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Phytosome® a novel drug delivery system based herbal formulation
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  1. 1. Ruchi Shakya DEBAJYOTI BHATTACHARYA 1st year M. Pharrm Industrial pharmacy Under the guidance of Prof. SATEESHA S.B
  2. 2. Liposomes were first produced in England in 1961 by Alec D. Bangham. Hydrophilic Definition:   Liposomes are simple microscopic vesicles in which an aqueous volume is entirely enclosed by a membrane composed of lipid molecule. Structurally, liposomes are concentric bilayered vesicles in which an aqueous volume is entirely enclosed by a membranous lipid bilayers mainly composed of natural or synthetic phospholipids. Hydrohobic 2
  3. 3. PHOSPHOLIPID- Major component of biological cell membrane phospholipid Hydrophobic tail 2 fatty acid chain containing 10-20 carbon atoms 0-6 double bond in each chain Hydrophillic head or polar head Phosphoric acid bound to water soluble molecule
  4. 4. Natural phospholipid  PC- phosphatidyl choline  PE- phosphatidyl ethanolamine  PS –phosphatidyl serine Synthetic phosholipid  DOPC = Dioleoyl Phosphatidylcholine  DOPE = Dioleoyl phosphatidyl ethanolamine  DSPC = Distearoyl phosphatidyl choline  DSPE = Distearoyl phosphatidyl ethanolamine  DLPC = Dilauryl phosphatidyl choline
  5. 5. The most common phospholipid use is phosphatidylcholine PC  Phosphatidylcholine is amphipathic molecule containing A hydrophillic polar head group phosphochol ine A glycerol bridge A pair of
  6. 6.  Molecules of PC are not soluble in water  In aqueous medium they align themselves closely in planar bilayer sheet to minimize the unfavorable action between the bulk aqueous phase and longer hydrocarbon fatty acid chain i.e. they orient themselves such that fatty acid chain face each other and the polar head face the aqueous phase  This reduces the instability and close seal vesicle is formed
  7. 7. The rationale of encapsulating a drug within liposomes is to prevent its rapid metabolism and its rapid removal from blood circulation after its administration so that the drugs from depot liposomes are ideally suited for drug delivery. Advantages        Provide selective passive targeting to tumor tissues (liposomal doxorubicin). Increased efficacy and therapeutic index. Increased stability via encapsulation. Reduction in toxicity of the encapsulated agent. Improved pharmacokinetic effects (reduced elimination, increased circulation life times). Flexibility to couple with site-specific ligand to achieve active targeting
  8. 8. Incorporation of sterols in liposome bilayer can bring about major changes in preparation of these membranes. Cholesterol by itself does not form a bilayer structure Concentration upto 1:1 or even 2:1 molar ratios of PC. Cholesterol incorporation increases the separation between the choline head groups and eliminates the normal electrostatic and hydrogen-bonding interactions.
  9. 9.  Lamella are flat plate like structure that appear during the formation of liposome  Phospholipid bilayer appear as lamella before getting converted to sphere  Several lamella stack one upon other during formation of liposome to form a multilamellar structure
  10. 10. Uni lamellar vesicle Single phospholipid bilayer Multi lamellar vesicle Several phospholipid bilayer
  11. 11. Based on structural parameter MLV Multilamellar large vesicles >0.5 nm UV Unilamellar vesicles (all size range) OLO Oligolamellar vesicle 0.1-1 µm SUV Small Unilamellar vesicles 20-100 nm MUV Medium sized Unilamellar vesicles LUV Large Unilamellar vesicles >100 nm GUV Giant Unilamellarvesicles >1 µm MV Multi vesicular vesicle>1µm
  12. 12. REV-reverse-phase evaporation method Single or oligolamellar vesicles made MLV-REV Multilamellar vesicles made by reverse-phase evaporation method SPLV Stable plurilamellar vesicles On the basis of preparation FATMLV Frozen and thawed MLV VETVesicles prepared by extrusion technique DRV-dried reconstituted vesicle Dehydration-rehydration method
  13. 13. BASED UPON COMPOSITION AND APPLICATION Neutral or negatively charged phospholipid RSVE-Reconstituted sendai virus envelop Phospholipid such as PE or DOPE with either CHEMS Cationic ion with DOPE high temp made with cholesterol and 5-10% of PEG-DSPE CL or LCL with attached monoclonal antibody or recognition sequence
