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

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

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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.

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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

Inclusion (n=15)

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,

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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-

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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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