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Kawsar, et al / Journal of SUB 4(2): 89-102, 2013
Phosphatidylcholine: A Review
Md. Hassan Kawsar1, Md. Firoz Khan2 and
Md. Akbar Hossain3
Abstract: In recent years Phosphatidylcholine has greatly impacted the
drug delivery technology. The very first and most important advantage of
phospholipid based vesicular system is the compatibility of
phospholipids with membrane of human either internal membrane or
skin (external membrane). For a drug to be absorbed and distributed into
organs and tissues and eliminated from the body, it must pass through
one or more biological membrane(s)/ barrier(s) at various locations. Such
a movement of drug across the membrane is called drug transport. For
the drugs to be delivered to the body should cross the membranous
barrier, either it would be from oral route or topical/transdermal route.
Therefore the phospholipid based carrier systems are of considerable
interest in this era. A number of drug delivery systems are based entirely
on Phosphatidylcholine such as Liposomes, Ethosomes, Phytosomes,
Transferosomes and Nanocochelates.
Keywords: Phosphatidylcholine, Vesicular systems, Membrane
Introduction
Since last decades the popularity of vesicular systems has been
increased because of a lot of advantages associated with it.
Vesicular systems are mainly composed of phospholipids.
Phospholipids are amphipathic (having affinity forboth aqueous
and polar moieties) molecules as they have a hydrophobic tail and
a hydrophilic or polar head.
The hydrophobic tail is composed of two fatty acid chains containing 10-24 carbon atoms and each chain may be saturated or unsaturated (upto 6 double bonds). The polar end of the molecule is mainly phosphoric acid bound to a water-soluble molecule. The hydrophilic and hydrophobic domains/ segments within the molecular geometry of amphiphilic lipids orient and self organize in order supramolecular structure when confronted with solvents1. 1 Associate Professor, Department of Pharmacy, State University of Bangladesh 2 Lecturer, Department of Pharmacy, State University of Bangladesh 3 Assistant Professor, Department of Pharmacy, Dhaka International University Kawsar, et al / Journal of SUB 4(2): 89-102, 2013
Some commonly used synthetic phospholipids are dioleoyl-phosphatidyl-choline ethanolamine (DOPE), Distearoyl-phosphatidyl-choline (DSPC), Distearoyl-phosphatidyl-ethanolamine (DSPE)2. Figure 1: Phophatidylcholine3
Among all these phospholipids, phosphatidylcholine classes of phospholipids are very important in the drug delivery technology. The very first and most important advantage of phospholipid based vesicular systems is the compatibility of phospholipids with membrane of human either internal membrane as well as skin. For a drug to be absorbed and distributed into organs and tissues and eliminated from the body, it must pass through one or more biological membranes/ barriers at various locations. Such a movement of drug across the membrane is called drug transport. The cellular membrane consists of a double layer of amphiphilic phospholipids molecules arranged in such a fashion that their hydrocarbon chains are oriented inwards to form the hydrophobic or lipophilic phase and their polar heads oriented to form the outer and inner hydrophilic boundaries of the cellular membrane that face the surrounding aqueous environment. Globular protein molecules are associated on either side of these hydrophilic boundaries and also interspersed within the membrane structure. In short, the membrane is a mayonnaise sandwich where a bimolecular layer of lipids is contained between two parallel monomolecular layers of proteins. The hydrophobic core of the membrane is responsible for the relative impermeability of polar molecules. Aqueous filled pores or perforations of 4 to 10A° in diameter are also present in the membrane structure through which Kawsar, et al / Journal of SUB 4(2): 89-102, 2013
organic ions and small organic water-soluble molecules like urea can pass. In general, the biomembrane acts like a semipermeable barrier permitting rapid and limited passage of some compounds while restricting that of others4. The GI linings constituting the absorption barrier allows most nutrients like glucose, amino acids, fatty acids, vitamins, etc., to pass rapidly through it into the systemic circulation but prevent the entry of certain toxins and medicaments. Thus, for a drug to get absorbed after oral administration, it must first pass through this biological barrier4. And for topical/ transdermal delivery of drugs, it has to cross the skin. During the past decades there has been wide interest in exploring new techniques to increase drug absorption through skin5,6,7. Topical delivery of drugs by lipid vesicles has evoked a considerable interest. The skin, the heaviest single organ of the body, combines with the mucosal linings of the respiratory, digestive, and urogenital tracts to form a capsule, which separates the internal body structures from the external environment. The skin has various functions such as protection from external environment, maintenance of body posture, regulation of temperature, etc. Including these various primary functions, it also acts as a site for drug delivery. The skin itself has two main layers: the epidermis, which is the outermost layer of the skin, covering the dermis that is the active part of the skin, holding the hair muscles, blood supply, sebaceous glands and nerve receptors. There is a fat layer underneath the dermis. The skin is a very heterogeneous membrane and has a variety of cell types, but the layer that controls the penetration of drugs is called the stratum corneum and despite its thickness of only 15–20 μm, it provides a very effective barrier to penetration. The permeation of the drug through the skin has several routes: transcellular, intercellular, and appendageal (through eccrine glands or hair follicles). Since the appendages occupy a very low surface area, this means of permeation is less significant under normal conditions8. Nevertheless, in iontophoretics delivery transdermal route is more significant9. So for the drugs to be delivered to the body should cross the membranous barrier. Either it would be from oral route or Kawsar, et al / Journal of SUB 4(2): 89-102, 2013
