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WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES Shivprasad et al. World Journal of Pharmacy and Pharmaceutical Sciences Volume 2, Issue 6, 4485-4503. Review Article ISSN 2278 – 4357 PHOSPHOLIPID: AS NOVEL EXCIPIENT Palve Shivprasad P*, Warad Shubhangi, Solunke Rahul, Somwanshi Bhagwat, Deshmukh Vikrant, Jagdale Ganesh. Kasturi shikshan Sansthas College of pharmacy, Shikrapur, Pune, India. Article Received on 17 August 2013, ABSTRACT Revised on 15 Sept 2013, Accepted on 24 October2013 and as active ingredients, the present article summarizes particular Phospholipids become increase important as formulation excipients features of commonly use phospholipids and their application spectrum within oral drugformulation and elucidates current strategies to *Correspondence for Author: improve bioavailability and disposition of orally administered drugs. The phospholipid molecule makes up cell membranes. It is ultimately * Palve Shivprasad P responsible for controlling what goes in/out of the cell, maintaining Kasturi shikshan sansthas form and structure and many other things. Advantages of college of pharmacy, Shikrapur, Pune, India. [email protected] phospholipids formulations not only comprise enhanced bioavailability of drugs with low aqueous solubility or low membranepenetration potential, but also improvement or alteration ofuptake and release of drugs protection of sensitive active agents from degradation in the gastrointestinal tract, reduction of gastrointestinal side effects of non-steroidal anti-inflammatorydrugs and even masking of bitter taste of orally applied drugs.Technological strategies to achieve these effects are highly diverseand offer various possibilities of liquid, semi-liquid and solid lipid basedformulations for drug delivery optimization. Keyword: Phospholipid, Sources, enzymatic Hydrolysis, Novel Excipient, Drug delivery. INRODUCUION Phospholipids are complex lipids which contains one or more phosphate groups. Phospholipids are amphipathic in nature that is each molecule consists of a hydrophilic portion and a hydrophobic portion thus tending to form lipid bilayers. In fact, they are the major structural constituents of all biological membranes, although they may be also involved in other functions such as signal transduction. The lipid bilayer is a thin polar membrane made of two layers of lipidmolecules. These membranes are flat sheets that form a www.wjpps.com 4485 Shivprasad et al. World Journal of Pharmacy and Pharmaceutical Sciences continuous barrier around cells. The cell membrane of almost all living organisms and many viruses are made of a lipid bilayer, as are the membranes surrounding the cell nucleus and other sub-cellular structures. The lipid bilayer is the barrier that keeps ions, proteins and other molecules where they are needed and prevents them from diffusing into areas. Phospholipids refer to a kind of lipids, which are a main part of all biological membranes. They are important because they help in transportation of materials into living organisms. There are two classes of phospholipids, those that have a glycerol backbone and those that contains phingosine. Phospholipids that contain glycerol backbone are called as Glycerophospholipids, which are the most abundant class found in nature. The most abundant types of naturally occurring glycerol phospholipids are phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl serine, Phosphatidyl inositol, phosphatidyl glycerol andcardiolipin. The structural diversity within each type of phosphoglyceride is due to the variability of the head group variability of the chain length and degree of saturation of the fatty acid ester groups. PL molecular species distributions were determined by Fast Atom Bombardment Mass Spectroscopy (FAB MS) in negative ion mode. 1 Figure 1-phospholipid www.wjpps.com 4486 Shivprasad et al. World Journal of Pharmacy and Pharmaceutical Sciences SOURCES1 Phospholipids are present in many natural sources like human/animal tissues, plant sources and microbial source 1) Phospholipids in Human / Animal Tissues Almost all body cells contain PLs. The common animal PLs are made of sphingomyelin, PC, PE, PS, PI and other glycerol phosphatides of complex fatty acid composition. These phospholipids occur normally in cell membranes and lipid proteins, where they serve both structural and functional purposes. Animal phospholipids are highly valued for their desirable emulsifier and organoleptic properties. The exact composition of human/animal phospholipids depends on the source and the method of extraction and purification. The central nervous system especially has high phospholipids content. The liver is the site for their biosynthesis and the lipids of the mitochondria, which are the regulators of cell metabolism and energy production in the body, consist of up to 90% of PLs. Liver, Kidney, Muscles and Other Tissues: -Organ meats such as liver, kidney and muscles are major source of dietary phospholipids. In blood PC is quantitatively the most important