  14. 14. METHODS OF LIPOSOME PREPARATIONS Passive loading technique Involves loading of entrapped agent before or during manufacturing process Active loading technique Certain type of compound with ionizable group and those with both lipid and water solubility can be introduce in liposome after formation of vesicle • Mechanical dispersion method •Lipid film hydration •Micro emulsification •Sonication •French pressure cell •Membrane extrution •Dried reconstituted vesicle •Freeze thawed liposomes Solvent dispersion method •Ethanol injection •Ether injection •Double emulsion vesicles •Reverse phase evaporation vesicle •Stable plurilamellar vesicle Detergent removal method •Detergent - like cholate alkyl glycoside triton x 100 removal from mixed micelle by •column chromatography •Dialysis •Dilution •Reconstituted sendai virus envelop
  15. 15. Handshaking and non shaking  In this method a 250 ml round bottom flask is taken containing organic solvent with lipids.  Then this beaker is attached to a rotary evaporator and rotated at 60 rpm resulting in formation of stacks of lipids.  Then the beaker containing stacks is dried using nitrogen for 15 min and then the casted film is dispersed in aqueous medium.  This results in hydration of lipids which swell and peel of from the wall of flask resulting in formation of multilamellar vesicles. 
  16. 16.  Microfluidizer is used to prepare small MLVs. In this a lipid dispersion is placed in a microfluidizer pump which pumps the fluid at 600-700 bar pressure through a 5 µm orifice.  Then this dispersion is forced along micro channels, which make two streams of fluid to collide with each other at right angles at a high velocity.  Due to this transfer of energy takes place resulting in formation of multilamellar vesicles.
  17. 17. Separation into two streams Collision at right angle Vesicles of required dimension Interaction chamber Reservoir of MLVs air in air out
  18. 18.  In this method MLVs are exposed to UV radiations to get small vesicles.  There are two methods of sonication 1. bath sonicator 2. probe sonicator  Probe is used for high concentrated lipids while bath is used for large volumes of diluted lipids.  In probe a high energy is used which may result lipid degradation and also titanium particles may be released into dispersion.
  19. 19.  For these reasons bath sonicators are used for preparing MLVs. In this method dispersion is placed in a test tube which is placed In a sonicator  Sonication is done for 5-10 min until a transparent solution appears.  After sonication dispersion is placed in a plastic centrifugation tube and centrifuged for 30 min at 20º c to get large MLVs and 3-4 hrs to get SUVs.
  20. 20. Method used to increase the surface area of dry lipid film and to facilitate instantaneous hydration, keeping low aqueous volume  Lipid is dried over a finely divided solid support such as powdered sodium chloride or sorbitol or other polysaccharides to form pro-liposomes  These dried lipid coated particulates swell upon adding water to the support rapidly dissolves to give a suspension of MLVs.  This method overcome the problem encountered during lipid storage.  For preparing proliposomes Buchi rotary evaporator is employed. 
  21. 21.  In this method an ethanol solution of lipids is injected rapidly into an excess of saline or other aqueous medium, through a fine needle.  The force of the injection is sufficient to achieve complete mixing so that ethanol is diluted instantaneously in water and phospholipid molecules are dispersed evenly in medium.  This procedure yields high proportion of SUVs (25 nm).
  22. 22.  This is a simple method with low risk of degradation of sensitive lipids  A major limitation is the solubility of lipids in ethanol.
  23. 23.  This is a similar method as ethanol injection but contrasts in some respects.  This involves injecting the immiscible organic solution very slowly into an aqueous phase through a narrow needle at the temperature of vaporizing the organic solvent.  This method is used to treat sensitive lipids very gently. Disadvantage is the long time taken to produce a batch of liposomes.
