DRUG DELIVERY

Most pharma/biotechnology projects in drug (including biopharmaceutical) development field are still at preclinical stage! !

Awaiting approval 1% Approved 1% Clinical trials 34%

Preclinical trials 64%

One major reason for the gap between the numbers of preclinical trials and approved products is the lack of systems that can make drug candidates available at the diseased site at a therapeutic concentration for a required period of time.

Worldwide pharma/biotechnology projects in the drug development field

Source: C & EN, ACS Publications April 2, 2007

Development of drug delivery systems is necessary!

DRUG DEVELOPMENT PROCESS COVERS BOTH DRUG DISCOVERY AND DELIVERY

DISCOVERY/ PRODUCTION + DELIVERY DRUG DEVELOPMENT

THERAPEUTIC EFFICACY

LOWER IMPACT OF DISEASE ON HUMAN HEALTH & ECONOMY

DRUG DEVELOPMENT PROCESS

Figure was adapted from Darin Y. Furgeson, Division of Pharmaceutical Sciences, Department of Biomedical Eng, University of Wisconsin-Madison

STAGES IN DRUG DEVELOPMENT PROCESS

Approval

Clinical

Preclinical

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

U.S. Market for Drug Delivery Systems 2004-2011 ($ Billions)

TARGETED DRUG DELIVERY SYSTEMS

CONVENTIONAL DRUG DELIVERY SYSTEMS (all dosage forms)

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

WHAT IS A DRUG DELIVERY SYSTEM?

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.

FIRST CONTROLLED DRUG DELIVERY CONCEPT

(Hoffman AS, JCR, 2008)

ONE OF THE FIRST CONTROLLED DELIVERY SYSTEMS:SKIN PATCH FOR MOTION SICKNESS

(Hoffman AS, JCR, 2008)

DELIVERY SYSTEMS FOR BIOPHARMACEUTICALS: CASE STUDY (I)

Locteron
Locteron is a recombinant -interferon formulation with a polymer-based delivery system Treatment of Chronic Hepatitis C Locteron is designed to require less frequent administration and cause fewer side effects than free interferon solution Provides sustained-release profile, allowing for once every two weeks drug administration versus the current once a week regimen. Provides protection to IFN.

Sustained Relase of IFN

IFN Concentration in Serum

Serum IFN Concentration (IU/ml)

Protein solution Polymer solution

controlled delivery system

Phase separation

Emulsion formation

aquoeus solution

1 2 3 4 5 6 7 8 9 10 12
http://observer.octoplus.nl/index.cfm/octoplus/drugdelivery/overview/index.cfm

Time (days)

DELIVERY SYSTEMS FOR BIOPHARMACEUTICALS: CASE STUDY (II)

Concurrent Delivery of Two Growth Factors

Dual delivery of vascular endothelial growth factor (VEGF)-165 and platelet-derived growth factor (PDGF)-BB, each with distinct kinetics, from a single, structural polymer scaffold results in the rapid formation of a mature vascular network

Richardson-TP, Peters-MC, Ennet-AB, Mooney-DM., Nature Biotechnology, (2001) 19, 1029-1034

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HOW CAN WE DESIGN A DDS?

To design a DDS it is important to know: - how much drug is needed? - over what period of time (duration)? - at what delivery rate? - acting at which sites or on which cells?
For example; Insulin acts on cell surface receptors; Required dose: 10 units to maintain blood sugar between 11 - 16.5 mmol/l; In general, twothirds of the dose is given 30 minutes before breakfast and onethird 30 minutes before the evening meal.

HOW DO WE DECIDE ON SUFFICIENT DOSE AND SUITABLE DOSE REGIMEN? In order to answer this question, we need to know

The Dose-Effect Relationship

Dose Pharmacokinetics
PK

Plasma Concentration Pharmacodynamics PD Effect

Pharmacokinetics /Pharmacodynamics
Drug Concentration

PK
Drug Effect

PD

Typical bolus delivery by pills or shots

Time

Drug Concentration

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

Pharmacokinetic and pharmacodynamic principles are equally applicable to biopharmaceuticals as they are to conventional drugs.

Drug delivery systems generally deal with pharmacokinetics of drugs

Drug Levels in the Plasma
Therapeutic concentration range

Conventional administrations without a DDS (oral administ. by pills or systemic administ. by injections)

Desirable controlled delivery profile provided by DDS

Examples of Possible PK Profiles Using Controlled Drug Delivery Systems

Pulse + zero-order Zero-order ( 2 h to 24 h) Delayed zero-order

Multiple pulses Delayed pulse Ascending profile

Location specific delivery 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 dosage form 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 its metabolites are removed from the body (usually via kidney or in feces). How are biopharmaceuticals metabolised by body?

ADMINISTRATION & DISTRIBUTION OF BIOPHARMACEUTICALS

- common route for biological drugs - desired distribution

The disposition of chemicals entering the body (from C.D. Klaassen, Casarett and Doulls Toxicology, 5th ed., New York: McGraw-Hill, 1996).

MAJOR CLEARANCE ROUTES OF BIOPHARMACEUTICALS

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 administered dose reaching the bloodstream (for drugs administered via non-iv routes) or the target site (for drugs administered via iv route)
Metabolised by liver Excreted by kidney Limited diffusion through endothelial Limited passage through cellular membranes

Dose

Systemic circulation

Half-life (t1/2)= time for blood conc. to decrease by half.

KEY PARAMETERS DETERMINING SUCCESS WITH 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 ~ >150 kDa >100 amino acids Stability PolaritySolubility Polar-water soluble Polar-water soluble Charge

Monoclonal Antibodies Cytokines/ protein hormones/clotting factors/colony stimulating factors Vaccines Gene therapeutics Oligonucleotides

Protein Protein/ peptides

(+) charged charged

Protein/peptide DNA DNA/RNA

>100 amino acids >100 bp ds >19-mer ds or ss

Polar-water soluble Polar-water soluble Polar-water soluble

charged (-) charged (-) charged

List common properties!

BARRIERS TO THERAPEUTIC ACTIVITY (I): Physicochemical Properties of Biopharmaceuticals

Low 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 uptakekidney 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
Barrier
Liver uptake/kidney excretion Passage through endothelial/epithelial cells

At cell membranes, with membrane receptors in the circulation or tissue spaces Cytokine stimulation of signaling pathways Antibodies At intracellular targets DNA or RNA in the nucleus Antisense ODNs or siRNA in the cytosol Protein antigens in the MHC pathway -1

+
Recognition of target cell Transport through cellular membranes Nucleus membrane (for DNA)

BARRIERS TO THERAPEUTIC EFFECT (III): Availability at Intracellular Targets

Barriers to Intracellular Delivery

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 (IV):

Endocytosis is an important barrier to most biopharmaceuticals that act at intracellular sites
Cellular Uptake of Biomacromolecular Therapeutics

Endosome, pH 5.5 7.2

Lysosome, pH 4.5 5.5 lysosomal enyzmes: lipases, carbohydrase, proteases, nucleases

D.W. Pack, A.S. Hoffman, S. Pun, P.S. Stayton, Nature Biotechnology 2005, vol 4, 591.

Summary: Common Delivery Problems of Biopharmaceuticals

Prone to denaturation aggregation, precipitation (during storage) Prone to degradation in GI track due to digestive enzymes 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 (cell plasma membrane, paracellular junctions, endosome membrane, nucleus membrane etc.) Non-specific distribution (unable to recognize target tissue/cell)

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)

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