phospholipid. Total blood contains about 0.2 to 0.3% of phospholipids. Egg Phospholipids: -The phospholipids in egg are mainly present in the yellow yolk at least a portion of them is combined with protein and carbohydrates. Egg yolk has about 70% PC, 24% PE, 4% Sphingomyelin, 1% PS, 1% PI, PC and PE contribute the remaining 2% of the total phospholipids. Egg lecithin as a commercial ingredient with the exception of some medical feeding program, is comparatively expensive for the routine use in food. Milk Phospholipids: -Milk has a phospholipids content of about 0.035% associated with the fat by virtue ofbeing part of a colloidal membrane, which surrounds the fatty globule. Skim milk and milk serum have the highest portion of polar lipids as percent of the total lipids, while whole milk and cream have least of the polar lipids. PE constitutes the largest component with PC and sphingomyelin being present in about equal portions at a significantly lower level. Brain Phospholipids: - The brain is a rich source of phospholipids and, together it, the spinal cord, probably possesses the highest phospholipids content of any of the organs. www.wjpps.com 4487 Shivprasad et al. World Journal of Pharmacy and Pharmaceutical Sciences 2) Plant Sources of Phospholipids Vegetable materials usually contain only small amounts of phospholipids, ranging from 0.3 to 2.5 wt%. The major phospholipids present in plant sources are PC, PE and PI. The plant sources of phospholipids are soybean, rapeseed, sunflower, cottonseed and peanut, rice bran, palm, coriander, carrot, palash, janglibadam, papaya, olive, barley, cucurbit, corn, castor bean, cocoa, neem, sesame, pear, quince, tobacco. Phospholipids are removed as by product during the degumming process of vegetable oil refining. Crude vegetable oil lecithinare the starting materials of choice for further fractionation and purification process to obtain phospholipids compositions suitable for various industrial applications. Soybean phospholipids are obtained from commercial soybean lecithin. It is a complex mixture comprised of phospholipids, triglycerides with minor amounts of other substituent, i.e. phytoglycolipids, phytosterols,tocopherols and fatty acids. The world’s first industrial processing of soybean and production of lecithin was carried out in Hamburgand the driving force behind this development was Herman Bellman (1880-1934). Soybean lecithin mainly used because of its availability and excellent properties, especially emulsifying behaviour, colour and taste. Other lecithin like rice bran, corn, rapeseed, sunflower, cottonseed and peanut a are also good phospholipids sources and some of thislecithin is being exploited for commercial applications. 3) Microbial Sources of Phospholipids Microorganisms also contain phospholipids and these entities are of interest for clinical research. The diversity of lipid types is enormous, and all the major phospholipids of plants and animals have been recovered from at least one microorganism. APPLICATIONS OF PHOSPHOLIPIDS1 It Provides free choline in the blood for the manufacture of acetylcholine; regulates digestive, cardiovascular and liver functions. It use in Pharmaceutical preparations, such as cosmetics. It use for the production of stable liposomes, anti-spattering agent in margarine. It Provides less absorption of oil into raw materials, retains the intrinsic flavour of raw materials. It supports brain functions that decline with age, memory enhancer. www.wjpps.com 4488 Shivprasad et al. World Journal of Pharmacy and Pharmaceutical Sciences It useEmulsifier in foods. (E.g. chocolate). As a mediator in plants: In plants, phospholipids serve as a raw material to produce Jasmonic acid, a plant hormone that mediates defensive responses against any disease causing agents. In Food technology: Phospholipids can also act as an emulsifier, enabling oils to dissolve in water. Phospholipids called lecithin, are extracted out of cooking oil and then used as food additives in many things such as bread and can also be purchased separately in a health food store. Phospholipids act on Circulation Impaired blood cholesterol regulation continues to be an enormous health issue in Western populations. Mixtures of phospholipids prepared from soy, and containing PC together with smaller amounts of other phospholipids, were proven through twelve double-blind trials to consistently reduce blood cholesterol levels. Soy phospholipids mixtures also can improve blood flow and reduce the risk of clot formation in the circulation. These preparations offer the promise of costeffective circulatory improvement, and offer the very emulsification, dispensability, and surfactant characteristics that would enable the preparation of freeflowing and instant zed shake mixes, or chewy and sticky health bars. PC is not well suited for beverages. Phospholipids for Liposome Liposome technology came to the fore several decades ago, and in the ensuing years has evolved to become ever more sophisticated. While the lofty promises of liposome targeting of cancer drugs or gene