Polymeric Materials for the Development of Dual↓Working Gastroretentive Drug Delivery
Systems. A Breakthrough Approach
M Violante de Paz*, Roberto Grosso and M Gracia García Martín
Department of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Seville, Spain
Submission:January 23, 2021; Published: February 04, 2021
*Corresponding author: M Violante de Paz, Department of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Seville, Spain
How to cite this article:M Violante de P, Roberto G, M Gracia G M. Polymeric Materials for the Development of Dual↓Working Gastroretentive Drug Delivery Systems. A Breakthrough Approach. Academ J Polym Sci. 2021; 4(5): 555646.10.19080/AJOP.2021.04.555646
Oral route is the most convenient and widely used method of drug administration, representing about 90% of all therapies used. It displays great advantages, such as being non-invasive, easy to administer (with the consequent high patient compliance) and cost-effective. However, serious drawbacks to conventional oral dosage forms are imposed by the gastrointestinal tract. Large fluctuations in drug bioavailability are found due to the influence of physiological factors such as variations in pH, high enzymatic activity and gastric emptying. This is the reason why frequent drug administrations are required to maintain the therapeutic plasma level of the drug. Gastroretentive Drug Delivery Systems (GRDDS) have emerged as an ideal approach to overcome these drawbacks. They are designed to prolong the gastric residence time (GRT) of the dosage forms in the stomach so that the time between dose administration is lengthened. Although their development has partially overcome the drawbacks associated with conventional dosage form, further work is needed on its shortcomings. The overall objective of this minireview is to highlight the opportunities from the development of dual-working polymeric materials, suitable for their use as GRDDS with improved GRT and capable of overcoming common drawbacks associated with conventional GRDDS. This could be achieved by a combination of properties such as buoyancy, swelling, porosity, and bioadhesion of the synthesized materials.
Spain, with a population of 46.7 million people, is one of the countries with longer life expectancies in the word. The data have been improving substantially in the last two decades reaching the outstanding figures of 80.2 years for males and 85.8 years for women in 2017 (Figure 1). However, the population is aging, and their quality of life is not optimal. Most of our elders suffer from chronic diseases that must be treated continuously for long periods of time with the consequent enormous impact on people’s lives. But they do not have the exclusivity of suffering from chronic disorders; a relevant segment of middle-age population is getting into treatment of several diseases such as diabetes, cardiovascular diseases, neurological disorders, and chronic respiratory diseases, just to mention a few examples. This fact draws a notable
impact on the Healthy life expectancy (HALE)1 of the population. According to the Institute for Health Metrics and Evaluation (GBD
2017, University of Washington), life expectancy and HALE differ substantially from each other, not only for the Spaniards, but also
for all the population from developed countries. As an example, and for comparative reasons, Table 1 records the figures for both parameters, life expectancy and HALE, for population from Western Europe and Spain.
Globally, the market for pharmaceutical spending was expected to surpass $1.3 trillion by 2018 . Notably, the main difficulties encountered in achieving effective treatment are related to transport and precise delivery of drugs to specific damaged organs or tissues, because releasing the right amount of drug at the exact location at the suitable rate is not a trivial issue. In this sense, scientific policies should focus on: (a) promoting research on more effective drugs and, to a greater extent, (b) supporting research on more effective drug delivery systems.
1number of years that a person at a given age can expect to live in good health, considering mortality and disability.
Thus, the global outcomes obtained by this research support
strategy would conduct to more successful chemotherapeutic
effects. For example, some chronic and disabling pathologies,
which exert a marked negative impact on human welfare (such
as diabetes, Parkinson and peptic ulcer diseases), are treated
by the oral administration of active pharmaceutical ingredients
(APIs)2. As detailed below, the bioavailability of APIs used in the
treatment of these disorders experience fluctuations that may
endanger the health of patients. To highlight the relevance of this
health problem, Table 2 records the most relevant epidemiological
parameters for these three disorders for the inhabitants of Spain
and Western Europe.