  24. 24. In this method an organic solution containing water droplets is introduced into excess aqueous medium followed by mechanical dispersion.  By this a multi-compartment vesicle is formed described as w/o/w system or double emulsion.  These vesicles with aqueous core are suspended in a aqueous medium  The two compartments being separated by pair of phospholipid monolayer.  Organic solvent is evaporated using strong jet of nitrogen into double emulsion.  ULV is formed 
  25. 25.        In this method phospholipids are brought into intimate contact with the aqueous phase using detergents which associate with phospholipid molecule and screen the hydrophobic portions of the molecule from water. The structure formed as a result is known as micelles. The shape and size of the micelle depend upon chemical nature of detergent concentration and other lipid The concentration of detergent in water at which micelles just start to form is known as critical micellar Concentration Before CMC formation detergent exist in free solution. At higher CMC concentration large amount micelle is formed and concentration detergent in free form same as in CMC Mixed micelle-two or more detergent
  26. 26. In contrast to phospholipids detergents are highly soluble in both aqueous and organic media.  Equilibrium is indicated by critical micelle concentration  lowering the concentration of detergent in the bulk aqueous phase, the molecules of detergent can be removed from mixed micelle by dialysis.  High CMC indicate equilibrium shifted to bulk solution removal by dialysis easy  Commonly used detergents are sodium cholate and sodium deoxycholate.  Commercial version of dialysis system is LIPOREP. 
  27. 27.  Phospholipids in the form of either sonicated vesicles or as a dry film, at a molar ratio 2:1 with deoxy cholate form ULV of 100 nm on removal of deoxy cholate by Column chromatography.  This can be achieved by passing the dispersion over a Sephadex G-25 column presaturated with lipids and pre equilibrated eith hydrating buffer.
  28. 28.  Shape, size and its distribution  Surface charge  Percentage drug entrapment  Entrapped volume  Lamellarity  Phase behavior of liposome  Percentage drug release
  29. 29. 1. Size and its distribution-  Laser light scattering  Gel permeation  Microscopic method- electron microscopy  Most precise method since it allow to view individual liposome and obtain information about profile of liposome population over whole range of size  size Freeze etch-is particularly used to measure small vesicle diameters  freeze fracture – a method of preparing cells for electron microscopical examination  a tissue specimen is frozen at −150° C,  inserted into a vacuum chamber, and fractured by a microtome, a platinum carbon replica of the exposed surfaces is made, freed of the underlying specimen  then examined 2. Surface charge--Electrophoresis  Lipid samples are applied to cellulose acetate plate in a   sodium borate buffer pH 8.8 electrophoresis is carried at 4ºC on a flat bed apparatus for 30 min , plate is dried and phospholipids are visualized by molybdenum blue reagent
  30. 30. 3. Percent entrapment Two methods are used for this 1. protamine aggregation- (+,-)  In protamine aggregation liposome suspension 20 mg/ml in saline is placed in conical glass centrifuge tube,  0.1 ml protamine solution is added and allowed to stand for 3 min  30 ml saline is added and then tube is spun for 20 min.  supernatant is removed and assayed for unentrapped compound by standard ,method.  The suspended pellets are resuspended in 0.6 ml of 10% triton X -100 and material completely dissolve.  Volume is made up and assay is done 2. mini column-  Hydrated gel filled in barrel of syringe plunge with whatman GF/B filter paper  Spun in centrifuge tube at 2000 rpm for 3 min to remove excess saline  Gel column is dried  Elute solution remove from collection tube  Liposome suspension is added drop wise to gel bed again spun at 2000 rpm for 3 min to remove the void volume of liposome
  31. 31. 4. Entrapped volume- • The entrapped volume of liposome can be obtain by measurement of total quantity of solute entrap in the liposome • assuring that concentration of solute in aqueous medium inside liposome is same as in solution that is use in • assuming that no solute has leak out after separation from untrapped material • Invalid in two-phase method • Measure by NMR- adding spectroscopically inert substance and measure water signal. 5. .Lamellarity Average number of bilayers present are found by freeze electron microscopy and by 31P-NMR. • In NMR technique broadening agent manganese ions are added it before and after recording, it interact with outer leaflet of bilayer. 50% reduction in NMR signal means it is unilamellar liposome and 25 % reduction indicates presence of 2 bilayers in the liposomes • Freeze fracture electron microscopy is nowadays very popular for study of structural detail of aqueous lipid dispersion.
