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Burgess, June 28, 2001 1
REGULATORY SCIENCE OF LIPOSOME
DRUG PRODUCTS
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Burgess, June 28, 2001 2
Outline
What are liposomes? What are they used for?
What drugs?
Why liposomes?
Liposome formulation Liposome characterization
Safety concerns
Performance concerns
In vitrorelease testing stability
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Outline Continued
Purpose of in vitrorelease tests? Design of in vitrorelease test
Accelerated/stress tests
ethod !ariables affecting release
ethods under de!elopment
In vivofactors affecting release
In vivodata and models?
"#"#C? $esearch proposal
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L"POSO%SLiposomes are colloidal& lipid !esicles consisting of one
or more self'assembled lipid bilayers enclosing a
similar number of a(ueous compartments)
Lipids& such as lecithin *diacylphosphatidylcholine+& areamphiphilic molecules) Due to the bul,y nonpolar part
of the molecule they do not pac, into spherical micelles
in a(ueous phase but rather self'assemble into bilayers
-hich tend to self'close at lo- concentrations intospherical structures)
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L"POSO%S Contd)
Liposomes can be subcategorized into.
Small unilamellar !esicles *S#+& 01 to 233 nm in sizethat consist of a single lipid
bilayer
Large unilamellar !esicles *L#+& 233 to 433 nm in sizethat consist of a single lipid bilayer
ultilamellar !esicles *L#+& 033 nm to se!eral
microns& that consist of t-o or more concentric
bilayers#esicles abo!e 2 5m are ,no-n as giant !esicles)
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Burgess, June 28, 2001 6
LiposomesLocalized and rate controlled deli!ery.
"mpro!ed therapeutic response
Achie!e appropriate tissue or blood le!els
$educed ad!erse reactions
Less drug administered
6argeted drug release Lo-er dosing fre(uency
"mpro!ed patient compliance
Simpler dosing regimens
Lo-er cost per dose
tilization of other-ise un'useable compounds Poorly soluble drugs
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Drug Candidate Selection 7no-n therapeutics -ith clear to8icity and pharmaco,inetic
profiles Potent compounds
9ot :9arro- 6herapeutic "nde8; drugs
Problems associated -ith the current dosage forms
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Burgess, June 28, 2001 8
.APP$O#%D L"POSO% P$ODC6S. Do8il Daunorubicin 2>>1
Dauno8ome Daunorubicin 2>>
Ambisome Amphotericin @ 2>>
Depocyt Cytarabine 2>>>
APP$O#%D L"P"D COPL%B P$ODC6S.
Ambelcet Amphotericin @ 2>>1
Amphotec Amphotericin @ 2>>
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S%L%C6"O9 O< D%L"#%$ SS6%
Liposomes targeted deli!ery) 6hey can deli!er agentsdirectly into cells) $outes. i)!)& s)c)& i)m)& topical&pulmonary
Microspheres ' can pro!ide continuous drug deli!eryo!er periods of months to years) Systemic andlocalized) i)m)& s)c)& oral& pulmonary
Emulsions' can be used to ma,e highly -aterinsoluble compounds bioa!ailable) i)!)& oral& topical
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L"POSO%
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L"POSO%
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Burgess, June 28, 2001 12
Liposomes.
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Burgess, June 28, 2001 13
6ypes of Liposomesonventional Liposomes
- Prepared form natural neutral and anionic lipids and ha!e nonspecificinteractions -ith their en!ironment
- $elati!ely unstable& ha!e lo- carrying capacities& and tend to be :lea,y;to entrapped drug substances
- ay literally fall apart on contact -ith plasma& particularly those of highfluidity&
- Choleterol is often added to increase plasma stability
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Burgess, June 28, 2001 14
6ypes of Liposomes
"on#conventional Liposomes- Small sized *F 233 nm+& surface modified to o!ercome
some of the short comings of con!entional liposomes
- odified to reduce negati!e charge& decrease fluidity andcause steric hinderance to phagocytosis
- Properties altered *e)g) by incorporation of cholesterol+
- Polymerized liposomes more stable and less :lea,y;
- Polyetheylene glycol& :pegylated; liposomes& a!oid upta,eby the mononuclear phagocytic cells
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6P%S O< L"POSO%S
6arget specific ligands& such as antibodies&
immunoglobulins& lectins and oligosaccharidesattached to the surface to acti!ely target to specific
sites in the body
6argeting !ia particle size
Liposomes prepared -ith cationic and fusogenic
lipids are currently being utilized in gene therapy to
deli!er D9A into target cells
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6P%S O< L"POSO%S
Eighly reacti!e liposomes ' readily undergo phasetransition in particular situation
sensiti!e to pE& ions& heat and light
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Burgess, June 28, 2001 17
C$"6"CAL
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Liposomes.
