Minimizing bioavailability variations with oral controlled release formulations

Am J Drug Deliv 2003; 1 (2): 103-112HEALTHCARE TECHNOLOGY REVIEW 1175-9038/03/0002-0103/$30.00/0

© Adis Data Information BV 2003. All rights reserved.

Minimizing Bioavailability Variations with OralControlled Release FormulationsWhat is Possible?

Aditya Mohan Kaushal and Sanjay Garg

Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, SAS Nagar, Punjab, India

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

1. Bioavailability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

1.1 Types of Bioavailability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

1.2 Quantitation of Bioavailability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

1.3 Variations in Bioavailability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

1.4 Problems with Bioavailability Variations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

2. Minimization of Bioavailability Variations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

2.1 Reducing Fluctuations With Continuous Release Controlled Drug Delivery Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

2.2 Reduction in Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106

2.3 Overcoming Chronopharmacokinetic Variation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

2.4 Gastro Retentive Systems for Site-Specific Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

2.5 Food Induced Variability and Controlled Release Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110

3. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

Despite various routes of drug delivery being explored, the oral route has continued to be the most popularAbstractroute of drug administration. However, the complexities associated with the gastrointestinal tract lead to

variations in the rate and extent of bioavailability of drugs administered as oral dosage forms. This variation in

the bioavailability of drugs is responsible for the majority of adverse effects, lack of efficacy, and development

of tolerance, etc.

This review explores the possibilities of minimizing these bioavailability variations with the use of oral

controlled release (CR) dosage forms. The use of CR preparations, in lieu of the immediate preparations in itself,

leads to better control over plasma levels. Furthermore, the additional benefits offered by CR products, such as

the reduction in first-pass metabolism, enhanced and reproducible bioavailability with gastro retentive prepara-

tions, overcoming circadian rhythm variations, and the lesser effect of fed condition on bioavailability, can be

effectively utilized for bioavailability variation minimization. However, CR products cannot be use indiscrimi-

nately. The use of CR products to serve the purpose of bioavailability variation minimization should be based on

due consideration to the role of metabolizing enzymes, the permeability variations, and the area available for

absorption.

104 Kaushal & Garg

The oral route of drug administration has traditionally been the drug absorbed of the total amount of drug administered. Since the

preferred route of administration for most therapeutic agents and, assessment of absolute bioavailability necessitates the use of an

in general, is the first avenue investigated in the discovery and administration route that excludes doubt on the amount of drug

development of new drug candidates and formulations. Patient reaching the systemic circulation, the drug is also administered

acceptance, convenience of administration, cost of manufacturing, intravenously. The calculations involve the comparison of the area

etc., are some of the factors that have ensured a continued empha- under the curve (AUC) for the two routes of drug administration.

sis on the development of oral formulations. Among the oral On the other hand, the relative bioavailability is the extent and rate

formulations, for most of the drugs and therapeutic indications, the of bioavailability of a drug from one or more dosage forms given

conventional immediate release (IR) forms suffice. However, in by the same route of administration. One of the dosage forms

some conditions, the controlled release (CR) systems are superi- administered when relative bioavailability is measured is the refer-

or.[1] ence product and the rest are test formulations.[4]

The diversity and complexity of the gastrointestinal tract pro-

vides for a much greater flexibility in the design of oral drug 1.2 Quantitation of Bioavailabilitydelivery systems, than for other routes of drug delivery.[2] At the

same time, this very diversity and complexity can lead to differ- Mathematical parameters are required to quantitate andences in the behavior of the dosage form in the gastrointestinal compare the bioavailability of different formulations. In the caseenvironment. This can lead to differences in the bioavailability of of single dose studies, the parameters used are AUC, peak plasmadrugs from one patient to another, and within the same patient on concentration (Cmax), and the time to reach peak plasma concen-two different occasions or in different gastrointestinal conditions. tration (Tmax). To characterize the rate and extent of bioavailabil-Although bioavailability is not a direct measure of the therapeutic ity in multiple dose studies, AUC during an administration inter-efficacy per se, the variations in the bioavailability (in rate or val, and the percentage fluctuation, or the fluctuation index, areextent) are more likely to have an effect on therapeutic response most commonly used:than not have an effect. Hence, a predictable and reproducible

bioavailability is very much a desired attribute of an orally admin-Fluctuation C C C

