ROLE OF LIPIDS IN DRUG DELIVERY SYSTEM In our daily life we usually have 60% of lipids as our diet, and due to the similar nature of the biological system with the intake the lipidic food easily finds its way to the different body parts. What if this concept is applied to the drug delivery. What are lipids? The lipids are a heterogeneous group of compounds, including fats, oils, steroids, waxes, and related compounds, which are related more by their physical than by their chemical properties. They have the common property of being (1) relatively insoluble in water and (2) soluble in nonpolar solvents such as ether and chloroform.(1) Classification of lipids(1) ? Based o the composition of the lipids they are classified into Simple or Complex lipids. 1. Simple lipids: Esters of fatty acids with various alcohols a. Fats: Esters of fatty acids with glycerol. Oils are fats in the liquid state. b. Waxes: Esters of fatty acids with higher molecular weight monohydric alcohols. Cetyl alcohol is mostly used as alcohol here. 2. Complex lipids: Esters of fatty acids containing groups in addition to an alcohol and a fatty acid. a. Phospholipids: Lipids containing, in addition to fatty acids and an alcohol, a phosphoric acid residue. They frequently have nitrogen containing bases and other substituent's, eg, in glycerophospholipids the alcohol is glycerol and in sphingophospholipids the alcohol is sphingosine. b. Glycolipids (glycosphingolipids): Lipids containing a fatty acid, sphingosine, and carbohydrate. c. Other complex lipids: Lipids such as sulfolipids and aminolipids. Lipoproteins may also be placed in this category. 3. Precursor and derived lipids: These include fatty acids, glycerol, steroids, other alcohols, fatty aldehydes, and ketone bodies , hydrocarbons, lipid-soluble vitamins, and hormones. Because they are uncharged, acylglycerols (glycerides), cholesterol, and cholesteryl esters are termed neutral lipids. ? Based on the saturation of the lipid they are of two types 1) Saturated lipids: do not contain double bond Eg: butytric acid, valaric acid, capric acid, caproic acid, caprylic acid, lauric acid, myristic acid, palmitic acid, steric acid, arachadic acid, behlic acid, lignoceric acid. 2) Unsaturated lipids: contain a double bond in the moliecule Eg: palmitoleic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid. Physiological lipids: Most of the cells in our body have lipids as an very essential part, it can be a part of the cell wall or the cell components. The central architectural feature of biological membranes is a double layer of lipids, which acts as a barrier to the passage of polar molecules and ions. Membrane lipids are amphipathic: one end of the molecule is hydrophobic, the ther hydrophilic. Their hydrophobic interactions with each other and their hydrophilic interactions with water direct their packing into sheets called membrane bilayers. In this section we describe five general types of membrane lipids: o Glycerophospholipids: in which the hydrophobic regions are composed of two fatty acids joined to glycerol; o Galactolipids and sulfolipids: which also contain two fatty acids esterified to glycerol, but lack the characteristic phosphate of phospholipids; o Archaebacterial tetraether lipids: in which two very long alkyl chains are ether-linked to glycerol at both ends; o Sphingolipids: in which a single fatty acid is joined to a fatty amine, sphingosine;And Sterols, compounds characterized by a rigid system of four fused hydrocarbon Rings. Lipids and drug delivery: There are different route of drug delivery, the most profound route of drug delivery is the oral route. Nevertheless, drug absorption through the gastrointestinal tract (GIT ) is deeply hampered by different biological barriers (biochemical and/or physical), of which the first pass metabolism occurring both in enterocytes and in liver is but a good example. Biochemical barriers include enzymes existing in the gastrointestinal (GI ) lumen as well as efflux pumps present in the epithelial cells, whereas physical barriers consist of epithelial cell membranes, tight junctions and mucus layer. Overcoming these barriers is currently one of the most challenging goals in oral drug delivery Thus, several strategies have been developed aiming at improving drug bioavailability following oral administration Some of those strategies include maximizing the intestinal uptake of drug molecules while others focus on protecting the drug molecules