2Any substance or mixture of substances intended to be used in the manufacture of a drug product and that, when used in the production of a
drug, becomes an active ingredient in the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the
diagnosis, cure, mitigation, treatment or prevention of disease or to affect the structure and function of the body
3The sum of years lost due to premature death (YLLs) and years lived with disability (YLDs). DALYs are also defined as years of healthy life lost.
4The total number of cases of a given disease in a specified population at a designated time. It is differentiated from INCIDENCE, which refers to the
number of new cases in the population at a given time.
5The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in
a defined population. It is differentiated from prevalence, which refers to all cases, new or old, in the population at a given time.
Oral route is the most convenient and widely used method of
drug administration, representing about 90% of all therapies used
. It displays great advantages, such as being non-invasive, easy
to administer (with the consequent high patient compliance) and
cost-effective; they are also easy to store and transport, and the
formulations can be modified flexibly. However, serious drawbacks
to conventional DDS are imposed by the gastrointestinal tract
(GIT). Large fluctuations in drugs’ bioavailability are found due
to the influence of physiological factors such as variations in pH,
high enzymatic activity as well as gastric emptying. In addition,
rapid gastrointestinal transit can prevent not only the complete
drug release from the dosage form, but also the full drug intake
in the absorption zone (most drugs are absorbed in stomach
or the upper part of small intestine) with the consequent loss
of dose effectiveness. This is the reason why frequent drug
administrations are required to maintain the therapeutic plasma
level of the drug.
Gastroretentive Drug Delivery Systems (GRDDS) have
emerged as an ideal approach to overcome the mentioned-above
drawbacks. Their main goal is to prolong the gastric residence
time (GRT) of the dosage forms in the stomach up to several hours,
so that the time between dose administration is lengthened and
the drug release proceeds at the desired rate depending on their
therapeutic use .
Consequently, GRDDS can play a key role in
a. Prolonging the liberation in stomach of drugs with
local activity in the stomach or the upper part of the intestine
(Amoxicillin, for eradication of Helicobacter pylori in peptic ulcer
diseases, Table 3) .
b. Slowing down the release of drugs soluble at acidic pH
(Ranitidine, H2-receptor antagonists);
c. And prolonging the release of drugs with narrow
absorption window, i.e., with low absorption in the lower part of
the GIT (Levodopa and Carbidopa, drugs used in the treatment of
Parkinson disease), and drugs with low bioavailability such as the
Main advantages of current GRDDS
a. The benefit of low density/floating systems is rooted
on the buoyancy of the dosage in the gastrointestinal fluids.
Its bulk density must be lower than that found in gastric fluids
(1.004 to 1.010 g/mL). The bulk density is the density value
reached after a lag time that depends on the swelling rate of the
polymer used in the formulation. This property can be improved
by the incorporation of wicking agent or swelling enhancers [5-
9]. Moreover, the use of effervescent combinations, joint to the
swelling characteristic, can improve the overall floating behavior
of the dosage form .
b. Bio(muco)adhesive devices have also been formulated
as GRDDS. The dosage forms are designed to be attached to the
stomach wall and survive gastrointestinal motility for a longer
period. The use of mucoadhesive polymers is necessary .
c. Swelling and expandable systems (or “plug type
systems” due to their pyloric sphincter blocking attribute) have
achieved significant success both in vitro and in vivo in order to
retain the dosage form in the stomach . Once the polymer
meets the gastric fluid, it absorbs water and swells . The
selection of a polymer with the appropriate molecular weight and
swelling properties is crucial to enable the dosage form to exhibit
Inconveniences to overcome for the optimal final
performance of the pharmaceutical formulations
a. Low density/floating systems require high levels of fluid
in the stomach to float and work effectively. They also may stick
to each other and provoke obstruction in the GIT, causing gastric
irritation. Additionally, formulations consist of a blend of drug and
low-density polymers; therefore, the release kinetics of the drug
cannot be changed without changing the floating properties of the
dosage form and vice versa.
b. Bioadhesive formulations adhere to the stomach
mucosa, which is covered by mucus to protect it. The constant
turnover of this protection mucus layer, joint to the high stomach
hydration, might decrease the bioadhesion of the polymers.
c. Swelling and expandable systems are difficult in
maintaining the structural integrity; they may cause bowel
obstruction, intestinal adhesion, and gastropathy if they are not
constituted by an easily hydrolysable, biodegradable polymers.
