Satish Ethosomes2

Slide 1: 

Welcome 4/7/2011 1

ETHOSOMES : 

ETHOSOMES Seminar by N.Satish B.Pharmacy 4th year narra_satish@rediffmail.com Priyadarshini College Of Pharmaceutical Sciences Chowdharyguda,Narapally,ghatkesar(mandal)RangaReddy. 4/7/2011 2

CONTENTS : 

CONTENTS Introduction to TDDS Ethosomes Skin Advantages Disadvantages Mechanism of penetrarion Additives used in ethosomes Preparation of ethosomes Characterisation of ethosomes Applications Future aspects Conclusion References 4/7/2011 3

Introduction to TDDS : 

Introduction to TDDS Definition: Transdermal drug delivery systems are defined as self-contained, discrete dosage forms which, when applied to the intact skin, deliver the drug, through the skin, at a controlled rate to the systemic circulation For transdermal delivery of drugs, stratum corneum (SC) is the main barrier for permeation of drug. Now a days liposomes,niosomes,transferosomes and ethosomes (vesicular and non invasive drug delivery)are used to increase the permeation of drug through the stratum corneum. 4/7/2011 4

: 

4/7/2011 5

LAYERS OF SKIN : 

LAYERS OF SKIN The Òbrick and mortarÓ arrangement of corneocytes, Flattened mononucleated keratinocytes, with interspersed lipids and proteins makes the stratum corneum approximately 1000 times less permeable than other biological membranes. 4/7/2011 6

Layers of skin : 

Layers of skin Skin is an important site of drug application for both local and systemic effects. 3 layers: Epidermis: Stratum corneum Stratum granulosum Stratum spinosum Basal layer Dermis: Papillary dermis layer Reticular dermis layer Sub cutaneous layer 4/7/2011 7

Slide 8: 

The non-invasive approaches for providing transdermal drug delivery of various therapeutics substances are1 1) Drug and vehicle interactions    a) Selection of correct drug or prodrug    b) Chemical potential adjustment    c) Ion pairs and complex coacervates    d) Eutectic systems 2) Stratum corneum modification   a) Hydration   b) Chemical penetration enhancers 3) Stratum corneum bypassed or removed    a) Microneedle array   b) Stratum corneum ablated    c) Follicular delivery 4) Electrically assisted methods    a) Ultrasound ( Phonophoresis, Sonophoresis )    b) Iontophoresis    c) Electroporation    d) Magnetophoresis    e) Photomechanical wave 5) Vesicles and particles     a) Liposomes and other vesicles     b) Niosomes     c) Transfersomes 4/7/2011 8

ETHOSOMES : 

ETHOSOMES Ethosomes are noninvasive delivery carriers that enable drugs to reach the deep skin layers and/or the systemic circulation. Ethosomes are “soft vesicles” represents novel vesicular carries for enhanced delivery of active agents to/through skin. They are composed mainly of phospholipids, (phosphatidylcholine, phosphatidylserine, phosphatitidic acid), high concentration of ethanol and water  [3]. The size of Ethosomes vesicles can be modulated from tens of nanometers to microns. Touitou discovered and investigated lipid vesicular systems embodying ethanol in relatively high concentration and named them ethosomes [8]. 4/7/2011 9

INFLUENCE OF HIGH ALCOHOL CONTENT : 

INFLUENCE OF HIGH ALCOHOL CONTENT Ethanol is an established efficient permeation enhancer[4,5]. The concentration of ethanol (20-50%) in vesicular form in ethosomes is the main reason for their better skin permeation ability. Due to high ethanol concentration the ethosomal lipid membrane was packed less tightly than conventional vesicles but possessed equivalent stability as other vesicular delivary systems. 4/7/2011 10

ADVANTAGES : 