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Burgess, June 28, 2001 19
SA
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L"POSO% CEA$AC6%$"IA6"O9 Stabil"ty
Drug
Lipids
Liposome
Phase transition temperature
Percent drug loading
Percent free drug
Drug release rate/stability
Particle size
orphology *lamellarity+
Sterility
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Burgess, June 28, 2001 21
S6%$"L"6
6erminal sterilization?
Aseptic processing
ust consider both internal and
e8ternal sterility
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Burgess, June 28, 2001 22
S6A@"L"6 Acti!e
"nacti!es *especially the lipids+ Liposome as a -hole need
Any change in particle size can affect targeting& $%S upta,e&safety and efficacy)
In vivostability of -hole liposome is particularly important fortargeted liposomes& since they should remain stable in theplasma -ithout loss of contents until upta,e at the target site)
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L"POSO% D%S6A@"L"IA6"O9
Protein binding
embrane fusion
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Drug $elease from Liposomes$elease profiles are application dependent)
6argeted liposomes should remain intact until deli!ery at site
Other *short term C$ and solubilization+ release during appropriatetime scale)
$elease controlled by
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Burgess, June 28, 2001 25
In $itroDrug $elease
Apparatus?
edia?
Sampling methods?
6esting inter!als?
6otal percent release?
9o standard method at present
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Burgess, June 28, 2001 26
Liposome Performance In $itro
$elease and Stability
Separation of liposomes from dissolution
media complicates testing
Current SP methods designed for oral and
transdermal routes
In vitrotests need to ta,e into account the
e8pected in vivoperformance of liposomes
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Burgess, June 28, 2001 27
Liposome Performance In $itro
$elease and Stability
Release test for a targeted liposome -ould
need to sho-
2+ liposome is stable until upta,e at the site
0+ liposome releases drug at the site *based on
the mechanism of releasein vivo+)
$elease test for an immediate release
liposome -ould need to sho- Drug is released immediately in conditions
mimic,ing human plasma)
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Current ethods ofIn $itro6esting
of Liposome Systems embrane Diffusion 6echni(ue
Sample and Separate 6echni(ue
In Situ6echni(ue
Continuous
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Burgess, June 28, 2001 29
De!elopment of In $itro$elease and
Stability ethods for Liposomes
Purpose. methods to be used in setting
regulatory specifications for these products
for (uality control *JC+ purposes todifferentiate bet-een :good; and :bad;
batches)
6ests design -ill !ary depending on the
intended in vivoperformance of liposomes
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Purpose of In $itro$elease 6est?
Juality control and safety e!aluation
@atch to batch
anufacturing process changes
Substantiation of label claims
%!aluation of potential dose dumping
Assessment of in vivostability
:$eal time; !s accelerated/stress test
In vitro # in vivocorrelation
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Design of In $itro$elease ethod
Select media and apparatus to achie!e reproducibleresults Attempt to o!ercome limitations of e8isting methods
iniaturize methods
Prepare formulation !ariants -ith different in vivoperformance
6est formulation !ariants in vitroand in vivo
odify in vitrotest if not discriminatory
Determine in vivofactors that effect release odify in vitromethods to obtain "#"# relationship
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Accelerated In $itro$elease ethods
6hese tests should be predicti!e of :realtime; in vitrotests
Drug release mechanism should not bealtered
Accelerated test should not simply dissol!ethe liposome
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edia and ethods that can affect $elease
Sol!ents pE
6emperature
Agitation
%nzymes Cell culture
Sin, conditions
#olume Sampling inter!al
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Burgess, June 28, 2001 34
In $ivo
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In $ivo
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In $ivoData
Systemic deli!ery& then plasma le!elsmay be suitable
Localized deli!ery& plasma le!els -ill belo- and unrepresentati!e) $e(uires tissue le!els
se animal models in method de!elopment se @iomar,ers
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In $ivoData
se animal model to help design in vitrotest
%stablish relationship bet-een in vitrodata and
animal in vivodata
%stablish a relationship bet-een animal in vivo
data and human P7& biomar,ers& PD response
De!elop relationship bet-een in vitrodata
Euman data
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