from degradation, but combinations thereof have also been reported Following oral administration, a drug passes sequentially the mouth, esophagus, stomach, duodenum, jejunum (small intestine), colon (large intestine) and finally leaves the body if not absorbed. The first requirement for absorption to occur is drug dissolution, i.e. only dissolved drugs have the ability to permeate the GI membrane. As a result, drug solubility is a parameter of paramount importance. A drug molecule may pass through the layer of enterocytes in many different ways, but passive diffusion is the most important one. Besides passive diffusion, other mechanisms to reach systemic circulation include facilitated diffusion, paracellular transport, and endocytosis. Prior to reaching systemic circulation, the drug molecule may be metabolized during absorption by enzymes existing in the enterocytes. Furthermore, when the drug reaches the portal vein it will directly be delivered to the liver where further metabolism may also take place. After passage through the liver, the drug finally reaches systemic circulation and is duly carried by the blood towards specific targets. Thus the above all pharmacokinetic aspects are based on the nature of the molecule. if the carrier molecule of the drug is lipid in nature it will enable it's easy passage across the barriers. The following are the advantages of having lipids as a part of the delivery system(4). 1. Disperse, solubilize and maintain solubility of drug in GI fluids 2. Mitigate intestinal FPE and efflux 3. Transfer drug in to bile saltmixed micelle 4. Influence gut wall permeability 5. Mitigate hepatic FPE through enhanced lymphatic transport of drug 6. Normalize and/or modify pharmacokinetic parameters Lipids as components of the drug delivery(5) ? Triglycerides ? Long chain (14-18C) ? Medium chain: (6-12C): less viscous and higher solubilization ability than long chain triglycerides ? Are saturated and thus usually more chemically stable ? Mono-/di-glycerides: ? More hydrophilic than corresponding triglycerides ? Higher solubilization ability and dispersibility ? Propylene glycol esters ? High solubilization ability, purity, and stability ? Fatty acids ? Oleic acid LONG CHAIN TRIGLYCERIDES: Corn oil, Soybean oil, Safflower oil, Olive oil MEDIUM CHAIN TRIGLYCERIDES: Glyceryl tricaprylate/ caprate: Captex(r)300; Miglyol(r)810; Miglyol(r)812; Neobee(r)M-5 FATTY ACIDS: Oleic acid; Palmitic acid; Stearic acid; Linoleic acid MONOGLYCERIDES / DIGLYCERIDES : Glyceryl caprylate/caprate (Capmul(r) MCM, Imwitor(r) 742); Glycerol monocaprylate (Imwitor(r) 308, Glycerol monooleate (Capmul(r) GMO) PROPYLENE GLYCOL ESTERS : Propylene glycol monocaprylate (Capmul(r) PG-8); Propylene glycol monolaurate (Capmul(r) PG-12, Lauroglycol(r)) ? Surfactants ? Hydrophilic portion is typically based on PEG, which must be monitored for peroxide content Low HLB (10) emulsifiers (more hydrophilic) Polyoxyethylene20 sorbitanmonolaurate: Polysorbate20 (Tween(r)20) Polyoxyethylene20 sorbitanmonooleate: Polysorbate 80 (Tween(r)80) Polyoxyl35 castor oil: Cremophor(r)EL Polyoxyl40 hydrogenated castor oil: Cremophor(r)RH40 Polyoxyethylenepolyoxypropyleneblock copolymer: Poloxamer188 (Pluronic(r)F68); Poloxamer407 (Pluronic(r)127) PEG-8 Caprylic/Capricglycerides: Labrasol(r) PEG-8 Caprylic/Capric glycerides: Labrafac(r)CM10 Tocopherol PEG succinate: Vitamin E TPGS Polyoxyl 40 stearate: Myrj(r)52 Fate of lipid containing drug delivery in git: * Disintegration and dispersion of lipid droplets containing drug * Digestion of lipids to mono-/di-glycerides, glycerol, and fatty acids * Solubilizationby bile salts and phospholipids (mixed micelles) * Greater surfactant and/or mono-glyceridecontent: less dependence on digestion products for emulsification. The drug get's finally absorbed into the systemic circulation. And the general pharmacokinetics follows. The role of lipids in the novel drug delivery will be dealt in my future blogs This blog is free from plagiarism. REFERENCE: 1. Harpers illustrated biochemistry Lange Medical Books/McGraw-Hill, twenty sixth edition- Pg.no-111 2. Lehninger Principles Of Biochemistry 4th Edition, pg.no- 348 3. Lipid-based Systems for Oral Drug Delivery 4. David J. Hauss, Ph.D. Briistoll-Myers Squiibb Company Priinceton,, NJ .pdf 5. Lipid Based Formulation Approaches for Poorly Soluble Drugs John B. Cannon, Ph.D. Trinity international university Arden House Conference February 3, 2010 presentation.