neg- interacting with dietary lipids inhibiting their absorption. Additionally,
ative charges from anionic polymers, cell membranes, mucus and com- CS can reduce the liver damage associated with the oxidation of fatty
plex reactive oxygen species (ROS). When not protonated, amine acids, leading to a considerable reduction in liver enzymes aspartate
groups can still complex metallic ions like Cu2+ and are mainly used aminotransferase (AST) and alanine aminotransferase (ALT) and eleva-
in water treatment and clarification of beverages [29–31]. tion in activities of antioxidant enzymes such as superoxide dismutase
For biological applications, CS also requires dispersion in acidic (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px). Beyond
aqueous solutions with pH values lower than 6.5. In this condition, the that, diets rich in CS and chitooligosaccharides have shown the reduc-
CS amino groups (NH2) present in the N-acetyl-D-glucosamine units tion of serum triglyceride and LDL-cholesterol levels as well as regulate
act as nucleophiles becoming progressively protonated due to the ioni- the expression of liver peroxisome proliferator-activated receptor α
zation of acids present in the medium, forming a positively charged (PPARα) [48,59].
polyelectrolyte, as shown in Eq. (1) [32]. Most of studies have demonstrated that CS and their derivatives dis-
play anticancer properties. These biopolymers show low toxicity reduc-
ChNH 2 þ H 3 Oþ ¼ ChNH þ
3 þ H2 O ð1Þ ing side effects and tumor size by inhibiting tumor cells proliferation
and, consequently, provoking apoptosis [52,60].
Changes in the CS chain can directly affect its physicochemical prop- Considering CS applicable as new biomaterials, this biopolymer
erties, leading to different technological applications changing also its could be used to fabricate scaffolds for regenerative medicine [61]. CS-
biological activity [33,34]. Some types of CS have different degrees of based scaffolds exhibit advantages as biocompatibility, biodegradability
deacetylation (DD) and molecular weight (MW), which are determi- and malleability. In addition, these biomaterials can easily interact with
nant for their polycationic nature at pH b 6.5. Variations, such as high growth factors, glycosaminoglycans, and DNA making CS-based scaf-
DD and low MW can increase inter- and intra-chain electrostatic repul- folds excellent for bone, cartilage and intervertebral discs regeneration
sion, favoring biopolymer-water interactions and reducing biopolymer- [62]. CS-based scaffolds allow an efficient angiogenic response, favoring
biopolymer interactions. This effect is also responsible for increasing in- the oxygen supply to cells, nutrients and chemical mediators for cells
teractions with negative surfaces like lipids, cells, drugs and anionic proliferation and differentiation, promoting osteogenesis in vitro and
molecules, as well as mucus conferring mucoadhesive properties [35]. in vivo. CS hydrophilicity promotes cells adhesiveness by reducing im-
Interestingly, the CS interaction with anionic polymers can lead to mune reactions when applicable in implants [63].
gels formation by complex coacervation [36]. Interaction with smaller NH2 groups available in CS interact with erythrocytes promoting the
polyanions such as sodium tripolyphosphate leads to the formation of aggregation and the formation of a physical barrier that prevents the
bridges (junction zones) between the polymer chains forming gel by blood loss without rejection by the organism [64]. CS with low DD and
ionotropic gelation [37]. These kinds of interactions make protonated dispersed in acidified water can induce the complement pathway by
CS interesting biopolymer for the development of pharmaceutical sys- recruiting more erythrocytes, promoting rapid coagulation. Addition-
tems such as micro- and nanoparticles, gels and films [38]. ally, the CS MW showed less impact on the coagulant effect. In this sce-
The ability to form particles applied as GRDDSs is associated with nario, CS with MW between 105 and 106 Da displayed less coagulant
characteristics of the polymeric chain, such as DD and MW, as well as capacity whereas CS with higher MW in physiological saline solution
pH value of the dispersion medium. CSs with low DD are more effi- were more efficient in inducing erythrocyte aggregation. The effect of
ciently dispersible at high pH due to their high charge density that fa- MW in CS suggests that long chains can interact with more platelets,
vors more intensely interactions with polymers, drugs and cross- promoting greater efficiency in hemostasis. Therefore, when DD is
linking agents, such as sodium tripolyphosphate. On the other hand, high the influence of MW on platelet aggregation is reduced. This effect
CS with high MW shows greater capacity than low MW to increase is more pronounced by reducing DD, indicating that DD is the most im-
the media viscosity even at low concentrations, making the diluted/ portant factor for platelet aggregation [54,65]. In light of this, the impor-
semi-diluted dispersion concentration regime suitable for particles for- tance of CS to build GRDDSs orally administered is evident. However,
mation [37]. considering the harsh barriers imposed by the gastrointestinal tract
The knowledge about structural and biological properties may pro- (GIT).
vide a basis for exploring the potential and versatility of CS-based mate- An important aspect about the use of CS to develop drug delivery
rials applications as smart drug delivery systems. For instance, changes systems for GIT consists on understand CSgastrointestinal digestion
in CS rheological behavior in response to pH changes can favor the fab- process in humans. This process still lacks in-depth studies that describe
rication of suitable GRDDSs [39]. At acidic pH, CS can increase the viscos- it systematically. However, up to now, some studies have shown that CS
ity in the medium, promoting good adhesion. Beyond that, the cannot be digested in the upper GIT by human digestive enzymes
modification of CS structure can increase the possibilities of its biologi- whereas CS digestion can occur mainly in the intestine, through depoly-
cal applications [6] as shown in Table 1. merization catalyzed by enzymes [66–71].
Friedman et al. [56], demonstrated that CS anti-inflammatory ac- In 1990, Hirano et al. [67], from in vitro assays, showed that CS can be
tivity is related to the blocking of NK-κB in human type 1 mast cells degraded by chitosanase enzymes produced and released by bacteria
inhibiting the production of pro-inflammatory cytokines. This effect from the intestinal microbiota. Later, Varum et al. [68] demonstrated
can occur due to a downregulation of Ca2+-dependent pathways that CS can also be depolymerized in humans by the lysozyme present
[57]. In addition, CS antioxidant activity is directly associated with in the serum.
Table 1
Biological applications of distinct and modified CS-based materials.
Applications Materials/systems Remarks Refs.
Antimicrobial HTCC (N-(2-hydroxypropyl)-3-trimethylammonium The inhibitory effect of HTCC against SARS-CoV-2 and MERS-CoV viruses was tested [40]
chitosan chloride), degree of substitution of 57, 62, 63 in vitro with Vero and Vero 6 cells, as well as ex vivo on human airway epithelium
and 77%. (HAE).
- strongest inhibition by HTCC-62 or HTCC-77

