Download phospholipid: as novel excipient

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
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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
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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.
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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.
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 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
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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.
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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
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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
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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
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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.
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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.
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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
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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
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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.
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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
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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.
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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
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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
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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.
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