topical/transdermal route. Therefore the phospholipid based carrier systems are of considerable interest in this era. History: Phosphatidylcholine was first isolated in Odessa, Ukraine
some 50 years ago. This was followed by further research in
Germany and Russia. It has been marketed by Sanofi-Aventis for
over 30 years and, at present; the substance phosphatidylcholine is
registered in 53 countries. Its main application nowadays lies in the
intravenous treatment and prevention of fat embolisms in
polytraumatized patients in the treatment of metabolic disorders
and as a liver-protecting substance10.
Mechanism of Vesicle Formation: In aqueous medium the
molecules in self-assembled structures are oriented in such a way
that the polar portion of the molecule remains in contact with the
polar environment and at the same time shields the non-polar part.
Among the amphiphilic used in the drug delivery, viz soaps,
detergents, polar lipids, the latter (polar lipids) are often employed
to form concentric bilayered structures. However, in aqueous
mixtures these molecules are able to form various phases, some of
them are stable and others remain in the metastable state11. At high
concentrations of these polar lipids, liquid-crystalline phases are
formed that upon dilution with an excess of water can be dispersed
into relatively stable colloidal particles. The macroscopic
structures most often formed include lamellar, hexagonal or cubic
phases dispersed as colloidal nanoconstructs (artificial membranes)
referred to as liposomes, hexasomes or cubosomes, respectively12.
The
Phophatidylcholine (PC). Amphipathic molecule in which a glycerol bridge link to a pair of hydrophilic polar head group, phosphatidylcholine. Fatty chains are embedded in the hydrophilic inner region of the membrane surface, the hydrophilic head group, including the phosphate portion, points out towards the hydrophilic aqueous environment. Molecules of PC are not soluble rather dispersible in aqueous environment and they align themselves closely in planer bilayer sheets to minimize the unfavorable interactions between the bulk aqueous phase and long hydrocarbon fatty acyl chain. Such interactions are completely eliminated when the sheets fold over Kawsar, et al / Journal of SUB 4(2): 89-102, 2013
themselves to form closed sealed and concentric vesicles. The large free energy change between an aqueous and hydrophobic environment explains the most favored orientation of lipids to assemble confrontation between aqueous and hydrophobic domains. This distinctive behavior derives in the lowest free energy state and hence ensures the maximum stability to self-assembled structures11. The phosphatidylcholine and its synthetic analogues differ markedly from amphiphilic molecules of differ markedly from amphiphilic molecules of other origin (soaps, detergents, lysolecithin) in that they preferably orient to form bilayer sheets rather than micellar structures. This presumably attributed to the double fatty acid chain that imparts the molecule an overall tubular shape are more suitable for assemblage in planer sheets. In contrast, the detergent molecule with a polar head and single acyl chain has a conical shape and facilitate the formation of spherical micellar structures. Depending on the hydrophobic environment and aqueous phase, homogenous smectic phases of parallel lipid bilayers (lyotropic phases) or heterogeneous dispersion of multilamellar or single-walled vesicles can be observed. At lower water content and higher temperature, other lyotropic liquid crystalline phases exist, such as the hexagonal, the cubic and the ribbon phases. Advantages of Phospholipid Based Carrier Systems in
Comparison to Other Delivery Systems
1. These systems show enhanced permeation of drug through skin
for transdermal and dermal delivery. 2. These are platform for the delivery of large and diverse group of drugs (peptides, protein molecules). 3. Their composition is safe and the components are approved for pharmaceutical and cosmetic use. 4. Low risk profile- the toxicological profiles of the phospholipids are well documented in the scientific literature. 5. High market attractiveness for products with proprietary technology. Relatively simple to manufacture with no complicated technical investments required for production of Ethosomes. Kawsar, et al / Journal of SUB 4(2): 89-102, 2013
6. The vesicular system is passive, non-invasive and is available for immediate commercialization. Brief Introduction to the Phospholipid Based Carrier Systems
Liposome:
Liposomes are colloidal, vesicular structures composed
of one or more lipid bilayers surrounding an equal numbers of
aqueous compartments. Since, 1960's pharmaceutical researchers
used liposomes as therapeutic tools in medicinal field. A number
of liposomal formulations of such drugs have available in the
market such as Doxil® (Doxorubicin), Fungizone® (Amphotericin-
B), Novasome® (Smallpox vaccine) and NyotranTM (Nystatin).