- SARS-CoV-2: strong inhibition 24 h after virus inoculation.
- HTCC blocks interaction between MERS-CoV with its cellular entry receptor DPP4
- Inhibition of the virus may depend on the repeating units of the chitosan polymer
CS nano- and microparticles Low MW and DD presents to higher antimicrobial activity. At basic pH, CS loses [41]
antimicrobial activity.
CS dispersed-Different DD (51.04%–100%), and ultra high Optimal pH value was 6.0 for the highest bactericidal activity, high DD more effective [42]
6 −1
MW CS (Mw N 10 g mol ) against E. coli and S. aureus.
MIC for DD 81% was 0.0625% (E. coli) and 0.0313% (S. aureus)
MIC for DD 100% was 0.0156% for both microorganisms.
Anti-inflammatory CS with different MWs and chitooligosaccharide (COS) Larger MW (N29.2 kDa) CS usually exhibit anti-inflammatory activity. [43]
CS bind to CR3 receptor and TLR4 and CR3 receptors in macrophages down-regulated
the phosphorylation of MAPK signaling proteins ERK, JNK, and p38, inhibited the
LPS-induced NF-κB activation, abolished the production of TNF-α and IL-6 decreasing
NO production, reducing inflammation.
In-vivo (rats) test of anti-inflammatory activity in ulcer Anti-ulcerative and wound healing abilities. LMW CS reduced ulcerative wounds. [44]
model of CS high and low MW. HMW CS helped retain the stomachal folds rendering a gastro protective effect, also can
stimulate collagen synthesis.
Antioxidant CS of MW (0.5–1000 kDa) and DD (50% -low then 10%) Reduction of both DD and MW make CS more efficient in removing in vitro reactive [45]
oxygen species (ROS).
Gamma irradiated (5–50 KGy) and not irradiated CS DD Reduction of CS molecular weight by gamma irradiation at 50KGy, increased antioxidant [46]
(72–75%), dispersed in lactic acid capacity of CS dispersion
Lipid-lowering Dietary supplementation with CS DD (70.03%) and MW Comparison of the lipid-lowering and intestinal morphological effects of [47]
effects (estimated 500–1000 kDa) cholestyramine, CS and oat gum in rats. CS has hypolipidemic effects similar to
cholestyramine without deleterious changes in the intestinal mucosa. Oat gum was less
effective
Dietary supplementation with CS (4% DD) CS and chitooligosaccharides have the ability to regulate the body weight, liver and [48]
chitooligosaccharides cardiac indices, fat/body ratio, as well as serum, liver, and fecal lipids. Simultaneously,
COS b 1000 g mol−1, 4% DD maintain the appropriate activity of liver and serum superoxide dismutase (SOD),
COS b 3000 g mol−1, 9% DD alanine aminotransferase (ALT), aspartate aminotransferase (AST), as well as liver and
fecal total bile acids (TBA)
Scaffold for tissue Simvastatin-loaded CS nanoparticles CS induced new osteoid tissue formation, showing biodegradability and controlled [49]
regeneration simvastatin release. After 14 days, CS promoted increase of the enzyme ALP (indicator of
osteoblast mineralization). CS nanostructures presented porosity suitable for
angiogenesis and bone nutrition
CS-based hyaluronan hybrid polymer fiber Fibroblasts from patellar tendon of Japanese white rabbit. Fibroblasts had adhesion onto [50]
hybrid fibers and produced collagen fibers after 14 days of culture
CS Compare polyvinyl alcohol (PVA), CS, and polycarbonate (PC) as scaffold for culture of [51]
embryonal submandibular gland (SMG). Best results observed in CS scaffold secreted
extracellular matrices distributed in a reticular manner and formed thicker fibers
beyond the extents of cell attachment and were able to further enhance SMG branching
Anticancer CS and chitooligosaccharides Reduction of DD and MW of CS and its derivatives exhibiting good in vivo results, been [52]
efficient against prostate cancer, carcinomic human alveolar basal epithelial cells, and
hepatocellular carcinoma, been nontoxic for healthy cells
Crab (Chionoecetes opilio) CS and Shiitaki mushroom Shiitake CS had the best inhibitory effect on the growth of the human neuroblastoma [53]
(Lentinula edodes) CS cell line (IMR 32, BCRC 60014) and the human liver hepatocellular carcinoma cell line
(Hep G2, BCRC 60025), occurring because Shitake CS is more deacetylated
Hemostatic CS hydrogel containing nano bioglass Coagulation was twice faster than pure blood in in vitro hemocompatibility assay. [54]
In vivo test revealed the reduction to half the blood loss and coagulation time for both
organs and arteries
CS-based hemostatic dressing ChitoGauze® A commercial hemostatic dressing for temporary external control of wounds with [55]
severe bleeding. It is a CS dressing composed of a non-woven medical gauze of
polyester/rayon mixture coated with CS (HemCon Medical Technologies, Portland, OR,
USA). Used by US military forces, emergency medical services
The digestion by enzymes action from intestine is related to the de- Considering above mentioned properties, CS is widely used to de-
gree of deacetylation (DD) and molecular weight (MW) of CS. Authors sign colon-specific systems. Unlike when CS is associated with GRDDSs
reported that as higher the CS DD, lower is its degradability [68]. How- that release the drug in gastric media, in colon-specific systems the
ever, new studies have already shown that there are enzymes, but only dissolution of CS in acidic pH is overcome by association or coating
present in vegetables and some bacteria, capable of cleaving the glyco- with other polymers. These systems pass through the stomach quickly
sidic bond, both in CS with high and low DD including chitin [72]. without significant drug release, protecting the drugs until they reach
Another important factor in the CS degradability and digestibility is the intestine. In this organ, CS undergoes the action of enzymes from
MW. A study performed by Chae et al. [73], in which it was administered the intestinal microbiota and from its degradation can release the
orally 20 mg kg−1 marked (fluorescent) CS varying MW and DD in rats, drug [74].
exhibited that CS with 230 kDa presentedabsorption 20 times lower Thus, a deep anatomophysiology knowledge of the different por-
than CS of 3.8 kDa. These results indicate that greater CS digestibility tions that compose GIT is essential for the correct performance of
and consequent absorption could be achieved decreasing CS MW. GRDDSs.
Table 2 stomach, consisting of fundus and body, and the distal stomach,
Main characteristics of upper GIT. consisting of pylorus. The proximal stomach acts as a food reservoir
Length (m) Transit time (h) pH while the distal stomach has a role in food processing, forming the
Stomach 0.2 0.5–2 b3
chymus, which will be released later into the small intestine. The distal
Small intestine 6–10 3–4 5–8 stomach also acts as a propelling pump that assists in gastric emptying
(GE). The rate of GE is influenced by both food volume and gastric con-
tent composition [79,80]. Table 2 describes the main characteristics of
3. Anatomical and physiological aspects of the stomach upper GIT.
GE occurs during fasting and in the fed state. However, the motility
CS-based systems that present mucoadhesive, swelling, and acid pattern is different in both states. During fasting, a series of
erosion properties emerge as an alternative to explore different delivery interdigestive electrical events occur every 2 or 3 h [81]. As described
strategies for the gastric environment. The oral route is the most used by Wilson and Washington [82], this process is called migratory myo-
and convenient because it is a noninvasive way to access the stomach, electric cycle (MMC), which is divided into the following 4 phases, illus-
being a safe administration route that allows self-administration and trated in Fig. 3:
consequently, greater acceptance from the patient to the treatment
[75]. However, the bioavailability of orally administered drugs may be 1. Phase I (basal phase) lasts from 30 to 60 min with rare contractions;
influenced by several parameters such as gastric emptying and gastro 2. Phase II (preburst phase) lasts from 20 to 40 min with progressive
intestinal transit, gastric mucosa status, stomach pH [76]. high frequency and intensity contractions;
The stomach is located in the upper left part of the abdominal cavity 3. Phase III (burst phase) lasts from 10 to 20 min. Intense contractions
below the diaphragm. Stomach size can change according to the occur and all undigested material is carried from the stomach to
amount of distention. After meal, approximately 1500 mL whereas the the small intestine;
empty volume range from 25 to 50 mL [77]. Gastric pH in healthy con- 4. Phase IV lasts from 0 to 5 min and occurs between phases III and I.
ditions during fasting and fed state are 1.1 ± 0.15 and 3.6 ± 0.4, respec-
tively. The pH returns to basal level between 2 and 4 h [78]. After meal, the contraction pattern changes from the fasting state to
Anatomically, the stomach is divided in two parts: the proximal the fed state. It is known as digestive motility and comprises continuous
Fig. 3. Schematic representation of the gastric emptying stages.

