Bioavailability Enhancement Through Enhancement of Drug Permeability Across Biomembrane

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Chapter: Biopharmaceutics and Pharmacokinetics : Bioavailability and Bioequivalence

On several occasions, the rate-limiting step in drug absorption is transport through the intestinal epithelium owing to poor permeability.


On several occasions, the rate-limiting step in drug absorption is transport through the intestinal epithelium owing to poor permeability. Several approaches besides the use of lipophilic prodrugs that increase the drug permeation rate are discussed below.


1. Lipid Technologies: With an increase in the number of emerging hydrophobic drugs, several lipid-based formulations have been designed to improve their bioavailability by a combination of various mechanisms briefly summarized as follows:

Physicochemical—Enhanced dissolution and solubility.

Physiological—potential mechanisms include –

·           Enhancement of effective luminal solubility by stimulation of secretion of bile salts, endogenous biliary lipids including phospholipids and cholesterol which together form mixed micelles and facilitate GI solubilization of drug.

·           Reduction in gastric emptying rate thereby increasing the time available for dissolution and absorption.

·           Increase in intestinal membrane permeability.

·           Decreased intestinal blood flow.

·           Decreased luminal degradation.

·           Increased uptake from the intestinal lumen into the lymphatic system (and a reduction in first-pass hepatic and GI metabolism).

The various lipid-based dosage forms include – lipid solutions and suspensions, micelle solubilization, coarse emulsions, microemulsions, multiple emulsions, self-emulsifying drug delivery systems (SEDDS), self-microemulsifying drug delivery systems (SMEDDS), nanoparticles and liposomes.

The reasons for the increasing interest in lipid-based systems are due to the several advantages they offer and include:

Physicochemical advantages: such as

·            Solubilisation of drugs with low aqueous solubility

·            Stabilisation of labile drugs against hydrolysis or oxidation.

Pharmaceutical advantages: such as

·            Better characterization of lipidic excipients

·            Formulation versatility and the choice of different drug delivery systems

·            Opportunity for formulation as sustained release product.

Pharmacokinetic advantages: such as

·            Improved understanding of the manner in which lipids enhance oral bioavailability

·            Reduced plasma profile variability

·            Potential for drug targeting applications.

Pharmacodynamic advantages: such as

·            Reduced toxicity

·            Consistency in drug response.

a. Lipid solutions and suspensions: Some lipophilic drugs such as steroids have appreciable solubility in triacylglycerols alone. It is therefore comparatively straightforward to administer the drug in an oily liquid (e.g. encapsulated) and thereby achieve satisfactory absorption. One disadvantage of this formulation approach, however, is that oil alone rarely provides the solubilizing power to dissolve the required dose in a reasonable quantity of oil. This limits the option of using a simple drug/oil formulation system.

b. Coarse emulsions, microemulsions, SEDDS and SMEDDS: The ability of oil to accommodate a hydrophobic drug in solution can be improved by the addition of surfactants. The surfactants also perform the function of dispersing the liquid vehicle on dilution in gastrointestinal fluid. Hence, the drug is present in fine droplets of the oil/surfactants mixture which spread readily in the gastro-intestinal tract. Self-emulsifying/microemulsifying systems are formed using an oily vehicle (or a mixture of a hydrophilic phase and a lipophilic phase) a surfactant with a high HLB and if required, a co-surfactant. Unlike emulsions, the resultant liquid is almost clear. These pre-concentrates form spontaneously an emulsion/microemulsion in aqueous media (e.g. gastro-intestinal tract).

c. Solid lipid nanoparticles: To overcome the disadvantages associated with the liquid state of the oil droplets, the liquid lipid is replaced by a solid lipid leading to the formation of solid lipid nanoparticles. In contrast to emulsions, the particles consist of a solid core made from solid lipids. They are characterized by a mean diameter between approx. 100 to 1000 nm. There are two basic production techniques for solid lipid nanoparticles –

·           Homogenization of melted lipids at elevated temperature, and

·           Homogenization of a suspension of solid lipids at or below room temperature.

d. D, Liposomes: Liposomes are broadly defined as lipid bilayers surrounding an aqueous space. Liposoluble drugs can be embedded in the ―fatty‖ regions, while hydrophilic substances are held in the aqueous internal spaces of these globular vesicles.


2. Ion Pairing: The ion pairing approach involves co-administration of a hydrophilic or polar drug with a suitable lipophilic counterion, which consequently improves the partitioning of the resultant ion-pair (relatively more lipophilic) into the intestinal membrane. In fact, the approach seems to increase the oral bioavailability of ionizable drugs, such as atenolol, by approximately 2-fold. However, it is important that a counterion possess high lipophilicity, sufficient aqueous solubility, physiological compatibility, and metabolic stability.


3. Penetration Enhancers: Compounds which facilitate the transport of drugs across the biomembrane are called as penetration/permeation enhancers or promoters. This method is used mainly in cases of hydrophilic drugs which are expected to have difficulty in penetrating the lipid structure of the biomembrane. Penetration enhancers act interaction of its lipid part with the polar component of membrane phospholipids.

Penetration enhancers can be divided into three categories –

1. Substances that act very quickly have a strong effect and cause injury to the membrane (which is reversible), e.g. fatty acids such as oleic, linoleic and arachidonic and their monoglycerides.

2. Substances that act quickly, cause temporary injury but have average activity, e.g. salicylates and certain bile salts.

3. Substances having average to strong activity but cause sustained histological changes, e.g. SLS, EDTA and citric acid.

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