Delivery of Biopharm
Transcript of Delivery of Biopharm
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Most pharma/biotechnology projects in drug (including biopharmaceutical) development field are still at preclinical stage! !
DRUG DELIVERYDRUG DELIVERY
One major reason for the gap betweenthe numbers of preclinical trials andapproved products is the lack of systemsthat can make drug candidates availableat the diseased site at a therapeuticconcentration for a required period oftime.
Development of drug delivery systemsis necessary!
Source: C & EN, ACS Publications April 2, 2007
Preclinical trials64%
Awaiting approval1% Approved
1%
Clinical trials
34%
Worldwide pharma/biotechnology projectsin the drug development field
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THERAPEUTIC EFFICACYTHERAPEUTIC EFFICACY
DRUG DEVELOPMENTDRUG DEVELOPMENT
+ DELIVERYDELIVERYDISCOVERY/DISCOVERY/
PRODUCTIONPRODUCTION
LOWER IMPACT OF DISEASELOWER IMPACT OF DISEASE
ON HUMAN HEALTH & ECONOMYON HUMAN HEALTH & ECONOMY
DRUG DEVELOPMENT PROCESS COVERSDRUG DEVELOPMENT PROCESS COVERS
BOTH DRUG DISCOVERY AND DELIVERYBOTH DRUG DISCOVERY AND DELIVERY
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Figure was adapted from Darin Y. Furgeson, Division of
Pharmaceutical Sciences, Department of Biomedical Eng,
University of Wisconsin-Madison
DRUG DEVELOPMENT PROCESS
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STAGES IN DRUG DEVELOPMENT PROCESS
(Goddard P., Advanced Drug Delivery Reviews, 1991)
Preclinical
Clinical
Approval
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U.S. Market for Drug Delivery Systems
2004-2011 ($ Billions)
CONVENTIONALDRUG DELIVERYSYSTEMS (all dosageforms)
TARGETED DRUGDELIVERY SYSTEMS
(C & EN, ACS Publications April 2, 2007)
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Drug delivery system (DDS) is a formulation or device designed to
get the therapeutic agents to the desired (diseased) site at a therapeutic
concentration (at a rate determined by needs of body) for a required
period of time.
The main goal of DDS is to improve the effectiveness
(therapy+safety+cost) of drug therapies (for example: by simplifying
/reducing dosing regimens, improving administration, reducing toxicity
etc.)
DDSs may range from simple formulations to very sophisticated
“smart” systems.
The lack of efficient DDSs have delayed the translation of many
valuable biopharmaceuticals to clinically applicable treatments.
WHAT IS A DRUG DELIVERY SYSTEM?WHAT IS A DRUG DELIVERY SYSTEM?
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7(Hoffman AS, JCR, 2008)
FIRST CONTROLLED DRUG DELIVERY CONCEPTFIRST CONTROLLED DRUG DELIVERY CONCEPT
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8(Hoffman AS, JCR, 2008)
ONE OF THE FIRST CONTROLLED DELIVERY SYSTEMS:SKIN PATCHONE OF THE FIRST CONTROLLED DELIVERY SYSTEMS:SKIN PATCH
FOR MOTION SICKNESSFOR MOTION SICKNESS
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Locteron ®
Locteron ® is a recombinant αααα-interferonformulation with a polymer-based delivery system Treatment of Chronic Hepatitis C
Locteron ® is designed to require less frequentadministration and cause fewer side effects thanfree interferon solution Provides sustained-release profile, allowing for once every two weeks drug administration versus
the current once a week regimen. Providesprotection to IFN.