Liposomes used as potential carriers in field like tumor targeting,
gene
immunomodulation and skin care and topical cosmetics products. The present review highlights the composition, method of preparation, characterization, therapeutic applications of liposomes and its marketed products13. Ethosome: Ethosomes are soft, malleable vesicles composed
mainly of phospholipids, ethanol (relatively high concentration)
and water. These "soft vesicles" represents novel vesicular carrier
for enhanced delivery to/through skin. The size of Ethosomes
vesicles can be modulated from tens of nanometers to microns.
Ethosomes provide a number of important benefits including
improving the drug's efficacy, enhancing patient compliance and
comfort and reducing the total cost of treatment. The Ethosomes
were found to be suitable for various applications within the
pharmaceutical,
nutraceutical markets14. Phytosome: Phytosome are created when the standardized extract
and active ingredients of an herb are bound to the phospholipids on
a molecular level. Phytosome structures contain the active
ingredients of the herb surrounded by the phospholipids. The
phospholipid molecular structure includes a water-soluble head
and two fat-soluble tails, because of this dual solubility, the
phospholipid acts as an effective emulsifier which is also one of
the chief components of the membranes in our cells. Phytosomes
are advanced forms of herbal products that are better absorbed,
Kawsar, et al / Journal of SUB 4(2): 89-102, 2013
utilized, and as a result produce better results than conventional herbal extracts15. Transferosomes: In functional terms, may be described as lipid
droplets of such deformability that permits its easy penetration
through the pores much smaller than the droplet size.
Transferosomes have been developed in order to take advantage of phospholipids vesicles as transdermal drug carrier. These self optimized aggregates, with ultraflexible membrane, are able to deliver the drug reproducibly either into or through the skin, depending on the choice of administration or application, with high efficiency. Transferosomes overcome the skin penetration difficulty by squeezing themselves along the intracellular sealing lipids of stratum corneum. There is provision for this, because of the high vesicle deformability, which permits the entry due to mechanical stress of surrounding, in a self adapting manner. Flexibility of transferosomes membrane is achieved by mixing suitable surface active agents in proper ratios. The resulting flexibility of transferosome membrane minimizes the risk of complete vesicle rupture in the skin and allows transferosomes to follow the natural water gradient across the epidermis, when applied under non occlusive condition. Transferosomes can penetrate the intact stratum corneum spontaneously either through intracellular route or transcellular route16. Long circulating liposomes: The major limitation of liposomes is
their fast elimination from the blood and localization in
reticuloendothelial system primarily kupfer cells of liver.
