SURFACTANT SEMINAR

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WELCOME 1

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Presented by- Mr. Sachin M. Jadhav M.Pharm -I (Pharmaceutics) SVERI’s College of Pharmacy, Pandharpur . Biological implications of surfactants 2

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CONTENTS:- Introduction to surfactants Introduction to biological implications of surfactants Antimicrobial activity of surfactants Surfactants as permeability enhancers Cyclodextrin inclusion complexes Mucous controlling surfactants 3

What does surfactant do ? Substance which reduces surface/interfacial tension between two phases : 

What does surfactant do ? Substance which reduces surface/interfacial tension between two phases Water & Oil are mortal enemies Surfactants acts as clamp binding Water & Oil are together Surface Tension – Force between two liquids 4

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Compounds having tendency to gather around the interface between two different materials by altering the properties of interface remarkably Serves as good mediator to settle dispute between two phases which are not friends Interface 5

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Biological implications of surfactants Introduction:- Surfactants exhibit a variety of biological effects by themselves and additional effects through modification of the activity of other substances present in the system. some effects are highly desirable like antimicrobial action, while others are undesirable like toxicity . Still surfactants are used widely in various conditions either to enhance absorption , to enhance permeability , to increase bioavailability etc . These surfactants may be used directly with the drugs or either with adjutants to show their activity. 6

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Antimicrobial activity of surfactants:- This effect is generally associated only with quaternary compounds depending on their structure. These compounds show antimicrobial activity at relatively low concentrations All surfactants show antimicrobial activity but at higher concentrations ( about 30% ) by osmotic pressure. Only few surfactants show broad-spectrum antimicrobial activity in dilute solutions . 7

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compound Staphylococcus aureus Salmonella typhi Benzalkonim chloride 150-360 175-275 Benzethonium chloride 320 200 Cetylpyridinium chloride 350 130 Cetyl trimethylammonium bromide PH 5.0 300 PH 6.7 500 Phenol coefficients of quaternary antiseptic surfactants (at 37 0 C) 8

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Mechanisms for antimicrobial activity Protein denaturation . Enzyme inhibition. Disruption of cell membrane. Cell lysis. Quaternary compounds – substantive activity + ve charge of these compounds acts with – ve charge of surfaces . Use – mouthwashes. 9

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Anionic surfactants –lysis of cell Anionic surfactants have weak antimicrobial effect. Quaternary & some phosponium compounds used as topical disinfectants, preoperative scrubs,irrigation of skin wounds. Eg . Benzethonium chloride,cetylpyridinium chloride, cetyl trimethylammonium bromide,benzalkonium chloride,cetrimide Solution of iodine in surfactants known as iodophors Eg .( phenolic derivarives ) polyoxyethylene 10

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11 Structures of surfactants

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The head of the cationic surfactant is positively charged. Cationic surfactants are quartenary ammonium compounds and they are mostly used for their disinfectant and preservative properties as they have good bactericidal properties. They are used on skin for cleansing wounds or burns. Mostly used cationic surfactants are cetrimide which has tetradecyl trimethyl ammonium bromide with minimum amount of dodecyl and hexadecyl compounds. 12

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It consists of two back to back layers made up of three types: Phospholipids, Cholesterol, Glycolipids 13 Surfactant as permeability enhancer

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Ability of surfactants to increase drug absorption This implication of a surfactant comes with the ability of surfactant to alter the barrier properties of membranes from which the drug diffuses. This effect can be highly beneficial ,but on the other hand it may damage membrane and cause toxic effect. This property of surfactant is due to its ability to solubilize lipids , remove lipids from biomembranes , or react with proteins. 14

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Mechanistic studies on surfactant-induced membrane permeability enhancement. For a surfactant to permeabilize and acutely damage the intestinal wall, it must exhibit a surface pressure of greater than 25 dynes/cm. This threshold value is related to an intrinsic property of the phospholipid membranes. Since the surfactant surface pressure is a property of the surfactant monomer not the micelle , it is an obligate step in membrane permeabilization . Above CMC, micelles may act as a depot to continuously replace aqueous surfactant monomers taken up by the membrane. some surfactants above CMC , sufficient number of monomers can cause solubilization of membrane lipids in surfactant micelles. 15

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16 Possible role of adsorbed surfactant in controlling membrane permeability and function when indogenous surfactant is adsorbed to certain membranes in the body , it can similarly modify their permeability. Since adsorption can be a rapidly reversible process, this would provide a simple physical means of controlling the overall level of physiological activity of the membrane. And an additional means of differentiating membranes according to function.

