delivery of biopharm

8/6/2019 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



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



3

Figure was adapted from Darin Y. Furgeson, Division of

Pharmaceutical Sciences, Department of Biomedical Eng,

University of Wisconsin-Madison

DRUG DEVELOPMENT PROCESS



4

STAGES IN DRUG DEVELOPMENT PROCESS

(Goddard P., Advanced Drug Delivery Reviews, 1991)

Preclinical

Clinical

Approval



U.S. Market for Drug Delivery Systems

2004-2011 ($ Billions)

CONVENTIONALDRUG DELIVERYSYSTEMS (all dosageforms)

TARGETED DRUGDELIVERY SYSTEMS

(C & EN, ACS Publications April 2, 2007)



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?



7(Hoffman AS, JCR, 2008)

FIRST CONTROLLED DRUG DELIVERY CONCEPTFIRST CONTROLLED DRUG DELIVERY CONCEPT



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



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)



The Dose-Effect Relationship

Pharmacokinetics

Dose

Plasma Concentration

Pharmacodynamics

Effect

PK

PD



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.



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



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)



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?



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.



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)



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.



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

•



• 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



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



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)

delivery of biopharm

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