Fluctuatio

ss ss ss(%) {( ) / }[max] [min] (min)� �100

nn index C C AUCss ss� � �( ) /( / )[max] [min] 0 � �istered dosage form. In light of all this, the use of CR drug delivery

where Css (max) and Css (min) are the maximum and minimumstrategies for the minimization of the bioavailability variations ofconcentrations at steady state, respectively, AUC0–τ is the areaorally administered products is explored in this manuscript.under the curve during an administration interval, and τ is the

1. Bioavailability administration interval.[4,5]

Bioavailability is defined in the US Code of Federal Regula-1.3 Variations in Bioavailability

tions as ‘the rate and extent to which the active ingredient or active

moiety is absorbed from a drug product and becomes available atA variety of factors can lead to differences in the bioavailability

the site of action. For drug products that are not intended to beof orally administered products.[6] A few of the important factors

absorbed into the bloodstream, bioavailability may be assessed bythat lead to variations in bioavailability include:

measurements intended to reflect the rate and extent to which the• Blood flow: Blood flow or perfusion to the site of drug absorp-

active ingredient or active moiety becomes available at the site oftion varies during the day, as a result of movement, food intake,

action.’[3] This definition focuses on the processes by which theetc. The absorption of drugs that are perfusion rate-limited,

active ingredients or moieties are released from an oral dosagesuch as the small hydrophilic molecules, is greatly influenced

form and move to the site of action.[3]

relative to the diffusion rate-limited lipophilic molecules.[6]

• pH: The pH of the gastrointestinal tract is variable in the1.1 Types of Bioavailabilitydifferent regions, and also varies according to the time of the

Bioavailability can be expressed as either absolute or relative day, the food intake, and the type of food taken. The pH at the

bioavailability. The absolute bioavailability is the fraction of the site of release and absorption determines the amount of drug

© Adis Data Information BV 2003. All rights reserved. Am J Drug Deliv 2003; 1 (2)

Bioavailability Variation with Oral CR Formulations 105

present as the un-ionized moiety that is essential for passive 2. Minimization of Bioavailability Variationsdrug absorption.[6]

By definition, CR dosage forms release the drug at a planned,• Food and fluid volume: The amount and type of food influences

predictable, and lower rate than immediate-release formulations.the gastric motility cycle and the gastric retention time. In

On the other hand, the IR dosage forms are designed to release theaddition, the blood flow, acid and bile secretion, and change in

drug immediately upon ingestion, with no intended lag in thethe absorption of the drug in the presence of food components

release of the drug.[8] The rate of release of the drug from these twomay occur. All these indirectly lead to variations in rate and/or

types of dosage forms is thus very different, and this translates intoextent of bioavailability.[6]

a difference in the plasma profiles, or in other terms, the bioavaila-Thus, the sources of variation in bioavailability can either be

bility of these two types of dosage forms. The factors that affectthe physiologic factors such as blood flow, pH and, food and fluid

the bioavailability of the orally administered dosage forms canvolume, or the dosage form related factors. An understanding of

affect the IR and CR in different ways and to different extents.these factors is essential to minimize variations in bioavailability

