On several occasions, the rate-limiting step in drug absorption is transport through the intestinal epithelium owing to poor permeability.
BIOAVAILABILITY ENHANCEMENT THROUGH ENHANCEMENT OF DRUG PERMEABILITY
ACROSS BIOMEMBRANE
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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