  32. 32. 6. Phase behavior of liposomes • An important feature of lipid membrane is the existence of a temperature dependant, reversible phase transition, where the hydrocarbon chain of the phospholipids undergoes a transformation from a ordered state to more disordered fluid state. • These changes have been documented by freeze fracturing electron microscopy but most conveniently demonstrated by DSC. • The physical state of the bi-layer profoundly affects permeability, phase transition temperature (Tc), leakage rates and overall stability of liposomes. • Tc gives good clue regarding liposome stability,permeability,and drug entrapped 7. Drug release: • The mechanism of drug release from liposome can be accessed by the use of a well calibrated in-vitro diffusion cell. • In vitro assay of liposomal formulation is assisted to predict pharmacokinetics and bioavailability before costly in vivo studies. • Dilution induced drug release in buffer and plasma is employed as predictor for pharmacokinetics of liposome • Intra cellular drug release can also be induced by liposome degradation in the presence of mouse-liver lysosome lysate to determine the bioavailability of drug
  33. 33.  Lipid use in preparation of liposome are unsaturated and highly prone to oxidation  Volatile solvent such as chloroform which are very susceptible to evaporate from container.  So liposome should be store in inert atmosphere of nitrogen and in dark, glass vessel with securely fastened cap
  34. 34. 1.Cancer chemotherapy: Liposomes are successfully used to entrap anticancer drugs. This increases circulation life time, protects from metabolic degradation. 2.Liposomes as carrier of drug in oral treatment:  Steroids used for arthritis can be incorporated into large MLVs.  Alteration in blood glucose levels in diabetic animals was obtained by oral administration of liposome encapsulated insulin.
  35. 35. 3. Liposomes for topical applications: Drugs like triamcilone, methotrexate, benzocaine, corticosteroids etc can be successfully incorporated as topical liposomes 4. Liposomes for pulmonary delivery: Inhalational devices like nebulizers are use to produce an aerosol of droplets containing liposomes. 5.Ophthalmic delivery:  Drugs like idoxuridine, indoxol and carbochol are greater efficacy in the form of liposomes.  Potential advantage of ophthalmic liposome is their intimate contact with corneal and conjuctival surfaces
  36. 36. 6. Leishmaniasis :  In this parasitic disease antimonial drugs are used which are lethal at high concentrations as they damage heart, liver and kidney.  Such drugs can be encapsulated in liposomes. 7. Cell biological applications:  Liposomes are used to carry functional DNA and RNA molecules into cells. Liposomes are used to insert enzymatic cofactors and cyclic AMP into cells.
  37. 37. Type of Agents Anticancer Drugs Anti bacterial Antiviral DNA material Enzymes Radionuclide Fungicides Vaccines Examples Duanorubicin, Doxorubicin*, Epirubicin Methotrexate, Cisplatin*, Cytarabin Triclosan, Clindamycin hydrochloride, Ampicillin, peperacillin, rifamicin AZT cDNA - CFTR* Hexosaminidase A Glucocerebrosidase, Peroxidase In-111*, Tc-99m Amphotericin B* Malaria merozoite, Malaria sporozoite Hepatitis B antigen, Rabies virus glycoprotein *Currently in Clinical Trials or Approved for Clinical Use
  38. 38. Phytosome is novel drug delivery system is a patented technology (U.S. Patent #4,764,508) that combines hydrophilic bioactive phytoconstituents of herbs/ herbal extracts and bound by phospholipids.(soybean phospholipids ,lecithin)  More bioavailable than a simple/convential herbal extract due to its enhanced capacity to cross the lipidrich biomembranes and reach circulation.  As they are better absorbed and produces better results  Applied to standardized plant extracts, watersoluble phytoconstituents and many popular herbal extracts including , grape seed, hawthorn, olive fruits and leaves, milk thistle, green tea, ginseng etc into phospholipids to produce lipid compatible molecular complexes 
  39. 39.     Phytosome structures contain the active ingredients of the herb surrounded by the phospholipids. The presence of a surfactant i.e. the phospholipids in the molecule these are shielded from water-triggered degradation while, at the same time, allows obtaining a higher adhesion of the product itself to the surface it comes into contact with and a better interaction of various molecules with cell structure Example-PC is a bifunctional compound. Specifically the choline head (hydrophilic) binds to these compounds while the phosphatidyl portion (lipophilic) comprising the body and tail which then envelopes the choline bound material and forms phyto-phospholipid complex. Molecules are anchored through chemical bonds to the polar choline head of the PC, it can be demonstrated by specific spectroscopic techniques.
