extended release formulation of bcs class i drugs · 2019. 12. 10. · water-soluble or hydrophilic...

www.wjpps.com Vol 4, Issue 04, 2015.

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Dipti et al. World Journal of Pharmacy and Pharmaceutical Sciences

EXTENDED RELEASE FORMULATION OF BCS CLASS I DRUGS

Prof Dipti Phadtare*, Ganesh Phadtare, Nilesh Barhate and

Prof Dr Ashawat Mahendra singh

India.

ABSTRACT

The aim of extended release formulation is to increase the

bioavailability, as it is important in the optimization of the drug

development. BCS is a valuable tool in pharmaceutical science.

Formulation scientist can optimize the drug development by applying

the prediction of solubility & permeability which have influence on the

dissolution profile of a drug product & ultimately on Bioavailability &

Bioequivalence. In the present review the role of Biopharmaceutics

classification system (BCS) is given in the extended release drug

delivery system of BCS class I drugs. Mathematical models enable the quantitative analysis

of drug release kinetics which reduces time during drug formulation & serves as important

tool in product development & optimization.

KEYWORDS: Biopharmaceutics classification system, Bioavailability, Bioequivelence,

solubility, Permeability, extended release.

INTRODUCTION

Approaches to the formulation of new drug delivery system are based on deliberate control

on drug availability. At present various drug delivery systems are available, in which the oral

drug delivery system is most preferable. In which the extended release drug delivery system

is more reliable than the conventional drug delivery systems.

Extended release products aim at releasing the drug continuously at a predetermined rate to

increase the patient compliance.[1,2]

As these dosage formulated to release the drug over an

extended period of time after ingestion; thus, it reduces the dosing frequency as compared to

a conventional drug delivery system. These will release the drug slowly into the

Gastrointestinal tract and mainta in a constant drug concentration in the plasma for a longer

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*Correspondence for

Author

Prof Dipti Phadtare

India.

Article Received on

10 Feb 2015,

Revised on 05 March 2015,

Accepted on 30 March 2015


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period of time.[3]

It initially releases an adequate amount of drug to bring about the necessary

blood concentration (loading dose) for the desired therapeutic response & further amount of

drug is released at a controlled rate (maintenance dose) to maintain the blood levels for

desirable period of time.[4]

The main criteria for extended-release formulation is, that the drug product must have good

aqueous solubility, as they are uniformly absorbed from the gastrointestinal tract, narrow

therapeutic index, short biological half-life (t1/2

), small daily dose, site-dependent absorption

and marketing benefits.

Types of the extended release systems for drugs

ER solid oral dosage forms can be classified into two broad groups: (i) single unit dosage

forms (e.g. tablets) and (ii) multiple unit dosage forms or multiparticulate pellet systems.

Single unit dosage forms

1. Matrix systems: It includes

a. Water-soluble matrix formers

Water-soluble or hydrophilic matrices are a well known type of extended release oral

dosage forms.[5]

Hydroxypropyl methylcellulose (HPMC) is the most important hydrophilic

carrier material,several others are also available; including (i) cellulose derivatives:

hydroxypropyl cellulose (HPC), carboxymethylcellulose sodium (NaCMC), (ii) natural

polymers: sodium alginate, carrageenan, chitosan and (iii) synthetic polymers: polymerized

acrylic acid (Carbopol),polyvinyl alcohol (PVA), polyethylene oxide(PEO).

b. Water-insoluble matrix formers

Water-insoluble carrier materials include (i) lipid-base excipients: white wax, carnauba wax,

glyceryl monostearate, hydrogenated vegetable oil, paraffin and (ii) polymer-based

excipients: ethylcellulose (EC), cellulose acetate. In comparison to the hydrophilic

matrices,the system has a greater physical stability, resulting in the less variable drug release

and the lower incidence of „dose dumping‟ in presence of food.[6]

2. Reservoir systems

Reservoir systems are characterized by a drug-containing core surrounded by release-rate

controlling polymer(s). The mechanism of the drug transport across the polymeric membrane

has been extensively described by Lecomte (2004).[7]


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a. Coated tablets

The tablet core consists of the mixture of active drug and other excipients, subsequently

coated with a solution of water-insoluble polymers and water-soluble excipients. Upon

exposure to aqueous media, the surrounded coating is transformed into a semi-permeable

membrane through which the drug diffuses in a rate-limiting manner.[8]

b. Osmotic pump systems

Osmotic device is a special type of the reservoir systems, where the release rate of the drug is

controlled dynamically by an incorporated osmotic agent in the active drug core. The rigid

surrounding semi-permeable membrane consists for example of cellulose acetate. The drug is

released through a defined, laser drilled delivery orifice in the membrane.[9]

2. Multiparticulate pellet systems

The ER pellets are either filled into a capsule or are compressed into a tablet.[10]

a) Matrix systems

The matrix type of multiparticulate systems can be prepared by several techniques such as

extrusion/ spheronisation[11]

, spherical crystal agglomeration.[12]

and melt-solidification.[13]

b) Reservoir systems

Coated pellets as a mean to control drug delivery are widely used in the pharmaceutical

industry, although the development and optimization of the systems are rather complex[14]

Numerous aspects of the system performance have been investigated, for instance, the

influence of formulation and coating technique.