contractions as in phase II. These contractions result in size reduction of One of the main challenges that motivate the development of new
the food particles, which are propelled into the suspended pylorus. Dur- GRDDSs is associated to the drugs physicochemical characteristics
ing the onset of the fed state, MMC is delayed resulting in decreased such as narrow absorption windows, local activity in the stomach, insta-
emptying rate [83]. bility in the colon or distal small intestine and with low solubility at high
The short gastric retention time of dosage forms and the unpredict- pH [91]. The use of GRDDSs can circumvent these limitations mainly
able rate of GE are limiting factors that can be overcome by GRDDSs. when associated with biopolymers as CS. This kind of association leads
These systems can increase gastric retention time contributing to an en- to the design of promising controlled drug delivery systems [92].
hancement of drugs solubility and, consequently, bioavailability [79]. GRDDSs in contact with gastric medium can release the drug into
stomach. GRDDSs can furnish controlled release profile, more efficient
4. Mechanisms of gastroretention and adapted to different needs, promoting important advances in
pharmacotechnical aspects [92].
During the planning of GRDDSs using CS, some particularities should Regarding the design of pharmaceutical systems for gastric diseases
be taken into account like length of retention on the drug/dosage form treatment, controlled drug release, specific absorption in stomach and
in the stomach, penetration in the gastric mucosal layer, stomach pH pharmaceutical dosage form with tunable retention time are required.
and stability of the drug/pharmaceutical system and CS protonation, One of the strategies comprises the fabrication of GRDDSs with
drug's molecule physicochemical parameters, as well as its solubility. mucoadhesive properties. These systems can be obtained by using CS
Another important factor is the presence of lipids in the stomach. CS or CS combined with other polymers (polymeric blends). CS displays
may interact with these molecules and cause changes in the drug re- important and desirable characteristics for these smart systems such
lease profile or even not release it [84]. as biocompatibility, biodegradability, mucoadhesiveness, buoyancy, re-
The use of CS to obtain these types of systems has already been sistance to gastric pH and, in some cases, pharmacological activity
shown to be effective in terms of improving the gastric distribution of [18,77,92–94].
some drugs. Modi et al. [85] developed mucoadhesive CS nanoparticles
(NPs) with ketoconazole and observed a 5-hour increase in residence
and release time and, consequently, absorption of this drug by the stom- 4.1. GRDDSs mucus/bioadhesiveness
ach. In other study, Arora et al. [86] designed CS NPs containing alginate
and pluronic F-127 for gastric amoxicillin release. The authors observed Bioadhesive systems may be comprised of natural or synthetic poly-
that the drug was protected from acid degradation, CS NPs showed ad- mers that can interact attractively with a biological substrate. When the
herence and mucopenetration releasing amoxicillin to deep regions of substrate is the mucus or mucosa, such systems are called
gastric mucus, increasing its therapeutic effectiveness. In addition, sev- mucoadhesive [95]. CS has become a popular component of this type
eral research have already proven that CS is a polysaccharide that pro- of system because it is able to establish various types of mucus interac-
motes the improvement of gastric delivery of the most diverse drugs, tions with numerous hydrogen bonds and electrostatic interactions,
such as beberine [87], ranitidine hydrochloride [88], carvendilol [89] promoting the dosage form adhesion [96]. The application of this sys-
and moxifloxacin hydrochloride [90]. tem comes with several advantages: gastric drug release, including
Fig. 4. Schematic representation of mucoadhesion stages.

increased bioavailability, pharmaceutical dosage form (PDF) residence 4.1.1. Wetting theory
time in the stomach and reduction of first pass metabolism [89]. This approach is applicable to low viscosity liquid and semi-solid
For the adhesion process, the GRDDSs and mucus molecules mucoadhesive systems. This theory considers the interfacial tension to
must interact at the interface. These interactions can occur through estimate the spreadability degree of the system in the mucus. After
ionic and covalent bonds, Van der Waals interactions, hydrogen the spreading phenomenon, the system penetrates into deformations
bonds and hydrophobic interactions [97]. The adhesion is marked and mucus recesses modifying the surface characteristic, interactions
by two main steps, contact and consolidation stages, as shown in and interfacial tension leading to the adhesion phenomenon [99].
Fig. 4. A method to estimate whether a liquid will have good spreadability
and adhesion on a surface is the scattering coefficient (Sb) measure,
Stage I - The initial contact between the PDF and the mucus begins using the Eq. (2) where: energies of interfaces are represented by γB
with interpenetration of the chains in the mucus and adhesion to and γT - interfacial tension between the system and the mucus, and
the surface [97]. At this stage, the polymer chains begin to interact the interfacial tensions of each of the phases by γB - surface tension of
with the medium and mucus. In cases where GRDDSs is developed the system and γT - surface mucosal tension [97].
with CS, it is essential that the acidic medium solution acts by pro- As the contact angle is easily calculated, a relation is established be-
tonating and hydrating the CS chains expecting more effective inter- tween it and the system-mucus interfacial tension. In this technique, a
system with equal or close contact angles of 0° is sought [100].
actions with mucus and PDF.
Stage II - PDF adhesion consolidation occurs because the poly- Sb ¼ γT −γ B −γ BT ð2Þ
mers constituting the system are mostly hydrated, in the case
of CS, protonated and, therefore, presenting greater conforma-
tional freedom, being able to establish cooperative interactions 4.1.2. Diffusion theory
with the mucus. The main interactions that occur in this stage This theory proposes that adhesion is a two-way process (Fig. 5) due
are the hydrogen bonds, Van der Waals and electrostatic interac- to the diffusion of the polymer chains into the mucus glycoprotein net-
tions [97]. Due to the high conformational freedom of the poly- work, as well as mucus diffusion into mucoadhesive system [100]. It is a
process in which the penetration rate depends on the diffusion coeffi-
mer chains and the close contact of the mucus, these chains
cient, MW, cross-linking density, chain mobility/flexibility and expan-
diffuse through the mucosal layer, deepening and establishing
sion capacity of both [101].
more lasting interactions. Other important contribution to this From results based on rheological analysis and spectroscopic tech-
stage is the suction-type effect promoted using polymers with niques, the diffusion process is interpreted as a kinetic process, i.e.,
high affinity for water that causes dehydration of the mucus, time-dependent, so that it is possible to estimate the time required for
promoting the adhesion of the system; this mechanism is ex- maximum adhesion between two substrates during interpenetration
plained by the dehydration theory [98]. [102], as depicted in Eq. (3).
Nowadays, the phenomenon of mucoadhesion can be explained in t ¼ L2 =Db ð3Þ

part by six theories that individually or together are not able to exhaust
discussions on this topic, since it is a complex phenomenon [99]. For CS- where (L) is the depth of interpenetration, and (Db) the diffusion
based mucoadhesive systems, the principal theories that explain adhe- coefficient.
sion are wetting, diffusion, electronic interlocking, adsorption and frac- The adhesion strength of a polymer is maximal when the penetra-
ture, which are briefly described below. tion is close to the size of its chain. It is assumed that the depth of
Fig. 5. Schematic representation of diffusion and polymer interpenetration.

