Liposome Drug Products

7/24/2019 Liposome Drug Products

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Burgess, June 28, 2001 1

REGULATORY SCIENCE OF LIPOSOME

DRUG PRODUCTS


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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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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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.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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Liposomes.


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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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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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C$"6"CAL


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Liposomes.


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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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S6%$"L"6

6erminal sterilization?

Aseptic processing

ust consider both internal and

e8ternal sterility


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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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In $itroDrug $elease

Apparatus?

edia?

Sampling methods?

6esting inter!als?

6otal percent release?

9o standard method at present


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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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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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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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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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Burgess June 28 2001 38

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Liposome Drug Products