Lipid based drug delivery systems Lipid Lipid (solid） (liquid) Lipid nanoparticle Nanoemulsion Liposome
1 Lipid based drug delivery systems Lipid nanoparticle Nanoemulsion Liposome
Inner aqueous compartment Bilayer membrane Fatty G acid lipid Fatty acid Phosphate Alcohol CHs CHs Cholesterol CHs HO
2 lipid Cholesterol Cholesterol
(A) Phosphoglyceride 8 Sphingomyelin (B) Archaeal lipid Shorthand depiction Headgroup nompatidylchollne ( +-CHCHN'(CHa3 CH opaiythotmne (P) Pnosphatidlc acld (PA) ←州 +CH2CH-N'H3 coo' 上 CHCH(OH)CH2OH otyinoalt(P OH Salurated和竹y acids Acyl chain Laurie (12-0) CHa(CH2)10COOH yriatic(14:的 CH3/CHa)+2COOH Palmitic (1:0) CH3(CH2)COOH Stearic(18:0) CHa(CH2)1ECOOH Unsaturated fatty aclds Paimitelele [1C:140) CH(CHJ.CH-CH(CHJ/COOH Olele (18:149) CHa(CH2)7CH-CH(CH2.COOH Linoiele (10:209.12) CHa(CH2aCH-CHCH CH-CH(CH2)COOH
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Relevant lipid biophysics Determination of packing parameter(PP)of amphiphiles P determines the particle form as a result of self association of amphiphiles P-cross section of hydrophobic region cross section of hydrophilic region =Vlal V volume of the hydrophobic region a effective area per headgroup(hydrophilic region) length of the hydrophobic region Lipids Shape Organization Phase Soaps lsotropic Detergents hexagonal I Lysophospholipids ?7 Inverted cone P1 Trsaea Mixtures Lysophosphatidyl- chotne and 阴) Lamellar Phosphatidyl- cthanolamine P-1
4 Determination of packing parameter (PP) of amphiphiles P determines the particle form as a result of self association of amphiphiles P = cross section of hydrophobic region cross section of hydrophilic region V volume of the hydrophobic region a effective area per headgroup (hydrophilic region) l length of the hydrophobic region l V a Relevant lipid biophysics =V/al
Surfctant Phase Behavior micelle hexagoral reverse hexagunal reverse micelle Commercial liposome/lipid complex-based products US-FDA approved for human use(injectable drugs) Product Route of injection Drug Particle type Approved Indication Ambisome i.v. Amphotericin B Liposome (chemotherapy) (LUV) Severe fungal infections Abelcet iv. Amphotericin B Lipid complex (chemotherapy) (ribbons) Severe fungal infections Amphotec iv. Amphotericin B Lipid complex (chemotherapy) (disc) Severe fungal infections DaunoXome iv Daunorubicin Liposome (chemotherapy) (LUV) Blood tumors Doxil iv. Doxorubicin PEGylated(sterically stabilized)SUV-LUV Kaposi's sarcoma (chemotherapy) liposome Ovarian/Breast cancer Visudyne* iv. Benzoprophyrin Liposomes Age-related molecular degeneration(AMD) Multivesicular large Lymphomatos Depocyt Spinal Cytarabine liposomes meningitis (late stage lymphoma) 12-23um DepoDur Epidural Morphine sulfate Multivesicular Pain management liposomes
5 Commercial liposome/lipid complex-based products US-FDA approved for human use (injectable drugs) Product Route of injection Ambisome i.v. i.v. i.v. i.v. i.v. i.v. Depocyt Spinal Cytarabine Multivesicular large liposomes Lymphomatos meningitis (late stage lymphoma) DepoDur Epidural Morphine sulfate 12-23 μm Multivesicular liposomes Amphotericin B (chemotherapy) Liposome (LUV) Severe fungal infections Pain management Abelcet Amphotericin B (chemotherapy) Lipid complex (ribbons) Severe fungal infections Amphotec Amphotericin B (chemotherapy) Lipid complex (disc) Severe fungal infections DaunoXome Daunorubicin (chemotherapy) Liposome (LUV) Blood tumors Doxil Doxorubicin (chemotherapy) PEGylated (sterically stabilized) SUV-LUV liposome Kaposi’s sarcoma Ovarian/Breast cancer Visudyne* Benzoprophyrin Liposomes Age-related molecular degeneration (AMD) Drug Particle type Approved Indication
Theoretical consideration behind liposome formation by broad spectrum of methods.There is a lot in common(current status) 8 MLV 米 H88 e DI参8 IPATION OF能N月信￥ ⑤ 言 w2988 LUV pid re ao dire from pre using templ Functional Classification of Liposomes(1) Liposome Plasma clearance Plasma clearance for type Main features for large liposomes small liposomes High accessibility to interact with factors from extraliposomal medium Medium(tk~>1h)） Conventional (ie., opsonins,enzymes,low Fast (t.8h) Sterically Low accessibility to extraliposomal Slow (t >5 h) Saturation independent stabilized factors due to grafted steric barrier. Saturation liposomes low RES uptake independent Extravasation into tumors and sites of inflammation Vesicular to non vasicular transition upon contact with agent or medium components:(a)cationic liposomes- nucleic acid interaction induce lipoplex Actisomes formation.The lipoplexes when Very fast(t min exemplified injected i.v.accumulate in the lung range)Saturation Fast(t.-min range) by: where maximum transfection occurs. dependent Saturation dependent (b)pH sensitive liposomes,which fuse and release their content as a result of exposure to acidic pH(Drummond et al.2000). Based on Barenholz,1998