Although the development of simple-working GRDDS
has partially helped to overcome the drawbacks associated
with conventional dosage form, further work is needed on its
shortcomings. We propose herein the development of two types
of dual-working polymeric materials, suitable for use in GRDDS,
which will substantially lengthen the GRT.
The preparation of new polymeric materials with optimal
properties for the development of efficient dual-working
gastroretentive drug delivery systems (GRDDS) is a breakthrough
approach. It can improve the bioavailability of selected oral drugs
within an authentic biological matrix, which may benefit the 43.4
million people that suffer from diabetes, Parkinson disease and
peptic ulcer today in Western Europe (Table 3). This innovative
technology will provide reliable dosing of the drugs to the target
location and ultimately, the in vitro detection, ensuring proper
drug management, enabling personalized healthcare. To achieve
it, two routes have been identified to provide disruptive enabling
technologies which allows the formation of dual-working GRDDS
able to overcome common drawbacks associated to previous
systems: (a) The combination of swelling expanding properties
with buoyance features is a low-explored concept for improved
gastro-retention attributes; (b) the combination of muco-adhesion
and floating mechanism.
Therefore, it could be of interest the development of:
I. Floating expandable materials (System A), able to
behave not only as swelling-expandable GRDDS with improved
mechanical properties, but also as floating devices.
II. Reversible bioadhesive hydrogels (RBH)/low-density
microspheres composites (System B). These devices present the
advantages of bioadhesive systems in combination with lowdensity/
floating approaches (Figure 2).
The substantial gains of the target materials over conventional
systems are summarized as follows:
Floating expandable materials, over conventional
i. A substantial improvement in the final mechanical
strength of the system, keeping its efficacy over time.
ii. The porous structure will not depend on pH and keep
swell over time.
iii. Their floating properties will length their GRT.
iv. The highly porous structure will allow the inclusion of
large quantities of drugs, if required.
Reversible bioadhesive hydrogels / low-density
microspheres composites over conventional floating
systems and bioadhesive GRDDS
i. Thiomers-based hydrogels will enhance the bioadhesive
properties of the global composite.
ii. As the gel breaks down and separates from the mucosa,
floating microspheres will be delivered, increasing the GRT of the
iii. It is known that small-sized floating dosage forms are
less likely to be evacuated from the stomach by the migrating
myoelectric complex (MMC),f thus prolonging the GRT.
iv. Due to their size, risk reduction of obstruction in the GIT
will be achieved.
v. As the floating microspheres carry the drug into it, drug
release kinetics can be modified by just adjusting the number of
microspheres in the final formulation, without affecting to their
Interpenetrating polymeric networks (IPNs) are unique
“alloys” of cross-linked polymers in which at least one network
is synthesized and/or cross-linked in the presence of the
other . Depending on the chosen polymer, they enable the
formation of SPHs (Figure 3), which can absorb large amounts of
water or aqueous fluids (10–1000 times of their original weight
or volume) in short periods of time. The formation of (semi)
IPN based on hydrophilic natural occurring polymers (sodium
alginate, hyaluronic acid and chitosan), or synthetic water-soluble
polymers (PVA, and Carbopol®) could be ani interesting choice.
The second polymer will grow into the colloidal medium by
means of an orthogonal polymerization/complexation method.
The interconnected porous patterns of the new SPHs can
encapsulate large doses of hydrophilic drugs, such as Metformin
and Ranitidine (Table 3), making them ideal as GRDDS . It is
relevant to highlight that these systems must rapidly swell and
expand, as well as maintain their integrity in the harsh stomach
environment while releasing the pharmaceutical active ingredient
. Therefore, the physical entanglement of the polymer chains
is a key factor and could help improve the mechanical strength and
resiliency of the material. Moreover, floating properties (Table 4 &
Figure4) will be imparted by the free volume generated into the
hydrophilic matrices, with the help of comb- like materials .