The biopharmaceutics classification system (BCS) divides theof orally administered products. The physiologic factors are relat-

drugs into four categories, based on their solubility and permeabil-ed to the patient and are beyond the control of a formulation

ity characteristics.[9] Class I includes drugs with high solubilityscientist; at best, they can be well understood and minimized, if

and high permeability; class II drugs have low solubility but highpossible, by suitable formulation approaches. The influence of

permeability; class III drugs have high solubility but low permea-these factors is avoided while carrying out a bioavailability or

bility; and class IV drugs have both low solubility and lowbioequivalence study by proper design of the study.[4] However,

permeability. This classification is used by the US FDA to providewhen the product reaches the market, it is subject to intra- and

less stringent conditions for bioequivalence of oral drug productsinter-patient variability. The possibility of overcoming these fac-

for class 1 drugs. Although the drugs belonging to class 1 of thetors by the use of CR products is explored in the present manu-

BCS are considered to present minimal problems in their absorp-script. The second type of factors is the dosage form related

tion, due to the wide array of factors discussed earlier, variations infactors. Strictly considering, any bioavailability variations due to

the bioavailability may still arise. Hence, problems of variation informulation related factors should be intended and controllable.

the bioavailability can arise for any BCS class of drugs.For example, the rate of bioavailability is deliberately desired to be

Oral controlled drug delivery can be used in more than one waylower in the case of CR products.

to minimize the variations associated with conventional IR prod-The variations in bioavailability can be quantified in terms of

ucts. The basic approach in making a CR system is to provide athe parameters discussed earlier, i.e. AUC, Cmax, Cmin, percentage

slower, preprogrammed rate of delivery compared with IR. Thefluctuation, etc.

controlled drug delivery systems can be designed as:[2]

• continuous release systems, e.g. diffusion, dissolution, and1.4 Problems with Bioavailability Variations

osmosis controlled systems

• delayed transit and CR systems, e.g. density altered and bioad-Bioavailability variations are manifested in terms of nonrepro-

hesive systemsducible plasma drug profiles, from one patient to another, as well

• delayed release systems, e.g. intestinal or colon release.as within the same patient from one time to another. The plasma

The following subsections discuss the opportunities whereinprofiles of a drug moiety administered as an oral dosage form

CR products can minimize variations and lead to better therapeuticfluctuate as per the properties of the drug and dosage form. The

efficacy.additional variations in the profiles, as a result of the above-

discussed factors, can lead to problems of loss of efficacy (due to2.1 Reducing Fluctuations With Continuous Release

fall of plasma levels below minimum effective level), and toxicityControlled Drug Delivery Systems

(higher peaks crossing toxic levels). In addition, specific problems

such as the development of tolerance against antibacterials, or Among the variety of CR dosage forms delivering drugs in

compliance problems due to severe adverse effects, may devel- pulsatile, delayed, timed release, and colon targeted fashion, the

op.[7] continuous CR dosage forms are by far the most common. These


106 Kaushal & Garg

dosage forms release the drug in a continuous fashion all along the

gastrointestinal tract. Belonging to this category of dosage forms

are the matrix tablets, multiparticulate systems, and the osmotic

pumps.[7] Among all these, OROS®1 systems have proven to be the

most reliable and predictable over the years, and hence are dis-

cussed as representative examples of the class of continuous

release controlled drug delivery systems.[10] The reduction in

bioavailability variabilities is mainly due to the change of rate-

limiting step from absorption to drug release. Hence, the bioavail-

ability is controlled by dosage form rather than by the physiologic

factors. Some of the examples of studies carried out with these

systems are discussed below.

Methylphenidate is used for the treatment of attention deficit

hyperactivity disorder (ADHD). The OROS® system for methyl-

phenidate HCl is an osmotic CR delivery system designed for once

daily oral administration. The pharmacokinetics of this system

were compared against sustained-release and the IR formulation.

