Phospholipids: Unique carriers for drug delivery systems

Accepted Manuscript Phospholipids: Unique carriers for drug delivery systems Rudra Pratap Singh, H.V. Gangadharappa, K. Mruthunjaya

PII:

S1773-2247(17)30111-9

DOI:

10.1016/j.jddst.2017.03.027

Reference:

JDDST 334

To appear in:

Journal of Drug Delivery Science and Technology

Received Date: 8 February 2017 Accepted Date: 28 March 2017

Please cite this article as: R.P. Singh, H.V. Gangadharappa, K. Mruthunjaya, Phospholipids: Unique carriers for drug delivery systems, Journal of Drug Delivery Science and Technology (2017), doi: 10.1016/j.jddst.2017.03.027. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Phospholipids: Unique Carriers for Drug Delivery Systems Rudra Pratap Singh1, H. V. Gangadharappa*1, K. Mruthunjaya2 *1 & 1

Department of Pharmacognosy, JSS College of Pharmacy,

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2

Department of Pharmaceutics, JSS College of Pharmacy,

Jagadguru Sri Shivarathreeswara University, Mysuru – 570015, Karnataka India.

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[email protected]

Corresponding Author:

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H.V. Gangadharappa

Department of Pharmaceutics, JSS College of Pharmacy,

JSS University, Mysuru - 570015, Karnataka, India. Telephone: +91-9986042737 E-mail: [email protected]

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Contents 1. Introduction 2. Structure of Phospholipids 2.1. Glycerophospholipids (GP)

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2.2. Sphingomyelins (SM) 3. Sources of Phospholipids 3.1. Natural phospholipids 3.2. Synthetic phospholipids

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4. Properties of Phospholipids 4.1. Physiological properties

4.3. Biological properties 5. Applications of Phospholipids 5.1. In food technology 5.2. In human body 5.3. In signal transduction

5.4.1. Liposomes

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5.4 In drug delivery systems

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4.2. Physical properties

5.4.2. Lipid emulsion

5.4.3. Permeation enhancer

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5.4.4. Solubility enhancer 5.4.5. Emulsion stabilizer

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5.4.6. Solid dispersion 5.4.7. Lipospheres

5.4.8. Vesicular phospholipids gel 5.4.9. Ethosomes

5.4.10. Phytosomes

5.4.11. Pharmacosomes 5.4.12. Micelles 6. Conclusion Acknowledgement & References 2

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Abstract The aim of this review is to draw attention on potential applications of phospholipids in drug delivery system through different sources, structure, properties and as carrier. Phospholipids have the exceptional biocompatibility and remarkable amphiphilicity characteristics that make

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phospholipids the major and suitable agent or excipient for the formulation and to achieve better therapeutic applications in drug delivery system. The applications of phospholipids in the drug delivery systems are enhancement of bioavailability of drugs with low aqueous solubility or low membrane penetration, an improvement or alteration the uptake and release profile of drugs,

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protection of sensitive active agents from degradation in the GIT tract, reduced the side effects and masking of bitter taste of drugs. These properties offer various possibilities in formulation

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and potential applications.

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Keywords: Drug delivery system, Phospholipids, Bioavailability, Drug release, Applications

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1. Introduction There are many therapeutic drugs or molecules such as nucleic acid, proteins, peptide, anticancer drugs and other agents that have less bioavailability, low solubility profile, rapid clearance, high toxicity, rapid elimination from body, side effects and adverse effects. Therefore,

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there is a huge require to develop delivery methods and also drug delivery carriers, that will convey needful and effective delivery for therapeutic agent or drugs. Drug delivery systems (DDS) are proficient in design and bioavailability of drugs, control and sustained release of drug delivery and also capable to maintain the drug intact transport to the specific site while avoid the

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non diseased mass tissues.

The main objectives of DDS are to achieve the best therapeutic effect, reduce the dose, use

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suitable dose and mode of administration, reduce the side effects and enhance the solubility and bioavailability of drug or drug molecules.

The main component of cellular membrane, Phospholipids have the following characteristics: •

Self assembly amphiphilicity structure: Phospholipids self - assembly generates different super molecular structures, when it mixes with aqueous media which are dependent on their specific properties and conditions.

Excellent biocompatibility: Phospholipids are compatible with drug or phyto-compound

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•

which can be employed as the drug carriers (Cullis et al., 1979). •

Emulsifying: Phospholipids have good emulsifying property which can stabilize the emulsions (Yang et al., 2013).

Wetting characteristics: As surface-active wetting agents, Phospholipids can enhance the

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•

hydrophility of hydrophobic drugs through the surface coat of crystals.

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Phospholipids based DDS have promising better and significant effects to deliver of drugs and provide appropriate systematic drug delivery. Doxil® (Allen et al., 2013), Cleviprex® (Hippalgaonkar et al., 2010), Valium® (Rupp et al., 2010) and Silybin Phytosome™ (Bhattacharya, 2009) are some phospholipids formulation, which have been used in clinic, hospital and market and achieved excellent significant effects. The phospholipids have the following advantages and disadvantages that described as: Advantages: •

Marked enhancement of bioavailability of drug

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Reduce the dose of drug

•

Increases the Entrapment efficiency through conjugation with drug to form vesicles

•

Increases the stability profile by forming of chemical bonds between drug and lipid

•

Phospholipids have significantly greater clinical benefit

•

Enhanced the ability of drug to cross cell membranes and enter cells

•

Decreases the adverse or toxic effects

•

Improved patient compliance

Rapidly eliminated form body

•

Lead to hemolysis after iv injection

Structure of phospholipids

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2.

•

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Disadvantages:

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•

Phospholipids are a lipid class molecule, which are a key component of all cell membranes. Phospholipids have amphiphilic characteristic so it can form lipid bilayers. In the structure of Phospholipids molecules, consists of two hydrophobic fatty acid "tails" and a hydrophilic phosphate "head", joined together by an alcohol or glycerol molecule. The 'head' is

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hydrophilic (attracted to water) that contains the negatively charged phosphate group and glycerol while the hydrophobic 'tails' consists of 2 long fatty acid chains which are repelled by water and are forced to aggregate. When placed in water, phospholipids form a variety of structures depending on the specific properties of the phospholipids. These specific properties

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allow phospholipids to play an important role in the lipid bilayer. In biological systems, the phospholipids often occur with other molecules (e.g., proteins, glycolipids, sterols) in a bilayer

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such as a cell membrane. Lipid bilayers occur when hydrophobic tails line up against one another, forming a membrane of hydrophilic heads on both sides facing the water. The variation in head and tail groups, aliphatic chains and alcohols leads to the existence of a large range of phospholipids. According to the alcohols contains in the phospholipids, it can be divided into two types as glycerophospholipids and sphingomyelins. 2.1. Glycerophospholipids (GP) Glycerol backbone based glycerophospholipids, which are the main phospholipids in eukaryotic cells.