interpenetration required to produce an efficient mucoadhesion bond 4.2. CS-related factors that interfere with mucoadhesion
lies in the range 0.2–0.5 μm [99].
The theoretical approach to be considered when working with
mucoadhesive systems will depend on factors that may influence PF ad-
4.1.3. Electronic theory
hesion, and it is necessary to take into account some parameters for the
In this theory, when chains with different electrical charges, solvated
development of the system. In this session, we will discuss the main fac-
or not, approach to form ionic pairs, the mucoadhesive process is
tors to consider when the polymer used is CS.
established. However, the most accepted approach is the occurrence
of bidirectional [103,104] electrons transference from the mucus to
4.2.1. Concentration
the polymers. This bidirectional electronic transfer at Fermi level is re-
During the development phase of the mucoadhesive systems it is
sponsible for promoting the formation of an attractive electric double
important to establish the optimum concentration of the polymer
layer at the muco-polymer interface. The strength of adhesion is propor-
used, especially in semi-solid systems [111]. In solid systems, it is ob-
tional to the attraction intensity exerted on this interface [99,104,105].
served that, to some extent, the adhesion force increases proportionally
with the polymers concentration. Systems obtained with reduced poly-
4.1.4. Adsorption theory mer concentrations can lead to poor adhesion and short duration due to
According to this theory, after contact between the interfaces, adhe- the reduced number of interactions between the systems and polymer.
sion occurs as the product of two groups of forces, primary and second- Very high concentrations of polymer impart an excessive stability to PF,
ary. The primary ones are ionic and covalent, while the secondary forces in which the chains are folded and less accessible to the solvent, reduc-
are Van der Waal's forces, hydrogen bonding, and hydrophobic forces ing the freedom of the chains, in order to reduce the adhesion [112,113].
[106].
Interface characteristics determine which types of forces will pre- 4.2.2. Crosslinking
dominate in mucoadhesion. In most systems, adhesion occurs through The crosslinking degree is an important factor to consider when
secondary type forces, which are individually weak, but due to their using CS to fabricate mucoadhesive systems, because the main method
high number they become globally significant [107]. of obtaining solid systems such as nano and microparticles is ionotropic
gelation using sodium tripolyphosphate (TPP) or glutaraldehyde
4.1.5. Fracture theory [114–117]. A high crosslinking density immobilizes the polymer chain,
This theory is substantially different from the others, because it mea- reducing its conformational freedom, affecting its flexibility and in
sures the necessary force to separate one material from the other one, turn on penetration and entanglement with the mucus. When CS is
correlating it with the intensity of the adhesive forces. Thus, it is as- crosslinked, it can hydrated and swell. Swelling is positive for the adhe-
sumed that adhesion failure occurs between interfaces, ignoring the sion of these systems by increasing the area of contact with the mucus, it
fact that failure usually occurs due to the low cohesion within one of can additionally provide control characteristics in the drug release [98]
the components involved in the adhesion process [97,108] (Fig. 6). pH/DA and hydration.
Larger chains as well as systems with lower cross-linking densities Acidic media (pH b pKa 6.5) exert a strong effect on the adhesive-
have higher fracture forces, indicating higher adhesion strength [109]. ness of CS-containing mucoadhesive systems. This is due to the
The adhesion force is calculated indirectly by Eq. (4), where: Sm is polycatalytic CS character, which contributes to the establishment of
the adhesion force, Fm is the force required for the detachment of the electrostatic interactions and hydrogen bonding with solvent and
materials and A is the total area of contact between the interfaces. mucus. The CS DD is the main factor responsible for the cationic nature
of this polymer, so that the reduction of the DD is directly associated
with the increase in the positive charge's density of the chain, which
Sm ¼ F m =A0 ð4Þ contributes to the inter- and intra-chain CS repulsion. Thus, in acid
media, the chains with the lowest DD will be more protonated and sep-
arated from each other, because of the electrostatic repulsion. The poly-
It is a very suitable approach for solid and semi-solid systems in mer protonation exposes groups previously inaccessible to the solvent,
which there is little penetration of the mucus chains [110]. increasing the capacity to establish more hydrogen bonds, having an
Fig. 6. Schematic representation of the fracture of the hydrated layer of the system.
Table 3
Mucoadhesive CS-based GRDDSs.
Polymer(s)/drug Objective Methods Results Refs.
CS/Scorpion Venom Obtain CS nanoparticles containing Nanoparticles (NP) were fabricated by Particles obtained using CS 2 mg mL−1 and [119]
Mesobuthus eupeus scorpion venom in order to promote the ionotropic crosslinking with TPP in different CS/TPP mass ratio of 2 containing
animals hyperimmunization. CS concentrations. 500 μg mL−1 of M. eupeus venom presented
NPs were characterized. encapsulation efficiency of 91.1%, loading
In vitro release assays were performed and capacity of 76.3% and size mean of the
the efficiency and encapsulation capacity 300–400 nm range (polydispersity index:
determined. 0.429).
The release occurred in two stages: an initial
stage with release of 60% of the venom in the
first 10 h, followed by the controlled release
for 60 h.
CS, Tween 80, pluronic Obtain, characterize and test the inhibition CS-coated emodin-loaded pluronic The encapsulation efficiency was [120]
F127/Emodin effect of nanomicelles loaded with F127/Tween 80 mixed nanomicelles were approximately 97.74% using 140 mg Pluronic
mucoadhesive beads (NFM-Beads) on prepared by thin film hydration method, F127 and 10 mg Tween 80.
tumor cells. tested against human gastric carcinoma.
NFM-Beads were prepared by ionotropic The size of the nanomicelles were in a range
gelation using sodium of 206.8–288.6 nm, PDI of 0.162–0.295, and
carboxymethylcellulose (CMC) and their zeta potential was around +30.76 mV,
aluminum chloride. suggesting physical stability.
Release, floating and mucoadhesion of the Emodin-loaded nanomicelles demonstrated
samples were evaluated in vitro and gastric better antitumor efficacy compared to
retention evaluated in vivo. corresponding emodin suspensions.
NFM-Beads showed suitable buoyancy.
Emodin release occurred by an anomalous
process guided by swelling and erosion. In
vivo gastroretention assays showed that the
systems were maintained in the stomach of
the rats after 8 h of administration,
indicating strong adhesion to the gastric
mucosa.
CS-HPMC/flavonoid Obtain, characterize and test CS Inclusion complex taxofolin-Syloid AL-1 was In vitro [121]
taxofolin-Syloid AL-1 mucoadhesive GRDDS microparticles in prepared using the solvent evaporation 90% of the TAX permeated pig mucus in 2 h,
the inclusion complex of Taxofolin (TAX) method, in Tax:Syloid® AL-1 ratio of 30:70, during the 45 to 120 min interval, the
and Syloid® AL-1, with proton pump w/w average permeation rate was
inhibitory action. Microparticles were prepared using 3.3 mg cm−2 min
spray-dried method, in 6:1 ratio, CS:HPMC. Ex vivo
Mucoadhesion and the drug release profile The average flux calculated across the
from the systems were tested. mucosa in the interval of 45–120 min was
0.8 10−3 mg cm−2min.
CS microparticles released taxifolin for 5 h in
simulated gastric fluid.
Microparticles adhered to gastric mucosa for
5 h avoiding TAX intestinal degradation.
Microparticles favored Tax absorption in the
stomach, achieving rapid therapeutic onset in
the treatment of gastric ulcer, and made it
possible to avoid Tax degradation in the
small intestine.
CS/Ranitidine Preparation and characterization of CS The microparticles were obtained by means The particles could be obtained with [122]
mucoadhesive microparticles containing of CS ionotropic gelation using TPP, both in concentrations between 4–5% of TPP and 2%
ranitidine. different concentrations. of CS showing an average size of
Size, shape, encapsulation efficiency, in vitro 620–720 μm. These systems encapsulated
bioadhesion using agar plate method, in vitro between 41.67 and 87.58% of ranitidine. The
release kinetics were successfully performed. bioadhesion test showed that between 62
and 83% of the particles remained adhered
for 8 h. At least, 75% of the formulations
showed buoyancy for 12 h. The release of
ranitidine obeyed zero-order kinetics, with
86% of ranitidine being released in 10 h.
Micromotors coated with Preparation and characterization of Mg-micromotor was prepared by an The systems demonstrated security in animal [123]
CS/Clarithromycin Clarithromycin (CLR)-loaded asymmetrical coating of the Mg model (mouse). Although the therapeutic