Different methods have been reported to achieve long circulation of liposomes in vivo, including modification with certain lipids such as monosialoganglioside, palmityl-D-Glucoronic acid and PEG-PE. These liposomes show significantly longer circulation in blood than the liposomes without these lipids17, 18, 19, 20, 21. Nanocochelates: Nanocochelates consists of a purified soy based
phospholipid that contains at least about 75% by weight of lipid
which can be phosphatidyl-serine (PS), dioleoyl-phosphatidyl-
serine (DOPS), phosphatidic acid (PA), phosphatidyl-inositol (PI),
phosphatidyl glycerol (PG) and /or a mixture of one or more of
Kawsar, et al / Journal of SUB 4(2): 89-102, 2013
these lipids with other lipids. Additionally or alternatively, the lipid can include phosphatidylcholine (PC), phosphatidyl-ethanolamine (PE), diphosphotidyl-glycerol (DPG), dioleoyl phosphatidic acid (DOPA), distearoyl phosphatidylserine (DSPS) and phosphatidylserine phosphatidylgycerol (DPPG)7. A multivalent cation, which can be Zn+2 or Ca+2 or Mg+2 or Ba+2 and a drug, which can be protein, peptide, polynucleotide, antiviral agent, anesthetic, anticancer agent, immunosuppressant, steroidal anti inflammatory agent, non steroidal anti inflammatory agents, tranquilizer, nutritional supplement, herbal product, vitamin and/or vasodilatory agent22. Table 1: Therapeutic Applications of Liposomes
Targeted
Application
Diseases
Mycotic infection Decrease glucose Diabetic mellitus enzyme inhibitor Phosphodiesterase Protein synthesis inhibition Inhibition of nerve surface with pain sensory nerves Inhibit ergosterol Candida-albican's Rhamnose receptor Urtecaria, allergic free nerve ending Kawsar, et al / Journal of SUB 4(2): 89-102, 2013
Protein synthesis Ocular delivery, inflammatory Meningococal, Inhibit synthesis of bacterial cell wall reductase Inhibit DNA/ Protein synthesis Table 2: List of Marketed Products of Liposome
Marketed
Drug used
Target diseases
product
DoxilTM or
Kaposi's sarcoma Kaposi's sarcoma, cancer fungal infections, fungal infections, Prostaglandin-E1 Dry protein free diseases in babies Smallpox vaccine Avian retrovirus Kawsar, et al / Journal of SUB 4(2): 89-102, 2013
institute, Switzerland Refractory ovarian cancer Metastatic breast Bacterial infection NeXstar, USA Aronex Pharm, Kaposi's sarcoma Shigella Flexneri Shigella Flexneri Shigella flexneri 2A Infection Systemic fungal Table 3: Therapeutic Applications of Ethosomes
Comments
Treatment of Herpetic Improved drug delivery Treatment of AIDS Improved transdermal flux Increased drug entrapment efficiency, reduced side Trihexypenidyl HCl Parkinsonian syndrome effect & constant systemic Efficient healing of S. Improved drug penetration aureus-induced deep and systemic effect dermal infections Improved therapeutic Treatment of Diabetes efficacy of drug Treatment of male Enhance skin permeation hypogonodism Prevents inflammation Significant accumulation of the drug in the skin Hair growth promotion Higher skin retention effect Treatment of dermal Reduced drug toxicity
Table 4: Therapeutic Applications of Phytosomes
Molecule

Application
Targeted Diseases
Enhance bioavailability due to their complex with phospholipids and Botanical extracts Diabetic mellitus delivers faster and improved absorption in intestinal tract. To be better absorbed in intestinal For treatment of Kawsar, et al / Journal of SUB 4(2): 89-102, 2013
botanical extract Infections More skin Transdermal immunization penetration and have junction protein a high lipid profile Table 5: Therapeutic Applications of Transferosomes
Application
Targeted Diseases
Decreases glucose level Diabetic mellitus Interferons, for example Antiviral, antiproliferive For treatment of leukocytic derived interferone-α (INF-α) immunomodulatory effects Soluble protein like integral membrane protein, human serum Transdermal immunization albumin, gap junction protein Corticosteroids Treatment of skin diseases Skin diseases For the operation Topical anesthesia Table 6: Therapeutic applications of Nanocochelates Molecule
Application Targeted Diseases

Application
Stabilize and protect an Sialic acid and glyco- extended range of micronutrients and the potential to increase the nutritional value of processed foods To deliver proteins, peptides for vaccine and gene therapy applications In the delivery of For reducing the toxicity antibacterial agents: and improving the bactericidal activity Conclusion
A number of drug delivery systems are emerging today. But the
delivery systems based on Phosphatidylcholine are of much
importance because of intense advantages associated with them.
The delivery systems described above have proved their ability and
efficacy to deliver the active moiety to the desired location of the
body. But this is not the limit of these Phosphatidylcholine based
drug delivery systems. In future the Phosphatidylcholine based
Kawsar, et al / Journal of SUB 4(2): 89-102, 2013
drug delivery systems can be utilized to the maximum to proof these systems as a revolution in drug delivery technology. This review is only an attempt to attract the attention of researchers to these types of systems. References
1. Lasic, D.D.; 1995; Liposome- A Practical Approach; Oxford University Press, Oxford; pp. 112-114. 2. Vyas, S.P. and Khar, R.K.; 2002; Liposome, Targeted & Controlled Drug Delivery; CBS Publisher & Distributors, New Delhi; p. 174. mm.1e0189bdb.html 4. Brahmankar, D.M. and Jaiswal, S.B.; 2006; Biopharmaceutics and Pharmacokinetics– A Treatise; Ed. First, Reprint, Vallabh Prakashan, Delhi; pp. 6-7. 5. Barry, B.W.; 2001; Novel mechanisms and devices to enable successful transdermal drug delivery; European Journal of
Pharmaceutical Sciences
; 14:101-114.