The dose-normalized methylphenidate Cmax for the OROS®

800

700

600

500

400

300

200

100

96 120 128 136 144 152 160 168

Time after first dose (h)

Pla

sma

conc

entr

atio

n (n

mol

/L)

Day 5 Day 6 Day 7 Day 8

Conventional metoprolol tabletsMetoprolol CR/ZOKMetoprolol OROS®

Fig. 1. Mean plasma concentrations of metoprolol on days 5 through 8following once daily administration of metoprolol controlled-release/zero-order kinetics (CR/ZOK), metoprolol OROS®, and conventional (immediaterelease) metoprolol tablets (reproduced from Sandberg et al.,[13] with per-mission from Kluwer Academic/Plenum Publishers).

methylphenidate HCl system was significantly lower than for IR

and sustained release methylphenidate.[11] At the same time, the 2.2 Reduction in Metabolismbioavailability of methylphenidate from OROS® compared to the

Metabolism of the drug released from an oral system in theIR and sustained release formulations was complete.[11]

gastrointestinal tract is one of the factors affecting the ultimateIn another study with the OROS® system, for amitriptyline

bioavailability. The drugs that are metabolized to inactive metabo-hydrochloride, the mean maximal plasma amitriptyline concentra-

lites present the greatest problem since metabolism results in a losstion Cmax was lower, and the mean tmax was longer than that

of activity. Of concern here is metabolism due to the luminalassociated with the equivalent IR dose administered at night-

enzymes, and the first-pass metabolism (both metabolism in thetime.[12] The relative bioavailability of amitriptyline via OROS®

gut wall and liver).[6] The concentration of gut wall enzymes thatversus IR administration was 95%. The metabolite-to-drug ratios

belong to the category of cytochrome oxidase is variable throughafter the OROS® and IR administration were similar, suggesting

the gastrointestinal tract, with concentrations decreasing fromno change in metabolism between treatments.

proximal to distal intestine.[14] The conventional controlled drugIn yet another study, the steady-state bioavailability and day-to- delivery systems release the drugs from the system at a continuous

day variability of plasma levels were evaluated for two novel oral rate (with or without a lag time). In these systems, the position ofdrug delivery systems (OROS® and a multi-unit system) of meto- release of the drug from the system is not controlled, and aprolol and an immediate release tablet. The extended drug release substantial part of the drug is released in the lower intestine (as aand absorption observed after administration of metoprolol CR/ result of normal gastrointestinal transit). Hence, a greater percent-zero-order kinetics (ZOK) and metoprolol OROS®, resulted in age of the drug released (compared with IR oral dosage forms)similar steady-state plasma concentrations after once daily admin- from these systems is presented to a lower concentration of drugistration. Compared with the IR tablet, they produced considerably metabolizing enzymes. The bioavailability of drugs that are me-lower plasma peaks, 3- to 4-fold higher trough concentrations, 8–9 tabolized by the gut wall enzymes can, therefore, be increased by

hours longer mean residence times, and 20% lower relative bio- their incorporation into CR systems (single- or multi-layer matrix

availability.[13] Figure 1 shows the comparative plasma profiles. tablets, multiparticulate systems, OROS® system, etc.). Further-

1 The use of tradenames is for product identification purposes only and does not imply endorsement.



more, the application of a mechanism that introduces an even rious dosage forms (including a transdermal system) are given in

greater delay in the start of drug release, such as enteric coatings table I. The results demonstrate the metabolism of oxybutynin by

on the CR dosage forms, can protect the drug from a hostile gut wall enzymes, and a consequently improved bioavailability

environment in the stomach, and further enhance the bioavailabil- and reduced adverse effects by CR dosage forms.

ity. A few examples that exhibit this are discussed below. In another study, a novel once daily ‘coat-core’ formulation of

the calcium channel antagonist nisoldipine was compared againstOxybutynin is a muscarinic receptor antagonist that has beenIR or intravenous formulations.[20] The mean residence time andavailable for a number of years in its original IR formulation.apparent terminal half-life of nisoldipine in the coat-core formula-While oxybutynin IR has proven effective for the treatment oftion were significantly increased compared with administration viaoveractive bladder, its extended use can be limited by adversethe intravenous route or the oral IR formulation. At steady-state,effects, particularly dry mouth. The CR formulation of oxybuty-the coat-core formulation produced a plateau-shaped profile ofnin, based on the OROS® system, allows once daily administra-nisoldipine plasma concentrations throughout the 24-hour admin-tion. In a comparative in vivo study of the immediate and OROS®

