Download Oral lipid-based drug delivery systems

Oral lipid-based drug delivery systems
• Most of the newly discovered chemical entities are of high
molecular weight and belong to biopharmaceutical classification
system (BCS) – II, with poor aqueous solubility and limited the
bioavailability of orally a dministered drugs.
• This poor solubility not only gives low oral bioavailability but also
leads to high inter- and intra-subject variability and lack of dose
proportionality
• Some of these drugs have enhanced bioavailability when
coadministered along with food
• Lipids have gained much interest as carriers for the delivery of drugs
with poor water solubility
• The availability of novel lipid excipients with acceptable regulatory
and safety profiles coupled with their ability to enhance oral
bioavailability has helped in the development of lipid based
formulations as a means for drug delivery.
• The bioavailability of some of the drugs is increased when coadministered
with food. However, many drug molecules have negligible interaction with
food. BCS class I drugs are not affected by the presence or absence of food, but
class II drugs have an altered absorption when co-administered with food. The
reason for such enhanced bioavailability might be attributed to solubility,
permeability and inhibition of efflux transporters in the presence of food.
Some of the drugs which show enhanced bioavailability when administered
along with food are griseofulvin, halofantrine , danazol, troglitazone and
atovaquone. A guidance document entitled “Food-Effect Bioavailability and Fed
Bioequivalence” was issued by FDA in December 2002. The US FDA
recommended high fat meals for food-effect studies because such fatty meals
(800–1000 cal, 50%–65% fat, 25%–30% carbohydrates and 15%–20% proteins)
affect GI physiology and maximize drug transfer into the systemic circulation.
• In particular, it is the lipid component of the food that plays a vital role in the
absorption of lipophilic drugs, leading to enhanced oral bioavailability. This
can be explained by the ability of a high fat meal to stimulate biliary and
pancreatic secretions, to decrease metabolism and efflux activity, to increase
intestinal wall permeability, and to a prolongation of gastrointestinal tract
(GIT)
• A water-insoluble drug can be formulated as a lipid-based
formulation when the drug itself is an oil-like substance (e.g.,
tocopherol nicotinate), or when conventional formulation
approaches like granulation or soluble liquids in capsules do not
enhance the oral bioavailability
 Lipid-based drug delivery systems (LBDDS)
A variety of lipid-based systems composed of simple oil
solutions to complex mixtures of oils, cosolvents, surfactants
and co-surfactants can be obtained based on the type of
excipients and formulation variables.
Indeed, these systems can be filled into hard gelatin capsule
or converted to solid intermediates (powders, granules and
pellets) by various techniques and can be filled in hard
gelatin capsules or can be compressed into tablets after
blending with suitable tableting excipient. For example,
liquisolid technique has shown promise for
improved dissolution rate of poorly water-soluble drugs. The
liquisolid technique is a novel concept, where a liquid may
be transformed into a free flowing, readily compressible,
and apparently dry powder by simple physical blending with
selected carrier, such as Avicel, and coating material, such as
colloidal silica. The liquid mixed into the porous carrier
material. As the carrier is saturated with liquid, a liquid layer
is formed on the particle surface which is instantly adsorbed
by the fine coating particles, upon its addition with further
mixing.
Drug absorption
A. Digestion: After oral administration of lipid-based , gastric lipase initiates the
digestion of exogenous dietary triglyceride (TG) and formulation TG.
Simultaneously, the mechanical mixing (propulsion, grinding and retropulsion) of
the stomach facilitates formation of a crude emulsion (comprised of aqueous
gastric fluid and lipid digestion products). Later in the small intestine, TG is
broken down to diglyceride, monoglyceride and fatty acids by pancreatic lipase
together with its cofactor colipase, acting primarily at the sn-1 and sn-3 positions
of TG to produce 2-monoglyceride and free fatty acid.
Pancreatic phospholipase A2 digests the formulation-derived or biliary-derived
phospholipids (PL) by hydrolyzing at the sn-2 position of PL to yield
lysophosphatidylcholine and fatty acid. The presence of exogenous lipids in the
small intestine stimulates the secretion of endogenous biliary lipids from the gall
bladder, including bile salt (BS), PL and cholesterol. Previously formed
monoglycerides, fatty acids, and lysophospholipid (products of lipid digestion)
are subsequently incorporated into a series of colloidal structures, including
micelles and unilamellar and multilamellar vesicles in the presence of bile salts.
The solubilization and absorptive capacity of the small intestine for lipid
digestion products and drugs (D) is significantly enhanced due to these formed
lipid metabolites.
• The hydrophilic exterior surface of the micelles, facilitates rapid micellar
diffusion across the aqueous GIT fluid to the intestinal membrane.