The concept of Biopharmaceutical classification system & it’s role in extended release

formulation of class I drugs.

The Biopharmaceutical classification system is an important tool in the development of new

drug product. The knowledge of BCS help the formulation of dosage form based on

mechanistic rather than empirical approaches.[15]

(FDA Guidelines, 2000). It enables to test

the dissolution of product in vitro mechanistically rather than in vivo empirically.

The BCS has been used as a regulatory tool for the replacement of certain BE studies (in

vivo) with accurate in vitro dissolution tests. It reduces the time for drug development &

reduces clinical & preclinical studies.


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The introduction of the Biopharmaceutics Classification System (BCS) in 1995 was the

result of continuous efforts on mathematical analysis for the elucidation of the kinetics and

dynamics of the drug process in the gastrointestinal (GI) tract.[16]

Classifications

The BCS is a scientific framework for classifying a drug substance based on its aqueous

solubility and intestinal permeability,[17]

which have influence on the dissolution profile of a

drug product & ultimately on bioavailability & bioequivalence.

Class boundary parameters i.e., solubility, permeability, and dissolution are for easy

identification and determination of BCS class.[18,19,20]

The following Biopharmaceutics Classification System (BCS) is recommended in the

literature (Amidon 1995): Based on drug solubility and permeability.

Class I: With high solubility, high permeability e.g. metoprolol, diltiazem, verapamil, and

propranolol.

Class II: With low solubility, high permeability e.g. glibenclamide, phenytoin, danazol,

mefenamic acid, nifedinpine, ketoprofen, naproxen, carbamezapine, and ketoconazole.

Class III: With high solubility, low permeability e.g. cimetidine, ranitidine, acyclovir,

neomycin B, atenolol, and captopril.

Class IV: With low solubility, low permeability e.g. hydrochlorothiazide, taxol, and

furosemide

The solubility of a drug is determined by dissolving the highest unit dose of the drug in 250

mL of buffer adjusted between pH 1.0 and 8.0.

High-permeability drugs are generally those with an extent of absorption that is greater than

90%

The drugs of Class I exhibit high absorption number and high dissolution number. The

bioavailability of the drug is not limited by dissolution. In these cases, the rate limiting step

for drug absorption is gastric emptying. These compounds are well absorbed, and their


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absorption rate is usually higher than the excretion rate.[21,22]

Examples include metoprolol,

diltiazem, verapamil, and propranolol.

For orally administered dosage forms, extended drug action is achieved by affecting the rate

at which the drug is released from the dosage form and/or by slowing the transit time of the

dosage form through the gastrointestinal tract.[23]

Class I drugs which exhibit high

permeability across the GI epithelium their absorption rate is controlled exclusively by the

rate of release from the dosage form.[24]

The absorption rate can be controlled by retarding the release rate with the application of

suitable biocompatible polymer material & in order to increase the gastric empting time .In

these circumstances in vitro dissolution rates can possibly be used to correlate the in vivo

absorption rates and to optimize the formulation development.

FACTORS AFFECTING DESIGN & PERFORMANCE OF CONTROLLED

RELEASE DOSAGE FORMS

According to the BCS In early drug development, knowledge of the class of a particular drug

is an important factor influencing the decision to continue or stop its development. The

factors that affect the formulation of extended release formulation of class I drugs includes

the physicochemical parameters & pharmacokinetic &/or pharmacodynamic parameters.

Physicochemical parameters

Molecular size & diffusivity: In addition diffusion through biological membrane drug in

extended release must diffuse through a rate controlling matrix. The ability to diffuse in

polymer is called diffusivity & is function of molecular weight .High molecular weight drugs

shows slow release kinetics in extended release devices thus diffusion is releasing

mechanism.

Aqueous solubility: unionized form of drug in the stomach show excellent absorption in

acidic environment & for weakly basic drug exist in the ionized form have poor absorption at

the same site. Different segment of GIT have different pH range so release of an ionizable

drug from extended release .In the upper portion of small intestine pH is basic (pH = 5 to

7) & reverse for weak acids & bases. Extended release system should be programmed in

accordance with the variation in pH of different segment of GIT thus plasma level of drug

will be constant throughout the course of drug.