istration interval, and the peak-trough fluctuation was reduced byforms of oxybutynin, the mean oxybutynin degree of fluctuationapproximately 4-fold, compared with the IR tablet in a twice dailywas much lower for OROS® oxybutynin chloride (78%) than forregimen. The relative bioavailability of the novel formulation wasIR oxybutynin (371%).[15] Furthermore, with OROS® oxybutyningreater by 1.5-fold compared with the IR tablet. This was attribut-chloride, mean relative bioavailability was higher (153%) fored to release of the drug in the colon where the contribution of theoxybutynin, and lower (69%) for N-desethyloxybutynin, com-gut wall to presystemic metabolism is reduced, resulting in anpared with IR oxybutynin.[16] The latter has been implicated inincrease in bioavailability compared with the stomach and smallmediating a major part of the adverse effects of oxybutyninintestine.treatment.[16] This increased bioavailability may be due to reduced

first-pass metabolism. The OROS® systems are thought to reach Yet another study compared the pharmacokinetics of intrave-

the colon within 3–5 hours after administration, where cytochrome nous, oral IR, and oral OROS® formulations of hydromor-

P450-mediated oxidation (the primary metabolic pathway for oxy- phone.[21] The mean absolute bioavailability for the 8mg OROS®

butynin) is less extensive than in the small intestine.[15] The formulation was significantly larger than for the 8mg IR formula-

comparative pharmacokinetic parameters of oxybutynin from va- tion. The CR formulation of hydromorphone produced less fluctu-

Table I. Comparative pharmacokinetic parameters of oxybutynin using different systems[17-19]

Cmax (μg/L) tmax (h) AUC0–t (μg • h/L) AUC0–∝ (μg • h/L)

Immediate release tablets (5mg)

R-oxybutynin 2.2 ± 1.7 1.0 3.8 ± 3.1 3.8 ± 3.1

R-N-desethyloxybutynin 15.5 ± 3.7 1.0 45.7 ± 17.1 62.3 ± 30.8

S-oxybutynin B 4.1 ± 0.7 0.8 5.5 ± 3.3 5.5 ± 3.3

S-N-desethyloxybutynin 10.9 ± 3.1 1.0 31.8 ± 11.7 42.2 ± 19.4

Controlled release OROS® tablets (10mg)

Oxybutynin 2.5 2.0 30 ND

N-desethyloxybutynin 43.2 2.0 39.1 ND

Transdermal system (36mg)

R-oxybutynin 1.2 ± 0.3 48.0 85.8 ± 26.4 ND

R-N-desethyloxybutynin 1.2 ± 0.5 48.0 83.9 ± 43.0 ND

S-oxybutynin 1.6 ± 0.4 48.0 121.4 ± 34.0 ND

S-N-desethyloxybutynin 1.4 ± 0.7 48.0 101.1 ± 52.6 ND

AUC = area under the concentration-time curve; Cmax = maximum plasma drug concentration after single-dose administration; ND = no data; tmax = time to

reach maximum concentration following drug administration.


108 Kaushal & Garg

ation of plasma concentrations compared with IR formulations. 2.3 Overcoming Chronopharmacokinetic Variation

The increased bioavailability from the OROS® formulation was

attributed to decreased metabolism by a first-pass effect. The temporal difference in the absorption, distribution, meta-

bolism, and elimination lead to differences in the bioavailabilityMany of the drugs are metabolized by hepatic first-pass meta-and pharmacologic response of drugs. Out of all of these, thebolism, leading to a lower bioavailability for the parent molecule.differences in absorption and metabolism can possibly be over-