insertion are still under investigation, liposome’s may yet prove useful for a modest yet important application. Figure 2 - Phospholipids for liposome www.wjpps.com 4489 Shivprasad et al. World Journal of Pharmacy and Pharmaceutical Sciences This is to protect biochemically vulnerable nutrients against premature breakdown in the stomach, until they can reach the intestine for absorption. The closed sphere environment of the liposome is a stabilizing influence against degradation by digestive enzymes or other potentially harmful influences. New technology offers phospholipids concentrates that conveniently generate liposome-encapsulated nutrients simply upon stirring into water. METHOD OF PREPARATION1 Enzymatic and Chemical Methods for the Preparation of Structural Phospholipids The molecular structure of PL can be changed by either enzymatic or chemical means. The aim of all these process is to obtain tailor-made PLs. The interest in new PLs and PL analogues results from their potential use in different fields of application, for example as biodegradable surfactants, as carriers of drugs or genes or as biologically active compounds in medicine and agriculture. The synthesis of new PLs and PL analogues using both enzymatic and chemical methods had gained importance. In recent years, enzymatic catalysis particularly with lipases and phospholipases has gained increasing importance to replace chemical methods or to permit synthesis of compounds which have not been accessible by chemical means. Best way for the partial synthesis of PLs is enzymatic modifications. Different enzymes are employed to tailor PLs with defined fatty acid composition at the sn-1 and sn-2 positions. Using enzymatic acyl exchange.it would be possible to acquire PLs for specific application requirements in food, pharmaceutical and cosmetics by altering the technical or physiological properties of the natural compounds. Most work in this direction focuses on the incorporation of saturated fatty acids (including both medium and long chain)or polyunsaturated fatty acids into PLs. Lipase catalysed enzymatic acidosis’sreaction between soy PLs and phospholipases D catalysedtransposphotidylation reaction between PLs and sterols were used to synthesize structured PLs with modified fatty acid and head group (sterol). Compared to chemical methods, enzymatic modifications of PLs have few advantages like selectivity or specificity of enzyme is one of the most important properties of enzymes that make the modification of PLs simple and easy. With possible and available enzymes, the manipulation of PL structure can be complicated but versatile.There are various ways to chemically modify PL molecules, but only few of them are commercialized. The reason is that none of the resulting products have food grade status except products like hydroxylated and acetylated lecithin. www.wjpps.com 4490 Shivprasad et al. World Journal of Pharmacy and Pharmaceutical Sciences Structure 5 - Enzymatic Hydrolysis of Phospholipids However, a substantial development and application work has been reported on the chemically modified PLs for application in pharmaceutical and cosmetic products. Chemical and physical properties of PLs depend on their molecular structure. To meet different industrial application requirements, hydrolysis, hydroxylation, acetylating and hydrogenation have been applied to the chemical modifications of commercial lecithin to generate PLs, hydroxylated PLs, acylated PE, hydrogenated PLs and other PLs. PLs can also be prepared by utilizing natural PLs as precursors. However the glycerol derivatives or sphingosines obtained by chemical or enzymatic cleavage are usually structural or stereo mixtures that are difficult to be isolated and purified. The advantage of semi-synthesis is its low cost due to its naturally available source of precursors and fewer reaction steps. SEPARATION OF PHOSPHOLIPIDS1 The major portion of tissue lipids are bound to proteins and carbohydrates. Solvents such as chloroform, ether or benzene are generally used in combination with methanol or ethanol. Various methods for extraction of lipids, the most extensively used extraction procedure was reported by in which the tissue or seeds were extracted with chloroform methanol solvent mixture. The Bligh and Dyer method was also widely used for extraction of lipids, in which the tissue or seeds were extracted with solvent mixture of chloroform: methanol: water. But some plant tissues contain active enzymes, which are not inactivated either by chloroform or methanol and readily cause breakdown of phospholipids. In this case the method of was used in which the enzymes were deactivated by freezing the seeds with liquid nitrogen and washing with 2-propanol.Mostly the phospholipids from oil seeds and oils were isolated by extraction of source material method followed by acetone precipitation of the extract or by www.wjpps.com 4491 Shivprasad et al. World Journal of Pharmacy and Pharmaceutical Sciences extracting acetone defatted materials with chloroform: methanol. Phospholipids were further