All naturally occurring glycerophospholipids have α - structure and L-

configuration. 5

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According to the head group, length, saturation of hydrophobic side chains, types of bond, number of chains and glycerol backbone, the chemical structure of phospholipids can be classified into different types (Table 1) (Baer et al., 1961; Paltauf et al., 1990; Stafford et al.,

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1987). Table 1: Different types of Phospholipids Sub

Phospholipids

Types

Co-type

Other types

Glycero

Phosphatidyl-

1,2-Dilauroyl-sn-glycero-3-phosphocholine

phospholipids

choline

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Types of

% Contribution 45-55

(DLPC)

(PC)

1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC)

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1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC) 1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC)

Phosphatidyl ethanolamine (PE)

1,2-Dimyristoyl-sn-glycero-3-phosphoethanolamine

15-25

(DMPE)

1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamine

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1,2-Distearoyl-sn-glycero-3- phosphoethanolamine (DSPE)

1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine

Phosphatidic acid (PA)

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Variation in the head group

(DPPE)

Phosphatidyl

(DOPE)

1,2-Dimyristoyl-sn-glycero-3-phosphate (DMPA) 1,2-Dipalmitoyl-sn-glycero-3-phosphate (DPPA) 1,2-Distearoyl-sn-glycero-3-phosphate (DSPA) -

5-10

-

10-15

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serine (PS)

Phosphatidyl inositol (PI)

Phosphatidyl glycerol (PG)

2-Dimyristoyl-sn-glycero-3-phosphoglycerol (DMPG) 1,2-Dipalmitoyl-sn-glycero-3-phosphoglycerol (DPPG) 1,2-Distearoyl-sn-glycero-3-phosphoglycerol (DSPG) 1,palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG)

Cardiolipin (CL)

-

-

6

moieties

the polar

groups

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Plasmalogen

-

-

Lyso

-

-

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chains

aliphatic

-

Distearoyl

5-10

phospholipids

phospholipids

Glyco Sphingolipids

Sterols

-

Distearoyl

Sphingomyelin

-

-

Cholesterol

-

2.2. Sphingomyelins (SM)

-

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Sphingo

-

Dimyristoyl,

Dioleoyl, aliphatic

length of saturation of

in the the

Dipalmitoyl,

bonding number of

The

Type of

Variation in

Variation

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2-5

-

10-20

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Sphingosine backbone based sphingomyelins are the main component of animal cell membranes and play an important role in the formation of lipid bilayers. Even though, phosphatidylcholine and sphingomyelin are very similar in their molecular structure but still have several differences that described as in Table 2.

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Table 2: Differences between Sphingomyelin and Phosphatidylcholine Sphingomyelin (SM)

Phosphatidylcholine (PC)

Backbone

Sphingosine

Glycerol

Contains molecule

0.1- 0.35 cis-double bonds in

1.1 - 1.5 cis-double bonds

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Properties

Saturation of hydrophobic

amide-linked acyl chains Higher

Less

More than 20, asymmetric

16 – 18, symmetric molecules

regions

Length of Chains

molecules Forming of bond

Intermolecular

Intermolecular

and Intramolecular hydrogen

hydrogen bonds

bonds

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30 – 45oC

30 – 40oC

Interaction with

Higher Compressibility and lower

Lower Compressibility and

steroid(cholesterol) nucleus

permeability to water

higher permeability to water

Range of phase transition

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temperature (Tc)

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Structure

3. Source of phospholipids

The different sources of phospholipids have the variation in their chemical structure

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based on their category, such as natural phospholipids (soyabean phosphatidylcholine, egg phosphatidylcholine) and synthetic phospholipids (synthetic phosphatidylcholine, hydrogenated phosphatidylcholine) that are frequently used in different types of formulations. The different varieties of Phospholipids have offered various options to select suitable phospholipids according to the drug properties and actions to achieve better therapeutic effects and to design of

3.1. Natural phospholipids

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DDS. The main sources of phospholipids are described below:

Choline component contains lecithin is a good example of natural phospholipids. The definition of lecithin has defined by various literatures in different words such as: From a business perspective, “lecithin” mainly includes glyceropholipids, triglycerides,

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fatty acids and carbohydrates. From a historical point of view, “lecithin” refers to as lipids containing phosphorus

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isolated from eggs and brains.

•

From a scientific point of view, “lecithin” refers to PC.

Phospholipids are widely distributed in animals and plants and the main sources for the production of phospholipids are vegetable oils (soybean, cotton seed, corn, sunflower and rapeseed) and animal tissues (egg yolk and bovine brain). Hence, some differences between soybean and egg yolk are shown in Table 3.

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Table 3: Differences between soybean and egg yolk Properties

Soybean

Egg yolk

Amount of PC

Less

Higher

Long chain polyunsaturated fatty acids

Arachidonic acid (AA) and

of n-6 and n-3 series

docosahexaenoic acid (DHA)

docosahexaenoic acid

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are absent

Arachidonic acid (AA) and

(DHA) are present

characteristic of SM

Absent

Present

Saturation level

Less

Oxidative stability

Not good

At sn-1 and sn-2 position

Only, unsaturated fatty acid

Higher Better

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Saturated and unsaturated

at both position

fatty acid

From animals and plants, Phospholipids can be isolated and purified for food and pharmaceutical

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grade purpose like lipoid E80 that contains PC, PE, lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), SM and trace amounts of triglycerides, cholesterol, fatty acid and water. The isolation and purification cost of phospholipids from natural sources are always less than as compare to synthetic or semi-synthetic methods. 3.2. Synthetic phospholipids

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The synthesis of phospholipids can be divided into semi-synthesis and total synthesis because isolation and purification techniques cannot get any single molecule of natural phospholipids and also, researchers focus on synthetic phospholipids with defined structure and configuration. In semi-synthesis method (eg. Glycerophospholipids, Sphingomelins), require less

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reaction steps as compare to the total synthetic method (eg. Sphingomelins).The semi-synthetic methods of glycerophospholipids mainly include three different steps to obtain phospholipids

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that shown in Fig. 1 and the total synthesis methods of glycerophospholipids are shown in Fig. 2.