A subcase of such a phenomenon could involve drugs that primari-come by use of CR dosage forms. Although a number of mechan-

ly act in the liver. The use of oral CR dosage forms could offer isms, such as passive or facilitated diffusion, active transport, anddose-sparing advantages. Lovastatin is a HMG-CoA reductase filtration through pores, etc., are involved in the absorptive pro-inhibitor indicated for lowering of cholesterol. A study was under- cess, passive diffusion is by far the most important. The differ-

ences in absorption result from differences in the perfusion, gastrictaken to compare the short-term pharmacodynamics and pharm-pH, acid secretion, motility, and gastric emptying.[23] Lipophilicacokinetics of multiple doses of lovastatin extended release (ER)drugs have been shown to be absorbed faster in the morning than

with those of lovastatin IR in patients with hypercholesterolemia.the evening.[24]

Compared with lovastatin IR, lovastatin ER produced a 3.9%A small number of studies have demonstrated that the differ-

greater reduction in low-density lipoprotein-cholesterol. The Cmaxences in the absorption process over the 24-hour period can be

values for lovastatin, lovastatin acid, and inhibitors of HMG-CoAovercome by use of oral CR dosage forms. Examples where the

reductase were lower at day 28 with lovastatin ER than with variations in the bioavailability seen with IR products was over-lovastatin IR. The AUC0–24 ratio for lovastatin was 1.91, reflect- come with CR dosage forms include preparations of nifedipine,[25]

isosorbide mononitrate,[26] and theophylline.[27] In the latter study,ing higher bioavailability of the prodrug with lovastatin ER; in

a proprietary once daily oral CR beadlet technology for theophyl-contrast, the ratios for lovastatin acid, and active and total inhibi-line was compared with a twice daily preparation. It was found thattors of HMG-CoA reductase were <1. Because lovastatin is effi-the diurnal variation associated with theophylline could be over-

ciently extracted by the liver, and because its administration income by a formulation approach. Figure 2 shows the comparative

divided doses is associated with increased efficacy, ER formula- profiles of theophylline once daily formulation, given in the morn-tion was suggested to have the potential for a dose-sparing advan- ing and evening. The observed circadian rhythm was due to thetage relative to the IR formulation in the treatment of hypercholes- slower absorption of theophylline when the body was at rest.

Similar results were reported for another CR theophylline prepara-terolemia.[22]

tion that was prepared using acrylic resins. The study concluded

that there was a lower risk of toxic plasma concentrations, or

concentrations under the therapeutic level, than with formulations

that exhibit circadian rhythm.[28]

In the case of nifedipine, IR, sustained-release, and intravenous

solution were studied in healthy volunteers and patients with

hypertension.[25] The pharmacokinetics of IR, but not sustained-

release and intravenous nifedipine, were dependent on the time of

day. IR nifedipine had a higher Cmax and shorter tmax after the

morning application compared with the evening application, and

bioavailability in the evening was reduced by about 40%.

A similar possibility of decreasing the variability seen with

metabolism (due to variations in hepatic blood flow) remains with

the use of CR products. The effects of hepatic blood flow are most

relevant for high extraction ratio drugs.[23]

12

10

9

7

5

3

2

00 5 10 15 20 25

Time (h)

Ser

um le

vel (

μg/m

L)

Administered in the morning

Administered in the evening

Fig. 2. Mean serum theophylline concentrations on day 5 in patients given900mg of a once daily, controlled release formulation in the morning orevening (reproduced from Harrison et al.,[27] with permission from JohnWiley & Sons, Inc., and the copyright© holder Wiley-Liss, Inc.)



hours post-administration, and then releases the drug at a zero

order rate for 16 hours.[31]

2.4 Gastro Retentive Systems for Site-Specific Absorption

The phenomenon of drugs being preferentially absorbed from a

specific area of the gastrointestinal tract is termed as absorption

window. The existence of the absorption window is considered to

be a rational against the development of CR dosage forms, since

the criteria of general absorption throughout the gastrointestinal

tract is considered to be a prerequisite for CR form develop-

ment.[32] The variation in the bioavailability of an IR preparation

could result from the existence of an absorption window. CR

dosage forms utilizing the principle of gastro retention have been

reported for drugs having an absorption window in the upper

gastrointestinal tract. One such study reported enhanced bioavaila-

bility of furosemide (frusemide) from a floating dosage form.[33]