• In the microclimate adjacent to the intestinal membrane, the pH is lower
than that in the intestinal lumen. This promotes demicelization at the
membrane and local release of the lipolytic products and drug at the
membrane to supersaturate the intestinal membrane. Supersaturation cause
rapid absorption by passive diffusion into the enrerocytes .
 Once inside the enterocyte, fatty acids and monoglyceride are
transported into the endoplasmic reticulum, where they are used to
synthesize triglyeride. Beginning in the endoplasmic reticulum and
continuing in the Golgi, triglyceride is packaged with cholesterol,
lipoproteins and other lipids into particles called chylomicrons.
 Instead of being absorbed directly into capillary blood, chylomicrons
are transported first into the lymphatic vessel that penetrates into each
villus. Chylomicron-rich lymph then drains into the system lymphatic
system, which rapidly flows into blood. Blood-borne chylomicrons are
rapidly disassembled and their constitutent lipids utilized throughout
the body.
 Some of the advantages of lymphatic transport of drug are avoidance
of first-pass metabolism and targeting of specific diseases which are
known to spread via lymphatics, such as certain lymphomas and HIV.
Lipid-based drug delivery systems (LBDDS)
A LBDDS is typically composed of lipids and surfactants, and may also
contain a hydrophilic co-solvent. According to the lipid formulation
classification system (LFCS), these systems are divided into four groups (I–
IV), depending on their composition and the possible influence of dilution
and digestion on their ability to prevent drug precipitation.
Class I systems: include simple oil solutions without surfactants, containing
only mono-, di-, and/or tri-glycerides.
Class II: contain lipophilic surfactants in addition to the oil phase in order to
increase the solubilization capacity of the systems for incorporated drugs,
and to facilitate the stability of the emulsion formed upon dilution. These
LBDDS are known as self-emulsifying drug delivery systems (SEDDS).
Class III : The addition of hydrophilic components (surfactants and/or cosolvents) to the oil phase of class II creates self-microemulsifying drug
delivery systems (SMEDDS), which belong to Class III systems.
Class IV: Representatives of the most hydrophilic group, Class IV, are
systems that are only composed of surfactants and hydrophilic co-solvents,
which form a colloidal micellar dispersion upon dilution with aqueous
media
Triglycerides
The most common excipients used in lipid based drug delivery are triglyceride vegetable
oils. This is one class of lipid which does not present any safety issues, since they are
fully digested and absorbed. A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is
an ester derived from glycerol and three fatty acids.
Example of an unsaturated fat triglyceride . Left part: glycerol; right part, from top to
bottom: palmitic acid, oleic acid, alpha-linolenic acid.
Triglycerides can be further classified as long chain triglycerides (LCT), medium chain
triglycerides (MCT) and short chain triglycerides (SCT). The MCTs in coconut oil are
saturated fats that range in length from 6 to 12 carbon chains. In contrast, the long
chain triglycerides (LCTs) found in most other foods (such as soybean and safflower oils)
are 18 to 24 carbons long. The LCTs are not only the most abundant fats found in
nature, they are also the form of storage fat in our bodies as well.
MCTs passively diffuse from the GI tract to the portal system (longer fatty acids are
absorbed into the lymphatic system) without requirement for modification like longchain fatty acids or very-long-chain fatty acids.
MCT have a higher solvent capacity for drugs than LCT and are less prone to oxidation
Diglycerides
A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains
covalently bonded to a glycerol molecule through ester linkages. Two possible forms
exist, 1,2-diacylglycerols and 1,3-diacylglycerols.
Monoglycerides
Monoglycerides (also: acylglycerols or monoacylglycerols) are a class of
glycerides which are composed of a molecule of glycerol linked to a fatty
acid via an ester bond. As glycerol contains both primary and secondary
alcohol groups two different types of monoglycerides may be formed; 1monoacylglycerols where the fatty acid is attached to a primary alcohol, or a
2-monoacylglycerols where the fatty acid is attached to the secondary
alcohol
Monolaurin (Lauric acid ester)
Glycerol monostearate
Water-insoluble surfactants
A group of lipid excipients with intermediate hydrophiliclipophilic balance (HLB
of 8–12) that adsorb at oil–water interfaces are available.
These substances can form micelles but are unable to self-emulsify due to their
insufficiently hydrophilic nature.
Sorbitan esters (also known as Spans) are nonionic surfactants that are
theesterfication of sorbitan ring with fatty acid (s)
Sorbitan monostearate
(Span 60)
Sorbitan monolaurate (Span 20)
Sorbitan tristearate (Span 65)
Water-soluble surfactants
These are the most commonly used surfactants for the formulation of selfemulsifying drug delivery systems. The materials with HLB value of approximately
12 or greater can form micellar solutions at low concentrations by dissolving in
pure water above
their critical micellar concentration. They have high tendency for self
emulsefication.