Proteinsolution
Polymer solution
Phaseseparation
Emulsionformation
Sustained Relase of IFN
aquoeus solution
controlled
delivery system
1 2 3 4 56 7 8 9 10 12
IFN Concentration in Serum
S e r u m I F
N
C o n c e n t r a t i o n
( I U / m l )
Time (days)
DELIVERY SYSTEMS FOR BIOPHARMACEUTICALS: CASE STUDY (I)DELIVERY SYSTEMS FOR BIOPHARMACEUTICALS: CASE STUDY (I)
http://observer.octoplus.nl/index.cfm/octoplus/drug-
delivery/overview/index.cfm
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Concurrent Delivery of Two Growth Factors
Richardson-TP, Peters-MC, Ennet-AB, Mooney-DM.,Nature Biotechnology, (2001) 19, 1029-1034
Dual delivery of vascular endothelial growth factor (VEGF)-165 andplatelet-derived growth factor (PDGF)-BB, each with distinct kinetics,
from a single, structural polymer scaffold results in the rapidformation of a mature vascular network
DELIVERY SYSTEMS FOR BIOPHARMACEUTICALS: CASE STUDY (II)DELIVERY SYSTEMS FOR BIOPHARMACEUTICALS: CASE STUDY (II)
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The Dose-Effect Relationship
Pharmacokinetics
Dose
Plasma Concentration
Pharmacodynamics
Effect
PK
PD
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Pharmacokinetics /Pharmacodynamics
Pharmacokinetics (PK)• “What the body does to
the drug”
• Fairly easy to measure(e.g., “biodistribution”)
• PK used to get the PD
Pharmacodynamics (PD)• “What the drug does to
the body”
• Less well understood• PD has clinical relevance
PKTypical bolus deliveryby pills or shots
PD
D r
u g E f f e c t
Drug Concentration D r u g C
o n c e n t r a t i o n
Time
Pharmacokinetic and pharmacodynamic principles are equallyapplicable to biopharmaceuticals as they are to conventional drugs.
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Drug Levels in the Plasma
Conventional administrations
without a DDS (oral administ.by pills or systemic administ.
by injections)
Desirable “controlleddelivery” profileprovided by DDS
Drug delivery systems generally deal withpharmacokinetics of drugs
Therapeuticconcentration
range
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Examples of Possible PK Profiles Using
Controlled Drug Delivery Systems
Delayed pulse
Zero-order ( 2 h to 24 h)
Pulse + zero-order
Delayed zero-order
Multiple pulses
Location specific delivery
Ascending profile
Alza Corp.Slide was kindly provided by Prof. A.S. Hoffman (University of Washington, USA)
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What happens to biopharmaceuticals once
they enter body? Steps before reaching to action site:
Administration: drug must first be administrated in a suitable dosageform at an appropriate site. What is the appropriate admin. site for
biopharmaceuticals?
Absorption and Distribution: it must then be absorbed from the site of administration and distributed in body. What are the key factors
affecting biodistribution?
Metabolism and Excretion: drug structure is biotransformed (altered in
the body- usually in liver) to eliminable metabolites. Drug and/or itsmetabolites are removed from the body (usually via kidney or in feces).
How are biopharmaceuticals metabolised by body?
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ADMINISTRATION & DISTRIBUTION OFBIOPHARMACEUTICALS
The disposition of chemicals entering the body (from C.D. Klaassen, Casarett and Doull’s Toxicology , 5thed., New York: McGraw-Hill, 1996).
- desireddistribution
- common routefor biologicaldrugs
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MAJOR CLEARANCE ROUTES OFBIOPHARMACEUTICALS
Kidney Excretion• molecules smaller than ~ 5kDa
are excreted unrestrictedly.
• molecules smaller than ~60kDa
are excreted restrictedly.
• little or no excretion for molecules larger than ~60kDa
(molecular size > 4.5 nm).
Liver Elimination• larger molecules and particles
usually activates the human
complement system and are
hence eliminated from the blood
by RES (liver, spleen etc.).Molecules entrapped usually by
Kupffer cells of liver are degraded
into smaller, hydrophilic,
eliminable metabolites.
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Bioavailability of Biopharmaceuticals
Bioavailability = the fraction of the administereddose reaching the bloodstream (for drugs administered via
non-iv routes) or the target site (for drugs administered via iv
route)
Dose
Metabolisedby liver
Excretedby kidney
Limited diffusionthrough endothelial
Systemiccirculation
Limited passagethrough cellular membranes
Dose
Metabolisedby liver
Excretedby kidney
Limited diffusionthrough endothelial
Systemiccirculation
Limited passagethrough cellular membranes
Half-life (t1/2)= time for blood conc. to decrease by half.