Mg-micromotors coated with CS in H. microspheres with a thin TiO2 layer using efficacy of standard treatment and
pylori treatment. atomic layer deposition, after Mg-TiO2 Janus micromotors have been similar. The systems
microparticles were then coated with a PLGA further reduced the bacterial load of H. pylori
film containing the CLR antibiotic payload. and showed an efficient distribution and
After the drug-loading step, the retention in the mouse stomach.
microparticles were coated with an outer The micromotors were capable to load
thin CS layer (thickness ~ 100 nm). antibiotic cargo with high-loading efficiency-
Micromotors were evaluated for drug 1032 ± 37 μg per 2 mg micromotor.
carrying capacity.
In vivo: Capacity to retain micromotors in the
mouse stomach, anti-H. pylori therapeutic
efficacy and toxicity assessment.
Interpolimeric blend (IPB) Develop and test IPB gastroretentive Poly-x-lipo nanoparticles: Both IPB and PXLNET matrices were [124]
Table 3 (continued)
Polymer(s)/drug Objective Methods Results Refs.
and Poly-x-lipo CS system as well as nano-enabled Eudragit and CS were dispersed in HCl. After mucoadhesive, the adhesion force and
nanoparticles and gastroretentive levodopa delivery system. levodopa (L-dopa) and benserazide were adhesion work for IPB matrices were found
Eudragit-enabled tablets added into dispersion, lecithin was dissolved to be significantly more than the values
(PXLNET)/l evodopa in chloroform and added to the observed for a PXLNET matrix.
L-dopa-loaded polymeric solution. TPP IPB presented triple mechanism of
dissolved in acetic acid was added under gastroretention (high density, swelling and
stirring and the nanoparticles produced were gastro-adhesive).
thereafter frozen and lyophilized. Levodopa release from IPB exhibited a more
IPB- Dissolved methacrylate copolymer was linear profile than Madopar® HBSa and
added to the NaCMC solution under vigorous Sinemet® CRb.
stirring with locust bean addition and In pH = 1.5 medium, IPB matrices released
nanoparticles incorporation. PXLNET was 90% of levodopa in 24 h vs Madopar® HBS
achieved by incorporating L-dopa-loaded 100% of the levodopa was released by the
nanoparticles into IPB with other 16th h.
components and compressed directly with In comparisons to the conventional dosage
carver hydraulic press. forms, both matrices have exhibited constant
delivery over a prolonged time period and
L-dopa-loaded and IPB matrices were the
best fit for zero-order release.
a
ADMadopar® HBS - hydrodynamically balanced system Madopar (levodopa+benzerazide).
b
Sinemet® CR - controlled release Sinemet (carbidopa + levodopa).
impact on PF hydration. The hydrated chains swell, increasing the adhe- 12.8 ± 7 mm) [129]. However, some authors relate that the cutt-off size
sion area, interpenetration and interaction with mucus and water, of pylorus cannot be determined exactly [130]. For example,
through electrostatic interactions and hydrogen bonds. These interac- Timmermans [131] stated that the size of GRDDSs can vary from 7 to
tions are the result of a pronounced increase in the conformational free- 10 mm, while Khosla and Davis [132] noted that sizes up to 15 mm in
dom of these hydrated chains [112,115]. diameter were not sufficient to provide gastric retention.
According to Klausner et al. [133], the expandable systems should
4.2.3. Molecular weight (MW), shape and flexibility of the polymer chains combine a number of characteristics, of which retention in the stomach
The increase in polymers MW can enhance the adhesiveness of is cited after facilitated oral administration, high degradability of the
mucoadhesive pharmaceutical systems as well as chains flexibility dosage form preferentially in the stomach, no interference in the gastric
[118]. Long and flexible polymer chains such as high MW CS are able motility, prolongation of the shelf-life, among others. These systems,
to enter deeper into mucus and establish more interactions because it also called plug type systems [134] receive this classification precisely
presents greater mobility than polymers of very short and excessively because after administration they undergo a great expansion of their
enveloped chains. However, the use of polymers with excessively long structure, which may be related to both a high swelling or unfolding,
chains is deleterious to mucoadhesive systems because they lose the blocking their passage through the pylorus. In this way, the permanence
ability to diffuse and entangle the mucus. In the development of these of the system in the stomach is increased until drug release begins with
systems, it is essential to establish an optimum size for each polymer, subsequent reduction in size as the system is evacuated through the GIT.
since the shape and flexibility of the polymer chain is also a factor to It is important to point out the three basic configurations associated
be considered along with the size [97,107]. with expandable GRDDSs that make clear the understanding of its
Table 3 lists some mucoadhesive GRDDSs obtained from CS and their gastroretention mechanism. First one, an initial state represented by ex-
particularities. pandable GRDDSs reduced dimensions that facilitate oral administra-
Considering the Table 3, CS applicability is vast, and it can integrate tion, followed by a second state represented by its maximum state of
different types of gastroretentive systems. Despite the use of this bio- expansion which is responsible for gastroretention, and then, the third
polymer as carrier since 1980s [125], recent advances in nanotechnol- and last state of minimal dimensions related to the release and
ogy favored the development of efficient drug delivery systems such depuration of the drug from the system [101,133,135].
as CS-based micromotors and nanosystems. CS remains contemporane- Several mechanisms of gastroretention for expandable GRDDSs have
ous and promising biopolymer to develop gastroretentive/ been explored, but it should be mentioned that they all show many ad-
mucoadhesive systems with controlled release profile. Although CS vantages and also disadvantages over each other [134]. Two basic mech-
gastroretention properties are usually ascribed to its mucoadhesivity, anisms are responsible for the expansion of structures, which are
other action mechanisms will be discussed in the next sessions. swelling and unfolding, the former being related to an osmotic effect,
and the latter to shape memory.
4.3. Expandable GRDDSs The main mechanism for swelling and drug release is diffusion
through hydrophilic polymers, which can absorb water from the gastric
Expandable gastroretentive systems were originally designed to fluid through the appearance of pores in the device surface, creating
treat veterinary pathologies with high dimensions of about 15 × 3 cm channels along its entire length, leading to a capillary effect [134]. In
(length × diameter) by Laby [126] in order to avoid regurgitation after unfolding systems, the previously large system (uncompressed) with
administration and arrival of the pharmaceutical dosage form in the adequate mechanical properties is folded (compressed) to just open
rumen. Posteriorly, they were also adapted for treatment of humans after reaching the stomach when capsules are dissolved in the gastric
by Johnson and Rowe [127]. Early, veterinary devices exploited the juice [133]. Different geometrical shapes have been attributed to
unfolding mechanism and had a ring-shape or multilayer insoluble unfolding systems, such as tetrahedron, ring or planner membrane [15].
polymeric sheet from Griffin and Brewer [128]. On the other hand, the A recurrent problem that can occur with unfolding systems is the
first device for human use was a tablet based on thiolated gelatin fact that their shape memory is often not sufficient, in addition to
which after hydration in the stomach and swelling to a larger size, mak- being influenced by storage stress, and may lead to performance prob-
ing it impossible to pass through the pyloric sphincter (mean diameter, lems in the stomach [136]. Some strategies have emerged to overcome
this problem, mainly by exploiting polymers that do not present plastic Although the scientific literature brings many studies on the devel-
deformation, but only elastic deformation. opment of gastroretentive systems exploring the high swelling capacity
Other forms of expandable GRDDSs have been reported, such as the of CS, great care must be taken when classifying such systems as ex-
use of hydrogels that swell to the significant extent primarily as a func- pandable. Since this mechanism acts to avoid the clearance of the phar-
tion of polymer content, such as those made of polyvinyl pyrrolidone maceutical form through of the pylorus, a pronounced swelling is
cross-linked with albumin [137]. Superporous hydrogels (those with required which promotes a considerable increase in the size of the
pores of a size of hundreds of micrometers) have been also used as ex- structures. This means that although many hydrophilic polymers un-
pandable GRDDSs. In this case, the high porosity of these systems has dergo swelling when in contact with gastric fluid, it may not occur to
