Vol 5, Issue 1, 2023 (368-376)
http://journal.unpad.ac.id/idjp
*Corresponding author,
e-mail : nabil17001@mail.unpad.ac.id (N. A. Murad)
https://doi.org/10.24198/idjp.v4i3.40492
© 2023 N. A. Murad et al
Review: Increased Oral Bioavailability of Atorvastatin Calcium With Various
Encapsulation Methods
Nabil Arvel Murad*, 1, Faisal Budiman2, Taofik Rusdiana3
1Pharmacy Bachelor Program, Faculty of Pharmacy, Universitas Padjadjaran
2PT. Kimia Farma
3Department of Pharmaceutical and Formulation Technology, Faculty of Pharmacy,
Universitas Padjadjaran
Jalan Raya Bandung-Sumedang KM 21, Jatinangor 45363, Indonesia
Submitted : 22/07/2022,Revised : 14/08/2022,Accepted : 10/09/2022, Published : 08/06/2023
Abstract
Atorvastatin calcium is a statin class dyslipidemia drug that belongs to the
class 2 Biopharmaceutical Classification System (BCS) drug, namely drugs that
have high permeability and low water solubility. Low solubility in water makes
atorvastatin calcium also has low bioavailability (12%). The encapsulation
method as a drug delivery system enables the bioavailability enhancement of a
drug. This literature review aims to discover encapsulation methods that can
enhance the oral bioavailability of atorvastatin calcium in recent research and to
explain how obtained encapsulation method could enhance the bioavailability of
atorvastatin calcium. The obtained research article was from the PubMed
database. Several forms of encapsulation showed an enhancement in
bioavailability, namely nanoparticles, nanocrystals, nanosponges, nano lipid
carriers (NLC), micro and nanoemulsions, and inclusion complexes. The highest
increase in oral bioavailability of atorvastatin calcium was obtained by the
formation of nanosponges using β-cyclodextrin material with the condensation-
polymerization preparation method succeeded in increasing oral bioavailability by
14 times when compared to pure calcium atorvastatin formulations.
Keywords: Atorvastatin calcium, Bioavailability, Encapsulation
N. A. Murad et al / Indo J Pharm 5 (2023) 367-376
369
1. Introduction
Bioavailability refers to the
availability of a drug substance for its
intended biological purpose. Accurately
bioavailability is a measurement of the speed
with which a drug dose reaches the target
receptor or body fluids where the drug can
reach the target without obstruction. The
route of administration and dose of the drug
has a strong influence on the magnitude of its
bioavailability (Price & Patel, 2021). It is
important to understand the bioavailability of
a drug when determining the formulation,
dosage, dosage, route of administration, and
timing of drug administration (Hoag &
Hussain, 2001).
Atorvastatin Calcium is an
antihyperlipidemic drug that belongs to the
class 2 BCS (Biopharmaceutical
Classification System) class, which is a drug
that has high permeability and low water
solubility. The low solubility of atorvastatin
calcium (0.1 mg/ml) results in low
bioavailability as well (12%) (Choudhary et
al, 2012). Bioavailability is the rate and speed
of drug absorption (Atkinson, 2022).
Drug delivery systems can increase
drug absorption by increasing the dissolution
rate and keeping the drug in a soluble state in
biological fluids. Several techniques have
been developed to overcome this problem
including micronization (Zhang et al, 2009),
nanostructured lipid carriers (Tiwari &
Pathak, 2011), and self-nano emulsifying
drug delivery systems (SNEDDS) (Kassem et
al, 2017). -The formulation method is
included in the encapsulation method.
Encapsulation is defined as a process in
which droplets or particles of the active
substance are surrounded by a layer, or
embedded in a homogeneous or
heterogeneous (polymer) matrix, to form
small particles with many uses (Sagalowicz
& Leser, 2010).
The purpose of this article is to
determine the encapsulation method that can
increase the oral bioavailability of
atorvastatin calcium in a recent study and to
explain how the obtained encapsulation
method can increase the bioavailability of
atorvastatin calcium.
2. Method
The references used are primary and
secondary reference sources, namely
research journals and books related to the
literature review theme. In the results of the
literature review, the references used are
primary reference sources in the form of
research journals published in the last 10
years (2012 – 2022). Research journals were
obtained from the PubMed journal database
with the keywords “atorvastatin calcium”,
“atorvastatin”, “bioavailability”,
“encapsulation”, and “drug delivery system”.