Porosity, swelling properties, floatability and drug loading and
release behaviors can be controlled by the appropriate choice of
network forming polymers and their rate.
For the development of reversible bioadhesive hydrogels/lowdensity
microspheres composites, properties, materials needed,
and polymerization procedures are summarized in Figure 4.
Preparation of floating micro (nano)spheres as
lipophilic drug carriers
Being poly(meth)acrylates biocompatible materials with
extensive use in humans,[18,19] the preparation of amphiphilic
materials based on (meth)acrylate and (meth)acrylamide
derivatives, capable of self-assemble in core-shell structures
could be of great interest. To achieve it, extensively tested living
polymerization techniques have been already used such as
Atom Transfer Radical Polymerizations (ATRP),  Oxyanionic
Polymerizations  and Reversible Addition-Fragmentation
Chain Transfer Polymerizations (RAFT) [22,23]. They have
demonstrated to be excellent tools for the preparation of
amphiphilic block-copolymers. Macromonomers based on PEG,
poly(monoglycerol methacrylate) (PGMA), POEGMA, PPO and
PDMS will also be used in the polymerization process. They will
provide flexibility and low density/floating properties to the final
assembled particles (Table 4 & Figure 4).
Thiomers. Preparation from natural occurring
Thiolated polymers or “thiomers”, which display thiol
bearing side chains, have proved to behave very effectively as
mucoadhesive. Their bioadhesive mechanism is based on thiol/
disulfide exchange reactions. Thiomers can form disulphide
linkages between them and cysteine-rich subdomains of mucus
glycoproteins in the mucus gel layer. This also occurred between
the disulphide linkages from polymer backbone and thiol groups
in the mentioned glycoproteins . In order to improve the
mucoadhesive properties of the materials to use (Table 4),
thiolation can be a straightforward method . Although
thiolation of natural occurring polymers has already been
conducted, . low degree of functionalization were achieved
in most cases  probably because the sulfhydryl groups are
prone to oxidation. The thiolation of natural (chitosan and sodium
alginate) and commercial polymers [Carbopol® and poly(vinyl
alcohol) PVA] can be conducted by amide-coupling chemistry
and the use of thiol-protected molecules such pyridyl disulfide
reactants . Based on our experience [28,29] the formation of
disulphide containing monomers for polymer total synthesis, can
also be addressed.
Flexible chains: Preparation of bioadhesive comb-like
Entanglement seems to be one of the preferred modes of
mucin molecular association. Chain flexibility is critical for
interpenetration and entanglement with the mucus gel (Table 4
& Figure 4) . It has been demonstrated that the incorporation
of flexible polymer chains into a hydrogel can promote its
mucoadhesion by movement of the polymer chains from hydrogel
to mucosa . Hence, the use of flexible comb-type polymers
based on PEG, PEGMA, PPO and PDMS will be the first choice.
They provide an extra bonus on free volume in hydrogels since
physiological temperature is well-above their glass transition
The benefit of prolonging the release of therapeutic molecules
in the stomach whilst reducing the side effects associated with them
is evident. The current prescribed, non personalized, traditional
oral dosage approach generally involves relatively high doses of
the drug in the hope that a portion, although minor, will go to the
target tissues. Not only does this overdose lead to a nonsignificant
efficiency in combating patients’ disease, it also leads to major side
effects. Embeddeding the drugs into dual-working GRDDS that
posses a double retartant systems for drug delivery, will conduct
to a significant improvement in the sustainable drug release over
longer time periods. Accurately time delivery of the selected drugs
is the only method to reduce drug dosages, mitigate side effects on
the other healthy tissues and increased rapidity of the action. In
addition, by the designed methods it is possible to maintain the
therapeutic drug releases while time intervals between doses is
shortened, with the consequent reduction in patient’s discomfort.
Development of these systems is a key deliverable of the current
The authors would like to thank El Ministerio de Ciencia,
Innovación y Universidades (MICINN) of Spain (Grant MAT2016-
77345-C3-2-P), and La Junta de Andalucía (Grant P12-FPM-1553)
for their financial support.