been related to a very rapid rate of swelling (generally 1 min and an in- the extent necessary to prevent its clearance from the upper GIT. In
crease of up to 1000× initial weight), as well as the ability to absorb a these cases, its importance is more related to the mucoadhesiveness
greater volume of liquids, both factors contributing effectively to a fast and/or flutuation of the gel layer formed by CS swelling, as is the case
size-increasing [138]. with works that explore the dual mechanism of gastroretention, for ex-
Regardless of the mechanism responsible for the expansion, after ample, floating and swelling [141]. The said gel layer of the swollen CS is
suffering a large increase in size, these systems must have adequate me- also related to the decreased toxicity of some drugs interacting with
chanical properties so that immediate erosion does not occur as a result their cationic groups by the presence of negative charges (alendronate
of loosening the polymer chains together with the intense peristalsis of sodium, for example).
the stomach. Thus, the extensive expansion for swelling GRDDSs, for ex-
ample, must be attributed to the presence of physical/chemical 4.4. Superporous hydrogels (SPHs)
crosslinking in the hydrophilic polymer network. These crosslinks pre-
vent the dissolution of the polymer and hence maintain the physical in- Several studies have combined different strategies for development
tegrity of the dosage form [139]. of gastroretention systems, in order to obtain a larger time of gastric res-
Despite the effectiveness of these systems in increasing the resi- idence [142]. developed CS superporous hydrogel with floating proper-
dence time in the stomach, they must have some properties to ensure ties for sustained delivery of ranitidine hydrochloride. This system
patient safety. Therefore, such devices should not interfere with gastro- showed an increased gastric residence time of ranitidine hydrochloride
intestinal motility, should not irritate the stomach mucosa due to its with a floating and drug release time of 17 h.
local retention, the device must have rounded edges, and re- Yin et al. [143] combined the mechanisms of swelling and
administrations should only be performed after the biodegradation of mucoadhesion of the superporous hydrogels containing poly(acrylic
the previous system present in the stomach to avoid accumulation acid-co-acrylamide)/O-carboxymethyl CS. The in vitro results demon-
with high doses. strated the swelling ratios, mechanical properties, mucoadhesive force
As it is known, alendronate - a drug belonging to the class of and loading capacity were improved through varying the O-
bisphosphonates - is the drug of choice for treating osteoporosis, acting carboxymethyl CS content.
mainly through specific inhibition of bone resorption. However, its bio- In another study, Park and Kim [144] developed glycol CS
availability after oral administration is significantly low (b1%) due to re- superporous hydrogels using a gas blowing method and glyoxal as the
duced intestinal absorption and the fact that when administered with crosslinking agent. The results showed an increase in mechanical
food it leads to the formation of complexes that cannot be absorbed strength accompanied by the decrease in swelling kinetics without
[140]. Although alendronate is mainly absorbed in the upper portions loss of water absorption capacity, important properties for the develop-
of the GIT, the short transit time further contributes to low absorption ment of efficient gastric retention devices.
and bioavailability. Another marked limitation is the local irritation Superporous hydrogels of rosiglitazone loaded with CS were synthe-
caused in the upper portions of the GIT. Thus, treatment requires daily sized using glyoxal as a crosslinking agent for Gupta et al. [145]. The au-
a strict fasting state close to the medication schedule, reducing patient thors explored CS precisely because it is a polyelectrolyte that gives rise
compliance. In this sense, it seems evident that the development of deliv- to pH-dependent hydrogels which, when in contact with acidic solu-
ery systems that manage to overcome the rapid transit time of the upper tions, show a high swelling due to the presence of positive charges in
GIT by increasing its residence time at the absorption site, should contrib- the network, expanding its volume. Swelling rates were dependent on
ute significantly to improving the therapeutic efficacy of alendronate. the extent of crosslinking, so that the higher the amount of crosslinking
In line with this reasoning, Su and coworkers [8] developed agent, the lower the swelling ratio. Ionic strength was also another fac-
hydrogels of CS with ring-opened polyvinyl pyrrolidone (CS/roPVP) as tor that affected swelling, which ranged from 11% for HCl solution
GRDDSs to enhance the bioavailability of alendronate for the treatment (pH 1.2) with 1 M NaCl to 156% for lowest ionic strength (0.0001 M).
of osteoporosis. The excellent properties seen in CS, such as a high de-
gree of swelling and mucoadhesiveness in gastric media, are decisive 4.5. Magnetic systems
to delay clearance through the pyloric sphincter, as well as making the
system's contact with the gastric mucosa more intimate, respectively, Among the strategies used to increase the gastric residence time,
contributing to the enhancement of alendronate absorption. However, magnetic systems are the only gastroretentive delivery systems based
it is known that CS rapidly dissolves in the stomach, which would im- on the attraction between two magnets. This approach contain a small
pair the prolongation of the alendronate release rates, reason why internal magnet present in dosage form, and an external magnet at-
ring-opened (ro) polyvinyl pyrrolidone (PVP) was rationally added to tached to the abdomen over the position of the stomach, which retains
the composition. In this way, gastroretentive properties were evaluated the system in the gastric region [101,139,146]. The extracorporeal
in terms of swelling ability and mucoadhesive measurements. Authors magnet allows the control of gastrointestinal transit of the dosage
stated that tablets from CS/roPVP hydrogels showed an optimal swell- form for a prolonged period of time [139].
ing (up to 500%) which higher axial than lateral swelling ratio, which Ito et al. [147] described the first magnetic system in 1990, per-
was attributed to the application of compression force axially. Likewise, formed for application to targeting therapy for esophageal cancer. Mag-
increasing proportions of CS in CS/roPVP complex were responsible for netic granules containing ultrafine ferrite (γ-Fe2O3) were guided to the
the raise of forces of mucoadhesion. It was interesting to note that esophagus with an external magnet for the initial 2 min and almost the
in vitro release profile of the reference FOSAMAX® was 100% in only entire amount of granules were retained in the region after 2 h of ad-
30 min, while the complexes promoted sustained release of ministration [147].
alendronate. The set of acquired properties contributed to 3-fold en- Although there are successful works, few systems with CS using the
hancement of the oral alendronate bioavailability. magnetic approach have been reported in literature. Magnetic hollow
spheres coated with multilayer of CS/PAA developed by Zhang et al. dosage forms comprising a) effervescent and b) non-effervescent sys-
[118] showed a sustained drug release and a strong magnetic response tems; (2) multiple unit floating dosage forms comprising
to magnetic field, which should provide the drug targeting to a desired a) effervescent, b) non-effervescent and c) hollow microspheres sys-
tissue and/or organ through the external magnetic field [148]. tems and, finally, (3) raft forming systems [79,151,154].
The main advantages of magnetic systems are absolute drug
targeting for target organs and tissues, the increase absorption and bio- 4.6.1.1. Single unit dosage systems. Single unit dosage systems are easier
availability of encapsulated drug, as well as the reduction of the concen- fabricated than multiple unit dosage forms. However, the application of
tration of the drug at non target sites [149]. However, the applicability of single unit dosage forms are less effective due to their all or nothing
these systems depends of an external magnet, which must be posi- emptying process from stomach generating distinct bioavailability and
tioned with high precision degree to allow drug release in the appropri- high drug concentration delivered in others sites causing irritation
ate place, without compromising patient compliance [101,139]. [79,154].
Moreover, magnetic technical is expensive and requires specialized Effervescent systems (or gas-generating systems) can be prepared
manufacturing, correct position degree on the stomach is very difficult by using swellable polymers and compounds that can generate gas bub-
to achieve and the magnets must have relatively constant gradients in bles [79,135,154]. The most common useful swellable polymers as ma-