ADVANTAGES Ethosomes are enhanced permeation of drug through skin. Ethosomes are platform for the delivery of large and diverse group of drugs. Ethosome composition is safe and the components are approved for pharmaceutical and cosmetic use. Low risk profile. High patient compliance: can be used in the form of gel, patch. High market attractiveness for products with proprietary technology. Various application in Pharmaceutical, Veterinary, Cosmetic field. It contains non‐toxic raw material in formulation. 4/7/2011 11

DISADVANTAGES OF ETHOSOMES : 

DISADVANTAGES OF ETHOSOMES Drugs that require high blood levels cannot be administered – limited only to potent molecules, those requiring a daily dose of 10mg or less. Ethosomal administration is not a means to achieve rapid bolus type drug input, rather it is usually designed to offer slow, sustained drug delivery. Adequate solubility of the drug in both lipophilic and aqueous environments, to reach dermal microcirculation and gain access to the systemic circulation. The molecular size of the drug should be reasonable that it should be absorbed percutaneously. Adhesive may not adhere well to all types of skin. Uncomfortable to wear. May not be economical. Skin irritation or dermatitis due to excipients and enhancers of drug delivery system. 4/7/2011 12

MECHANISM OF DRUG PENETRATION : 

MECHANISM OF DRUG PENETRATION 1. Ethanol effect Ethanol acts as a penetration enhancer through the skin. Ethanol penetrates into intercellular lipids and increases the fluidityof cell membrane lipids and decrease the density of lipid multilayerof cell membrane. 2. Ethosomes effect Increased cell membrane lipid fluidity caused by the ethanol results increased skin permeability. The ethosomes permeates very easily inside the deep skin layers, where it got fused with skin lipids and releases the drugs into deep layer of skin. 4/7/2011 13

Mechanism of penetration of drug : 

Mechanism of penetration of drug 4/7/2011 14

Slide 15: 

Different Additives Employed In Formulation of Ethosomes 4/7/2011 15

Method for Preparing Ethosomes : 

Method for Preparing Ethosomes There are two methods for preparing ethosomes: Cold Method Hot method 4/7/2011 16

COLD METHOD : 

COLD METHOD Phospholipid +Drug Dissolve in ethanol Add propylene glycol Mixture heated to 30±1 °C Double distilled water is added with constant stirring for 5 min at 30°C Vesicle size is contolled by using sonication[10] and extrusion [11]method Formulation is stored in refrigerator[9] 4/7/2011 17

HOT METHOD : 

HOT METHOD Phospholipid is disersed in water by heating in waterbath at 40°C Colloidal solution is obtained In a separate vessel ethanol and propylene glycol are mixed and heated to 40°C The organic phase is added to aqueous phase Drug is dissolved in water or ethanol based on hydrophilic or hydrophobic properties Vesicle size is contolled by probe sonication[10] or extrusion [11]method 4/7/2011 18

Characterization of ethosomes : 

Characterization of ethosomes Drug Entrapment Efficiency Vesicle Size and Size distribution Permeation Characteristics Vesicle Skin Interaction Study Vesicle morphology Stability studies Drug uptake studies Elasticity Measurement 4/7/2011 19

Characterization of ethosomes : 

Characterization of ethosomes Vesicle morphology: Visualization by electron microscopy reveals an ethosomal formulation exhibited vesicular structure 300-400 nm in diameter. 4/7/2011 20

Slide 21: 

4/7/2011 21

Vesicle Size and Size distribution : 

Vesicle Size and Size distribution As the alcohol concentration increases the vesicular size decreases. As the phospholipid concentration increases the vesicular size increase 4/7/2011 22

Permeation Characteristics : 

Permeation Characteristics Srudy of permeation characteristics of the drug zidovudine by various routes 4/7/2011 23

Vesicle skin interaction study : 

Vesicle skin interaction study For evaluating the mechanism of better skin permeation of ethosomal formulation different visualization techniques used are transmission electron microscopy, fluorescence microscopy and confocal scanning laser microscopy{12-17}. 4/7/2011 24

Slide 25: 

4/7/2011 25 Fluorescence photomicrograph of rat skin after application of hydrophilic fluorescence probe 6-carboxyfluorescein from (A) Liposomal formulation (x 100); (B) Ethosomal formulation (x100) and Rhodamine 123 - (C) Liposomal formulation; (x 100) (D) Ethosomal formulation (x100).