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Fig 1.Semi-synthetic methods of glycerophospholipids

Fig 2.Total synthetic methods of glycerophospholipids According to the uses and properties, the phospholipids have to be used to prepare the pharmaceutical formulations. For example, the content of unsaturated fatty acids in soybean

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phospholipids is higher than that in egg yolk phospholipids. Therefore, it is difficult to obtain quality controlled pharmaceutical product using soybean lecithin. There are some differences

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between natural and synthetic sources of phospholipids that are shown in Table 4. Table 4: Differences between natural and synthetic phospholipids

Properties

Natural Phospholipids

Synthetic Phosphlipids

Stability

Unstable

Relatively stable

Purity

Less and difficult to control

High

Price

Low

High

4. Properties of phospholipids Phospholipids have the various properties such as amphiphilicity, wettability, emulsifier, stabilizer, solubilizer but it described as in specific categories: 10

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4.1. Physiological properties Phospholipids are commonly circulated in human beings, animals, plants and it is a vital substance of all cellular and sub-cellular membranes for assemble so on these basis phospholipids requires essentially for the body to retain life cycle and activity continue and also

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to arrange bilayer membranes. Phospholipids have the property of assemble of membranes and transport of lipoproteins like lipophilic triglycerides and cholesterols by hydrophilic blood. Human beings are using phospholipids as emulsifiers that form mixed micelles with cholesterol and bile acids in the gallbladder to promote the absorption of fat soluble substances and also

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using as the surface active wetting agents in the lung, pericardium, joints, etc (Kidd, 2002). The various types of phospholipids have some different properties as shown in Table 5 (Little et al.,

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1985; Dowhan et al., 2002; Pepeu et al., 1996, Lentz et al. 2003; Bansal et al., 1990; Hoch, 1992; Chiu et al., 2003).

Table 5: Different properties of phospholipids Phospho-

Structure

Polymorphic

lipids

Bilayer

Hexagonal

Cylinder

PI

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PS

Synthesize of the neurotransmitter

acetylcholine, nourishing the brain and improving intelligence.

Cone

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PE

Functions

phase

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PC

Shapes

Membrane fusion.

Improving function of nerve cells, Bilayer and

Cylinder and

regulating the conduction of nerve

Hexagonal

Cone

impulse, enhancing the memoryfunction of brain and involved in the clotting process.

Bilayer

Cylinder

Processing the transmission of messages in neural system.

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Plays an important role in mitochondrial CL

Bilayer and

Cylinder and

bioenergetics by affecting the activity of

Hexagonal

Cone

key proteins of mitochondrial inner membrane.

SM

Bilayer

Cylinder

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Key components of the stable, detergentresistant nanodomains in membranes, protein transport and sorting of membrane components.

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4.2. Physical properties

Phospholipids are soluble in aqueous and oily mediums because having a polar and non-polar portion in their structures and also have amphipathic molecules that can form various types of

phospholipids

like

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assemblies like micelles, liposomes, phytosomes and hexagonal (HII) phase. Glycerol based phosphatidylcholine,

phosphatidylinositol,

phosphatidylethanolamine,

phosphatidylserine, cardiolipin and Sphingolipids are the major component of the mammalian cell membrane for lipid fraction. 4.3. Biological properties

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After oral administration, the soya phospholipids have more than 90% absorption rate and peak plasma concentration about 6 h. In phospholipids, mainly phosphatidylcholine have used as incorporator in cell membrane for replacement of cellular phospholipids and alter the fluidity of the membrane. The essential or soya phospholipids have shown to be hepatoprotective in nature

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and prevent liver damage by alcohol, drugs and other toxins (Gundermann et al., 2011). They have also been reported to aid in clearance of serum cholesterol and increase circulating HDL levels in plasma [Cohn et al., 2008]. The presence of proportionally larger amounts of poly-

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unsaturated fatty acids in soy phospholipids makes it potentially useful in reducing the risk of coronary heart disease. Essential phospholipids have also shown to possess antilipemic and antiatherogenic effects by impeding the upsurge of total lipids in dietetic hypercholesterolemia in therapeutic as well as prophylactic doses (Leuschner et al., 1976). Dietary phospholipids also have some significant medicinal effects.

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5. Applications of phospholipids The application of phospholipids have widely used in drug delivery system in the form of liposome, phytosome, ethosome and other nano formulations of different administration route drugs like oral, topical and parenteral for the improvement of bioavailability, reduction of

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toxicity, increased the penetration, alter the release profiles. Phospholipids have also used in pharmaceutical formulations for better stability profile, good entrapment efficiency. The applications of phospholipids are described as: 5.1. In Food Technology

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Phospholipids have the property of emulsifier that enables oils to form colloid with water. Phospholipids are one of the major components of lecithin which is found in egg yolks, as well

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as being extracted from soy beans and is used as a food additive in many products and can be purchased as a dietary supplement. Lyso lecithin is typically used for w/o emulsions like margarine due to their higher HLB ratio. 5.2. In Human Body

Phospholipids are the building blocker of cellular membrane that enclose all living matter within a cell and play a vital role for healthy cellular and body functions. The human body

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naturally produces phospholipids that help as a dietary source and booster for body energy. Phospholipids are generally and most of times found in lecithin containing foods such as egg yolks, wheat germ, soy milk, lightly cooked meats and in some vegetable oils. 5.3. In Signal Transduction

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Some types of phospholipid can be used to produce products that function as secondary messengers in signal transduction. Examples include phosphatidylinositol (4,5) bisphosphate

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(PIP2), that can be split by the enzyme Phospholipase C into inositol triphosphate (IP3) and diacylglycerol (DAG), which both carry out the functions of the Gq type of G protein in response to various stimuli and intervene in various processes from long term depression in neurons to leukocyte signal pathways started by chemokine receptors. Phospholipids also interfere in prostaglandin signal pathways as the raw material used by lipase enzymes to produce the prostaglandin precursors. In plants they serve as the raw material to produce jasmonic acid, a plant hormone similar in structure to prostaglandins that mediates defensive responses against pathogens. 5.4. In Drug Delivery Systems 13

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Phospholipids based formulations in the drug delivery system can completely alter the absorption of active ingredients through the following mechanisms (Alexander et al., 2016) Modification of drug release

•

Enhance the bioavailability

•

Modification of the composition and hence the character of the intestinal location

•

Motivation of the lymphatic transport

•

Reduction of drug induced side effects

•

Modification of transdermal permeation.