  40. 40. PHYTOSOMES LIPOSOMES  In phytosomes active chemical constituents molecules are anchored through chemical bonds to the polar head of the phospholipids.  In liposomes, the active principle is dissolved in the medium of the cavity or in the layers of the membrane. No chemical bonds are formed.  In phytosomes, PC and the individual plant compound form a 1:1or 2:1 complex depending on the substance.  In liposoes, hundred and thousands of phosphatidyl choline molecules surround the water soluble molecule
  41. 41. Marked enhancement of bioavailability  valuable components of the herbal extracts are protected from destruction by digestive secretions and gut bacteria  Assured delivery to the tissues.  No compromise of nutrient safety.  Dose requirement is reduced due to absorption of chief constituent.  Phytosomes shows better stability profile because chemical bonds are formed between phospholipid molecules and phytoconstituent  Phospholipid used in the phytosome process besides acting as a carrier also nourishes the skin, because it is essential part of cell membrane. 
  42. 42.  Phytosomes are prepared by reacting natural or synthetic phospholipids with active components like bioflavonoid, flavolignan and polyphenolic constituents.  Solvent Evaporation method is the most common technique used for the preparation of phytosomes
  43. 43. The behavior of phytosomes in both physical and biological system is governed by the factors such as  Physical size  Membrane permeability  Percent entrapped solute  Chemical composition as well as quality and purity of the starting material
  44. 44. They are lipophilic substances with a definite melting point, freely soluble in non polar and aprotic solvents in which the hydrophilic moiety is not.  They are moderately soluble in fats and insoluble in water.  When treated with water, they assume a micelle shape, forming structures which resemble liposome.  In these complexes, the polar head of the phospholipidis involved while the fatty acid moieties retain a high degree of mobility conferring marked lipophilia at the new molecule. 
  45. 45. In the 1H-NMR spectrum, the signals of the complexes substances undergo a strong broadening .  In the13 C-NMR spectrum, the signals of the complex substances as well as those of the choline and glycerin portion of the phospholipid can no more be recorded .  The phosphorous nucleus itself undergoes a band broadening which indicates that it is involve in complex formation.  The kind of signals proves the interaction between polar head and active sites of the complex whereas the lipid chains are not involved since they are free to rotate and give complex its lipophilic character. 
  46. 46.      Various spectroscopic and in-vitro and in-vivo evaluations are applied on phytosomes on the basis of therapeutic activity of biologically active phytoconstituents present in phytosomes These complexes can be characterized by TEM(Transmission Electron Microscopy), 1H-NMR,13-CNMR,31 P-NMR FT-IR. A chemical spectral characteristic is determined in phospholipids complexes using IR and UV spectroscopic study. Liquid chromatography/atmospheric pressure chemical ionization mass spectrometry proved to be a very powerful tool for pharmacokinetic studies of phytochemicals In-vivo studies are performed on Beagle dogs, rodents, wistar rats to compare pharmacokinetics parameters between pure extracts and its phospholipid
  47. 47. HERBAL DRUG PHYTOSOME PHYTOCONSTITUENTS INDICATION Ginkgobiloba Ginkgoselect Phytosome -Dimeric flavonoids -terpenoids (gikgolides and Bilobalide (a) Vasoactive agent (b)Anti-inflammatory agents Silybum marianum Silybin Phytosome -Flavolignan Silybin -Flavanolignan (Silymarin (a)Antioxidant and Hepatoproptective (b)Anti-inflammatory Anti-aging Crataegus oxyacantha Hawthorne Phytosomes Flavonoids Antioxidant, cardioprotective, Food product Camellia Sinensis Greenselect Phytosome Catechins and their gallate derivatives. Antioxidant,cardio protective, food product Panax Ginseng Ginselect TM Saponins Anti-aging Vaccinium Myrtillus Mirtoselect Phytosome Antcinocide Antioxidant Vitis vinifera Leucoselect Monomeric flavan-3- Cardiovascular
  48. 48.  Target and controlled drug delivery-novel carrier system by S.P Vyas, R.K Khar  Controlled and Novel Drug Deliver system, chapter 15,liposomes as a drug carrier by Sanjay k Jain and N.K. Jain
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