Different Studies Related to the Application of Ethosomes as a Carrier System : 

Different Studies Related to the Application of Ethosomes as a Carrier System Pilosebaceous Targeting Transdermal Delivery of Hormones Delivery of anti-parkinsonism agent Transcellular Delivery Topical Delivery of DNA Delivery of Anti-Arthritis Drug Delivery of Antibiotics Delivery of Anti-Viral Drugs Delivery of Problematic drug molecules 4/7/2011 26

PILOSEBACEOUS TARGETING : 

PILOSEBACEOUS TARGETING Hair follicles and sebaceous glands are increasingly being recognized as potentially significant elements in the percutaneous drug delivery. Interest in pilosebaceous units has been directed towards their use as depots for localized therapy, particularly for the treatment of follicle-related disorders such as acne or alopecia. Furthermore, considerable attention has also been focused on exploiting the follicles as transport shunts for systemic drug delivery . Minoxidil is a lipid-soluble drug used topically on the scalp for the treatment of baldness by pilosebacious delivery. 4/7/2011 27

Transdermal Delivery of Hormones : 

Transdermal Delivery of Hormones Oral administration of hormones is associated with problems like high first pass metabolism, low oral bioavailability and several dose dependent side Effects. Transdermal delivery of hormones increased the absorption of drug Eg: Nearly 30-times higher skin permeation of testosterone from ethosomal formulation as compared to that marketed formulation. The amount of drug deposited was significantly higher in case of ethosomal formulation 4/7/2011 28

Delivery of anti-parkinsonism agent : 

Delivery of anti-parkinsonism agent Ethosomal formulation of psychoactive drug trihexyphenidyl hydrochloride (THP) and compared its delivery with that from classical liposomal formulation. THP is a M1 muscarinic receptors antagonist and used in the treatment of Parkinson disease. THP has a short biological half-life (3hr) and its oral administration is difficult due to motor disorders and neurogical manifestations associated with parkinsonian syndrome . skin permeation potential of ethosomal-THP formulation and its use for better management of Parkinson disease. 4/7/2011 29

Delivery of Antibiotics : 

Delivery of Antibiotics Topical delivery of antibiotics is a better choice for increasing the therapeutic efficacy of these agents. Conventional oral therapy causes several allergic reactions along with several side effects. Conventional external preparations possess low permeability to deep skin layers and subdermal tissues . Ethosomes can circumvent this problem by delivering sufficient quantity of antibiotic into deeper layers of skin. Ethosomes penetrate rapidly through the epidermis and bring appreciable amount of drugs into the deeper layer of skin and suppress infection at their root. The results of this study showed that the ethosomal formulation of antibiotic could be highly efficient and would over come the problems associated with conventional therapy. 4/7/2011 30

Delivery of Anti-Viral Drugs : 

Delivery of Anti-Viral Drugs Zidovudine is a potent antiviral agent acting on acquired immunodeficiency virus. Oral administration of zidovudine is associated with strong side effects. Ethosomes could increase the transdermal flux, prolong the release and present an attractive route for sustained delivery of zidovudine. Acyclovir is another anti-viral drug that widely used topically for treatment of Herpes labialis . The conventional marketed acyclovir external formulation is associated with poor skin penetration of hydrophilic acyclovir to dermal layer resulting in weak therapeutic efficiency . It is reported that the replication of virus takes place at the basal dermis . Significant improvement in all evaluated clinical parameters was observed when disorder was treated with ethosomal formulation in comparison to marketed formulation. 4/7/2011 31

Slide 32: 