•

Used as solubilizers, surfactants, antioxidants, permeation enhancer, release modifiers,

Act as carrier for various drug delivery systems.

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coating agent.

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The applications of phospholipids in the drug delivery systems are described as: (Fig. 3)

Fig 3.Different applications of phospholipids in DDS

5.4.1 Liposomes

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Liposomes are the biodegradable and biocompatible nanovesicles that have the similar structure as cellular membrane, prepared with one or more bilayers of phospholipids. As a DDS, liposomes have many advantages as follows: Delivering both hydrophilic and lipophilic drugs (Fig. 4)

•

Possessing targeting,

•

Controlled release properties,

•

Cell affinity and tissue compatibility,

•

Reducing drug toxicity and

•

Improving drug stability.

•

Liposomes can serve as the carriers of antitumor drugs, antifungal drugs, analgesic drugs,

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gene therapeutics and vaccines.

Fig 4.Structure of liposome

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During the researches, the different types of liposomes like stimuli – responsive liposomes, long – circulating liposomes, cationic liposomes and ligand – targeted liposomes have seen. The

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various examples of liposome formulations by using phospholipids are shown in Table 6. Table 6: Examples of liposome formulations by using phospholipids

Bioactive

Phospholipids

Polymers/ Others

Applications

References

Soyabean lecithin

Cholesterol

Drug target

(Cauchetier et

drug/ingredient Atovaquone

Palmityl-D-

Dipalmitoylphosphatidyl

glucuronide

choline (DPPC),

(PGlcUA)

al., 1999) Polyethylene glycol, Cholesterol

Tumour Target

(Oku'ii et al., 1996)

Dipalmitoylphosphatidyl glycerol(DPPG),

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Distearoylphosphatidyl ethanolamine (DSPE) -

1,2-dipalmitoyl-sn-glycero-3phospho choline (DPPC), 1,2-bis-[(2E, 4E)-octadeca-

Cholesterol (Chol)

Target drug

(Akama et al.,

and stearic acid

delivery

2000)

(SA)

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dienoyl]-sn-glycero-3phospho-choline (DODPC), 1-Acyl-2-[(2E,4E) octadecadienoyl]-sn-glycero-

Lyso-L-α-phosphatidyl choline -

1-palmitoyl-2-oleyl-sn-

(POPC) Atractylone

Cholesterol

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glycero-3-phosphocholine

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3-phospho-choline (AODPC),

Phosphatidylcholine (PC)

Cholesterol,

-

-

Poloxamer l88,

(Wiedmer et al., 2002)

(Zhen et al., 2011)

Tween 80,

Deoxycholic acid sodium (DAS)

Asolectin (L-α-

monophosphate

phosphatidylcholin)

Doxorubicin

Tropicamide

L-Asparaginase

CHAPS

-

(Nordmeier et al., 1992)

N-Trimethyl

Tumor

(Xian et al.,

Chitosan,

Vasculature-

2011)

cholesterol

Targeted

Egg phosphatidylcholine

Cholesterol

Gastric And

(Soehngen et

(EPC)

hemisuccinate-Tris

Intestinal

al., 1988)

salt (CHS),

Ulceration

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Indomethacin

Lecithin

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(cGMP )-

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Cyclic guanosine

Polyethylene glycol400 (PEG-400) and methylcellulose

Phospholipon 90 and

Stearylamine and

Phospholipon 90H

cholesterol

Soya lecithin

Cholesterol, Stearylamine and

Ocular delivery

(Nagarsenker et al., 1999)

Cytotoxicity

(De et al., 2012)

Dicetyl phosphate

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Soya lecithin

Clotrimazole

Cholesterol (CHOL)

Egg phospholipids (ES)

Ketoconazole

Soya lecithin

Topical

(Patel et al.,

Delivery

2010)

Cholesterol and

In vitro mucosa

(Ning et al.,

Dicetyl phosphate

permeability

2005)

(DCP)

study

Cholesterol

-

(Patel et al.,

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Tacrolimus

2009)

Pilocarpine Nitrate

Phosphatidylcholine

Cholesterol, dicetylphosphate, stearylamine

Soya lecithin

Cholesterol

-

(Murthy et al., 2015)

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5.4.2. Lipid emulsion

(Rathod et al., 2010)

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Mupirocin

-

Phospholipids have used as an emulsifier or zwitter ionic surfactant for the preparation of o/w type of injectable emulsion. The injectable emulsions are mainly composed from oil core and emulsifier on the surface that holds many more advantages like reduce the drug toxicity, target the sites for better and quick effects. The intravenous emulsions have also a long term stability profile that are suitable and useful for the large – scale industrial production of lipophilic drugs.

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The various examples of lipid formulations by using phospholipids are shown in Table 7. Table 7: Examples of Lipid formulations by using phospholipids Bioactive drug/ingredient Clarithromycin

Phospholipids

Polymers/ Others

Applications

References

Egg phospholipid (E

-

Irritation study

(Hao et al.,

EP

80), Soyabean

2007)

phospholipid (SPC) -

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Propofol

Etoposide

Soybean lecithin

Poloxamer 188,

In vivo toxicity

(Cho et al.,

poloxamer 407,

and anesthetic

2010)

polyethylene

activity

glycol 660 hydroxystearate Tween-80

Anti-tumor

(Chen et al.,

activity

2010)

Plutonic F-

Anti-tumor

(Yu et al.,

68 (F-68)

activity

2008)

(VP-16) Brucea javanica oil (BJO) and Coix seed

Egg phospholipid (E80)

oil (CSO)

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5.4.3. Permeation enhancer Phospholipids are the main component of cell membranes in the epidermis. Phospholipids have the property of liquid crystalline state at body temperature which can alter and fluidize the structure of barrier layer of membrane, resulting in an improved permeability of

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bioactive. 5.4.4. Solubility enhancer

The amphiphilic nature of phospholipids has the facility to increase the solubility of poorly aqueous soluble drug(s) or bioactive through the formation of complex or micelles or cell

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like structure. 5.4.5. Emulsion stabilizer

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Phospholipids have the ability to emulsify oils and lipophilic drugs to form water-in-oil

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or oil-in-water emulsions as shown in Fig. 5 (A) & (B).

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Fig 5.Structures of (A) conventional emulsion, (B) PEGylated emulsion 5.4.6. Solid dispersion

The various phospholipids and its derivative such as phosphatidylcholine (PC),

dipalmitoylphosphatidylcholine (DPPC) and dimyristoylphosphatidylcholine (DMPC) have been used to enhance the dissolution rate and bioavailability of poorly aqueous soluble drugs. In some cases, several phospholipids have used as a potential carrier for rapid dissolution of solid formulation. The various examples of solid dispersion formulations by using phospholipids are shown in Table 8.

