Methods For Enhancement of Bioavailability

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Chapter: Biopharmaceutics and Pharmacokinetics : Bioavailability and Bioequivalence

As far as the definition of bioavailability is concerned, a drug with poor bioavailability is the one with


As far as the definition of bioavailability is concerned, a drug with poor bioavailability is the one with -

·            Poor aqueous solubility and/or slow dissolution rate in biological fluids.

·            Poor permeability through the biomembrane owing to inadequate partition coefficient or lipophilicity or large molecular size such as that of protein or peptide drugs such as insulin.

Both solubility as well as permeability of a drug depends upon its physicochemical characteristics as discussed in Chapter 2.

Based on the intestinal permeability and solubility of drugs, Amidon et al developed Biopharmaceutics Classification System (BCS) which classifies the drugs into one of the 4 groups as shown in the table 11.8. The table also shows the approaches employed to overcome formulation challenges in each class of drugs.

TABLE 11.8.

The Biopharmaceutics Classification System for Drugs

Class V drugs: are those that are metabolically or chemically unstable thus limiting their bioavailability. The various approaches to overcome these problems are aimed at enhancing their stability by use of methods such as –

·            Prodrug design.

·            Enteric coating (protection from stomach acid).

·            Enzyme inhibition or lymphatic delivery (to prevent presystemic metabolism).

·            Lipid technologies.

Class I drugs (high solubility/high permeability) are well absorbed orally since they have neither solubility nor permeability limitation.

Class II drugs (low solubility/high permeability) show variable absorption owing to solubility limitation.

Class III drugs (high solubility/low permeability) also show variable absorption owing to permeability limitation.

Class IV drugs (low solubility/low permeability) are poorly absorbed orally owing to both solubility and permeability limitations.

Class V drugs – are the ones that do not come under the purview of BCS classification but includes drugs whose absorption is limited owing to their poor stability in GI milieu –

·            Gastric instability (omeprazole).

·            Complexation in GI lumen.

·            First pass metabolism – by intestinal enzymes (peptide drugs), hepatic enzymes, microbial enzymes, etc.

The BCS classification of a drug depends upon its three key parameters that control absorption – solubility, dissolution rate and permeability that correlates with three respective dimensionless parameters – dose number, dissolution number and absorption number (see table 11.9 and figure 11.4).

TABLE 11.9.

Drug Properties that Determine BCS Classification

Fig. 11.4 Classification of Drugs on BCS basis

Solubility Determination – Methods for determining drug solubility are

·           pH-solubility profile of test drug in aqueous media with a pH range of 1 to 7.5.

·           Shake-flask or titration method.

Permeability Determination The methods are further classified as

Determination of extent of absorption in humans:

·           Mass-balance pharmacokinetic studies.

·           Absolute bioavailability studies.

Intestinal permeability methods:

·           In vivo intestinal perfusions studies in humans.

·           In vivo or in situ intestinal perfusion studies in animals.

·           In vitro permeation experiments with excised human or animal intestinal tissue.

·           In vitro permeation experiments across epithelial cell monolayers.

Dissolution Determination – Methods for determining drug product dissolution are USP apparatus I (basket) at 100 rpm or USP apparatus II (paddle) at 50 rpm. Dissolution media (900 ml): 0.1 N HCl or simulated gastric fluid, pH 4.5 buffer, and pH 6.8 buffer or simulated intestinal fluid.

Compare dissolution profiles of test and reference products using a similarity factor (f2).

Besides identifying the challenges in formulation design, the BCS is designed to guide decisions with respect to in vitro and in vivo correlations (IVIVC).

The three conceptual approaches in overcoming the bioavailability problems of drugs are:

1. The Pharmaceutical Approach which involves modification of formulation, manufacturing process or the physicochemical properties of the drug without changing the chemical structure.

2. The Pharmacokinetic Approach in which the pharmacokinetics of the drug is altered by modifying its chemical structure. This approach is further divided into two categories –

·            Development of new chemical entity (NCE) with desirable features

·            Prodrug design.

3. The Biological Approach whereby the route of drug administration may be changed such as changing from oral to parenteral route.

The second approach of chemical structure modification has a number of drawbacks of being very expensive and time consuming, requires repetition of clinical studies and a long time for regulatory approval. Moreover, the new chemical entity may suffer from another pharmacokinetic disorder or bear the risk of precipitating adverse effects. Only the pharmaceutical approach will be dealt herewith.

The pharmaceutical attempts, whether optimising the formulation, manufacturing process or physicochemical properties of the drug, are mainly aimed at altering the biopharmaceutic properties of drug in one of the several ways

A. Enhancement of drug solubility or dissolution rate, as it is the major rate-limiting step in the absorption of most drugs. This approach applies to class II drugs according to BCS.

B. Enhancement of drug permeability. This approach applies to class III drugs according to BCS.

C. Enhancement of drug stability. This approach applies to class V drugs according to BCS.

D. Enhancement of gastrointestinal retention. This approach can apply to class II, III or V drugs.

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