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A drug with low solubility & slow dissolution rate show dissolution –limited absorption but

extended release system for these substance may not provide benefits over conventional form

as diffusion of drug of drug through polymer is rate limiting step in release which is not

possible with the poorly soluble drug as driving force for diffusion is drug concentration in

polymer & this concentration is low for low solubility drugs. While drug with high solubility

& rapid dissolution is often difficult to decreased it‟s dissolution.

A drug with high solubility dissolves in GIT fluid & tends to release from the dosage form in

burst & absorbed quickly leading to sharp increase in blood concentration .For this purpose

preparing a slightly soluble form of drug with normally high solubility is one of the possible

method for producing extended release formulation.[25]

pH dependent solubility is another problem for controlled release because variation in pH

range throughout GIT tends variation in dissolution rate e.g. phenytoin. pka – Ionization

constant: pka is measure of strength of acid or base .Unionized molecule cross the lipoidal

membrane than ionized form .For drug to be absorbed it must be in unionized form at the

absorption site. Drug which exist in ionized form at absorption site are poor candidates for

sustained release.

Partition coefficient

Partition coefficient influences permeation of drug across the biological membrane

&diffusion across the rate controlling membrane. Drug with extremely large value of

Partition coefficient are very lipid - soluble. There is also optimum partition coefficient below

this optimum result in decreased lipid solubility & drug will remain in aqueous phase while

large lipid soluble drug will not partition out of lipid membrane once it gets in. Drugs with a

partition coefficient higher or lower than optimum are poorer candidates for formulation.

Pharmacokinetic & Pharmacodynamic parameters

Release rate

For extended release dosage form rate of release from the dosage form is the rate limiting

step. Release from the dosage form should follow zero-order kinetics & should eliminated by

first order kinetics. To achieve a therapeutic level & sustain the level for given period of time

dosage form consist of two parts initial loading dose & maintenance dose.


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Dose of drug

If dose of drug is high it becomes more challenging to develop a sustained release .For short

half –life to provide once a day it require large amount of drug but it is difficult to

swallowing. The requirement for small size would leave little space in the dosage unit for

other ingredient needed to control the drug release. The size of dosage unit becomes very

critical for highly water soluble drugs since even a large amount of inactive ingredient is

usually needed to provide the sustained property.

Biological factors

Absorption

Rate ,extent & uniformity of absorption of a drug are important factor in formulation if the

transit time of drug through GIT between 9- 12 hrs & absorption t½

should be 3-4 hr then

Corresponding absorption rate constant Ka value of 0.17-0.23 /hr necessary for 80-95% in

9-12 hr transit time so for with a very slow rate of absorption less than 0.17/hr result in poor

bioavailability which is difficult to be formulated into extended release formulation.

Distribution

Drug which have apparent volume of distribution than real volume of distribution,

elimination half life is decreased i.e drug leaves body gradually provided drug elimination

rate is limited by release of drug from tissue binding sites. Drug release from tissue give

therapeutic concentration suggest that drugs are inherently sustained. Larger the volume of

distribution more drug concentration in tissue as compared to blood.

Metabolism

There are two possibilities that restrict the sustained release product design.1) if a drug upon

chronic administration is capable of either inducing or inhibiting enzyme systhesis.2) if there

is a variable level of a drug through either intestinal metabolism or through first pass effect.

This will be difficult to make formulation of sustained dosage form.

Elimination half life

Drug with short half lives(< 2 hrs) & high dose impose a constraints on formulation into

sustained /controlled release system because of the necessary dose size &drug with long

half-lives(> 8 hrs) are inherently sustained.


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Drug – protein binding

Drug – protein binding is reversible process as the free drug concentration in the blood

decreases, the drug – protein complex dissociates to liberate the free drug & maintain

equilibrium. Due to reversible binding of a drug, the free drug levels of the drugs are

maintained for long time leading to a long biological half-life. A protein - bond drug not

available as a substrate for liver enzymes thereby further reducing rate of metabolism.

Therapeutic Index

It measures the margin of safety of a drug .Drugs with very small value of T.I. are poor

candidates for formulation into extended release products. A drug is considered to be safe if

it‟s T.I. value is greater than 10.

CHALLENGES AROUND EXTENDED RELEASE FORMULATION OF BCS CLASS

I DRUGS

The major challenge in development of extended release drug delivery system for class I

drugs is to achieve a target release at predetermined rate over an extended period of time

associated with a particular pharmacokinetic and/or pharmacodynamic profile. Formulation

approaches include both control of release rate and certain physicochemical properties of

drugs like pH-solubility.