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Table 8: Examples of solid dispersion formulations by using phospholipids Bioactive

Phospholipids

Polymers/ Others

Applications

References

drug/ingredient Terbinafine

-

PEG 6000,Mannitol

Antifungal

al., 2013) Polyvinyl pyrrolidone

Enhanced

(Kanaze et

Naringenin,

(PVP), polyethylene

dissolution

al., 2006)

hesperetin

glycol (PEG)

Enhanced

(Sharma et

dissolution

al., 2010)

Carvedilol

-

Itraconazole

-

Rutaecarpine

-

Aloe-Emodin

-

PVP K30

Polysorbate 80

PVP K30

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-

Hepatic disease

(Parka et al.,

treatment

2007)

Antihypertensive

(Dinga et al.,

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Naringin, hesperidin,

RI PT

Hydrochloride

(Debnath et

Polyethylene glycol 6000

2008)

Enhancement of

(Duan et al.,

Dissolution and Oral

2009)

Bioavailability

ER-34122 (5-{[1, 5-

-

bis(4-methoxy

benzamide) Curcumin

(Ikou et al., 2002)

methylcellulose (MC),

TE D

methyl}-2-chloro

Anti – inflammatory

cellulose,

phenyl)pyrazol3-yl]dimethoxy

Hydroxypropylmethyl

hydroxypropylmethyl cellulose phthalate

-

Hydroxypropylcellulose

Improved Oral

(Onoue et al.,

Bioavailability

2010)

Hydroxypropyl

Inflammatory

(Onoue et al.,

cellulose SL (HPC-SL), o-

Diseases Treatment

2011)

AC C

EP

SL (HPC-SL),

hydroxypropyl methyl cellulose acetate succinate (HPMC-AS), dimethyl sulfoxide (DMSO), dioxane, Polyethylene glycol 400 (PEG400), sodium dodecyl sulfate (SDS), and Tween-80

Tranilast

-

phenylenediamine (OPD), sodium dodecyl

19

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sulfate (SDS), and Triton X100 Ketoconazole

-

polyvinlypyrrolidone 17

Improvement of In

(Kanaujia et

(PVP 17),

Vitro Dissolution

al., 2011)

VA64) Phenytoin

-

Nitrendipine

-

RI PT

PVP–vinyl acetate (PVP–

Polyethylene Glycol

Improvement of the

(Stavchansky

6000

Bioavailability

et al., 1984)

-

(Wang et al.,

Carbopol, HPMCP, sodium

2005)

SC

dodecyl sulfate (SDS)

5.4.7. Lipospheres

M AN U

Lipospheres are the water-dispersible lipid microparticles that composed by single layer of phospholipids and solid lipid matrix stabilization surrounded in the microparticles surface. Lipospheres have the particle size range between 0.2 – 100 µm in diameter. The solid lipospheres can be prepared by multiple microemulsion technique, in which firstly form the primary microemulsion by using amide contained chemical with an aqueous solution then transferred it into an aqueous media of phospholipids. The examples of lipospheres formulation by using

TE D

phospholipids are shown in Table 9.

Table 9: Examples of lipospheres formulation by using phospholipids Bioactive drug/ingredient

Polymers/Others

Egg phosphatidyl

Polyoxyethylene

Improvement

sorbitan monoolate

Bioavailability

EP

Cyclosporin

Phospholipids

AC C

Choline

Pilocarpine

Bupivacaine

Egg lecithin

Applications

References

of

(Bekerman et al., 2004)

(Tween 80), Sorbitan monooleate (Span 80) Stearic acid

Improvement

of

lipophilicity

(Cavalli et al., 1995)

Dimyristoyl

Tristearin (TS),

Improvement of

(Toongsuwan

phosphatidyl

Tricaprin (TC), trilaurin

gelation time

et al., 2004)

Choline (DMPC),

(TL), triarachidin (TA),

Dipalmitoyl

carboxymethyl

phosphatidyl

cellulose (CMC)

Choline (DPPC) and Distearoyl

20

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phosphatidyl Choline (DSPC) Carbamazepine

Precifac

Span 20,Tween 20,

Improvement of

(Barakat et

Poloxamer

Bioavailability

al., 2006)

Topical

(Bhatia et al.,

(pluronic F-68) Lecithin

Tween 80

RI PT

Benzocaine

2007)

Aceclofenac

L-α-

Tristearin

Topical Delivery

Phosphatidylcholine,

2007)

2016)

Improvement of

(Chopparau

Phospholipin 80H,

(Tyloxapol)

Bioavailability

et al., 2013)

Cetostearyl alcohol

Improvement of

(Pandit et al.,

(CSA), Poloxamer 407

Bioavailability

2009)

Ceftriaxone sodium

Improvement of

(Attama et

(Avicel), sorbitol

drug lipophilicity

al., 2009)

Dika wax,

Activated

Improvement of

(Brown et al.,

Phospholipon 90G

charcoal, Sorbitol

Bioavailability

2013)

Bees wax, paraffin wax

Tween 80

Improvement of

(Khulbe et

Bioavailability

al., 2012)

-

Phospholipon 90H

TE D

Vinpocetine

(Singh et al.,

Triton WR 1339

Lercanidipine

Piroxicam

Oral Delivery

Phospholipon 90H,

soy lecithin

Ceftriaxone sodium

-

M AN U

Fenofibrate

Phosphatidylcholine

SC

Soybean lecithin Rifampicin

(Nasr et al.,

EP

5.4.8. Solid lipid nanoparticles (SLN)

Solid lipid nanoparticles are sub – micron sized colloidal carrier for the emulsions,

AC C

liposomes, polymeric nanoparticles in the drug delivery system that composed of physiological lipid and dispersed system like water or an aqueous surfactant solution. Solid lipid nanoparticles have unique properties such as small size (10 – 1000nm), large surface area, high drug loading and the interaction of phases at the interfaces. SLNs have also used as a carrier for intravenous applications and in pharmaceuticals and neutraceuticals. The various examples of solid lipid nanoparticle formulations by using phospholipids are shown in Table 10.