4/7/2011 32

FUTURE ASPECTS : 

FUTURE ASPECTS Introduction of ethosomes has initiated a new area in vesicular research for transdermal drug delivery. Different reports show a promising future of ethosomes in making transdermal delivery of various agents more effective. Further, research in this area will allow better control over drug release in vivo, allowing physician to make the therapy more effective. Ethosomes offers a good opportunity for the non-invasive delivery of small, medium and large sized drug molecules. The results of the first clinical study of acyclovir-ethosomal formulation support this conclusion. Thus, it can be a logical conclusion that ethosomal formulations possess promising future in effective dermal/transdermal delivery of bioactive agent. 4/7/2011 33

Conclusion : 

Conclusion Ethosomes are characterized by simplicity in their preparation, safety and efficacy and can be tailored for enhanced skin permeation of active drugs. Ethosomes have been found to be much more efficient at delivering drug to the skin. Ethosomes have been tested to encapsulate hydrophilic drugs, cationic drugs, proteins and peptides. Most of the device-induced transdermal drug delivery techniques are still in the early stages of commercialization. 4/7/2011 34

ACKNOWLEDGEMENT : 

ACKNOWLEDGEMENT With deep sense, of gratitude, I express my heartfelt thanks to Sri. ASHOK MATETI. Who has suggested me . I thank our beloved principal and other staff members for patient listening and for giving valuable suggestions.

References : 

References [1]    Albery, W.J. and Hadgraft, J. (1979) J. Pharm. Pharmacol. 31,129-139. [2]    Kanitakis, J. (2002) Eur. J. Dermatol. 12, 390-399. [3]    Barry, B.W. (2001) Eur. J. Pharm. Sci. 14, 101-114. [4]    Hadgraft, J. (2001) Int. J. Pharm., 2001, 224, 1-18. [5]    Hadgraft, J. (2001) Skin Pharmacol. Appl. Skin. Physiol. 14, 72-81. [6] Braun-Falco, O.; Kortung, H.C.; Maibach, H.I. Liposome Dermatitis, Springer-Verlag, Berlin Heideberg, 1992. [7]  Berner, B.; Liu, P. (1995) Alcohol, In Percutaneous Enhancer, Smith, E.W.; Maibach, H.I., Ed.; CRC Press, Boca Raton, FI, pp 45-60. [8] Touitou, E. Composition of applying active substance to or through the skin., US patent, 5,716,638, 1996. [9] Touitou, E. Composition of applying active substance to or through the skin., US patent, 5,540,934, 1998 [10] Jain, S.; Umamaheshwari, R.B.; Bhadra, D.; Jain, N.K. (2004) Ind. J. Pharm. Sci. 66(1), 72-81. [11]  Verma, D.D. and Fahr, A. (2004) Synergistic penetration effect of ethanol and phospholipids on the topical delivery of Cyclosporin A. J. Control Release. 97, 55-66. [12]vanden Berge, B.A.I.; Swartzendruber, V.A.B.; Geest, J. (1997) J. Microsc., 187, 125-133. [13] Van Kuijk-Meuwissen, Marly E.M.J.; Junginger, H.E.; Bouwstra, J.A. (1998) Biochim. Biophys. Acta. 1371, 31-39. [14] Betz, G.; Imboden, R.; Georgios, I. (2001) Int. J. Pharm. 229, 117-129. [15] Ogiso, T.; Yamaguchi, T.; Iwaki, M.; Tanino T.; Miyake. Y. (2001) J. Drug Targeting. 9(1), 49-53 [16] Grams, Y.Y. and Bouwstra, J.A. (2002) J. Control Release. 83, 253-262. [17] Bouwstra, J.A.; Honeywell-Nguyen, P.L.; Gooris, G.S.; Ponec, M. (2003) Progress in Lipid Research. 42, 1-36. 4/7/2011 36

Slide 37: 

4/7/2011 37