6 Theoretical consideration behind liposome formation by broad spectrum of methods. There is a lot in common (current status) Functional Classification of Liposomes (1) Plasma clearance for small liposomes Plasma clearance for large liposomes Main features Liposome type Medium (t½ ~> 1h) Saturation dependent Extravasation is feasible Fast (t½ 8 h) Saturation independent Extravasation into tumors and sites of inflammation Slow (t½ >5 h) Saturation independent Low accessibility to extraliposomal factors due to grafted steric barrier, low RES uptake Sterically stabilized liposomes Fast (t½-min range) Saturation dependent Very fast (t½~ min range) Saturation dependent Vesicular to non vasicular transition upon contact with agent or medium components: (a) cationic liposomes– nucleic acid interaction induce lipoplex formation. The lipoplexes when injected i.v. accumulate in the lung where maximum transfection occurs; (b) pH sensitive liposomes, which fuse and release their content as a result of exposure to acidic pH (Drummond et al., 2000). Actisomes exemplified by: aBased on Barenholz, 1998
Fate of liposomes and encapsulated drug after intravenous administration i.v.injection of liposomes Uptake RES/MPS Liposome disintegration in Long circulating liposomes blood (SSL) Release in cell Slow release of agent in blood,and/or:accumulation Release of(in)active Release in blood at non-MPS tumor and agent from cell inflammation sites Reticuloendothelial system=RES Mononuclear phagocyte system=MPS Proposed Liposome Classification Based on Pharmacologic Behavior ·Vehicle -Majority of drug rapidly released into central compartment prior to MPS uptake of liposome -Possible safety advantages over other vehicles (i.e.,cremophor/ethanol,Tween)>less hemolysis,allergic reactions -Infusion reactions to liposomes well documented,so safety trade-off uncertain
7 Fate of liposomes and encapsulated drug after intravenous administration Reticuloendothelial system = RES Mononuclear phagocyte system = MPS i.v. injection of liposomes Uptake RES/MPS Liposome disintegration in blood Long circulating liposomes (SSL) Release in cell Release of (in)active agent from cell Release in blood Slow release of agent in blood, and/or: accumulation at non-MPS tumor and inflammation sites
Proposed Liposome Classification (Cont.) ·MPS Uptake -Superior to subcutaneous where dose is concentrated in confined area>extracellular matrix cellular localization.local iritation,rapid entry into central compartment -Distributes dose to greater number of cells (volume)> MPS cells -Forms MPS "depot">slow re-release into central compartment resembles prolonged infusion Avoids peaks and associated adverse effects while maintaining AUC -Clinical benefit documented(Myocet,AmBisome) Proposed Liposome Classification (Cont.) ·MPS Avoid -Surface modification slows MPS uptake -Drug retained in liposome in plasma -Circulates for several days -Small enough to extravasate in tissues -Preferential uptake at sites with compromised endothelium -Drug released in tissue compartment
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Evolution of IV Therapeutic Liposomes IV Therapeutic Liposomes MPS Uptake MPS Avoid Vehicle Famly Pue Lipi Modried Design DSPCiChol SMChol LEDo勇 c711 (Vinc) LEP (Taro0 0ye0Pm礼 AmBisome DOXIL 话arketed Dexenblchl Iauncrubicn Dasnb6enl Products Liposome Pharmacology: Critical Influences ·Drug -Pharmacology Encapsulation stability -Release kinetics ·Size ·Structural lipid ·Surface properties
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Critical Influences:Drug Itself .Drug class (cytotoxic,biologic,anti-infective) Intrinsic PK,safety profile -Plasma clearance,tissue distribution -Dose-related toxicities(single-dose,cumulative) -Toxic sites .Target ·Encapsulation -Payload -Stability -Release kinetics Critical Influences:Liposome Size ·Physical aspects -Size distribution-outliers Size growth ·in suspension during/after reconstitution -Size measurement issues ·Safety issues Micro-capillary occlusion -MPS saturation Extravasation window Sterilization by filtration
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