21

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Table 10: Examples of solid lipid nanoparticle formulations by using phospholipids Bioactive

Phospholipids

Polymers/ Others

Applications

References

Soy isoflavone

Softisan 601,

Topical

(Deshmukh et

aglycones

Tefose 63

Glycerol

Pluronic- F68 (PL-F68),

drug/ingredient

Repaglinide

monostearate,

sodium lauryl sulphate

tristearin, Soya

(SLS), sodium carboxy

lecithin

al., 2013)

methylcellulose (NaCMC)

Improve the

2011)

SC

Heparin, dimethylsulfoxide

HIV /AIDS

(Alukda et

albumin(BSA),

(DMSO)

Prevention

al., 2011)

Proteolysis,

(Qi et al.,

protection of

2012)

(PLL) Soybean phosphatidyl choline

Poloxamer 188

Trimyristin (TM)

TE D

Egg phosphatidyl

M AN U

hydrochloride)

Paclitaxel

(Rawat et al.,

Bovine serum

poly(L-Lysine

Tripalmitin (TP)

Cytotoxicity,

bioavailability

F68 Tenofovir

RI PT

-

functional food Enzyme Cytotoxicity

choline and

(Lee et al., 2007)

pegylated

phospholipid

Monostearin

AC C

Gonadorelin,

Cetyl palmitate

EP

Meloxicam

n-dodecyl-ferulate

®

Precifac ATO5, ®

Dynasan 114,

Propylene glycol(PG), tween

Skin permeation

(Khurana et

80, polyethylene glycol 400

and deposition

al., 2013)

(PEG 400), Carbopol 940 Polyvinyl alcohol(PVA)

Prolong release

(Hu et al., 2004)

®

TegoCare 450, Miranol

®

Improvement of

(Souto et al.,

®

bioavailability

2005)

Improving the

(Venishetty et

bioavailability

al., 2007)

Ultra C32 and Tyloxapol

®

Softisan 154

Nitrendipine

Tripalmitin,

Poloxamer 188

glyceryl mono stearate and cetyl palmitate Curcuminoids

Glyceryl

Poloxamer 188, Arlacel 165,

Improving the

(Tiyabooncha

monostearate

Dioctyl sodium

bioavailability

i et al., 2007)

22

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(GMS),

sulfosuccinate (AOT)

Stearic acid Insulin

Soybean

Sodium cholate (SC),

Improve the

(Liu et al.,

phosphatidyl

poloxamer 188

liposolubility

2007)

Poloxamer 188 (F68)

Cytotoxicity

(You et al.,

Vinorelbine bitartrate

Glyceryl

2007)

monostearate (GMS), lecithin E80 and

Glyceryl

Sodium cholate

monostearate

Stearic acid, soybean phosphatidyl choline (SPC) Penciclovir

Egg-phosphatidyl choline (EPC)

Ketoprofen

Beeswax, carnauba

Poloxamer 188, Brij 78,

Tween 80

2008)

Topical delivery

(Lv et al.,

Phospholipon R 80H

2009) Improvement of

(Kheradmand

drug release

nia et al., 2010)

Clobetasol, Polyvinyl alcohol

EP

Carbamazepine

TE D

propionate

Monostearin

delivery

Tween 80, Tween 20

wax, egg lecithin

Clobetasol

(Liu et al.,

M AN U

(GMS),

Pulmonary

SC

oleic acid Insulin

RI PT

choline (SPC)

Chitosan

Prolonged release

(Hu et al.,

and lipophilicity

2002)

Treatment of

(Nair et al.,

Epilepsy

2012)

AC C

5.4.9. Vesicular phospholipids gel

Vesicular phospholipids gels are vesicular type of drug delivery system that prepared by

using high – pressure homogenization technique, where egg phosphatidylcholine (Phospholipids) used as a carrier. The various bioactive drugs such as Vincristine, Cefrorelix, Gemcitabine, 5Fluorouracil were used for the formulation of vesicular phospholipid gels to improve better entrapment efficiency as shown in Table 11.

23

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Table 11: Examples of vesicular phospholipid gel formulations by using phospholipids Bioactive

Phospholipids

Polymers/ Others

Applications

References

Lecithin

Mannitol, stearic acid,

Topical

(Kurakula et

pharmacotherapy

al., 2012)

Prednisolone

Cholesterol Erythropoietin

Egg lecithin (E 80)

(EPO)

Trifluoroacetic acid

Improvement of

(Tian et al.,

(TFA), Triton X-100,

drug release profile

2010)

Polysorbate 80 (Tween 80), Octyl β-

Hydrogenated soy

Cholesterol

phosphatidyl choline

Vincristine

Hydrogenated egg phosphatidyl choline (EPC-3)

Exenatide acetate

Phosphatidyl choline (PC) Phospholipon 90

hydrochloride

H/ 80 H,

Cholesterol (Chol)

EDTA-Na

(Kaiser et al.,

Treatment

2003)

Antitumor activity

(Gˇthlein et al., 2002)

Type II diabetes

(Zhang et al., 2015)

Spans (Span 40),

Skin permeation and

(Rita et al.,

Tweens (Tween 20 &

skin deposition

2012)

TE D

Hydroxyzine

Anticancer

M AN U

(HSPC)

SC

D-glucopyranoside 5-Fluorouracil

RI PT

drug/ingredient

soyaphosphotidyl

Tween 60), propylene

choline 70

glycol, cholesterol

Leuprolide

Soya phosphatidyl

Medium chain tri-

Sustained release

(Longa et al.,

acetaterrh

choline (SPC)

glyceride (MCT),

delivery

2016)

AC C

5.4.10. Ethosomes

EP

ethanol

Ethosomes are phospholipid based non-invasive nanocarrier that have the ability to

penetrate the stratum corneum and enable the bioactive ingredients to reach the deep skin layer or systematic circulation. In ethsosomes, contains a high concentration of ethanol that makes it unique, stable and higher transdermal flux drug delivery carrier for skins (Fig. 6). Ethanol has an efficient permeation enhancer property that has used for the preparation of elastic ethosomes/ nanovesicles that shown in Table 12. The structural difference between ethosome, noisome, transferosome and liposome are shown in Fig. 7.

