Liposomal drug delivery system

liposome...

1. Presented By Zahid husain M.Pharm (Pharmaceutics) Faculty of pharmacy, iu, lucknow UNDER GUIDANCE OF DR. S.P SINGH LIPOSOMAL DRUG DELIVERY SYSTEM

2. INTRODUCTION Liposomes are concentric bilayered vesicles in which an aqueous core is entirely enclosed by a membranous lipid bilayer mainly composed of natural or synthetic phospholipids. The size of a liposome ranges from 20 nm up to several micrometers. The lipid molecules are usually phospholipids- amphipathic moieties with a hydrophilic head group and two hydrophobic tails.

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4. ADVANTAGES OF LDDS Suitable for delivery of hydrophobic, hydrophilic and amphipatic drugs and agents Chemically and physically well characterized entities Biocompatible Use as carrier for suitable for controlled release drug delivery. Suitable to give localized action in particular tissues . Suitable to administer via various routes Increased efficacy and therapeutic index. Reduction on toxicity of the encapsulation agent. Improved pharmacokinetic properties. Can be made into Varity of drug. Minimum antigenicity.

5. Disadvantage of LDDS Their rapid clearance from circulation due to uptake, by the reticuloendothelial system(RES), primarily in the liver Leakage of encapsulation drug delivery during storage. Batch to batch variation. Once administered, can’t removed. Difficult in large scale manufacture and sterilization. Physical /chemical stability Very high production cost Possibility of dumping due to faulty administration.

6. CLASSIFICATION OF LIPOSOME'S 1) Based on structural parameters: MLV : Multilamellar large vesicles- >0.5 μm GUV : Giant unilamellar vesicles->1 μ m LUV : Large unilamellar vesicles->100nm MUV : Medium sized unilamellar vesicles SUV : Small unilamellar vesicles-20-100nm UV : Unilamellar vesicles (all in size) OLV : Oligolamellar vesicles- 0.1-1 μ m MV : Multivesicular vesicles->1 μ m

7. Cont… 2) Based on method of liposome preparation: REV : Single or oligolamellar vesicles made by reverse-phase evaporation method MLV-REV : Multilamellar vesicles made by reverse phase evaporation method SPLV : Stable plurilamellar vesicles FATMLV : Frozen and thawed MLV VET : Vesicles prepared by extrusion technique DRV : Dehydration-rehydration method

8. Cont… 3) Based on the composition and application: Conventional liposome : Neutral or negatively charged Phospholipid Fusogenic liposome : Reconstitute sendai virus envelop Cationic liposome : Cationic lipid Long circulatory liposome : Neutral high Transition temperature liposome pH sensitive liposome : Phospholipid like Phosphatidyl ethanolamine Immuno liposome : Long circulatory liposome with attached monoclonal antibody

9. METHODS OF LIPOSOME PREPARATION PASSIVE LOADING: Involves loading of the entrapped agents before or during the manufacturing procedure ACTIVE OR REMOTE LOADING: Certain types of compounds with ionizable groups and those with both lipid and water solubility , can be introduced into the liposomes after the formation of the intact vesicles

10. 1. Passive loading technique A) Mechanical dispersion method: Lipid hydration by hand shaking or freeze drying Micro emulsification Sonication French pressure cell Membrane extrusions Dried reconstituted vesicle Freeze thawed liposome

11. Cont… B) Solvent dispersion method: Ethanol injection Ether injection Double emulsion vesicle Reverse phase evaporation vesicle Stable pluri lamellar vesicle C) Detergent removal method: Detergent (cholate, alkyl glycoside, Triton x-100) removed from mixed micelles Dialysis Column chromatography Dilution Reconstituted sendai virus enveloped vesicle

12. 1. PASSIVE LOADING TECHNIQUE A. MECHANICAL DISPERSION METHOD

13. 1. Hand Shaken MLV

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15. 2. Non Shaken vesioles

16. 3. Pro Liposome

17. 4. Freeze Drying

18. ETHANOL/ETHER INJECTION ETHANOL INJECTION: An ethanol solution of lipids is injected rapidly through a fine needle into an excess of saline or other aq. medium This method has low risk of degradation of sensitive lipids The vesicles of 100 nm size may be obtained by varying the conc. Of lipid in ethanol or by changing the rate of injection of ethanol solution in preheated aqu. solution. ETHER INJECTION : Involves mixing of organic phase into aqu. Phase at the temp. of vaporizing the organic solvent It has low encapsulation efficiency