The search results obtained from the PubMed
database amounted to 46 journals. From the
search results, the final journals selected for
review amounted to 15 journals.
N. A. Murad et al / Indo J Pharm 5 (2023) 367-376
370
Table 1. Methods performed for review
3. Results & Discussion
Table 1. Study parameters of atorvastatin calcium formulation with encapsulation method
Articles from the database: 46 articles
Exclusion
(n=31)
- Research articles
with intended study
parameters (n=15)
- encapsulation not related
to pharmaceutical
application (n=15)
- research without intended
study parameters (n=12)
N. A. Murad et al / Indo J Pharm 5 (2023) 367-376
371
Remarks: A1 = pure calcium atorvastatin formulation/market product; A2 = atorvastatin
calcium encapsulated formulation
From the results of several research
articles on several modifications of formulas and drug delivery systems included in the
encapsulation method of atorvastatin calcium,
N. A. Murad et al / Indo J Pharm 5 (2023) 367-376
372
the increase in bioavailability is the main
parameter of the focus of this literature review.
The increase in bioavailability itself can be
seen by comparing the AUC value between the
modified calcium carrier atorvastatin
formulation and pure calcium
atorvastatin/market product.
The modified encapsulation
formulation method used in each research
article is the encapsulation method. The
encapsulation method is a method in which the
active ingredient is enveloped, coated, or
coated by a protective material that covers or in
many research articles is called a carrier or
polymer material (Sonawane et al, 2020). There
are various encapsulation structures formed
between the active ingredient and the protective
material, including those discussed in the
research article obtained are nanoparticles,
nanocrystals, nano, nanosponges, nano lipid
carriers (NLC), micro and nanoemulsions, and
inclusion complexes.
3.1 Nanoparticle
In a study (Shaker et al, 2020), encapsulation
using ethylcellulose with preparation for the
formation of emulsification-evaporation
nanoparticles can increase bioavailability by
3.87 times. This is because the nano-sized
particles allow the ability of drug particles to be
phagocytosed by M cells and then delivered to
the lymphatic channels to the systemic
channels. In a study (Li et al, 2016) that used
Poly lactic glycolic acid (PLGA) with the
ultrasonication-evaporation preparation
method, the increase in bioavailability
increased by 4.7 times. Absorption of
atorvastatin calcium is low due to acid catalysis
in the stomach. In the atorvastatin calcium-
PLGA encapsulated formulation, the presence
of a protective barrier from the PLGA polymer
allows the minimization of gastric acid
catalysis due to pH and enzymes. In addition to
PLGA and ethylcellulose, gelatin was also used
as an encapsulation material in studies (Shilpi
et al, 2017) and (Kasekar et al, 2020). (Shilpi et
al, 2017) using modified type A gelatin and the
desolvation preparation method succeeded in
increasing the bioavailability by 4.84 times.
The increase in bioavailability occurs due to an
increase in the affinity of mucus in the small
intestine epithelium with drug nanoparticles,
this occurs due to electrostatic interactions
between the positive charge of drug
nanoparticles and the negative charge of mucus
in the intestine. In addition, the presence of
lymphatic absorption through M cells may also
play a role in the increase in bioavailability
(Shilpi et al, 2017). Gelatin is also used in
research (Kasekar et al, 2020), using type B
gelatin with the desolvation preparation
method to form nanoparticle encapsulation
succeeded in increasing bioavailability by 11
times compared to pure calcium atorvastatin
formulations. Atorvastatin-gelatin
nanoparticles have better drug release because
the hydrophilic nature of gelatin makes it easier
for body fluids to penetrate the body thereby
increasing diffusion-mediated drug absorption.
In the study (Kumar et al, 2017) the
encapsulation material used was eudragit with
the emulsification-evaporation preparation
method successfully increasing bioavailability
by 2.37 times compared to pure drug
formulations. The increase was due to systemic
absorption and increased systemic residence
time due to the nanoparticle size range and
bioadhesive properties of eudragit.