purified by silicic acid column chromatography. Commercially the phospholipids were isolated from oils by degumming with steam or weak boric acid or with sodium chloride solution or with acetic anhydride. ANALYSIS OF PHOSPHOLIPIDS1 The quantitative and qualitative analysis of total phospholipids is carried out by several methods namely 1. Solvent fractionation 2. Counter-current distribution 3. Paper chromatography 4. Thin layer chromatography 5. Column chromatography 6. High-performance liquid chromatography, 7. Proton nuclear magnetic resonance spectroscopy 8. Mass spectra and gas chromatography The total phospholipids were fractionated into alcohol soluble and insoluble based on the solubility of phospholipids in solvents used counter current distribution technique to soybean and corn phospholipids using hexane and 95% methanol solvents. The composition was found to be 29% lecithin, 31% cephalin and 40% PI. However these classical techniques are laborious and require large amounts of the sample. Hence these have been substituted by modern chromatographic methods. Paper chromatographic technique was used to study the qualitative identification of phospholipids. This technique was significantly improved by use of modified papers such as acetylated, formaldehyde treated, impregnated with phosphate and alumina. The most commonly used method consists silicic acid impregnated paper, which has been used by several authors to analyse phospholipids classes.Thin-layer chromatography (TLC) technique is extensively used in area of phospholipids research. The various forms of TLC like qualitative, quantitative and preparative methods have been used to isolate and to determine the composition of the individual phospholipids classes from phospholipids mixture. Hydroxyl apatite, cellulose, polyamide, silicic acid. The commonly used adsorbent was silica with 15 % calcium sulphate as binder to separate phospholipid. The adsorbent used were alumina, cellulose, polyamide, silicic acid. The commonly used adsorbent was silica PE and PS using silica gel-H (without binder) plates which were prepared in 1 mm aqueous www.wjpps.com 4492 Shivprasad et al. World Journal of Pharmacy and Pharmaceutical Sciences sodium carbonate solution with 15 % calcium sulphate as binder to separate phospholipids classes. Achieved the separation ofthe complex mixture of phospholipids was efficiently separated by TLC technique.The preparative TLC was used to separate individual phospholipids in large quantities. Spanner reviewed some well-tried systems for different phospholipids with their RF values. The quantitative TLC method was used by several workers to determine the phospholipids composition.TLC coupled with densitometry estimation of phospholipids was also used to study the phospholipids composition. ROLE OF PHOSPHOLIPIDS3 Phospholipids form a barrier to the outside world in cells.The phospholipids form a bilayer with embedded proteins that allows certain materials to pass in and out of cells. Thecells could not exist without the phospholipids bilayer because it makes a selectively permeable membrane allowing certain materials to pass through and regulates the water and salinity of the cell. The Phospholipidscomplex lipid molecules forming core of all biological membranes. The Substituted triglyceride with phosphate replacing one of fatty acids three subunits. Glycerol three C alcohol with each carbon hydroxyl backbone of phospholipid molecule. Fatty acids arelong chains of hydrocarbon chains ending in carboxyl group. Two fatty acids attached to glycerol backbone in phospholipids membrane. Phosphate group is attached to one end of glycerol with charged phosphate usually having organic molecule linked to it polar head and one end and two long nonpolar tails essential for function. Nonpolar tails aggregate away from water forming spherical micelles with tails inward. Hydrophilic ends outward forming bilayers a basic framework of biological membranes. IMPORTANCE OF PHOSPHOLIPID Phospholipid-mediated signaling systems as novel targets for treatment of heart disease The phospholipases associated with the cardiac sarcolemmal (SL) membrane hydrolyze specific membrane phospholipids to generate important lipid signaling molecules, which are known to influence normal cardiac function. However, impairment of the phospholipases and their related signaling events may be contributory factors in altering cardiac function of the diseased myocardium. The identification of the changes in such signaling systems as well as understanding the contribution of phospholipid-signaling pathways to the pathophysiology of www.wjpps.com 4493 Shivprasad et al. World Journal of Pharmacy and Pharmaceutical Sciences heart disease are rapidly emerging areas of research. I provide an overview of the role of phospholipid-mediated signal transduction processes in cardiac hypertrophy and congestive heart failure, diabetic cardiomyopathy, as well as in ischemia-reperfusion. From the cumulative evidence presented, it is suggested that phospholipid-mediated signal transduction processes