24

SC

RI PT

ACCEPTED MANUSCRIPT

TE D

M AN U

Fig 6. Structure of ethosomes

EP

Fig 7: Structural difference between (A) liposomes, (B) ethosomes, (C) niosomes and (D) transferosomes

AC C

Table 12: Examples of ethosome formulations by using phospholipids Bioactive

Phospholipids

Polymers/ Others

Applications

References

Soya lecithin

-

Topical delivery

(Barupal et

drug/ingredient Aceclofenac

Clotrimazole

-

al., 2010)

Soya Lecithin

-

Carbopol

Improvement of

(Parmar et al.,

bioavailability

2016)

Decyltrimethyl ammonium

Dermal drug

(Liu et al.,

bromide (DeTMAB),

delivery

2012)

sodium

25

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dodecylsulfate(SDS), cholesterol, Ethanol Lipoid S 100-

6GO or 5-FU

Matrine

Skin and

(Zhang et al.,

phosphatidyl

hypertrophic scar

2012)

choline (PC)

tissue

Soybean lecithin

Ethanol

Cholesterol, Ethanol

or Methylnicotinate Diclofenac sodium,

Soya phosphatidyl

Carbopol, cholesterol,

choline

Phospholipon 90

Potassium Isotretinoin

Ethanol, chloroform, methanol

Soy lecithin (Lipamin PC 50)

Lamivudine

Cholesterol, Ethanol

soyaphosphatidyl choline

permeation

al., 2009)

Transdermal

(Jain et al.,

Application

2016)

Percutaneous

(Keyao et al.,

penetration

2011)

Skin permeation

(Vijayakumar

SC

Diclofanac

Soybean lecithin

(Zhaowu et

Ethanol, propylene glycol

Topical delivery

M AN U

Simvastatin

Percutaneous

RI PT

Rhodamine

et al., 2010) (David et al., 2013)

Ethanol, Cholesterol,

Transdermal

(Jain et al.,

Sephadex-G-50,

Delivery

2007)

Carbopol 930,

Transdermal

(Bhale et al.,

pluronic F127

Delivery

2013)

Ethanol

Transdermal

(Kumar et al.,

Delivery

2016)

Ethanol, Propylene glycol,

Transdermal

(Sujitha et al.,

Carbopol 934

Delivery

2014)

Ethanol, Carbopol 934

Transdermal

(Vijayakumar

Delivery

et al., 2014)

Triton-X 100

Piroxicam

Gliclazide

Phospholipon 90

Soya lecithin

AC C

5.4.11. Phytosomes

Soya lecithin

TE D

Econazole Nitrate

Soya lecithin

EP

Etodolac

Phyto – phospholipid complex or phytosome are the micelle or cell like novel drug

delivery that formulated by the attachement of herbal extract or active phytoconstituents (flavonoids, terpenoids, tannins, xanthones) to natural or synthetic phospholipids such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine in a non-polar solvent. The water soluble drug or phytoconstituents have incorporated into stoichiometric amount of the phospholipids to achieve for better absorption and bioavailability, to cross the lipid membrane, to enter into systemic circulation. Some phytoconstituents such as green tea, hawthorn, grape seed,

26

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milk thistle, green tea, ginkgo biloba, lawsone, ashwagandha, curcumin marsupsin, olive fruits and leaves, hawthorn, grape seed, milk thistle, green tea, ginseng, Ginkgo biloba and curcumin have been used for the preparation of phyto-phospholipid complex (Fig. 8). The various

M AN U

SC

RI PT

examples of phytosome formulations by using phospholipids are shown in Table 13.

Fig 8.Structure of Phytosomes

Table 13: Examples of phytosome formulations by using phospholipids

Aegle Marmelos (Bael)

Ashwagandha

Soya lecithin

Soya lecithin

Soya lecithin

AC C

Lawsone

Rutin

Polymers/ others

TE D

drug/ingredient

Phospholipids

EP

Bioactive

Phosphatidylcholine

Cholesterol

Applications

References

Anticancer, Antioxidant

(Dhase et al., and

Antiproliferative

Potassium ferric

Antioxidant Activity

cyanide, ferric

(Keerthi et al., 2014)

Chloride -

-

Antifungal Activity,

(Singh et al.,

Anti – inflammatory

2015)

Skin permeation

(Das et al.,

(PC) (Egg lecithin)

Ellagic Acid

2015)

2014)

Lipoid® S 75, Glyceryl

Poloxamer 188,

Anti-tyrosinase

(Tokton et al.,

monostearate (GMS),

Dioctyl sodium

activity, topical

2014)

Lexol, isopropyl

sulfosuccinate

palmitate (IPP),

(AOT),

isopropyl

polyethylene glycol

myristate (IPM)

400 (PEG 400),

application

27

ACCEPTED MANUSCRIPT

Span 80 Boswellia Serrata

-

Cholesterol,

Improvement of

(Sahu et al.,

propylene glycol

bioavailability

2015)

PEG

Targeted Drug

(Li et al.,

Delivery

2014)

Soya bean

(MMC)

phosphatidylcholine

Curcumin

Hydrogenated soy

Ethylene diamine

Hepatoprotective

(Maiti et al.,

phosphatidyl choline

tetra acetic acid

activity, antioxidant

2007)

(HSPC)

(EDTA),

RI PT

Mitomycin C

thiobarbituric acid,

acid, sodium carboxy methyl

SC

trichloroacetic

cellulose, sodium

Insulin

Soyabean phosphatidylcholine (SPC)

5.4.12. Pharmacosomes

M AN U

dodecyl sulphate PLA, PLGA

Hypoglycemic

(Cui et al.,

effect and relative

2006)

bioavailability

TE D

Pharmacosomes are amphiphilic phospholipid complexes that contains phospholipid and both positive and negative charge, water loving and fat loving active ingredient or phytoconstituent.

In pharmacosomes, the lipid and active constituent have conjugated by

electron pair sharing and electrostatic forces or by formation of hydrogen bond with lipid (Fig.

EP

9). Pharmacosomes have been used for various therapeutic applications such as non-steroidal anti-inflammatory drugs, proteins, cardiovascular and antineoplastic and also for the

AC C

improvement of bioavailability and solubility as shown in Table 14.

28

SC

RI PT

ACCEPTED MANUSCRIPT

Fig 9.Structure of Pharmacosome

Table 14: Examples of pharmacosome formulations by using phospholipids Phospholipids

Applications

References

Soya

Improvement of solubility and

(Mali et al.,

bioavailability

2014)

Skin permeation

(Pal et al.,

drug/ingredient Ketoprofen

M AN U

Bioactive

phosphatidylcholine (Lipoid S-80) Rosuvastatin

Soya Lecithin

Improvement of bioavailability

TE D

Soya

Aceclofenac

phosphatidylcholine

2016) (Semalty et al., 2010)

(Lipoid S-80)

Glyceryl monostearate

Improvement of bioavailability

(Han et al., 2010)

Improvement of bioavailability

(Yiguang et al., 2006)

AC C

Acyclovir

Soya Lecithin

EP

Protopanaxadiol

5.4.13. Micelles

Micelles are the collection or supramolecular assembly of surfactant molecules that

dispersed in a liquid colloid. Micelles can be formed by various methods such as hydration, evaporation, solvent evaporation, precipitation, and sonication. Micelles are available in different shapes such as spherical, ellipsoids, cylinders and bilayers. Micelles have the amphiphilic property that contain both polar head group (hydrophilic) and long hydrophobic chain (hydrophobic). The contain part of polar head group of micelles are responsible for the formation

29

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of outer surface of micelles that shown in Fig. 10. The various examples of micelle formulations

M AN U

SC

RI PT

by using phospholipids are described in Table 15.

