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8/3/2019 liposome PPT2 HCU
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Dr. M. A. HalablabDr. M. A. Halablab
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PhospholipidsPhospholipidsPolar Head Groups
Three carbon glycerol
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What is a liposome?What is a liposome? Spherical vesicles with a phospholipid bilayerSpherical vesicles with a phospholipid bilayer
Hydrophilic
Hydrophobic
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Cell MembraneCell Membrane
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UsesofLiposomesUsesofLiposomesChelation therapy for treatment of heavy metal
poisoning
Enzyme replacement
Diagnostic imaging of tumors
Study of membranes
Cosmetics
Drug Delivery
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Why Use Liposomes in DrugWhy Use Liposomes in Drug
Delivery?Delivery?
Inactive: Unmodified liposomes gather in specific tissue
reticuloendothelial systemActive: alter liposome surface with ligand (antibodies,
enzymes, protein A, sugars)
Directly to sitePhysical: temperature or pH sensitive liposomes
Drug Targeting
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ReleaseAffect the time in which the drug is released
Prolong time -increase duration of action and
decrease administration
Dependent on drug and liposome propertiesLiposome composition, pH and osmotic gradient, and
environment
Why Use Liposomes in
Drug Delivery?
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ModesofLiposome/CellModesofLiposome/Cell
InteractionInteractionAdsorption Endocytosis
Fusion Lipid transfer
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ClassesofLiposomesClassesofLiposomesConventional Long circulating
ImmunoCationic
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Liposomes Help ImproveLiposomes Help ImproveTherapeutic indexRapid metabolism
Unfavorable pharmokineticsLow solubilityLack of stabilityIrritation
Custom designLipid contentSizeSurface charge
Method of preparation
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Current liposomal drugCurrent liposomal drug
preparationspreparationsType of Agents ExamplesAnticancer Drugs
Anti bacterial
Antiviral
DNA material
Enzymes
Radionuclide
Fungicides
Vaccines
*Currently in Clinical Trials or Approved forClinical Use
Malaria merozoite, Malaria sporozoite
Hepatitis B antigen, Rabies virus glycoprotein
Amphotericin B*
In-111*, Tc-99m
Hexosaminidase A
Glucocerebrosidase, Peroxidase
Duanorubicin, Doxorubicin*, Epirubicin
Methotrexate, Cisplatin*, Cytarabin
Triclosan, Clindamycin hydrochloride,
Ampicillin, peperacillin, rifamicin
AZTcDNA - CFTR*
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CFTRCFTRGene Therapy
Deliver cDNA ofCystic Fibrosis Transmembrane Conductance
Regulator (CFTR) to epithelial tissue of respiratory system
Fuse to cell membrane and
incorporate cDNA into cellClinical trials - no significant
change in symptoms
Now trying adeno associated
virus
Cationic liposome
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DoxilDoxilChemotherapy drug doxorubin
Anemia, damage to veins and tissue at injection, decrease
platelet and WBC count, toxic to
Treats Kaposis sarcoma lesions or cancer tumorsModifications of liposome stealth
keeps doxorubin in blood for 50 hours instead of20 minutes
concentrates at KS lesions and tumors
*Just approved by FDA*
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Amphotericin BAmphotericin B
Side effects: nephrotoxicity, chills, and fevers
Systemic fungalinfections in immune compromised patients
Fungizone - AmB with deoxycholate
AmB - kills ergosterol-containing fungal cells, also
kills cholesterol-containing human cells
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No decrease in effectiveness of drug against fungi
Liposomal Formulation of AmB
Decrease in toxicity
Exact Mechanism of liposomes not understood
Cholesterol - only few %moles
Phospholipid:AmB ratio
Diffusion
Lipid transfer
AmB
Lipid
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Problems with LiposomalProblems with Liposomal
PreparationsofDrugsPreparationsofDrugs$$$$
Fungizone $40.58 Amphotec $2334
Doxil $1200 per treatment, twice the cost of normal protocolof chemotherapy and drugs
Lack long term stability (short shelf life)
Freeze dry and pH adjustment
Low Pay Load - poor encapsulation
Physical and chemical instability
Polar drugs and drugs without opposite charge
Modifications
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Possibility of new side effectsDoxil hand and foot syndrome
Problems continued
EfficacyCFTR
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Studies with insulin show that liposomes may
be an effective way to package proteins
and peptides for useClinical Trials for several liposomal formulations
More studies on the manipulation of liposomes
Future
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JournalsAllen, Theresa M. "Liposomal Drug Formulations: Rationale for Development and What We Can
Expect for the Future." Drugs 56: 747-756, 1998.
Allen, Theresa M. "Long-circulating (sterically stabilized) liposomes for targeted drug delivery."
TiPs 15: 214-219, 1994.
Allen, Theresa M. "Opportunities in Drug Delivery." Drugs 54 Suppl. 4: 8-14, 1997
Janknegt, Robert. "Liposomal and Lipid Formulations of Amphotericin B." Clinical Pharmacokinetics.
23(4): 279-291, 1992.
Kim, Anna et al. "Pharmacodynamics of insulin in polyethylene glycol-coated liposomes."
International Journal of Pharmaceutics. 180: 75-81, 1999.
Quilitz, Rod. "Oncology Pharmacotherapy: The Use of Lipid Formulations of Amphotericin B in Cancer
Patients." Cancer Control.5:439-
449, 1998.Ranade, Vasant V. "Drug Delivery Systems: Site-Specific Drug Delivery Using Liposomes as Carriers."
Pharmacology. 29: 685-694, 1989.
Storm, Gert and Daan J.A. Crommelin. "Liposomes:quo vadi?" PSTT1: 19-31, 1998.
Taylor, KMG and JM Newton. "Liposomes as a vecicle for drug delivery." British Journal of Hospital
Medicine. 51: 55-59, 1994
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WebsitesJames, John S. "Doxil Approved for KS." www.immunet. org.imminet/atn.nsf/page/a-235-03.
Wasan, Ellen. "Targeted Gene Transfer." Member.tripod.com/~rrishna/lipos1.html
"Introduction to Controlled Drug Delivery Systems." www5.bae.ncsu.edu/bae/reearch/blak
k/otherprojects/drugDeliver_97/
http://www. Mssm.edu/medicine/thrombosis/phosphol.html"Doxorubicin." http://tirgan.com/adria.htm
"Clinical Pharmacology Online." http://www.cponline.gsm.com/scripts/fullmono/showmono.
"Drugstore.com" http://www.drugstore.com/pharmacy/prices/Amphotec.
"Sequus' Doxil Becomes First Liposome Product Approved In U.S." www.slip.net/~mcdavis/
database/doxor_1
"Liposomes." www.collabo.com/liposom0.htmPaustin, Timothy. Cellular Membranes.www.bact.wisc.edu/microtextbook/bacterialstructure/Membranegen.html
www.cbc.umn.edu/~mwd/cell_www/chapter2/membrane.html#PHOSPHOLIPIDS
BooksJones, Macolm N. and Chapman, David. Micelles, Monolayers and Biomembranes. Wiley-Liss.
New York (1995).
Garrett, R. and Grisham C. Biochemistry, 2nd
ed. Saunders Colleges Publishing. New York (1999). 264.