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0.00 4 8 12 16 20 24 28 32 36

Time (h)

Sal

iva

theo

phyl

line

(μg/

mL)

Nonfloating CR tablets (TheoDur™) - fasting Nonfloating CR tablets (TheoDur™) - nonfastingFloating CR tablets - fastingFloating CR tablets - nonfasting

Fig. 3. Comparative plasma profiles of floating and nonfloating theophyllinecontrolled release (CR) tablets given under fasted and nonfasted states(reproduced from Desai and Bolton,[35] with permission from Kluwer Aca-demic/Plenum Publishers).

The solubility of the drug was first enhanced by preparing an

inclusion complex of furosemide with β-cyclodextrin in a 1 : 1In addition to decreasing the variability associated with chro-

proportion. The values of plasma AUC obtained with the floatingnopharmacokinetics, CR dosage forms can be formulated accord-

dosage form were about 1.8 times those of the conventional tablet.ing to the circadian need of the body in the disease condition. Similar results were obtained in another study employing bufferedExamples of diseases where chronotherapy is most desired are buoyant furosemide capsule formulations.[34]

cardiovascular complications (hypertension), cancer, arthritis, and In another study, a floating CR oral tablet containing 300mg

theophylline was compared with a conventional tablet.[35] Scin-asthma. The chronotherapy involves either changing the time oftigraphic studies of floating and nonfloating tablets, under fastingadministration or altering the release pattern of the drug from theand nonfasting conditions, showed that food significantly in-dosage form. A number of attempts have been made to preparecreased gastric retention time and tablet density did not affect

timed-release dosage forms.[29,30] The systems utilize a variety ofretention time. However, positions of floating and nonfloating

formulation strategies to provide a delayed release of the drug. Thetablets in the stomach were different. Bioavailability studies under

delayed release dose could either be IR or CR. One of the success- fasting and nonfasting conditions showed results comparable toful dosage forms for hypertension control is verapamil in a con- those of the conventional tablet. The floating tablet maintained

trolled onset ER system. The system starts to deliver the drug 5 constant theophylline levels of about 2 mg/ml for 24 hours. It was

Table II. Pharmacokinetic parameters for oxycodone hydrochloride controlled release (CR) tablet and immediate release (IR) solution (reproduced from

Benziger et al.,[37] with permission from from John Wiley & Sons, Inc., and the copyright© holder Wiley-Liss, Inc.)

Pharmacokinetic CR tablet (40mg) IR solution (20mg)

parameters fasted state fed state fasted/fed (%) fasted state fed state fasted/fed (%)

Cmax (μg/L) 18.8 17.1 92 36.7 30.3 82

AUC0–36 201 195 97 174 209 120

AUC0–∞ 203 4.8 97 174 209 120

tmax (h) 3.1 4.5 159 1.1 1.4 120

AUC = area under the concentration-time curve; Cmax = maximum plasma drug concentration after single-dose administration; tmax = time to reach

maximum concentration following drug administration.


110 Kaushal & Garg

system employed and the drug meant to be delivered. Some of the

examples where the effect of food on the bioavailability of CR

products was investigated are given below.

The effects of a high-fat meal on the bioavailability of oxyco-

done hydrochloride, administered as a 40mg CR tablet or a 20mg

IR solution, were evaluated. There was no significant food effect

with CR oxycodone, as judged by the analysis of AUC0–∞ and

Cmax values under fed and fasted conditions. However, for the IR

solution, both the bioavailability and peak plasma oxycodone

concentration were significantly altered by consumption of the

high-fat meal.[37] Table II summarizes these results.