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20. 2. ACTIVE LOADING TECHNIQUE 1. PROLIPOSOME: Lipid and drug are coated onto a soluble carrier to form free-flowing granular material in pro-liposome which forms an isotonic liposomal suspension on hydration. The pro-liposome approach may provide an opportunity for containing particularly lipophilic drugs . 2. LYOPHILIZATION: The removal of water from products in the frozen state at extremely reduced pressure is called lyophilization (freeze drying). The process is generally used to dry products that are thermolabile which may be destroyed by heat-drying. This technique has a great potential to solve long term stability problems with respect to liposomal stability. Leakage of entrapped materials may take place during the process of freeze- drying and on reconstitution.

21. Why Use Liposomes in Drug Delivery? Drug Targeting at specific -Cell -Tissue - Receptor -pH range Inactive : Unmodified liposomes gather in specific tissue reticuloendothelial system Active: alter liposome surface with ligand (antibodies, enzymes, protein A, sugars) Protection: Decrease harmful side effects (Change where drug accumulates in the body)

22. C ont… Pharmacokinetics - Efficacy and toxicity - Changes the absorbance and biodistribution - Deliver drug in desired form - Deliver drug in desired form Protection - Decrease harmful side effects (Change where drug accumulates in the body) Release - Affect the time in which the drug is released - Prolong time - Increase duration of action and decrease administration Dependent on drug and liposome properties Liposome composition, pH and osmotic gradient, and environment.

23. CHARACTERIZATION OF LIPOSOMES Physical Characterization : Vesicle shape and surface Morphology: Transmission electron microscopy, freeze-fracture electron microscopy. Surface charge: Free-flow electrophoresis. Lamellarity: Small angle X-ray scattering, freeze-fracture electron microscopy, 31P-NMR. Phase behaviour: Freeze-fracture electron microscopy, differential scanning calorimetry. Percent capture/percent of free drug: Minicolumn centrifugation, gel exclusion, ion-exchange chromatography, radiolabelling.

24. Cont… 2. Chemical Characterization: Phospholipid concentration: Lipid phosphorous content using Barlett assay, HPLC Cholesterol concentration: Cholesterol oxidase assay and HPLC Drug concentration: Appropriate method given in monograph Phospholipid peroxidation: UV absorbance, TBA , indometric and GLC Phospholipid hydrolysis: HPLC and TLC Cholesterol auto-oxidation: HPLC and TLC

25. Cont… pH: pH meter Osmolarity: Osmometer Anti-oxidant degradation: HPLC and TLC 3 . Biological Characterization: Sterility: Aerobic or anaerobic cultures Pyrogenicity: Limulus amebocyte lysate (LAL) test Animal toxicity: Monitoring survival rates, histology and pathology

26. APPLICATION OF LIPOSOMES Liposomes as drug/protein delivery vehicles. Enhanced drug solubilization. Enzyme replacement therapy and lysosomal storage disorders. Liposomes used in antimicrobial, antifungal and antiviral therapy. Increase bioavailability. Liposomes used in tumour therapy. Vehicle for macromolecules as cytokines genes.

27. Cont… Carrier of small cytotoxic molecules. Genetic vaccination Liposomes as artificial blood surrogates Liposomes as radiopharmaceutical and radio diagnostic carriers Liposomes used in cosmetics and dermatology Liposomes used in enzyme immobilization and bioreactor technology. Liposomes in gene delivery

28. REFERENCE S.P.VYAS, R.K.KHAR “Targeted and Controlled Drug Delivery Novel Carrier Systems, first edition 2002, CBS publisher and distributer pvt. Ltd Pg.no;172-212 Encyclopaedia of controlled released drug delivery system, volume 2. http//www.liposome.com Slideshare Wikipedia

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