Lipid based formulations have several advantages. They increases the effective luminal drug solubility, alters or reduces the gastric transit there by slowing delivery to the absorptive area and exposes the drug to dissolution medium for longer period of time
Oral administration of drug has many advantages for chronic therapy. Homolipids and heterolipids can be selected as excipients for oral drug delivery system of lipophilic drugs. Lipid based formulations can reduce the limitation of slow and incomplete dissolution of poorly water soluble drugs and facilitates the formation of solubilized phases from which absorption may occur.
Lipids are the functional units that play fundamental role in architecture and functionality of all living cells and are present most abundantly in foodstuffs. It is one of the three main classes of foods along with carbohydrate and proteins. They are responsible for storing energy that animals do not immediately need. It is a natural substance having molecular structure in one chain of at least ten carbon atoms.
The lipids are of physiological importance for human and have four major functions like they serve as structural components of biological membrane, provide energy reserves predominately in the form of triacylglycerols. Both lipids and lipid derivatives serve as a source of vitamins and hormones and lastly the lipophilic bile acids aid in lipid solubilization.
For oral drug delivery systems consisting of lipid as a vehicle mainly consist of a drug dissolved in a mixture of one or more excipients which may be triglycerides oil, partial glycerides, surfactants or co-surfactants.
Lipid based formulations have several advantages. They increases the effective luminal drug solubility, alters or reduces the gastric transit there by slowing delivery to the absorptive area and exposes the drug to dissolution medium for longer period of time. They change the physiological and biochemical barrier function of GIT. The examples are surfactants and lipids, which are known to have permeability enhancing properties. For highly lipophilic drugs lipids may enhance the lymphatic transport by stimulating the intestinal lymphatic system.
The physical/chemical characteristics of lipid based systems are highly complex because of the existence of a variety of lipid assembly morphologies. To simplify the vast group of heteroclites molecule a lipid nomenclature was proposed by International Union of Pure and Applied Biochemical nomenclature in 1976 into three major classes.
Simple or neutral lipids
They contain one or two different types of compounds generally neutral except for fatty acid and have apolar properties. The examples are acylglycerols, aldehydes, amino group containing lipids, amino alcohols and carotenoids.
Complex lipids
These complex lipids are polar in nature and can be subdivided into three groups namely phospholipids, glycolipids and lipoamino acids. Glycolipids may be of different types like glycoglycerolipids, glycosphignolipids, lipopolysaccharides, sterylglycolipids and glycosides of fatty acid or alcohol.
Proteolipids (fatty acylated proteins)
This global classification is fairly comprehensive but remains only a guide. One way of classifying lipids is based on their chemical composition as homolipids, heterolipids and complex lipids.
Homolipids are the esters of fatty acids with various alcohols.These include cerides (waxes), glycerides (fats, oils) and steroids. Triacylglycerols are naturally occurring fatty acids both from plant and animal origin are in natural foods like milk, meat, seeds oil from different families like Ranunculaceae and some modified dietary fats like margarine. Marine lipids obtained from fish oils are widely used as pharmaceutical excipients.
Complex lipids: This class of lipids mainly comprises of lipoproteins. Lipoproteins are a complex of lipid and protein. They are responsible for the transport of cholesterol and other lipids through systemic circulation.
Formulation approaches
Lipid based formulations recently have gained considerable interest in overcoming the absorption limitations of poorly water soluble drugs. Bioavailability of lipophilic drugs when administered by oral route is considerably low, due to their poor solubility
or dissolution in the lumen of gastrointestinal tract.
Classification of lipid delivery systems
Lipid solutions: Lipid solutions are those in which the drug is dissolved in digestible oil, usually a vegetable oil or medium chain triglycerols (fractionated coconut oil). These are nontoxic. This system is mainly used for oil soluble vitamins (A and D).
Self-emulsifying drug delivery system (SEDDS): This system has been described as isotropic mixture of natural or synthetic oils, solid or liquid surfactant, solvents or co-solvents. The ability of such system is to form a fine oil-in-water (o/w) emulsion upon mild agitation by the motility of gastrointestinal tract following dilution by aqueous phase. This makes this system a good candidate for oral drug delivery system.
For lipophilic drugs, which show dissolution rate limited absorption this system may offer an improvement in the rate and extent of absorption producing better blood-time profile. This type of formulation is likely to retain its solvent capacity after drug dispersion. At present there are four products as SEDDS, Sandimmune and Sandimmune Neoral (cyclosporine A), Norvir (ritonavir), and Fortovase (saquinavir) on pharmaceutical market.
Liposomes
Liposomes are spherical lipid bilayers composed of amphilic phospholipids ranging from 50 nm to 1000 nm in diameter. It may be used as a convenient delivery vehicle for biologically active molecules. They are easy to form and their properties for particular purpose can be adjusted.
The main advantages of using liposomes are that they can protect the drug from degradation, increase in circulation time and the possibility to achieve partial or total selectivity, which increases drug potency, eliminates side effects and reduces dose.
Potential carriers
There are abundant numbers of lipid based carriers obtained from natural sources like vegetable oil, animal fats and oils that can be used for oral drug delivery system. A number of vegetable oils, world wide, have been in use in pharmaceutical industries for a long time like olive oil, seasome oil, cotton seed oil etc. Vegetable oils used for industrial purpose or as cooking oil are not fit for human consumption without further processing. Vegetable oils are obtained by extraction and then they are subjected to hydrogenation or refining.
Carriers used for oral drug delivery is mainly the medium chain triglycerides as they are free from any pharmacological action on their own. They are hydrolyzed in the lumen of gastrointestinal tract and absorbed as free fatty acids. Cyclosporin, an immune suppressant drug is absorbed significantly from medium chain triglycerides. For sustained release unsaturated monoacylglycerols can be used as a potential carrier for amphiphillic drug. Medium chain fatty acid esters act as an emulsifier in microemulsion system due to its tensoactive properties.
Biopharmaceutical issues and formulation design
The effect of lipid vehicle on lipophilic drug pharmacokinetic parameter may be discussed with respect to lipid composition and carrier system. The effect of lipids on the bioavailability of orally administered drug is highly complex due to numerous mechanisms by which the lipid can alter the biopharmaceutical characteristic of the drug.
Dose of the drug
The required dose and fate of the drug after administration of the system to the gut are the factors to be considered while formulating the dosage form. Dose of the drug will affect the solvent capacity of the lipid vehicle. In many cases the choice of formulation will be limited by the solvent capacity.
Role of lipolysis
Dietary triglycerides are more rapidly digested in the intestine by the enzyme pancreatic lipase. Digestion of lipids has profound effect on the state of dispersion of lipid formulations.
Most of the drug exhibit poor aqueous solubility and have formulation problems. So the pharmacopoeial lipids can be used as carriers for lipophilic drugs. Large number of new phospholipids can have industrial application in pharmaceutical dosage forms. The various lipid delivery systems can overcome the formulation difficulties expected
in lipophilic drugs.
(The authors are with Department of Pharmaceutics, Al-Ameen College of Pharmacy, Bangalore)