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17 The use of surfactants to enhance the permeability of peptides It has recently been reported that the permeability of peptides across Caco-2 cells, an in vitro model of the intestinal mucosa, was limited by an apically polarized efflux mechanism. Since surfactants (e.g. Cremophor EL, Polysorbate 80) have been reported to inhibit similar efflux systems in tumor cells, we determined whether they could enhance the permeability of peptides across monolayers of Caco-2 cells. Initially,mannitol flux studies were conducted to find concentrations of the surfactants that did not cause damage to the cell monolayer. Based on these studies, Polysorbate 80 and Cremophor EL were selected for further study .

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18 for [14C]- Acf (N- Mef )2NH2 polypeptide Conc.of cremophor w/v values for permeability cm/s 0 % 3.75 x 10(-6) 0.01 % 8.58 x 10(-6) 0.1 % 10.29 x 10(-6) 1 % 7.48 x 10(-6) 10% 1.46 x 10(-6)

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Cyclodextrin inclusion complexes Complexation of drugs with cyclodextrins has been used to enhance aqueous solubility and drug stability. Cyclodextrins of pharmaceutical relevance contain 6, 7 or 8 dextrose molecules (α, β, γ- cyclodextrin ) bound in a 1,4-configuration to form rings of various diameters . The ring has a hydrophilic exterior and lipophilic core in which appropriately sized organic molecules can form noncovalent inclusion complexes resulting in increased aqueous solubility and chemical stability. 19

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Structures of cyclodextrins 20

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Derivatives of β- cyclodextrin with increased water solubility (e.g. hydroxypropyl - β- cyclodextrin HP- β- CD) are most commonly used in pharmaceutical formulation. Cyclodextrin complexes have been shown to increase the stability , wettability and dissolution of the lipophilic insect repellent N, N-diethyl-m- toluamide (DEET) and the stability and photostability of sunscreens . Cyclodextrins are large molecules, with molecular weights greater than 1000Da , therefore it would be expected that they would not readily permeate the skin. 21

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Skin penetration study of Cyclodextrin Complexation with cyclodextrins has been variously reported to both Increase ,and decrease skin penetration . In a recent review of the available data, Loftsson and Masson concluded that the effect on skin penetration may be related to cyclodextrin concentration , w ith reduced flux generally observed at relatively high cyclodextrin concentrations , while low cyclodextrin concentrations resulting in increased flux. As flux is proportional to the free drug concentration, where the cyclodextrin concentration is sufficient to complex only the drug which is in excess of its solubility, an increase in flux might be expected. 22

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However, at higher cyclodextrin concentrations, the excess cyclodextrin would be expected to complex free drug and hence reduce flux. Skin penetration enhancement has also been attributed to extraction of stratum corneum lipids by cyclodextrins. complexation with HP- β-CD had no effect on the flux of cortisone through hairless mouse skin by either of the proposed mechanisms . Lipophilic drug- cyclodextrin complexes, commonly known as inclusion complexes, can be formed simply by adding the drug and excipient together, resulting in enhanced drug solubilization cyclodextrins are nontoxic in normal doses while lipophilic ones may be toxic; hence, methyl, hydroxypropyl , sulfoalkylated and sulfated derivatives of natural cyclodextrins that possess improved aqueous solubility are preferred for pharmaceutical use 23

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The permeability through biological membrane is enhanced by the presence of cyclodextrins. poorly water soluble drugs in presence of the CDs acts as permeation enhancers by carrying the drug through the aqueous barrier which exists before the lipophilic surface of biological membranes. This can also be achieved through the double characteristics of the CDs, CDs can also be used as nasal permeation enhancers acting by interaction with nasal epithelium by modifying tight junction & lipid and protein content of the membrane, which enhances the permeation of the membrane. 24