100

80

60

40

20

00 5 10 15 20 25

Time (h)

nmol

/L

Extended release matrix tabletProcardia XL®

Fig. 4. Mean nifedipine plasma concentrations for extended release matrixtablet and Procardia XL® at steady state after administration under fastingconditions (reproduced from Abrahamsson et al.,[38] with permission fromElsevier Science). In another study on nifedipine, the hydrophilic matrix tablet

(ER) and a push-pull osmotic pump tablet (Procardia XL®) wereconcluded that the floating theophylline tablet floats in the stom-

compared for bioavailability with and without food.[38] Althoughach and provides a gradual release profile (figure 3).

both the ER and XL formulations provided almost constant drug

delivery over 24 hours after administration under fasting condi-2.5 Food Induced Variability and Controlled

tions, and were found to be bioequivalent, food significantlyRelease Products

increased the AUC for ER. The rate of absorption was increased to

a higher degree for ER than XL, as indicated by a Cmax that wasThe administration of food can result in marked differences inalmost twice as high for ER compared with XL. This finding wasthe bioavailability of orally administered drug products. This isshown to be related to an increased tablet-erosion rate for ER,also considered by the regulatory agencies, which recommend aleading to more rapid drug release.[38] Figure 4 and figure 5 showfood effect study of orally administered products. Food, compared

with fasting conditions, can change the bioavailability of a drug

and can influence the bioequivalence between test and reference

products. Food effects on bioavailability can have clinically sig-

nificant consequences. Food can alter bioavailability by a change

in the following:

• delay of gastric emptying

• stimulation of bile flow

• changes in gastrointestinal pH

• increase in blood flow

• changes in luminal metabolism of a drug substance

• physical or chemical interactions with a dosage form or drug

substance.

Depending on the drug substance, the drug product, and the

characteristics of the meal taken, a more or less pronounced effect

may be observed. Drug absorption may be decreased, delayed,

increased, or remain unaffected upon taking with food.[36] The CR

dosage forms normally contain a greater amount of the drug

loaded on to a single dose, and a dose dump could result in

toxicity. One of the objectives of a food study for CR products is to

rule out the possibility of dose dumping. The CR products differ

with regard to the effect the food has on them, depending upon the

1.0

0.8

0.6

0.4

0.2

0.00 10 20 30 40

Time (h)

Frac

tion

abso

rbed

ER fed-study IIER fed-study IIIER fasting-study IIER fasting-study IIIProcardia XL®-fed

Fig. 5. Mean absorption time profile of nifedipine for ER and Procardia XL®

after administration with food, and ER without food (reproduced fromAbrahamsson et al.,[38] with permission from Elsevier Science). ER = ex-tended release.



the nifedipine plasma profiles for ER and XL formulations under indiscriminately used for the above purpose. In many cases they

fasted and fed conditions. can themselves be a cause of decreased or variable bioavailability

due to the variable nature of the gastrointestinal tract with respectIn two independent studies with different CR systems forto the metabolizing enzymes, permeability, and area available foroxybutynin delivery, Lukkari and co workers[39] observed that theabsorption. It is important, therefore, to understand the gastroin-food did not change the AUC of oxybutynin, but increased thetestinal physiology, and design the CR systems accordingly to turnAUC of N-desethyloxybutynin (the metabolite) by about 20%.this limitation to our advantage.The Cmax values for oxybutynin and N-desethyloxybutynin were

2-fold higher when the drug was administered after breakfast,

compared with the fasting state. On the other hand, Gupta and AcknowledgementsSathyan[15] reported that the bioavailability of oxybutynin from the

The authors gratefully acknowledge CSIR, New Delhi, for providingOROS® system was unaffected when taken with food.funding for research project no. 01(1712)/01/EMR-II. The views expressed by

A new dosage form of carbamazepine was developed consist- the authors do not necessarily reflect the views of CSIR. The authors have noing of three different types of pellets (IR, CR, and enteric release). conflicts of interest that are directly relevant to the content of this manuscript.

To explore the influence of food on the absorption of carbamaze-

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Minimizing bioavailability variations with oral controlled release formulations