Polysorbates (Tweens): polysorbate-type nonionic surfactant formed by the
ethoxylation of sorbitan before the addition of fatty acid (s) .
Polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate)
Polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate)
Polysorbate 60 (polyoxyethylene (20) sorbitan monostearate)
Polysorbate 80 (polyoxyethylene (20) sorbitan monooleate)
Water-soluble surfactants
Cremophor : is pegylated (ethoxylated) castor oil (glycerol triricinoleate) or
hydrogenated castor oil and is a complex mixture of relatively hydrophobic
and hydrophilic molecules (glycerol POE triricinoleate). Cremophors are
synthesized by reacting either castor oil or hydrogenated castor oil with
varying amounts of ethylene oxide
Ricinoleic acid
Cremophor is a formulation vehicle used for various poorly-water
soluble drugs, including the anticancer agent paclitaxel (Taxol). In
contrast to earlier reports, CrEL is not an inert vehicle, but exerts a
range of biological effects, some of which have important clinical
implications. Its use has been associated with severe
anaphylactoid hypersensitivity reactions, hyperlipidaemia,
abnormal lipoprotein patterns, aggregation of erythrocytes and
peripheral neuropathy.
Alternatively, paclitaxel was formulated as bovine serum albumin
nanoparticles, BSA (the drug is dispersed in the matrix of the
nanoparticles). This was marketed under the trade name
Abraxane, in which NO cosolvent or surfactant is used.
Polyglycolyzed glycerides
They are non-ionic surfactants generally used to formulate water-insoluble
drugs in lipid-based formulations such as self-emulsifying drug delivery systems
(SEDDS) in order to improve oral bioavailability.
Mono- and di-fatty acid esters of PEG
TPGS
The micelle-forming molecule d-α-tocopherol polyethylene glycol 1000 succinate (TPGS)
was first discovered in 1950 and “it has been recognized as an effective oral absorption
enhancer for improving the bioavailability of poorly absorbed drugs and as a vehicle for
lipid-based drug delivery. TPGS is also a water-soluble source of the water-insoluble oil
Vitamin E. The HIV protease inhibitor, amprenavir, is poorly water soluble and is
solubilized in a combination of ∼23% TPGS, ∼60% PEG 400, and ∼5% propylene.
TPGS forms micelles at concentrations  0.2 mg/ml in water and improves the
aqueous solubility of amprenavir from 36 μg/ml to 720 μg/ml. It was also shown, by
directional transport through Caco-2 cell monolayers, that TPGS is a potent inhibitor of
an active efflux even at concentrations 10-fold below the critical micelle concentration,
suggesting that monomeric TPGS is capable of inhibiting the efflux mechanism.
Therefore, TPGS not only improves in vivo performance by solubility enhancing
micelle formation, but also by increasing the overall intestinal permeability via
inhibiting an efflux mechanism.
Poloxamers or Pluronics
Poloxamers or Pluronics are nonionic triblock copolymers
composed of a central hydrophobic chain of polyoxypropylene
(poly(propylene oxide)) flanked by two hydrophilic chains of
polyoxyethylene (poly(ethylene oxide)).
All poloxamers have similar chemical structures but with different
molecular weights and composition of the hydrophilic PEO block (a)
and hydrophobic PPO block (b). Two of the most commonly used
poloxamers are poloxamer 188 (a=80, b=27) with molecular weight
ranging from 7680 to 9510 Da, and poloxamer 407 (a=101, b=56)
with molecular weight ranging from 9840 to 14600 Da.
Cosolvents
In order to enhance the solubilization process, most marketed
drug products use cosolvents. The popular cosolvents used
include ethanol, glycerol, propylene glycol and polyethylene
glycols (PEG)-400. The reason for their use can be attributed to
an increase in the solvent capacity of the formulation for drugs
and to aid the dispersion of systems which contain a high
proportion of water soluble surfactants. However, there are
several practical limits related to these cosolvents, including
precipitation of the solubilized drug from the solvent due to
loss of the solvent capacity following dilution, immiscibility of
some cosolvents with oils, and incompatibilities of low
molecular weight solvents with capsule shells
Antioxidants
In order to protect the formulation from oxidation, various
lipid soluble antioxidants such as α-tocopherol, β-carotene,
propyl gallate, butylated hydroxyl toluene (BHT) or butylated
hydroxyanisole (BHA) can be used.