could serve as novel targets for the treatment of the different types of heart disease. Phospholipids in Health and Disease The choline phospholipids and cell signaling, cell suicide pathways, Phosphatidylcholine biosynthesis, and various issues related to choline and health. Of particular interest to the ODS was the session on choline and brain function. Animal model studies have shown consistent results on choline-induced memory improvements in young as well as with aged animals. Sex differences were observed with perinatal treatment that demonstrated longlasting improvement in memory capacity with male animals, but the effects were of smaller magnitude and shorter duration with female animals. The role of the phospholipid sphingomyelin in heart disease The Sphingomyelin (SM) is an integral component of mammalian cell membranes and nerves. However, the inability to catabolize SM may lead to its accumulation in various tissues and organs, resulting in pathological disorders such as Niemann Pick disease. Elevated levels of SM have also been identified as an independent risk factor for coronary heart disease. During the past two decades, data have emerged that support an important role for metabolites of SM, such as ceramide and sphingosine-1-phosphate, in the regulation of phenotypic changes such as cell proliferation, cell-cycle arrest, apoptosis and angiogenesis. Further studies of the molecular and path biological basis of these phospholipids may facilitate advances in the discovery of drugs with which to mitigate diseases that may result from an elevation in SM and its metabolites. Phospholipid therapy Phosphatidylcholine (PC) is one of the most exciting therapies now available in our clinic. PC has only recently received increased clinical focus because of its ability to dramatically improve the outcomes of patients in a wide range of disorders such as ALS , Lyme, Parkinson’s, Alzheimer’s, MS, Fibromyalgia, Chronic Fatigue, Autism, Bipolar, Seizures, Hepatitis C, Environmental Illness, Cardiovascular disease and eye disease. www.wjpps.com 4494 Shivprasad et al. World Journal of Pharmacy and Pharmaceutical Sciences The eye ranks as one of the highest in lipid cellular complexity. There are over 100 million rods and cones in each eye and each one has up to 2000 layers of lipid membrane. Each membrane contains 140 million rhodopsin proteins which are responsible for capturing photons to produce sight. Each day a portion of this membrane and the rhodopsin proteins are sloughed off. Each cell discards about 7% of its lipid membrane stack each day. The entire photo-receiving structure is regenerated every 14 days. the PC directly up-regulates the fluidity of the membrane, improving its vitality which is essential for all of metabolism including neuronal transmission. Poor neuronal response is degraded in all the neurological disorders and is directly improved with Phosphatidylcholine (PC) therapy. Raising PC levels plays an important role in improving memory and recall, and has clinically shown to improve the flow of information of all the senses and most significantly eyesight. PC given either orally or intravenously helps restore the proper integrity of the cell membrane thereby restoring proper function of organ systems, especially the liver, the gut, the brain, immune system, heart, and hormonal system, which ultimately improves the total health of the individual. FUNCTIONS OF PHOSPHOLIPIDS3 1. Act as building blocks of the biological cell membranes in virtually all organisms. 2. Participate in the transduction of biological signals across the membrane. 4. Play an important role in the transport of fat between gut and liver in mammalian digestion. 5. An important source of acetylcholine which is the most commonly occurring neurotransmitter substance occurring in mammals. 6. Thereservoir of intracellular protein messengers such as phosphoinositolbiphosphate. This is obtained from the cleavage of phosphatidylinositol by Phospholipase C. 7. Phosphoinositolbiphosphate is one of the most important secondary messengers in the cell signalling pathway of human. 8. Anchors to cell proteins On the other hand, phospholipids also exist out of cell membrane. 9. Dipalmitoyl Phosphatidylcholineis a component of lung surfactant. Secreted by granular pneumocystis, it decreases surface tension of fluid layer, reducing pressure required to rein flat alveoli. 