High solubility

Development of oral sustained release matrix systems for highly water-soluble drugs posses

one of the major challenges to the formulation scientist. This challenge can be attributed to

key factors like high water solubility of drug leading to burst release, lack of control over

polymer relaxation/disentanglement related to drug dissolution and diffusion, compensation

for an increase in the diffusional path length which is not easily achieved with time.[26]

Because of high solubility, fabrication of an extended release matrix formulation becomes

extremely challenging hence hydrophilic matrix polymers are the preferred systems for

developing an extended release formulation. Highly soluble drugs, fails to retard drug release

alone hence there is need of addition of other hydrophilic or lipophilic release retardants e.g.

Metoprolol succinate, a BCS class I drug belongs to cardioselective beta blocker. It is readily

and completely absorbed throughout the intestinal tract.[27,28,29]

but is subjected to extensive

first pass metabolism resulting in incomplete bioavailability (about 50%). The plasma half-

life of the drug varies from 3 to 6 hours which necessitates administration of conventional


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formulations up to 4 times daily[30]

& includes adverse effects such as hypotension, dizziness,

fatigue or headache warrants the development of extended release formulation of metoprolol.

MATHEMATICAL MODEL

For a considerable proportion of compounds, controlled release formulations are developed,

when the immediate release formulations are not appropriate.

Mathematical model enables us for quantitative analysis of dissolution rate or drug release

kinetics from drug delivery system reduces time during drug formulation & serves as

important tool in product development & optimization of extended release formulation of

BCS class I drugs.

Models Used in the Assessment for Release Kinetics

Extended release formulation initially releases an adequate amount of drug to bring about the

necessary blood concentration (loading dose) for the desired therapeutic response & further

amount of drug is released at a controlled rate (maintenance dose) to maintain the said blood

levels for desirable period of time. Initially drug release at a slow zero or first order rate

followed by slow zero or first order release of sustained component.[31]

The release kinetics was evaluated using following different models zero-order, first-order,

Higuchi, and Korsmeyer–Peppas.

Zero-order model

Qt = Q0 + K0t

where Qt is the amount of drug dissolved in time t,

Q0 is the initial amount of drug in the solution (most times, Q0 = 0) and

K0 is the zero order release constant expressed in units of concentration/time.

To study the release kinetics, data obtained from in vitro drug release studies were plotted as

cumulative amount of drug released versus time.[32,33]

First order model

This model has been used to describe absorption and/or elimination of drugs First-order

kinetics log Qt = log Q0 + (K1t)/2.303

Where Q0 is the initial concentration of drug, k is the first order rate constant, and t is the

time[34]


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The basic requirement of controlled release systems is that they release drug in vivo,

according to a predictable rate and the principal release mechanism for these systems is

diffusion. The mathematical modeling of drug release from diffusion-controlled systems

relies on the Higuchi model published in 1961.[35]

This model is based on the hypotheses that

(i) initial drug concentration in the matrix is much higher than drug solubility, (ii) drug

diffusion takes place only in one dimension (edge effects must be negligible), (iii) drug

particles are much smaller than system thickness, (iv) matrix swelling and dissolution is

negligible,(v) drug diffusivity is constant and (vi) perfect sink conditions are always attained

in the release environment.

Accordingly, model expression is given by the equation

ft = Q = A C0 > Cs

where Q is the amount of drug released in time t per unit area A, C0 is the drug initial

concentration, Cs is the drug solubility in the matrix media and D is the diffusivity of the

drug molecules (diffusion coefficient) in the matrix substance.

Korsmeyer -Peppas model

Korsmeyer (1983) derived a simple relationship which described drug release from a

polymeric devices.[35]

Mt / M∞ = Ktn

Where Mt / M∞ is a fraction of drug released at time t, k is the release rate constant and n is

the release exponent. The n value is used to characterize different release for cylindrical

shaped matrices.

In vitro drug release time profile as described by empirical equations, can usually be used in

vivo as these systems are made to release the drug at a consistently specific rate.

FUTURE TECHNOLOGIES INEXTENDED RELEASE FORMULATION OF BCS

CLASS I DRUGS

Many of new drugs do not have the suitable pharmacokinetic profile to make a conventional

drug delivery system .The extended release drug delivery techniques of BCS Class I have a

influence on future scope in the treatment of chronic diseases in which the patient comfort &


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compliance by reducing the dosing frequency like once-a-day which reduces the side effect &

improve the tolerability.

This delivery system has a wide future scope by using variety of biocompatible polymers &

novel techniques like multiparticulate technology ,nanotechnology ,reservoir–type devices

in the advanced field of Site specific targeted drug delivery system , Chronopharmacokinetic

system.

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extended release formulation of bcs class i drugs · 2019. 12. 10. · water-soluble or hydrophilic...

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