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CDs can also be utilized as permeation enhancer in pulmonary drug delivery systems . Rifampicin is a so- called concentration-dependent antibiotic, the rate and extent of bacterial kill is related to the attainment of high maximum concentration relative to the minimal inhibitory concentration. The rifampicin -CD inclusion compound can improve the lung transport of drug when nebulized with compatible pulmonary deposition and achieve required concentration of drug in broncho -alveolar epithelium lining-fluid when administered as aerosolized solution. 25

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Disadvantages- The compound has to be able to form complexes with selected ligand . The compounds with very limited solubility to start with, solubility enhancement can be very limited. Toxicity issue. Regulatory and quality control issue 26

Mucous Controlling Surfactants: 

Mucous Controlling Surfactants Mucus Composition 95% is water ,3% is protein, < .03% DNA 27

Mucus Controlling Agents: 

Mucus Controlling Agents Mucolytics - actually break down mucus Breaks down the disulfide bonds that keep mucus strands bonded Expectorants - increase the volume of bronchial secretions and increase cough volume 28

How Surface-active Agents Work: 

How Surface-active Agents Work Surfactants can be administered via aerosol in order to cause bubbles seen in edema fluid to collapse The collapse of the frothy edema fluid improves ventilation and decreases the work of breathing 29

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Artificial Surfactants Used to prevent lung complications in infants < 1350 grams Used to prevent Respiratory Distress Syndrome in low birth weight babies with evidence of immature lungs Used as a “rescue” therapy in infants with RDS Ethyl Alcohol It has been used via aerosol to treat severe frothy pulmonary edema. There is a lack of evidence that this actually works. It can also be toxic to mucus membranes. Mucus Wetting Agents Previously used to decrease surface tension of mucus thereby making it flow more easily Never actually showed clinical efficacy 30

How Exogenous Surfactant Works: 

How Exogenous Surfactant Works Used to replace the normally found surfactants absent in the lungs of premature newborns Instilled directly into the lungs of newborns through an endotracheal tube 31

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Examples Survanta ( Beractant )- made from extract of minced cow lung Other surfactant extracts made from pig lungs Synthetic Surfactants -Made from combinations of laboratory chemicals Exosurf ( Colfosceril Palmitate ) - Acetylcysteine ( Mucomist ) - for aerosol administration or direct instillation into the bronchial tree Available as 20% solution or 10% solution , Usual dose is 3 - 5 ml via SVN tid or qid 32

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References :- Martin M.Rieger M.& A.Rieger Associates,Morris Plains,New Jersey Loftsson, T.; Masson, M. Cyclodextrins in topical drug formulations: theory and practice, International Journal of Pharmaceutics, 2001; 225, 15-30. http://www.ncbi.nlm.nih.gov/pubmed/10888315 College of Pharmacy, University of Illinois at Chicago, 60612, USA . Loftsson T, Brewter ME. “Cyclodextrin as Pharmaceutical Excipients ”. Pharma Manager, 1997; 5, 22-31 . International Journal of Pharmaceutical Sciences Review and Research www.globalresearchonline.net , Volume 5, Issue 1 , November – December 2010; Article-007 33

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References :- Possible role of adsorbed surfactant in controlling membrane permeability and function Department of Physiology, University of New England, Armidale N.S.W. 2351, Australia http://www.sciencedirect.com/science/article/pii/0306987789900194 The use of surfactants to enhance the permeability of peptides through Caco-2 cells by inhibition of an apically polarized efflux system. http://www.ncbi.nlm.nih.gov/pubmed/8710741 Antimicrobial Activity of Native and Synthetic Surfactant Protein B Peptides http://www.jimmunol.org/content/176/1/416.abstract Antibacterial activity of surfactants against Escherichia coli cells is influenced by carbon source and anaerobiosis . http://www.ncbi.nlm.nih.gov/pubmed/12147079 34

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References :- Mucous Controlling Drugs; Surfactants By Jim Clarke. http://onlinelibrary.wiley.com/doi/10.1002/ps.2780060411/abstract Effect of surfactants on the antibacterial activity of preservatives. http://www.ncbi.nlm.nih.gov/pubmed/1758904 Basics and Potential Applications of Surfactants - A Review,International Journal of PharmTech Research Vol.1, No.4, pp 1354-1365, Oct-Dec 2009 35

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