3.2 Nano Lipid Carrier
Nano lipid carrier (NLC) is a form of nano-
sized lipid-based encapsulation. NLC has been
used as a new drug delivery system for
atorvastatin calcium. In the study (Khan et al,
2015) the encapsulation materials used were
stearic acid and oleic acid with a high-pressure
homogenization preparation method
successfully increasing bioavailability by 4.89
times. The increase in bioavailability occurred
because the presence of stearic acid and oleic
N. A. Murad et al / Indo J Pharm 5 (2023) 367-376
373
acid made the solubility of the lipophilic
atorvastatin increase. Components of NLC that
interact with gastrointestinal components such
as phospholipids, bile salts, etc. can lead to
micellar formation. These micelles can create a
high concentration gradient so that the drug
particles can diffuse through the epithelial cells
of the small intestine wall. NLC can also adhere
to the small intestine wall to prolong the
residence time of the drug on the small intestine
wall. In the study (Elmowafy et al, 2017) the
NLC materials used were gelucire 43/01 and
capryol PGMC with the emulsification-
ultrasonic preparation method succeeded in
increasing the bioavailability by 3.6 times that
of the pure atorvastatin formula. The increase
in bioavailability is not only due to the
interaction of NLC with bile salts resulting in
the formation of micelles, gelucire 43/01
material can also reduce the secretion of
paraglyco-protein (PGP), the transporter of
atorvastatin which plays a role in the enzymatic
degradation of atorvastatin. With decreased
secretion of PGP, the bioavailability of
atorvastatin increases.
3.3 Nanospheres
Nanospheres are nanoparticles with a
spherical structure with a smooth surface
without any cracks. The form of the nanosphere
is the encapsulation form that was produced in
the study (Hashem et al, 2015a) using zein as
encapsulation material with the liquid-liquid
phase separation preparation method. The
increase in bioavailability was 3 times that of
the pure atorvastatin formulation. The
nanosphere form increases the solubility as
well as the permeability of atorvastatin thereby
increasing the paracellular absorption of the
drug. The fine shape of the nanosphere also
increases the surface area, thereby decreasing
the particle diameter in the diffusion path.
3.4 Emulsion
The drug delivery system is in the form of
an emulsion with micro and nano-sized
particles. The micro-sized emulsion is called
the self-micro emulsifying drug delivery
system (SMEDDS) and the nano-sized one is
called the self-nano-emulsifying drug delivery
system (SNEDDS). In a study (Hashem et al,
2015b), nanoemulsions formed using oleic
acid, tween 80, propylene glycol with nano
emulsification preparation method succeeded
in increasing bioavailability by 2.7 times. This
happens because the smaller drug particles
dispersed in the globules of the nanoemulsion
have a larger surface area and faster drug
release increases the absorption and
bioavailability of the drug. In a study, (by
Yeom et al, 2016) micro-sized emulsions
formed from capmul MCM, tween 20, and
tetraglycol with the emulsification preparation
method succeeded in increasing bioavailability
by 3.4 times. The increase in bioavailability
occurs because, in the digestive tract, the drug
is released from the smedds and forms a
microemulsion. In a previous study (Yeom et
al, 2015), better membrane fluidity helped the
drug to be able to diffuse across cell
membranes faster so that the dissolution and
bioavailability of SMEDDS increased
compared to the pure atorvastatin formula. In
addition to SMEDDS and SNEDDS, the
research (Qin et al, 2016) used the form of
encapsulation that was submicron emulsion as
the second layer and phospholipid complex as
the first layer. The encapsulation materials used
were ovolecithin as a phospholipid complex
builder and soybean oil as a submicron
emulsion former using the high-pressure
evaporation-homogenization preparation
method, which increased the bioavailability by
4 times compared to the Lipitor market
atorvastatin formula. This is due to the
increased absorption into the lymphatic vessels,
especially in the large intestine, from the
atorvastatin-submicron-phospholipid complex
emulsion. Compared to pure atorvastatin
formula.