order to avoid overdosing of toxic drug [149]. trix in these systems are methylcellulose,
hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC),
4.6. Density drug delivery-based systems hydroxypropylcellulose (HPC), sodium carboxymethylcellulose
(NaCMC), polyacrylated polymers, polyvinyl acetates, polycarbonates,
4.6.1. Floating drug delivery systems agar, CS and alginate [79,135,154]. As effervescent compounds sodium
Specifically, the design of controlled drug delivery systems (CDDSs) bicarbonate, tartaric acid and citric acid are the most commonly chosen
with efficient action on GIT is still a challenge due to the inability to re- [79,135,154]. The mechanism of action occurs when the fabricated sys-
strain DDSs in specific regions of the GIT as well as the dependence of tem (swellable polymer+gas generator compounds+drug) is placed in
the unpredictable gastric emptying time [150]. These drawbacks can contact with the fluid gastric leading to CO2 elimination while the poly-
be overcome by GRDDSs, showing great potential for improving the bio- mer swelling with water. The combination of these actions generate ef-
availability and site-specific absorption of drugs [150,151]. Among sev- fective density less than gastric fluid increasing the time buoyancy
eral GRDDSs approaches, floating drug delivery systems (FDDSs) are of besides to favor the controlled and site-specific drug delivery as
particular interest due to their local active and narrow drugs absorption shown in Fig. 7 [79,155].
window for specific area. Jiménez-Martínez et al. [156] designed effervescent single unit dos-
FDDS was first reported by Coupe [152] and comprises a system with age systems (SUFS) based on the introduction of captopril into Metolose
density lower (usually lower than 1 g cm−3) than gastric fluids that re- SH 4000 SR (matrix) containing sodium bicarbonate (NaHCO3) as gas
main buoyant in the stomach for prolonged time and, consequently, generator. Properties as compounds proportion (Metolose and sodium
leading to slow drug release at the specific rate. Additionally, gastric re- bicarbonate) and distinct compaction pressures can influence floating
tention time is increased as well as the adsorbed drug concentration and drug release from proposed matrix. In vitro assays showed that at
[150,151,153]. FDDS can be designed and classified according to the lower pressure (55 MPa) floating time higher than 8 h were achieved.
dosage forms and mechanism of buoyance: (1) single unit floating The system density decreases by reducing the compaction pressure
Fig. 7. Gastroretentive drug delivery system based on combination of polymer swelling and effervescence.
and increasing the sodium bicarbonate content. On the other hand, au- of these dosage forms such as the design of bilayer formulations, as
thors displayed that increasing sodium bicarbonate and polymer con- displayed in Fig. 9. In these dosage forms, one layer promotes the fluctu-
tents favor the reduction of drug dissolution rate from this system. ation in gastric liquid whereas the other one control the drug release
Tadros [157] prepared effervescent SUFS using HPMC K15M and/or so- [135]. Oth et al. [161] fabricated a bilayer floating dosage unit containing
dium alginate as release-retarding polymers and NaHCO3 or calcium misoprostol aiming to treat gastric and duodenal ulcers. As shown in
carbonate (CaCO3) as a gas former agents containing ciprofloxacin hy- Fig. 9A, both layers are composed by the same swellable polymer (in
drochloride (Cipro HCl). The tablet formulations (F7: HPMC K15M this case HPMC) but only one containing the misoprostol allowing this
(21.42%, w/w), Na alginate (7.14%, w/w), NaHCO3 (20%, w/w) and a bifunctional system performed buoyance and drug delivery indepen-
F10: HPMC K15M (21.42%, w/w), Na alginate (7.14%, w/w), CaCO3 dently in gastric media. Authors demonstrated that the production of
(20%, w/w)) exhibited good floating total and lag time, swelling ability, large capsules lead to an increasing in gastric retention time (GRT). In
adhesion and sustained drug release rate acting as a promising GRDDS. vivo studies exhibited GRT dependent to the meal regimen. After a sin-
On the other hand, non-effervescent systems (such as hydrodynam- gle meal, GRT was higher than 3 h whereas after several meals, the GRT
ically balanced systems, HBS) present one or more gel-forming or high was higher than 10 h. He et al. [160] produced bilayer floating tablet for-
swellable polymers. This system is prepared by mixing drug and poly- mulation (Fig. 9B) containing the combination of two distinct drugs
mer generally encapsulated by gelatin. The mechanism comprises fast such as metformin hydrochloride (MH) and pioglitazone hydrochloride
dissolution of the capsule in gastric fluid followed by swelling of the (PG) to treat type 2 diabetes mellitus (T2DM). This formulation com-
polymers producing a buoyance gelatin mass with density lower than prises the incorporation of each drug into two separate layers in order
1 g cm−3. The formed gelatinous barrier retains the capsule shape, to achieve sustained MH release followed by immediate PG release.
avoiding the system disintegration promoting controlled drug release. The bilayer tablet was fabricated by using wet granulation method
The gelatinous surface erosion favors water permeation into inner with HPMC E5 for both layers as matrix and then compressed into tab-
layers preserving the surface hydration and the air trapped by the swol- let. In vitro assays showed buoyance time up to 24 h and floating lag
len polymers promotes buoyancy to the dosage forms, as depicted in time of 5 min besides sustained MH release controlled by diffusion man-
Fig. 8 [79,135,151]. In addition, drug release is controlled by diffusion ner (for 12 h) and fast PG release. In vivo tests performed in dogs sug-
and dependent on the gel barrier erosion/dissolution. If the formulation gested good absorption of PG and the enhancement of MH
is composed by fatty or viscous excipients, low-density systems could bioavailability with steady plasma concentration, decreased maximum
be achieved, decreasing water penetration and erosion process, which plasma concentration and reduced time of maximum concentration ap-
can reduce drug release rates [107,132]. pears as effective and promising GRDDSs to treat T2DM. Krögel and
Soni et al. [158] developed HSB systems by using natural and biode- Bodmeier [159] developed multifunctional floating drug delivery sys-
gradable polymer crushed puffed rice (CPR, as buoyance agent) combin- tems using HPMC as hydrophilic polymer containing drugs (chlorphen-
ing with auxiliary polymers as high molecular weight CS (HMWCS, as iramine maleate or ibuprofen). One of the designed GRDDSs consists of
swellable polymer) and HPMC (as gel-forming agent) as a single-unit two tablets (HPC + drug) fixed within two orifices of the cylinder
floating capsule for Metoprolol Succinate (MS) sustained delivery. Au- (Fig. 9C) with air entrapped in the middle of the two tablets resulting
thors reported that all evaluated samples displayed zero-order kinetics in low density and, consequently, buoyance to the proposed system. Au-
followed by Fickian diffusion model. This means that drug release from thors reported interesting GRDDSs that provides an enhancement on
these HBS systems are controlled by drug diffusion through the gel bar- drug release as a function of HPMC viscosity and content, aqueous
rier. Although the variation of pH and polymers could be evaluated, au- drug solubility and surface area of the matrix.
thors concluded that CPR associated with HPMC and HMWCS Harrigan [162] described the fabrication of intragastric FDDSs with
comprising a potential single-unit HBS systems for specific sustained re- drugs present inside microporous compartment with pores along its
lease of hydrophilic drugs showing absorption window upper GIT. top and bottom walls. In order to prevent a direct contact with the gas-
The main drawback of single layer HBS consists on the dependence tric surface, the peripheral walls of these systems are sealed aiming to
of the air arrested in the dry mass and the characteristics of the avoid the direct contact of undissolved drugs with gastric mucosal sur-
swellable polymers [135]. Considering the above mentioned, some ap- face. The containing entrapped air in the microporous compartment
proaches [135,159–161] have been developed to improve the efficiency promotes buoyance over gastric media. The gastric fluid permeates
Fig. 8. Hydrodynamically balanced system (HBS). The gelatinous polymer barrier formation results from hydrophilic polymer swelling. Drug is released by diffusion and erosion of the gel
barrier [135]. Copyright 2006.
Reproduced by permission of Elsevier Science Ltd.
Fig. 9. Three types of bilayer floating hydrodinamically balanced systems: (A) one layer with drug, (B) two layers containing drugs and (C) two layers containing drugs with gas entrapped.
the apertures favoring the drug dissolution and absorption in the stom- drying. The alginate beads show porous structure that promotes buoy-