9) Phospholipid is also an essential component ofbile, where their detergent properties (amphipathic) aid in the solubilization of cholesterol. Phosphatidylcholine (lecithin) and bile salts are both the major components of bile. www.wjpps.com 4495 Shivprasad et al. World Journal of Pharmacy and Pharmaceutical Sciences BIOSYNTHESIS OF PHOSPHOLIPIDS3 Phospholipids are a class of lipids that consist of two fatty acyl molecules esterifies at the sn1 and sn-2 positions of glycerol, and contain a head group linked by a phosphate residue at the sn-3 position . Structure 6 - Structure and major classes of phospholipids. The head group forms a hydrophilic region and determines the type of phospholipid. The fatty acyl side chains are hydrophobic; this amphipathic property of phospholipids provides the basis for the compartmentalization of cells. Phospholipids are the main constituent of biological membranes. The size, shape, charge, and chemical composition of different phospholipid classes play a role in the formation and maintenance of the plasma membrane bilayer of cells, as well as membranes surrounding sub cellular organelles and vesicles. An asymmetric distribution of phospholipid types within the membrane imparts different functional characteristics between the inner and outer leaflets. Phospholipids are involved in stabilizing proteins within the membrane, facilitating the active conformational structure of proteins, and as cofactors in enzymatic reactions. Phospholipids are essential for the absorption, transport and storage of lipids. Phospholipids are secreted into the bile to aid in the digestion and absorption of dietary fat. They form the monolayer on the surface of lipoproteins which function to transport neutral lipids throughout the body. Finally, phospholipids serve as a reservoir for signaling molecules, such as arachidonic acid, phosphatides, diacylglycerol and inositol triphosphate. This scope of this review is the www.wjpps.com 4496 Shivprasad et al. World Journal of Pharmacy and Pharmaceutical Sciences biological function and synthesis of the most abundant phospholipids in mammalian cells: Phosphatidylcholine, Phosphatidylethanolamine and Phosphatidylserine. Information gleaned from studies in knockout mice will highlight the novel links between phospholipid biosynthesis and various chronic conditions, including diabetes, obesity, fatty liver and cardiovascular diseases. COMBINATION OF PHOSPHOLIPIDS AND NUTRIENT2 The natural tendency of phospholipids to form ultra-fine molecular dispersions in water should be further explored to improve the bioavailability of non-phospholipids nutrients, especially those that are costly and relatively poorly absorbed. Monomolecular nutrient dispersion using phospholipids also will improve the physical characteristics of the phospholipidsnutrient combinations, such that the resulting functionalized product becomes considerably more convenient and effective for the consumer. This combined phospholipidsnutrient approach is suited to producing chewable tablets, confections, cookies, granulates, and spreads, bars, emulsified or purely aqueousphase beverages, even liquid sprays. Further product value comes from the health benefits of the phospholipids being combined with the benefits of the selected nutrient one prime combination would be phospholipids with omega-3 fatty acids. Their perfect safety record and well documented array of health benefits qualify PS, PC, and GPC as first-rate nutraceuticals. Their unique physical chemical characteristics make them premier functional food constituents. A wide range of consumers, whether aged, youthful or in ill health, all stand to benefit from the phospholipids’ life affirming properties. PHOSPHOLIPIDS FORMULATION TYPES4 Phospholipids offer a number of opportunities to formulate drug delivery systemwith drugs that exhibit poor water solubility. Liposome Liposomes are aqueous compartments enclosed by lipid bilayer membranes. Mixed Micelles Mixed micelles are micelles comprising at least two different molecular species. Detergent lipid mixed micelles represents disk-like structures. These micelles resemble small fragments www.wjpps.com 4497 Shivprasad et al. World Journal of Pharmacy and Pharmaceutical Sciences of lipid bilayer with detergent molecules shielding the unfavourable exposure of hydrophobic parts of lipid molecules against water at their edges. Emulsions A suspension of small droplets of one liquid in a second liquid with which the former is not mixable is an emulsion. Phospholipids can form oil-in-water as well as water-in-oil emulsions. Micro/Nano emulsions Micro and Nano-emulsions are based on lipids in fluid state atroom temperature. They are usually prepared by highpressure homogenisation leading to droplet sizes in the range of 50– 500 nm. Self-emulsifying Drug Delivery Systems It is mixtures of oil and surfactants, ideally isotropic, sometimes including co-solvent, which emulsify under conditions of gentle agitation, similar to those which would be encountered in the gastro intestinal tract. Solid Lipid Non particles It is based on “melt-emulsified” lipids, which are solid at room temperature. Further details can be found in paragraph “Solid Lipid-Based Systems.” Suspensions A suspension consists of a liquid and a homogeneously dispersed fine sized solid.Phospholipid Drug Complexes a phospholipidsdrug complex is formed by interaction of the phospholipids with a functional group of the drug. MOLECULAR MECHANISMS OF MEMBRANE FUSION7 StepduringPhospholipids: -The fusion ofphospholipidsmembranes is not the same molecular event as biological membranefusion and that specific biochemical steps should be proposed. It is useful to break up exocytosis into a sequence of component steps leading totransport of large molecular weight substances from the insides of granules to the extracellular space. 