Fig 10.Structure of micelle

Table 15: Examples of micelle formulations by using phospholipids Bioactive

Phospholipids

drug/ingredient -

Applications

References

Monomethoxy poly (ethylene

Oral delivery

(Zhang et al.,

TE D

Cyclosporine A

Polymers/Others

glycol)

Povidone

Phosphatidyl

Sodium cholate, PVP K17

choline

-

AC C

EP

Curcumin:

Paclitaxel

Apigenin

Methoxypoly (ethylene

2010) Improvement of

(Zhu et al.,

solubility and

2010)

bioavailability Parenteral

(Song et al.,

delivery

2011)

Monomethoxy poly(ethylene

Sustained drug

(Li et al. 2013)

glycol)

release,

glycol)-b-poly(εcaprolactone-co-pdioxanone) [MPEG-P(CL-coPDO)]

-

Cytotoxicity -

Pluronic F127, Pluronic F68,

Cell toxicity and

(Zhai et al.,

Pluronic P123, Solutol HS 15

sustained drug

2013)

release Docetaxel

-

Chitosan

Oral

(Dou et al.,

administration

2014)

30

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Paclitaxel

-

Camptothecin

-

Pluronic F127,

Enhanced oral

(Dahmani et

Pluronic P188

bioavailability

al., 2012)

Poly (ethylene glycol)–

Improvement of

(Watanabe et

polybenzyl l-aspartate) block

drug

al., 2006)

copolymer (PEG-PBLA)

incorporation

Capsaicin

Oxaliplatin

RI PT

and circulation Soya bean

PVP-K30, Sodium

Enhanced oral

(Zhu et al.,

lecithin

cholate

bioavailability

2014)

Stearic acid

Chitosan

Liver-targeting

(Yan et al.,

-

®

2014)

Solutol HS15, Pluronic F127

Soya lecithin

Pluronic F 127

(Hou et al.,

release

2016)

Skin irritation

(Agrawal et

activity

al., 2010)

M AN U

Sumatriptan

Enhanced drug

SC

Icariside

6. CONCLUSION

Phospholipids are endogenous and amphiphilic substances or molecules that have different properties and applications in the drug delivery systems, so need to understand their nature, sources, different properties and therapeutic applications. According to the properties, the

TE D

phospholipids has been used to design and formulate the different types of formulation and evaluated by in-vitro and in-vivo. The applications of phospholipids in the drug delivery system are not limited because phospholipids shows the various applications such as

EP

liposomes, phytosomes, pharmacosomes, solid lipid nanoparticles, micells, vasicular gels and others. Phospholipids are also used as excipients in pharmaceutical formulations that deliver the both lipophilic and hydrophilic drugs. In some cases, phospholipids have used as a carrier

AC C

for the improvement of bioavailability, skin penetration and to cross the lipid cell membrane barrier. In this article, the sources, properties and applications are discussed with potential examples and also it will be a good useful molecule or carrier for the various drug delivery systems.

CONFLICT OF INTEREST The authors declared that there are no conflicts of interest.

31

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SC

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TE D

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EP

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AC C

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SC

Cauchetier E., Fessi H., Boulard Y., Deniau M., Astier A., Paul M., 1999.Preparation and physicochemical characterization of atovaquone-containing liposomes. Drug Development

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Chiu S., Vasudevan S., Jakobsson E., 2003. Structure of sphingomyelin bilayers: a simulation study. Biophys J. 85,3624-3635.

TE D

Chen H., Shi S., Zhao M., Zhang L., He H., Tang X., 2010. A lyophilized etoposide submicron emulsion with a high drug loading for intravenous injection: preparation, evaluation, and pharmacokinetics in rats. Drug Development and Industrial Pharmacy.36, 1444–1453. Cho J., Cho J.C., Lee P., Lee M., Oh E., 2010.Formulation and evaluation of an alternative

EP

triglyceride-free propofol microemulsion. Arch Pharm Res. 33, 1375-1387. Chopparapu S., Palghat K.L., 2013.Formulation and optimization of fenofibrate lipospheres

AC C

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Dahmani F.Z., Yang H., Zhou J., Yao J., Zhang T., Zhang Q., 2012.Enhanced oral bioavailability of paclitaxel in pluronic/LHR mixed polymeric micelles: preparation, in vitro and in vivo evaluation. European Journal of Pharmaceutical Sciences.47, 179-189. Das M.K., Kalita B., 2014.Design and evaluation of phyto-phospholipid complexes

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Figures Captions:

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Fig 1. Semi-synthetic methods of glycerophospholipids Fig 2. Total synthetic methods of glycerophospholipids Fig 3. Different applications of phospholipids in DDS Fig 4. Structure of liposome Fig 5. Structures of (A) conventional emulsion, (B) PEGylated emulsion. Fig 6. Structure of ethosome Fig 7. Structural difference between (A) liposomes, (B) ethosomes, (C) niosomes and

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(D) transferosome Fig 8. Structure of Phytosomes

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Fig 9. Structure of Pharmacosome Fig 10. Structure of micelle Table captions:

Table 1: Different types of Phospholipids

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Table 2: Differences between Sphingomyelin and Phosphatidylcholine Table 3: Differences between soybean and egg yolk Table 4: Differences between natural and synthetic phospholipids Table 5: Different properties of phospholipids Table 6: Examples of liposome formulations by using phospholipids

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Table 7: Examples of Lipid formulations by using phospholipids Table 8: Examples of solid dispersion formulations by using phospholipids Table 9: Examples of lipospheres formulation by using phospholipids Table 10: Examples of solid lipid nanoparticle formulations by using phospholipids Table 11: Examples of vesicular phospholipid gel formulations by using phospholipids Table 12: Examples of ethosome formulations by using phospholipids Table 13: Examples of phytosome formulations by using phospholipids Table 14: Examples of pharmacosome formulations by using phospholipids Table 15: Examples of micelle formulations by using phospholipids

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