ach [139,163]. ance for over 12 h besides increasing the residence time in gastric
tract substantially (N5.5 h) [139,163]. Dey et al. [166] designed floating
4.6.1.2. Multiple units dosage systems. Multiple units floating systems and mucoadhesive beads based on sodium alginate and hydroxypropyl
(MUFS) appear as an interesting way to overcome high variability of methylcellulose (HPMC) as matrix polymers and CS as coating polymer.
gastrointestinal transit time favoring a regular absorption. Beyond Sunflower oil was entrapped in this system to improve floating time. All
that, fast and high drug concentration release could be avoided and, these polymers were chosen to encapsulate amoxicillin trihydrate
consequently, gastrointestinal tract irritation [79,154]. Hooda et al. aiming to treat Helicobacter pylori infection. The floating and
[122] reported the preparation of MUFS based on CS and sodium mucoadhesive system were prepared by ionotropic gelation method
tripolyphosphate (TPP) via ionotropic gelation method containing Ra- and CS used as polymer barrier promoting bioadhesion. Authors re-
nitidine hydrochloride (RHCl) as microspheres GRDDSs. RHCl has a nar- ported that these beads as interesting GRDDSs exhibiting good
row absorption window and is mainly absorbed in the proximal areas of mucoadhesion properties, excellent efficiency of drug encapsulation in-
GIT. Thus, conventional sustained-release dosage form reaches the creasing buoyance time and drug release for N24 h and 7 h, respectively
colon, where it gets metabolized, resulting in low absorption and poor [166].
bioavailability (52%). In this way, Hooda et al. [122] proposed to design As multiple units floating effervescent systems, Jyang et al. [167] fab-
microspheres GRDDs based on chitosan (CS) and sodium ricated a blend of Eudragit L100 and Eudragit RLPO containing
tripolyphosphate (TPP) via ionotropic gelation containing RHCl. In dipyridamole (antithrombotic agent) via solid dispersion technique
vitro buoyance and mucoadhesive tests suggested that these micro- and afterwards, the dispersion was incorporated into alginate beads
spheres present interesting floating (at least 12 h of buoyance) and prepared by ionotropic gelation method using CaCO3 as gas-forming
bioadhesive properties. The above mentioned properties allowed the agent. Buoyance tests were performed showing that 92% of alginate
fabricated microspheres adhere to the gastric mucosal surface remain- beads remained floating after 9 h suggesting that drug encapsulated
ing prolonged period in stomach ensuring RHCl stability in gastric envi- can be retained in the stomach indicating specific drug delivery. In
ronment which eventually leads to better bioavailability at much lower vitro release studies displayed the controlled dipyridamole release
dose. Additionally, in vitro drug release assays displayed a zero-order using the proposed formulation (ratio of dipyridamole:Eudragit L100:
model suggesting that the drug (RHCl) transport across polymeric ma- Eudragit RLPO = 1:2:3) with 70% of release up to 9 h. In vivo results ex-
trix occurred by a Fickian diffusion process [164]. hibited higher (about 2.52-fold) bioavailability for the FDDSs than com-
Talukder [165] fabricated MUFS based on crosslinking reactions mercial tablets corroborating this platform for stomach-specific drug
among sodium alginate, calcium chloride and low methoxylated pectin delivery by the oral route.
(anionic polysaccharide), in aqueous solution. The alginate beads can be
achieved by dropping sodium alginate solution into aqueous solution of 4.6.1.3. Hollow microspheres systems. Hollow microspheres (or
calcium chloride to precipitate calcium alginate beads. Separation and microballoons) comprise low-density polymers with low-density core
drying processes were performed by using air convection and freeze- relating to the shell. Most of them are MUFS fabricated by emulsion
Fig. 10. Microballoons (a) and foam-particles (b) as multiple units floating effervescent systems [135,168]. Copyright 2006.
Reproduced by permission of Elsevier Science Ltd.
solvent diffusion method that entraps oil or air in hollow core [135,163]. Raft forming systems usually form a low-density layer on gas-
Polymers such as polycarbonate, Eudragit S, cellulose acetate, calcium tric media with high surface area regarding tablets, favoring drug
alginate, agar, CS and low methoxylated pectin are commonly used to release and the bioavailability enhancement. Beyond that, these
fabricate hollow microspheres and foam-particles [168,169]. Great GRDDSs show fast buoyance than other floating dosage forms, im-
buoyancy and drug release from these systems depends on polymers proving therapeutic efficacy been easily administrated (once a
amount, the plasticizer polymer ratio and the solvent used for formula- day) to the patient [139]. On the other hand, the stability of
tions [135]. Fig. 10 displays hollow (low-density) microalloons these GRDDSs are susceptible to chemical modifications, like: oxi-
(Fig. 10a) and foam-particles (Fig. 10b) obtained by solvent dation and hydrolysis. Exposure to the temperature and pH varia-
evaporation. tion as well as types of radiation (ultraviolet-visible, X-ray, among
Pawar et al. [153] formulated microballoons as GRDDS based on others) could also promotes modification in these systems [139].
mucoadhesive and floating mechanisms to delivery norfloxacin (NFX). El Nabawari [170] demonstrated the preparation of a floating
These systems were fabricated by using HPMC and ethylcellulose (EC) raft system with Mebeverine HCl (MbH) using sodium alginate,
as core matrix by solvent evaporation method. CS coating was prepared HPMC K100M and precirol. The optimized formulation (FRS-11:
via ionotropic gelation method to improve mucoadhesion properties sodium alginate 3%/HPMC K100M 1%/precirol 2%) displayed float-
and increasing gastroretention time of the microballoons. Good ing lag time and total buoyance time near to 15 s and 12 h (in
in vitro buoyance was achieved for these systems. Pharmacokinetics re- simulated gastric media), respectively. In contrast, FRS-11 formu-
sults displayed an enhancement of NFX bioavailability for these sys- lation exhibited sustained drug release of 82% up to 8 h showing
tems. In vivo assays showed that the microcarriers could prolong half- good MbH bioavailability compared to the commercial product.
life of NFX and increasing plasma drug concentration. These results suggest the designed raft-forming system as a po-
tential GRDDS to prolong drug action aiming clinical trials
4.6.1.4. Raft-forming systems. Another system that has attracted great at- [170,171].
tention in the administration of drugs to treat gastrointestinal infections
is the raft forming systems. The mechanism of raft preparation consists 4.6.2. High-density drug delivery systems
on the formation of viscous cohesive gel containing entrapped CO2 gas Different of low-density systems, dosage forms with density
in contact with gastric fluid [79,135]. Usually, the formulation contain- next to 3 g mL−1 can sink to the bottom of the stomach to with-
ing gel forming agent and antiacids such as alkaline bicarbonates or car- stand in vivo peristaltic movement remaining intact independently
bonates to reduce gastric acidity. The buoyance of raft systems occurs by of the GIT disturbance as depicted in Fig. 12 [110]. By using high-
CO2 formation and elimination, acting as a blocker to preclude reflux of density systems (from 2.5 to 3.0 g mL −1 ) the gastric retention
gastric media [79,135]. Fig. 11 depicted a schematic illustration of raft time can increase up to 25 h [155]. These systems are formulated
forming systems as barrier in specific stomach region. with inorganic compounds such as barium sulphate, zinc oxide,
Fig. 11. Schematic illustration of the barrier formed by a raft-forming system.

Fig. 12. Schematic illustration of the gastroretentive drug delivery system based on high-density dosage form.
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International Journal of Biological Macromolecules 159 (2020) 804–822

Contents lists available at ScienceDirect

International Journal of Biological Macromolecules

journal homepage: http://www.elsevier.com/locate/ijbiomac

Highlighting the impact of chitosan on the development of

1. Introduction Despite the numerous advantages of controlled drug delivery sys-

2. Chitin and chitosan

Discovered in 1811 by Henri Braconot, chitin is a polysaccharide

Fig. 2. Deacetylation of chitin producing CS.

Applications Materials/systems Remarks Refs.

- strongest inhibition by HTCC-62 or HTCC-77

Fig. 3. Schematic representation of the gastric emptying stages.

Fig. 4. Schematic representation of mucoadhesion stages.

Nowadays, the phenomenon of mucoadhesion can be explained in t ¼ L2 =Db ð3Þ

Fig. 5. Schematic representation of diffusion and polymer interpenetration.

Polymer(s)/drug Objective Methods Results Refs.

Polymer(s)/drug Objective Methods Results Refs.

Fig. 11. Schematic illustration of the barrier formed by a raft-forming system.

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