1. Adhesion:- intimate contact between the two membranes that are to fuse, anddehydration of the inter-membrane space. www.wjpps.com 4498 Shivprasad et al. World Journal of Pharmacy and Pharmaceutical Sciences 2. Fusion/Pore Formation:-molecular mixing and rearrangement leading to aconnection of the granule interior with the extracellular space. Topologicalcontinuity from inside of the secretary vesicle to the external surface of the plasmamembrane. 3. Pore Widening:-a further opening up of the exocytosis pore. 4. Discharge of the contents to the outside:-once the exocytosis pore is larger thanthesecretarymolecule, typically one measures experimentally one or two of these events and takes thatmeasurement. Figure 3: – a)adhere b) fuse & pore formation c) pore must widen d) discharge e) inside INTRODUCTION OF DRUG DELIVERY8 Targeted drug deliverysometimes called smart drug delivery, is a method of deliveringmedication to a patient in a manner that increases the concentration of the medication in some parts of the body relative to others. The goal of a drug delivery system is to prolong, localize, target and have a protected drug interaction with the diseased tissue. The conventional drug delivery system is the absorption of the drug across a biological membrane, whereas the targeted release system is when the drug is released in a dosage form. The advantages to the targeted release system is the reduction in the frequency of the dosages taken by the patient, having a more uniform effect of the drug, reduction of drug side effects, and reduced fluctuation in circulating drug levels. The disadvantage of the system is high cost which makes productivity more difficult and the reduced ability to adjust the dosages. Targeted drug delivery systems have been developed to optimize regenerative techniques. The system is based on a method that delivers a certain amount of a therapeutic agent for a prolonged period of time to a targeted diseased area within the body. This helps maintain the www.wjpps.com 4499 Shivprasad et al. World Journal of Pharmacy and Pharmaceutical Sciences required plasma and tissue drug levels in the body. Therefore, avoiding any damage to the healthy tissue via the drug. The drug delivery system is highly integrated and requires various disciplines, such as chemists, biologist and engineers, to join forces to optimize this system. 1) Delivery vehicles There are different types of drug delivery vehicles, such as, polymeric micelles, liposomes, lipoprotein based drug carriers, Nano-particle drug carriers, phospholipids dendrimers etc. An ideal drug delivery vehicle must be non-toxic, biocompatible, non-immunogenic and biodegradable and avoid recognition by the host's defence mechanisms 2) Development of Drug Delivery System To obtain a given therapeutic response, the suitable amount of the active drug must be absorbed and transported to the site of action at the right time and the rate of input can then be adjusted to produce the concentrations required to maintain the level of the effect for as long as necessary. The distribution of the drug-to-tissues other than the sites of action and organs of elimination is unnecessary, wasteful, and a potential cause of toxicity. The modification of the means of delivering the drug by projecting and preparing new advanced drug delivery devices can improve therapy. Since the 1960s, when silicone rubber was proposed as an implantable carrier for sustained delivery of low molecular weight drugs in animal tissues, various drug delivery systems have been developed. At the beginning of the controlled drug delivery systems, a controlled release system utilizes a polymer matrix or pump as a rate-controlling device to deliver the drug in a fixed, predetermined pattern for a desired time period. These systems offered the following advantages compared to other methods of administration, 1. Thepossibility to maintain plasma drug levels a therapeutically desirable range. 2. The possibility to eliminate or reduce harmful side effects from systemic administration by local administration from a controlled release system. 3. Drug administration may be improved and facilitated in underprivileged areas where good medical supervision is not available. 4. The administration of drugs with a short in vivo half-life may be greatly facilitated. 5. Continuous small amounts of drug may be less painful than several large doses. 6. Improvement of patient compliance. www.wjpps.com 4500 Shivprasad et al. World Journal of Pharmacy and Pharmaceutical Sciences 7. The use of drug delivery systems may result in a relatively less expensive product and less waste of the drug. The first generation of controlled delivery systems presented some disadvantages that is possible toxicity, need for surgery to implant the system, possible pain, and difficulty in shutting off release if necessary. Two types of diffusion controlled systems have been developed. The reservoir is a core of drug surrounded with a polymer film. The matrix system is a polymeric bulk in which the drug is more or less uniformly distributed. Pharmaceutical applications have been made in ocular disease with the Ocusert, a reservoir system for glaucoma therapy that is not widely used, and in contraception with four systems. 