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KEY PARAMETERS DETERMINING SUCCESSWITH PK
Physicochemical properties of drug affect the
pharmacokinetics & bioavailability:Chemical structure: solubility, polarity, diffusivity,
functional groups
Stability
Molecular weight
Interactions with proteins
Administration route
Availability at the target site/tissue/cells/molecules(special barriers/active transport systems)
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COMMON PHYSICOCHEMICAL PROPERTIES
OF BIOPHARMACEUTICALS
Biopharmaceuticals Structure Molecular Size~
Stability Polarity-Solubility
Charge
Monoclonal Antibodies Protein >150 kDa - Polar-water soluble
(+) charged
Cytokines/ proteinhormones/clottingfactors/colony
stimulating factors
Protein/peptides
>100 aminoacids
- Polar-water soluble
charged
Vaccines Protein/peptide >100 aminoacids
- Polar-water soluble
charged
Gene therapeutics DNA >100 bp ds - Polar-water soluble
(-) charged
Oligonucleotides DNA/RNA >19-mer dsor ss - Polar-water soluble (-) charged
List common properties!
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BARRIERS TO THERAPEUTIC ACTIVITY (I):
Physicochemical Properties of BiopharmaceuticalsLow stability: easily destroyed by relatively mild conditions, stable
in a narrow pH range, prone to enzymatic attacks; oral
administration is usually not possible.
Large molecular size: affects metabolic processing (liver uptake-
kidney excretion) and passage through membranes.
Macromolecules cannot diffuse easily through cellular membranes
and also junctions between the endothelial cells inside blood vessels
to reach intra- and extra-cellular space.Pores between the endothelial cells allow unrestricted
diffusion of water-soluble molecules of molecular weight < ~ 5 kDa,
and relatively restricted diffusion of molecules < ~ 65 kDa.
Hydrophilic: cell membranes are composed of lipid bilayers which
allow diffusion of non-polar, lipid-soluble substances.
Charge: cell plasma membrane is negatively charged. Negatively
charged molecules are repelled by the plasma membrane.
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BARRIERS TO THERAPEUTIC EFFECT (II):
Availability at Action Site
Sites at which biopharmaceuticals act
• Liver uptake/kidneyexcretion•Passage throughendothelial/epithelial
cells
+
Barrier
• Recognitionof target cell
• Transportthrough cellular membranes
• Nucleusmembrane (for
DNA)
•
At cell membranes, with membrane receptors
in the circulation or tissue spaces
Cytokine stimulation of signaling pathwaysAntibodies
• At intracellular targetsDNA or RNA in the nucleus
Antisense ODNs or siRNA in the cytosolProtein antigens in the MHC-1 pathway
•
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• Reaching the target cell
• Uptake (e.g., endocytosis)
• Endosomal escape (avoid the lysosome!)
• Release of the active drug in the cytosol
• Desired action at the appropriate intracellular site
BARRIERS TO THERAPEUTIC EFFECT (III):
Availability at Intracellular Targets
Barriers to Intracellular Delivery
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Cellular Uptake of
Biomacromolecular Therapeutics
D.W. Pack, A.S. Hoffman, S. Pun, P.S. Stayton, Nature Biotechnology 2005, vol 4, 591.
Endosome, pH 5.5 – 7.2
Lysosome, pH 4.5 – 5.5
lysosomal enyzmes:lipases, carbohydrase,
proteases, nucleases
BARRIERS TO THERAPEUTIC EFFECT (IV):
Endocytosis is an important barrier to mostbiopharmaceuticals that act at intracellular sites
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Summary: Common Delivery Problems of
Biopharmaceuticals
• Prone to denaturationaggregation, precipitation
(during storage)
• Prone to degradation in GI track due to digestiveenzymes and acidic environment
• Prone to degradation in blood stream due to
enzymatic attacks
• Short half-life in circulation (retained in liver and/or
excreted via kidneys)
• Usually immunogenic
• Too large to diffuse through membrane barriers (cellplasma membrane, paracellular junctions, endosome
membrane, nucleus membrane etc.)
• Non-specific distribution (unable to recognize target
tissue/cell)
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Delivery systems for biopharmaceuticals- improve physicochemical stability (longer shelf-life)
- improve in vivo stability (protect against enzymes)
- improve in vivo half-life (reduce kidney filtration rate –reduce liver uptake- shield against reticuloendothelial
system)
-reduce immunogenicity
- reduce toxicity
- increase availability at target tissue (by increasing
transport through membranes and specific recognition
ability)