3.5 Nanosponges
Nanosponges are nanoparticles that form a
crosslinked polymer as a protective material
that has nano-sized hollow pores. In the study
(Zidan et al, 2018) the material used was β-
cyclodextrin with the condensation-
N. A. Murad et al / Indo J Pharm 5 (2023) 367-376
374
polymerization preparation method succeeded
in increasing the bioavailability by 2.13 times
compared to the pure atorvastatin formula. This
is because the nanosponges that increase the
concentration of free atorvastatin drug and
increase saturation in the gastrointestinal tract
so that the drug can be partitioned through the
membrane so that the plasma concentration and
bioavailability increase. In a study (Mathur &
Vemula, 2018) with the same ingredients and
preparation methods, the increase in
bioavailability was 14 times compared to the
pure atorvastatin formula. The increase was
due to the porous structure of the nanosponges
allowing easy encapsulation and drug release
from the nano ponds. The amphoteric nature of
β-cyclodextrin plays a role in drug release in
the microvilli of the small intestine. The
lipophilic membrane of the small intestine
allows the mucoadhesive nanosponges to
adhere for better drug release thereby
increasing bioavailability.
3.6 Nanocrystals
Nanocrystals are drug delivery systems
that have recently been developed due to their
high encapsulation efficiency. In the study
(Sharma & Mehta, 2019) poloxamer 188 was
used as an encapsulation material with the
high-pressure homogenization preparation
method successfully increasing the
bioavailability by 2.66 times compared to the
pure atorvastatin formula. This is because
poloxamer can increase permeability by
changing the viscosity of cell membranes in the
digestive tract. The increasing difference in
drug concentration gradient between the
gastrointestinal tract and the blood vessels also
results in increased solubility and dissolution
resulting in increased bioavailability.
3.7 Inclusion Complexes
Pemilihan aistem penghantaran obat
dengan kompleks inklusi memiliki kelebihan
yaitu proteksi dari metabolisme presistemik
pada saluran pencernaan. Pada penelitian (Qin
et al, 2016) bahan yang digunakan unutk
membentuk kompleks inklusi adalah dinatrium
glisirizat (Na2GA) dengan metode preparasi
mekanokimia berhasil menaikkan
bioavailabilitas sebesar 5,4 kali dibanding
formula atorvastatin murni. Ada beberapa
alasan hal tersebut bisa terjadi. Pertama, karena
atorvastatin-Na2GA kompleks yang berbentuk
amorf dibanding atorvastatin murni yang
berbentuk kristal, memiliki dispersibilitas dan
kebasahan yang lebih tinggi pada saat keadaan
jenuh sehingga mengakibatkan peningkatan
kelarutan air dan pada akhirnya
bioavailabilitas. Kedua, karena kemampuan
Na2GA unutk menghambat protein PGP yang
membuat degradasi enzimatik pada obat.
Dengan menghambat PGP, maka absorpsi obat
meningkat sehingga bioavailabilitas
meningkat.
The highest increase in oral bioavailability
of atorvastatin calcium was obtained by the
formation of nanosponges using β-cyclodextrin
material with the condensation-polymerization
preparation method succeeded in increasing
oral bioavailability by 14 times when compared
to pure calcium atorvastatin formulations.
Cyclodextrins have amphoteric properties
because chemically they have hydrophilic and
lipophilic groups. The hydrophilic group in
cyclodextrins is on the OH group in their
chemical structure. For the lipophilic group,
there exists the circular CH group with one
oxygen linking. A cross-linker is added as a
connector between the cyclodextrin particles.
The distance in the cyclodextrin-cross linker-
cyclodextrin is what makes the pores in the
nanosponge structure. As a drug delivery
system, cyclodextrins are commonly used for
drugs that tend to be insoluble in water such as
atorvastatin calcium. Atorvastatin calcium will
bind to the inner lipophilic group of the
cyclodextrin so that it closes/binds the
hydrophobic group of the drug. Due to this
interaction the solubility and dissolution into
the blood which tends to be hydrophilic due to
the water component in the blood plasma, there
is an increase in the solubility, dissolution, and
finally the bioavailability of atorvastatin
calcium-cyclodextrin nanosponges.
N. A. Murad et al / Indo J Pharm 5 (2023) 367-376
375
4. Conclusion
Based on 15 research journals, there is an
increase in the oral bioavailability of
atorvastatin calcium by encapsulation method
which was divided based on its shape/structure,
namely nanoparticles, nanospheres, Nano lipid
carriers (NLC), emulsions, nanosponges,
nanocrystals, and inclusion complexes.
The greatest increase in oral atorvastatin
calcium bioavailability was obtained in the
formation of nanosponges using -cyclodextrin
with condensation-polymerization preparation
method, which increased the oral
bioavailability by 14 times compared to pure
calcium atorvastatin formulation.
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