1. Sub dermal implants of non-biodegradable polymers, such as Norplant (6 capsules of 36mg levonorgestrel). 2. Sub dermal implant of biodegradable polymers. 3. Steroid releasing intrauterine device. 4. Vaginal rings, which are silicone coated. Other applications have been made in the areas of dentistry, immunization, anticoagulation, cancer, narcotic antagonists, and insulin delivery. Transdermal delivery involvesplacing a polymeric system containing a contact adhesive on the skin. Since the pioneering work in controlled drug delivery, it was demonstrated that when a pharmaceutical agent is encapsulated within, or attached to, a polymer or lipid, drug safety and efficacy may be greatly improved and new therapies are possible. 5. This concept prompted active and intensive investigations for the design of degradable materials, intelligent delivery systems, and approaches for delivery through different portals in the body. Recent efforts have led to development of a new approach in thefield of controlled drug delivery with the creation of responsive polymeric drug delivery systems. 6. Such systems are capable of adjusting drug release rates in response to a physiological need. The release rate of these systems can be modulated by external stimuli or selfregulationprocess. 3) Phospholipids Drug Carriers Drug delivery systems composed of lipid compounds have gained great importance in medical, pharmaceutical, cosmetic, and alimentary fields. Formulations based on phospholipids and other excipients represent an interesting field of application in the novel www.wjpps.com 4501 Shivprasad et al. World Journal of Pharmacy and Pharmaceutical Sciences research for delivery models. Lipid materials are characterized by their possibility to selforganize in different supramolecular arrangements as a function of some environmental factors (i.e., temperature, lipid concentration, type of medium, ionic strength, pH value, and presence of other compounds). Among the various supramolecular forms of aggregation, the bilayer structure, and hence the formation of vesicles (defined as a lipid bilayer surrounding an aqueous space) represents the most suitable device in terms of drug delivery. In fact, vesicles are boundary structures, in which it is possible to have at the same time various microenvironments characterized by different physicochemical properties, namely, a highly hydrophilic region made up of the intravascular aqueous compartment, a highly hydrophobic region of the bilayer core made up of the alkyl chains of the lipid constituent, and an amphipathic region at the level of the vesicular surface made up of the polar lipid headgroups. These peculiarities make vesicular systems a very versatile drug carrier being able to entrap and delivery hydrophilic (in the intravascular aqueous compartment), hydrophobic (in the core of vesicular bilayer), and amphipathic (at the level of vesicular boundary zone) drugs. An important feature that makes vesicles a unique drug delivery system is the biomimetic of having the same supramolecular lipid organization of natural membrane living cells. Therefore, the possibility to create a structure similar to the biological membrane for carrying out the delivery of drugs has represented an interesting challenge for a number of researchers. In particular, liposomes, ethosomes, transfersome and niosomes have been extensively investigated and are up to now the main vesicular systems used in drug delivery. CONCLUSION This article gives a summary of the most common therapeutic uses of dietary phospholipid to provide an overview of their approved and proposed benefits and to identify further investigational needs.The goal of a drug delivery system is to prolong, localize, target and have a protected drug interaction with the diseased tissue. There are different types of drug delivery vehicles, such as, polymeric micelles, liposomes, lipoprotein based drug carriers, Nano-particle drug carriers, phospholipids dendrimers etc. An ideal drug delivery vehicle must be non-toxic, biocompatible, non-immunogenic and biodegradable and avoid recognition by the host's defence mechanisms. Advantages of phospholipids formulations not only comprise enhanced bioavailability of drugs with low aqueous solubility or low www.wjpps.com 4502 Shivprasad et al. World Journal of Pharmacy and Pharmaceutical Sciences membrane penetration potential, but also improvement or alteration of uptake and release of drugs, protection of sensitive active agents from degradation in the gastrointestinal tract. REFERANCE 1. Chaudhari M.R, Kulkarni YA. Lipid. Text book of biochemistry and clinical pathology.26th ed. Pune: Nirali publication; 2010:p.1.1 - 9.12. 2. Vance JE, Vance DE. 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