6. Williams, A.; 2003 Transdermal and topical drug discovery; 1st ed.; Pharmaceutical Press, London; pp. 122-132. 7. Honeywell- Nguyen, P.L. and Bouwstra, J.A.; 2005; Vehicles as a tool for transdermal and dermal delivery; Drug Discov. Today:
techno l
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8. Hadgraft, J.; 2001; International Journal of Pharmaceutics; 184(1):1-6.
9. Jadoul, A., Doucet, J., Durand, D. and Preat, V.; 1996; Journal of Control Release; 42:165.
10. Hasengschwandtner, F.; Phosphatidyl- choline treatment to induce lipolysis; Journal of Cosmetic Dermatology; 4:308–313.
11. Lasic, D.D.; 1993; Liposomes; From biophysics to applications; Elsevier, New York; p. 9. 12. Lasic, D.D.; 1998; Trends in Biotechnol.; 16:307.
13. Patel, S.S; 2006; Liposome- A versatile platform for targeted delivery of drugs; Pharmainfo.net; 4(5):1-10.
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14. Patel, S.S; 2007; Ethosomes A Promising Tool for Transdermal Delivery of Drug; Pharmainfo.net; 5(2):1-10.
15. Darshan, D.; 2007; Phytosome- A Novel Dosage Structure; Pharmainfo.net; 5(1):1-10.
16. Jain, S., Sapee, R. and Jain, N.K.; 1998; Proultraflexible lipid vesicles for effective transdermal delivery of norgesterol.; Proceedings of 25th conference of C.R.S.; U.S.A.; pp. 32-35. 17. Allen, T.M. and Chonn, A.; 1987; Large unilamellar liposomes with low uptake into the reticuloendothelial system; FEBS Lett.; 223:42–
46.
18. Klibanov, A.L., Maruyama, K., Torchilin, V.P. and Huang, L.; 1990; Amphipathic polyethyleneglycols effectively prolong the circulation
time of liposomes; FEBS Lett.; 268:235–237.
19. Blume, G. and Cevc, G.; 1990; Liposomes for the sustained drug release in vivo; Biochim. Biophys. Acta; 1029:91–97.
20. Papahadjopoulos, D., Allen, T.M., Gabizon, A., Mayhew, E., Matthay, K., Huang, S.K., Lee, K.D., Woodle, M.C., Lasic, D.D.,
Redemann, C. and Martin, F.J.; 1991; Sterically stabilized
liposomes: improvements in pharmacokinetics and antitumor
therapeutic efficacy; Proc. Natl. Acad. Sci.; 88:11460-11464.
21. Namba, Y., Sakakibara, T., Masada, M., Ito, F. and Oku, N.; 1989; 1-O-Palmityl-glucuronate endows liposomes with long half-life in vivo; Chem. Lett.; pp. 2145–2148. 22. Tan, F. and Zarif, L.; 2005; Cochleates made with purified soy phosphatidylserine; European patent; 1494:690.

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Acupuncture and depression

ACUPUNCTURE AND DEPRESSION About depression Depression is a common mental health problem that affects people of all genders, ages, and backgrounds. About two thirds of adults will at some time experience depression severe enough to interfere with their normal activities (Mintel/YouGov, 2006, Stewart et al, 2004). Women are twice as likely as men to become depressed (Stewart et al, 2004) partly due to hormone changes occurring pre-menstrually, at menopause, during pregnancy or after childbirth. Depression is estimated to cost the UK £7.5 billion a year in medication, benefits and lost working days (McCrone et al, 2008). The World Health Organization predicts that by 2020 depression will be second only to chronic heart disease as an international health burden (WHO, 2008).

aaemrsa.org

Resident & Student Association rESidENt PrESidENt'S MESSagE 2012 Brings New Projects for aaEM/rSa Teresa M. Ross, MDAAEM/RSA President JM is a 35yo female with a history of recurrent calcium chloride, etomidate, fentanyl, furosemide, ketorolac, migraines. labetalol, ondansetron, phenytoin, prochlorperazine and rabies immunoglobulin.6 The majority of the medications are for iv use,